Journal articles on the topic 'Bible. O.T. Genesis I-III'

Achenbach, R 2005. Pentateuch, Hexateuch und Enneateuch. Eine Verhältnisbestimmung, ZAR 11:122–154. Albertz, R 2007. Die kanonische Anpassung des Johuabuches. Ein Neubewertung seiner sog.”Priesterschriftelike Texte”, in Römer and Schmid 2007:199–217. Aurelius, E 2003. Zukunft jenseits des Gerichts: Eine redaktionsgeschichltliche Studie zumEnneateuch. BZAW 319. Berlin: de Gruyter. Barrick, W B & Spencer, J R (eds) 1984. In the shelter of Elyon: essays on ancient Palestinian life in honour of GW Ahlström. JSOTSup 31. Sheffield: JSOT Press. Becker U, 2006. Endredaktionelle Kontextvernetzungen des Josua-Buches, in Witte, Schmid, Prechel and Gertz 2006:139–161. Bieberstein, K 1995. Josua-Jordan-Jericho. Archäologie, Geschichte und Theologie der Landnahmeerzählungen Josua 1–6. OBO. Friborg: Universitätsverlag, Göttingen: Vandenhoeck & Ruprecht. Blum, E 1990. Studien zur Komposition des Pentateuch. BZAW 189. Berlin/New York: de Gruyter. _______ 1997. Die Kompositionelle Knoten am Übergang von Josua zu Richter: Ein Entflechtungsvorschlag, in Lust and Vervenne 1997:181–212. _______ 2006. The literary connection between the books of Genesis and Exodus and the end of the book of Joshua, in Dozeman and Schmid 2006:80–106. _______ 2011. Pentateuch-Hexateuch-Enneateuch, in Dozeman , Römer and Schmid 2011:43–71. Carr, D M 1996. Reading the fractures of Genesis. Historical and literary approaches. Louisville: Westminster John Knox. _______ 2006. What is required to identify pre-Priestly narrative connections between Genesis and Exodus? in Dozeman and Schmid 2006:159–180. _______ 2012. The Moses story: literary and historical reflections, HeBAI 1–2:7–36. Dozeman, T B & Schmid, K (eds) 2006. Farewell to the Yahwist? The composition of the Pentateuch in recent European discussion. SBL Symposium Series 34. Atlanta: SBL. Dozeman, T B, Römer, T C & Schmid, K (eds) 2011. Pentateuch, Hexateuch, or Enneateuch. Identifying literary works in Genesis through Kings. SBL 8. Atlanta: SBL. Du Pury, A, Römer, T C & Macchi, J P (eds) 2000. Israel constructs its history. Deuteronomistic historiography in recent research. Sheffield: Sheffield Academic Press. Edenburg, C & Pakkala, J (eds) 2013. Is Samuel amongst the Deuteronomists? Current views on the place of Samuel in a Deuteronomistic History. Atlanta: SBL. Eisffeldt, O 1964. Einleitung in das Alte Testament. Tübingen: Mohr. Frevel, C 2000. Mit Blick auf das Land die Schöpfung erinnern. Zum Ende der Priestergrundschrift. HBS 23. Freiburg/New York: Herder. _______ 2011. Die Wiederkehr der Hexateuchperspektive. Eine Herausforderung für die These vom Deuteronomistischen Geschictswerk, in Stipp 2011:13–53. Frey, J, Schattner-Rieser, U & Schmid, K (eds) 2012. Die Sameritaner und die Bibel: Historische und literarische Wechselwirkungen zwischen biblischen und Sameritanischen Traditionen. Studia Judaica/Studia Samaritana 7. Berlin/New York. Fritz, V 1994. Das Buch Josua. Hat 1/7. Tübingen: Mohr Siebeck. Garciá-Martinez, F (ed.) 1998. Perspectives in the study of the Old Testament and early Judaism: a symposium in honour of Adam S. van der Woude on the occasion of his 70th Birthday. VTSup 73. Leiden: Brill. Gertz, J C 2000. Tradition und Redaktion in der Exoduserzählung. Untersuchungen zur Endredaktion des Pentateuch. FRLANT 186. Göttingen: Vandenhoeck& Ruprecht. Görg, M 1991. Josua. NEB 26. Würzburg: Echter Verlag. Gunkel, H 1910. Genesis. 3rd ed. GHK 1. Göttingen: Vandenhoeck & Ruprecht. Hjelm, I 2000. The Samaritans and early Judaism: a literary analysis. JSOTSup 303. Sheffield: Sheffield Academic Press. Keel, O 1973. Das Vergaben der “Fremder” Götter in Genesis xxxv 4b, VT 23:305–336. Knauf, E A 2000. Does Deuteronomsitic Historiography (DH) exist? in du Pury , Römer and Macchi 2000:388–398. _______ 2007. Buchschlüsse im Josuabuch, in Römer and Schmid 2007:217–224. _______ 2008. Josua. ZBKAT 6. Zurich: Theologisher Verlag. Knoppers, G N & McConville, J G (eds) 2000. Reconsidering Israel and Judah: recent studies on the Deuteronomistic History. SBTS 8. Winona Lake: Eisenbrauns. Köckert, M 1988. Vätergott und Väterverheisssungen. Eine Auseinandersetzung mit Albrecht Alt und seine Erben. FRLANT 142. Göttingen: Vandenhoeck & Ruprecht. Konkel, M 2008. Sünde und Vergebung:Eine Rekontruktion der Redaktionsgeschichte der hinterein Sinaiperikope (Ex 32–34). Vor dem Hintergrund aktueller Pentateuchmodelle. FAT 88. Tübingen: Mohr. Koopmans, W T 1990. Joshua 24 as poetic narrative. JSOTSup 93. Sheffield: JSOT Press. Kratz, R G 2000. Die Komposition der erzählender Bücher des Alten Testaments: Grundwissen der Bibelkritik. UTB 215.Göttingen: Vandenhoeck & Ruprecht. Levin, C 1993. Der Jahwist. FRLANT 157.Göttingen: Vandenhoeck& Ruprecht. Lipschits, O, Knoppers, G N & Albertz, R (eds) 2007. Judah and the Judeans in the fourth century B.C.E. Winona Lake: Eisenbrauns. Lust, J & Vervenne, M (eds) 1997. Deuteronomy and Deuteronomistic literature. BETL 133. Leuven: Peeters. Mckenzie, S L & Römer, T C (eds) 2000. Rethinking the foundations: historiography in the ancient world and the Bible. Essays in honour of John Van Seters. Berlin/New York: de Gruyter. Nelson, R D 1997. Joshua: a commentary. Louisville: Westminster John Knox. Nentel, J 2000. Trägerschaft und Intentionen des deuteronomistischen Geschichtswerks: Untersuchungen zu Refelexionreden: Jos1; 23; 24; 1 Sam12 und 1 Kön 8. BZAW 297. Berlin: de Gruyter. Nihan, C 2012. The literary relationship between Deuteronomy and Joshua: a reassessment, in Schmid and Person 2012:79–114. _______ 2013. 1 Sam 8 and 12 and the Deuteronomsitic edition of Samuel, in Edenburg and Pakkala 2013: 225–274. Na`man, N 2000. The law of the altar in Deuteronomy and the cultic site near Shechem, in Mckenzie and Römer 2000:141–161. Noll, K L and Schramm, B (eds) 2010. Raising a faithful exegete: essays in honour of Richard Nelson. Winona Lake: Eisenbrauns. Noort, E 1997. The traditions of Ebal and Gerizim: theological positions in the book of Joshua, in Vervenne and Lust 1997:161–180. _______ 1998. Zu Stand und Perspektiven: Der Glaube Israels zwischen Religionsgeschichte und Theologie, der Fall Josua 24, in Garciá-Martinez 1998:82–108. Noth, M 1943. Überlieferungsgeschichtliche Studien. Tübingen: Niemeyer. _______ 1953. Das Buch Josua. 2nd ed. HAT 7. Tübingen: Mohr Siebeck. O’Brien, M A 1989. The Deuteronomistic History hypothesis: a reassessment. OBO 92. Fribourg: Éditions. Universitaires/Göttingen: Vandenhoeck& Ruprecht. Otto, E 1999. Bruckensläge in der Pentateuchsforschung, TRU 64:84–99. _______ 2000. Das Deuteronomium im Pentateuch und Hexateuch. Studien zur Literaturgeschichte von Pentateuch und Hexateuch im Lichte des Deuteronomiumrahmens. FAT 30. Tübingen: Mohr Siebeck. Otto, E & Achenbach, R (eds) 2004. Das Deuteronomium zwischen Pentateuch undDeuteronomistischem Geschictswerk. FRLANT 206. Göttingen: Vandenhoeck & Ruprecht. Perlitt, L 1968. Bundestheologie im Altes Testament. Neukirchen-Vluyn: Neukirchener Verlag. _______ 1994. Priesterschrift in Deuteronomium34? VT 59:475–494. Popovich, M 2009. Conquest of the land, loss of the land. Where does Joshua 24 belong?, in von Ruiten and de Vos 2009:87–98. Rofé, A 2000. Ephraimite versus Deuteronomistic History, in Knoppers & McConville 2000:462–474. Römer, T C 2010. Book-endings in Joshua and the question of the so-called Deuteronomistic History, in Noll and Schramm 2010:85–99. Römer, T C & Brettler, M Z 2000. Deuteronomy 34 and the case for a Persian Hexateuch, JBL 119/3:401–419. Römer, T C and Schmid, K (eds) 2007. Les dernières rédactions du Pentatueque, de l` Hexateuge,et de l` Henneatuege. BETL 203. Leuven: Peeters. Rösel, H N 1980. Die Überleitungen vom Josua-ins Richterbuch, VT 30:342–350. Schmid K, 1999. Erzväter und Exodus: Untersuchungen zur doppelten Begründing der Ursprünge Israels innerhalb der Geschichtsbücher des Alten Testaments. WMANT 81. Neukirchen-Vluyn: Neukirchener Verlag. _______ 2007. The late Persian formation of the Torah: observations on Deuteronomy 34, in Lipschits, Knoppers & Albertz 2007:236–245. _______ 2012. Die Sameritaner und die Judaër. Die biblische Diskussion um ihr Verhältnis in Josua 24, in Frey, Schattner-Rieser & Schmid 2012:21–49. Schmid, K & Person, R (eds) 2012. Deuteronomy in the Pentateuch, Hexateuch, and the Deuteronomistic History. Tübingen: Mohr Siebeck. Schmidt, L 2009. P in Deuteronomium 34, VT 59:475–494. Schmitt, G 1964. Der Landtag von Sichem. Stuttgart: Calwer Verlag. Schmitt, H C 2004. DTN 34 als Verbindingstuck zwischen Tetrateuch und Dtr. Geschictswerk, in Otto and Achenbach 2004:181–192. Smend, R 1970. Das Gesetz un die Völker, in Wolff 1970:494–504. Sperling, S D 1987. Joshua 24 re-examined. HUCA 58:119–136. Steuernage, l C 1923. Das Buch Josua. GHK 1,3 (2). Göttingen: Vandenhoeck & Ruprecht. Stipp, H J (ed.) 2011. Das deuteronomistische Geschichtswerk. ÖBS 39. Frankfurt am Main: Peter Lang. Van Seters, J 1984. Joshua 24 and the problem of tradition in the Old Testament, in Barrick and Spencer 1984:139–158. _______ 2003. Deuteronomy between Pentateuch and Deuteronomistic History, HTS 59/3:947–956. Vervenne, M & Lust, J (eds) 1997. Deuteronomy and Deuteronomistic literature. FS C.H.W Brekelmans. BETL 133. Leuven: Peeters. Von Ruiten, J and de Vos, C (eds) 2009. The land of Israel in Bible, history and theology: studies in honour of Ed Noort. VTSup 124. Leiden: Brill. Weimar, P 2008. Studien zur Priesterschrift. FAT 56. Tübingen: Mohr Siebeck. Westermann, C 1994. Die Geschictsbücher des Alten Testaments: Gab es ein deuteronomsitisches Geschichtswerk? TB Altes Testament 87. Gütersloh: Gütersloher Verlag. Witte, M 1998. Die biblische urgeschichte. Redaktions-und Theologiegeschichtliche Beobachtungen zu Genesis 1,1–11:26. BZAW 265. Berlin: de Gruyter. Witte M, Schmid K, Prechel, D & Gertz, J C (eds) 2006. Die deuteronomistischenGeschichtswerke: Redaktions- und religionsgeschichtliche Perspektiven zur “Deuteronomismus”-Diskussion in Tora und vorderen Propheten. BZAW 365. Berlin: de Gruyter. Wolff, H W (ed.) 1970. Probleme biblischer Theologie: Gerard von Rad zum 70. Geburtstag. Munich: Kaiser Verlag. Würthwein, E 1994a. Erwägungen zum sog. Deuteronomistischen Geschichtswerk: eine Skizze, in Würthwein 1994b:1–11. Würthwein, E 1994b. Studien zum deuteronomistischen Geschichtswerk BZAW227. Berlin: de Gruyter, Zakovitch, Y 1980. The object of the narrative of the burial of the foreign gods at Shechem, BeTM 25:300–337. Zenger, E 2004. Einleitung in das Alte Testament. 5th ed. Stuttgart: Kohlhammer.

AbstractGenesis iii 16, which describes the unhappy consequences for Eve of her decision to eat from the forbidden fruit, is one of the most historically and theologically significant verses in the Hebrew Bible. Scholars have long debated certain cruces in the verse, among them the meaning of the phrase. I review various positions on the latter and then offer a new proposal.

Introduction: Mechanical jaundice (MJ) or bile duct blockage occurs when the bile ducts' patency is impaired, and the bile flow has stopped. One of the main pathogenetic factors developing complications with MJ is immune system imbalance, particularly its phagocytic link. The purpose of the study was to understand neutrophils' functional activity dependence with different blood bilirubin levels in men with mechanical jaundice. Methods: Forty-seven middle-aged men with mechanical jaundice were divided into three groups depending on the bilirubin levels in their blood: less than 60 μmol/L (n = 10), 60 – 200 μmol/L (n = 20), and more than 200 μmol/L (n = 17). The control group consisted of 50 practically healthy men of the same age. The neutrophils' functional state was assessed using the methods of spontaneous and induced luminol-dependent chemiluminescence of neutrophils. Results: In the group of patients with mechanical jaundice and a bilirubin level of less than 60 μmol/L, there was an increase in the values of T max spontaneous by 96%, I max spontaneous by 44.81%, S spontaneous by 224.6%, T max induced by 19.9%, I max induced by 13.5%, and S induced by 140.3%. In the group with bilirubin levels from 60 – 200 μmol/L, there was an increase in the values of T max spontaneous by 86.8%, I max spontaneous at 47.7%, S spontaneous at 204.6%, I max induced at 28.3%, S induced at 445%, and activation index at 70%. The group with bilirubin levels more than 200 μmol/L showed an increase in the level of T max spontaneous by 85.9%, I max spontaneous by 53.4%, S spontaneous by 927.3%, I max induced by 28.6%, S induced by 1045%, and activation index by 92.3% compared with the control values. The intergroup differences were found in S spontaneous levels, which were higher in the group with more than 200 μmol/L bilirubin levels compared with the 60 – 200 μmol/L group and less than the 60 μmol/L groups by 216.9% and 237.3% respectively. Conclusion: The revealed changes characterize the functional activity of neutrophils' increase with an increase in the bilirubin levels in patients with mechanical jaundice.

Background. The best surgical technique for large liver hydatid cysts (LHCs) has not yet been agreed on. Objectives. The objective of this study was to examine the role of perioperative endoscopic retrograde cholangiopancreatography (ERCP) and biliary drainage in patients with large LHCs. Methods. A 20-year retrospective study of patients with LHCs treated surgically at the University Clinical Center of Kosovo (UCCK). We divided patients into 2 groups based on treatment period: 1981–1990 (Group I) and 2001–2010 (Group II). Demographic characteristics (sex, age), the surgical procedure performed, complications rate, and outcomes were compared. Results. Of the 340 patients in our study, 218 (64.1%) were female with median age of 37 years (range, 17 to 81 years). 71% of patients underwent endocystectomy with partial pericystectomy and omentoplication, 8% total pericystectomy, 18% endocystectomy with capitonnage, and 3% external drainage. In Group I, 10 patients underwent bile duct exploration and T-tube placement; in Group II, 39 patients underwent bile duct exploration and T-tube placement. In addition, 9 patients in Group II underwent perioperative ERCP with papillotomy. The complication rate was 14.32% versus 6.37%, respectively (P=0.001). Conclusion. Perioperative ERCP and biliary drainage significantly decreased the complication rate and improved outcomes in patients with large LHCs.

The Buchans Group, central Newfoundland, represents an Ordovician continental bimodal calc-alkaline arc sequence that hosts numerous volcanogenic massive sulfide (VMS) occurrences, including both in situ and mechanically transported sulfide breccia–conglomerate orebodies. Diverse lithic clasts associated with transported deposits include rounded granitoid clasts. Earlier workers have suggested that Buchans Group VMS-hosting felsic extrusive units, small granodiorite intrusions (e.g., Wiley’s Brook), and granitoid cobbles associated with transported ore represent co-genetic products of the same magmatic system. The granitoid cobbles and small granodiorite intrusions are geochemically similar and closely resemble Buchans Group felsic volcanic units. U–Pb zircon age determinations show a (i) 466.7 ± 0.5 Ma crystallization age for the Wiley’s Brook granodiorite (WBG), (ii) 464 ± 4 Ma crystallization age for a granitoid cobble, and (iii) 466 ± 4 Ma maximum deposition age for a conglomerate–sandstone sequence associated with transported ore. Thus, Buchans Group felsic plutonic rocks are within experimental error of felsic volcanism and VMS deposition. Furthermore, εNd (T) (T, time of crystallization) values of four granitoid cobbles (–1.95 to –4.0) overlap values obtained from Buchans Group felsic volcanic units. Our results are compatible with plutonic and volcanic rocks being related through fractional crystallization or partial melting processes but do not support a petrogenetic link between VMS deposition and exposed felsic plutons. Comparisons to modern arc analogues favour exhumation of plutonic rocks by extension along caldera or rift walls and (or) subaerial erosion. Enigmatic rounding of Buchans granitoid clasts was likely accomplished in a subaerial or shallow marine environment, and the clasts transported into a VMS-active basin by mass flows.

Introduction. Musculoskeletal pain (MSP) — has now assumed the character of a non-infectious epidemic and ranks second among the causes of disability, leading to a significant loss of productivity among the working-age population in all industrialized countries. Spondyloarthrosis of the lumbar region and gonarthrosis are the main diseases that doctors face at outpatient appointments. The pathogenesis of the disease develops according to one scenario, accompanied by aseptic inflammation, involvement of the muscular and ligamentous apparatus in the process, leading to the formation of dissimilar locomotor disorders, antinociceptive insufficiency, peripheral and central sensitization. Presents the results of magnetic resonance imaging (MRI), which can be used for early diagnosis of MSD, as well as dynamic control during treatment. Aim — to assess of neuroimaging signs in patients with spondyloarthrosis and gonarthrosis, depending on the genesis of the disease. Methods. An analytical single-stage study was performed with 123 patients with an established clinical diagnosis of MSP, who were divided into four groups: primary gonarthrosis (36 people), post-traumatic (38 people), spondylogenic (30 people) and x-ray negative (19 people). To study neuroimaging signs, MRI was performed on the devices «OPENMARK 4000» 0.42 T of the company «ANKE», «OPART» 0.35 T of the company «TOSHIBA» and «Superstar» 0.35 T of the company «Neusoft medikal systems» in transversal, sagittal and coronary projections, in T1W, T2W and STIR modes with adipose tissue suppression. Results. During MRI examination, 47.2 % of patients revealed spondyloarthrosis of the III grade, 30,1 % — II grade. 33,3 % had damage in the form of fragmentation of the internal and external meniscus of the knee joint, 30.1 % of cases revealed damage to the internal meniscus in the form of longitudinal splitting and the same number of osteophytes. The most common cases were intervertebral disc sequestration (2,4 %) and expansion of the articular gap of the knee joint (4,1 %), and spondyloarthritis of the I grade (7,3 %). When compared in groups, more pronounced neuroimaging signs were detected in posttraumatic and primary gonarthrosis, and they were significantly lower in spondylogenic genesis. When examining the spine, no differences were found in the groups. Conclusion. The study showed high information content of MRI in CA and GA, which allows for early diagnosis of the disease and differential diagnosis.

Abstract The conjugate margins system of the Gulf of Lion and West Sardinia (GLWS) represents a unique natural laboratory for addressing fundamental questions about rifting due to its landlocked situation, its youth, its thick sedimentary layers, including prominent palaeo-marker such as the MSC event, and the amount of available data and multidisciplinary studies. The main goals of the SARDINIA experiment, were to (i) investigate the deep structure of the entire system within the two conjugate margins: the Gulf of Lion and West Sardinia, (ii) characterize the nature of the crust, and (iii) define the geometry of the basin and provide important constrains on its genesis. This paper presents the results of P-wave velocity modelling on three coincident near-vertical reflection multi-channel seismic (MCS) and wide-angle seismic profiles acquired in the Gulf of Lion, to a depth of 35 km. A companion paper [part II – Afilhado et al., 2015] addresses the results of two other SARDINIA profiles located on the oriental conjugate West Sardinian margin. Forward wide-angle modelling of both data sets confirms that the margin is characterised by three distinct domains following the onshore unthinned, 33 km-thick continental crust domain: Domain I is bounded by two necking zones, where the crust thins respectively from ~30 to 20 and from 20 to 7 km over a width of about 170 km; the outermost necking is imprinted by the well-known T-reflector at its crustal base; Domain II is characterised by a 7 km-thick crust with « anomalous » velocities ranging from 6 to 7.5 km/s; it represents the transition between the thinned continental crust (Domain I) and a very thin (only 4–5 km) “atypical” oceanic crust (Domain III). In Domain II, the hypothesis of the presence of exhumed mantle is falsified by our results: this domain may likely consist of a thin exhumed lower continental crust overlying a heterogeneous, intruded lower layer. Moreover, despite the difference in their magnetic signatures, Domains II and III present the very similar seismic velocities profiles, and we discuss the possibility of a connection between these two different domains.

The chemical composition of soil solution reflects the demand of soil biological processes and the solubility and ion-exchange equilibria between physical and biological components of the soil. The objectives of this study were to document soil-solution chemistry for representative phases of the primary successional sequence on the Tanana River floodplain near Fairbanks, Alaska, and to assess the effect of physical versus biological control on solution chemistry in these sites. Soil-solution samples were collected weekly using porous-cup soil-solution samplers located 20, 50, and 150 cm below the soil surface. In addition, groundwater and river water samples were collected at several sites that represented the successional stages typical of the Tanana River floodplain of interior Alaska. Magnesium, HCO3, Cl, Na, K, NO3, and PO4 showed the highest concentrations in the 50-cm layer at each site. Manganese, Fe, and Zn showed the highest concentrations at the groundwater level. Aluminum and Ca showed decreasing concentrations with depth from the surface. Silicon displayed no specific depth trends. Ammonium was the only ion that was more concentrated in river water than in soil solution. Soil-solution pH showed no specific depth trends. Conductivity of the soil solution was generally lower at greater depths and was much lower in the river water. Sulfate, K, Ca, and Mn decreased in concentration from the early successional stages to the later successional stages, although some year to year variability did occur. All measured concentrations except Zn displayed at least one significant change in concentration due to vegetation clearing. These differences can be summarized broadly as effects on nonbiologically cycled nutrients in the open willow stage (III) and changes in the biological cycling of nutrients in the poplar–alder and mature white spruce stages (V and VIII, respectively). Significant increases in concentration of Fe and Mn were found at III-B-T (stage III–site B–treated (i.e., cleared) plot) while Na, Mn, Fe, Ca, Mg, Si, and SO4 increased at III-A-T. At V-A-T significant increases were found in concentrations of NH4, NO3, PO4, SO4, K, Na, Ca, Mg, Mn, Fe, Al, Si, HCO3, and conductivity in 987. These same trends were repeated in 1988 with the exception of NO3, Fe, and Si, which showed no significant differences. As a result of clearing both V-A-T and V-B-T, Fe and Si significantly decreased in concentration at 50 cm, which was the opposite trend found at 150 cm. The Cl concentration at 50 cm decreased at V-A-T in 1987 but increased in 1988 as a result of clearing. V-B-T showed no effect of clearing in 1988 and only NO3, SO4, Ca, Mg, and conductivity increased in 1987. Chloride, Al, and Si decreased in concentration as a result of clearing in 1987 at V-B-T. Nitrate, NH4, Cl, and pH increased, while PO4, K, Na, Ca, Mg, Si, HCO3, and conductivity decreased, as a result of clearing in VIII-A-T. At VIII-B-T, NO3, K, Ca, Mg, Cl, HCO3, and conductivity increased as a result of clearing in 1987, while only NO3 increased in 1988. Bicarbonate, Cl, and pH showed significant decreases in 1987 and 1988 at VIII-B-T. The results of this study, combined with the results of other studies of these salt-affected floodplain soils, detailing the soil environment and control of evaporative movement of water to the soil surface support the hypotheses that: (i) the genesis and maintenance of surface salt crusts are controlled by the soil physical and chemical environments encountered on early-successional mineral soils and (ii) the disappearance of salt crusts and reduction in mineral soil salt concentrations are controlled by forest succession, which mediates the changing soil physical, chemical, and biological environment.

Abstract The newly discovered Shuangjianzishan Ag-Pb-Zn deposit, with 145 Mt of ore grading 128.5 g/t Ag (locally up to 32,000 g/t) and 2.2 wt % Pb + Zn, is located in the Great Hinggan Range metallogenic belt, northeastern China, and is currently the largest Ag deposit in Asia. The Ag-Pb-Zn orebodies occur as veins and are hosted primarily by a Permian slate. Recent drilling and core logging have identified a partially Mo mineralized granite porphyry intrusion adjacent to the Ag-Pb-Zn mineralized veins. This well-preserved magmatic-hydrothermal system therefore offers an excellent opportunity to evaluate the possible temporal and genetic relationship between Mo-mineralized porphyry intrusions and Ag-Pb-Zn veins. Three primary paragenetic stages of veining have been recognized: (I) early pyrite + quartz ± K-feldspar, (II) main ore sulfide + sulfosalt + quartz + calcite + sericite + chlorite ± epidote, and (III) post-ore quartz. The silver mineralization occurs mainly in the late paragenetic part of Stage II, in which canfieldite (Ag8SnS6), argentite (Ag2S) and freibergite [(Ag, Cu)12Sb4S13] are the dominant Ag-bearing ore minerals. A combination of ore mineral chemical and sulfur isotope geothermometers and physicochemical calculations suggest that the Ag-Pb-Zn mineralization took place at a temperature of 250° to 200°C, a pH of 6.7 to 5.6, and a Δlogfo2 (HM) of –2.4 to –8.7. A conspicuous enrichment of Sn and Se in the ore, which is represented by minerals containing the metal suite Ag-Pb-Zn-(Cu-Sn-Se-Sb), likely reflects a close genetic association between the base metal mineralization and a magma. In situ analyses show that the δ34S values of the sulfides and Ag-bearing sulfosalts from the Ag-Pb-Zn mineralized veins vary from –4.67 to +2.44‰; the mean value is –2.11 ± 1.49‰ (n = 77). The calculated mean δ34SH2S value of the ore-forming fluid is –1.65 ± 0.83‰, which is indicative of a magmatic sulfur source. In situ Pb isotope analyses of the ore minerals yielded a narrow range of values (206Pb/204Pb of 18.243–18.310, 207Pb/204Pb of 15.503–15.563 and 208Pb/204Pb of 38.053–38.203, n = 59). Comparisons to corresponding isotopic data for the various rock units in the area and sulfides from nearby ore deposits indicate that there were substantial contributions of Pb and other metals (e.g., Ag and Zn) to the Shuangjianzishan deposit from a Mesozoic granitic source. Diorite-granodiorite dikes and dacite are crosscut by the Ag-Pb-Zn veins, and therefore, predate ore formation. These rock units have zircon U-Pb ages of 250.2 ± 2.0 and 133.9 ± 1.4 Ma, respectively. A concealed, weakly Mo mineralized granite porphyry intrusion proximal to the Ag-Pb-Zn mineralized vein system yielded zircon U-Pb ages of 134.4 ± 1.0 (MSWD = 0.1) and 134.4 ± 1.0 Ma (MSWD = 0.2), for coarse- and fine-grained facies, respectively. These ages are indistinguishable within the uncertainty from the zircon ages for the dacite and a granite intrusion ~2 km north of the mineralized veins, which has a weighted mean zircon U-Pb age of 135.2 ± 1.4 Ma (MSWD = 0.78). Molybdenite from three quartz vein/veinlet samples hosted by slate immediately above the porphyry intrusion yielded Re-Os model ages from 136.3 ± 0.9 to 133.7 ± 1.2 Ma and a weighted mean Re-Os age of 134.9 ± 3.4 Ma. Finally, three pyrite samples separated from the Ag-Pb-Zn mineralized veins have a weighted mean Re-Os model age of 135.0 ± 0.6 Ma. The very similar zircon U-Pb ages for the Mo-mineralized granite porphyry and dacite, and Re-Os ages for molybdenite and pyrite in the Shuangjianzishan ore district indicate that the Mesozoic magmatic-hydrothermal activity was restricted to a relatively short time interval (~136–133 Ma). They also suggest that the weakly Mo mineralized granite porphyry was likely the source of the fluids and metals that produced the Ag-Pb-Zn mineralization. Based on our geological observations and an extensive analytical database, a model is proposed for the genesis of the giant Shuangjianzishan Ag-Pb-Zn deposit in which the ore-forming fluid and its metals (i.e., Ag, Pb, and Zn) were exsolved during crystallization of the final phase of a composite granite porphyry intrusion. This fluid transported metals to the distal parts of the system, where they were deposited in preexisting faults or fractures created by the withdrawal of magma during the waning stages of the magmatic-hydrothermal event. The present study of the Shuangjianzishan Ag-Pb-Zn deposit and those of other magmatic-hydrothermal ore deposits in the region provide compelling evidence that the widespread Mesozoic felsic magmatism and Ag-Pb-Zn mineralization in the southern Great Hinggan Range took place in an intracontinental extensional tectonic setting, which was synchronous with, and spatially associated to, Paleo-Pacific slab rollback and lithospheric delamination and thinning.

Abstract Mature microRNAs (miRNA) are recently discovered small RNA molecules of 21–25 nucleotides in length. They act as negative regulators of expression of important genes like those participating in cellular proliferation or apoptosis. There is evidence that miRNA play an important role in carcinogenesis. The objective of this study was to compare the miRNA expression patterns in normal lymph nodes and in lymph nodes from patients with HL. Moreover, we investigated the miRNA pattern of HL depending on Epstein-Barr Virus (EBV) expression. We assessed 156 mature miRNAs by Stem-loop RT-PCR and Real time PCR in ABI PRISM 7500 in 9 normal lymph nodes and 39 patients diagnosed with HL nodular sclerosis subtype (15 EBV+ and 24 EBV-)at a single institution. Patients median age was 27 years (range, 15–52), and clinical stage was I (n=1); II (n=22); III (n=8) and IV (n=8); 41% of the patients reported B symptoms. RNA was obtained in all cases from formalin fixed paraffin embedded tissues. miRNA expression data was normalized to let-7a miRNA and to global median. Relative quantification of miRNA expression was calculated with the 2−ΔΔCt method. The data were presented as log10 of relative quantity of target miRNA. Normal human lymph node tissue was used as calibrator for all samples. Data were analyzed by means of Significant Analysis of Microarrays (SAM), Student’s t-test (with random variance model) and Class prediction methods using BRB Array Tools version 3.4.0 and TIGR Multiexperiment Viewer version 3.1. Of the 156 miRNAs analyzed, 35 were differentially expressed between normal lymph nodes and HL (12 miRNAs were upregulated and 23 downregulated). The most differentially overexpressed miRNAs was miR-216, which inhibits apoptosis pathway. Other differentially expressed miRNAs were miR-140, 204, 19a, 20, 191 and 142-3p, which have been associated to the genesis of hematological and non-hematological malignances. With respect to EBV+ vs. EBV− cases, we found that miR-96 and miR-335 were underexpressed in the EBV+ cases as compared to EBV− (p=0.001). These miRNAs have RNF34 and BIRC2 genes as targets, which have an antiapoptotic function. We also found that miR-138 was more frequently overexpressed in clinical stages I–II versus clinical stages III–IV (p=0.004), and that miR-328 was more frequently overexpressed in stages III–IV (p=0.004). In conclusion, miRNAs might have a role in the pathogenesis of HL. The miRNA pattern is different between the EBV+ and EBV− cases, and the differentially expressed miRNAs seems to be related to the apoptotic pathway.

Introduction: Chemotherapy associated osteoporosis is a severe problem in patients with malignant diseases as it increases the risk for fractures and deteriorates quality of life. There are very limited data in the literature for the effect of chemotherapy on bone metabolism of adult patients with Non-Hodgkin Lymphoma (NHL). Thus, there is lack of formal recommendation regarding bone investigations at baseline or prophylactic bone management during treatment administration. The aim of this study was to perform a thorough assessment of bone remodeling in newly diagnosed patients with NHL, prior and post chemotherapy administration, to provide insight on the mechanisms of bone loss in these patients. Methods : Patients with NHL who received frontline treatment were eligible for participation in this study. Exclusion criteria included patients with lymphoma bone-involvement or with known osteoporosis under medication, previous bone fractures, BMD T-scores <-2.0, creatinine clearance <60 mL/min, prior bisphosphonate or significant steroid use for other medical reasons, dental and endocrine problems, metabolic bone diseases and previous radiotherapy to lumbar spine. Bone Mineral Density (BMD) of the lumbar spine (L1-L4, antero-posterior view), and femoral neck (FN) was measured on day 1 of cycle 1 (baseline) and on day 30 post the last cycle of chemotherapy. The following serum markers of bone remodeling were measured on samples collected on the days of DXA in NHL patients and in 44 healthy controls of similar age and gender, using ELISA methodology: (i) osteoclast regulators [sRANKL, osteoprotegerin (OPG)]; (ii) osteoblast regulators [dickkopf-1 (Dkk-1), parathyroid hormone (PTH) and vitamin-D]; (iii) bone resorption markers: NTX, CTX, and TRACP-5b; and (iii) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Results: Sixty-one newly diagnosed patients with NHL were prospectively enrolled: 42 (68.9%) patients had diffuse large B-cell lymphoma, 6 (9.8 %) follicular lymphoma (grade III), 4 (6.6%) mantle-cell lymphoma, 7 (11.5%) marginal-zone lymphoma and 2 (3.3%) T-cell NHL. Fifty-four patients (88.5%) received R-CHOP (47 every 21 days and 7 every 14 days), 4 (6.6%) received R-CVP and 3 (4.9%) CHOP as first-line therapy. At baseline, NHL patients had a median T-score of L1-L4 BMD of -0.71 (range -4.27 to +4.36) and of FN BMD of -0.79 (-4.01 to +2.49). The administration of chemotherapy resulted in a dramatic reduction of BMD in L1-L4 (median T-score: -1.12; range -4.49 to +4.34; p=0.001 and median T-score of the lumbar vertebra with the major loss: median T score -1.45; range: -4.84 to +29; p=0.001) and in FN BMD (median T-score: -0.95; range: -3.68 to +2.12; p=0.0001) compared to baseline values. The reduction of L1-L4 BMD post-chemotherapy and of vertebrae BMD with major loss was more profound in males than in females (p=0.001) and in patients of >55 years compared to all others (p=0.0001). Patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 (p=0.0001), of vertebra with major loss (p=0.003) and of FN (p=0.0001) BMD compared to patients who received 6 cycles of chemotherapy. This reduction was irrespective of the NHL stage (I/II vs. III/IV). At baseline, patients had decreased levels of OC (0.6 vs. 10.4 ng/ml in controls; p=0.001) and increased levels of TRACP-5b (1.82 vs. 1.52 U/L in controls; p=0.005), with no other alterations in bone markers studied. The administration of chemotherapy resulted in a dramatic increase of markers of bone resorption, CTX (6.93 vs. 0.6 ng/ml, p=0.008) and TRACP-5b (2.78 vs. 1.82 U/L; p=0.0001). Markers of bone formation and Dkk-1 were also increased: bALP (26.2 vs. 19.0 U/L; p=0.0001), OC (18.6 vs. 0.6 ng/mL; p=0.0001) and Dkk-1 (192.2 vs. 166.5 pg/mL, p=0.005 and), respectively. There was a greater increase of CTX (p=0.04), sRANKL/OPG (p=0.015), TRACP-5b (p=0-.03), bALP (p=0.003) and OC (p<0.0001) in patients who received 8 cycles of chemotherapy compared to all others. During study period, one patient had a pathological fracture in his right FN. Conclusions : Our study suggests that first-line chemotherapy (immuno-chemotherapy for the vast majority of patients) results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. These patients should benefit from the prophylactic use of bone-targeted agents, i.e. bisphosphonates, denosumab or romosozumab. Disclosures Terpos: Amgen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Vassilakopoulos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Makras:Amgen: Honoraria, Research Funding; Glaxo: Honoraria; Eli-Lilly: Honoraria; Pfizer: Honoraria; Leo: Honoraria; Genesis: Honoraria; UCB: Honoraria. Angelopoulou:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesiaPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Panayiotidis:Bayer: Other: Support of clinical trial. Dimopoulos:Sanofi Oncology: Research Funding.

Background. In recent years, as a result of the growing expansion of the pharmaceutical market, there has been a clear trend towards an increase in the incidence of chronic toxic drug-induced hepatitis of drug genesis (TDIH). The appearance of fibrosis is considered the most important histological change that determines the further course of the disease. Therefore, the search for non-invasive or minimally invasive markers for assessing fibrotic changes in the liver remains an urgent issue in clinical practice. The purpose was to determine the diagnostic value of immunological parameters for stratification of the severity of liver fibrosis in patients with TDIH. Materials and methods. The study included 41 patients with TDIH, who were divided into three groups: group I consisted of 12 people without liver fibrosis (F0), group II — 22 patients with moderate fibrosis (F1-F2), group III — 7 individuals with severe liver fibrosis (F3-F4). Shear wave elastography was performed using a Soneus P7 system (Ukraine-Switzerland). All patients underwent a biochemical blood test with the determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST). The subpopulation composition of lymphocytes, circulating immune complexes (CIC), the level of interleukins (IL-6, IL-10) and tumor necrosis factor α were assessed. Results. The progression of liver fibrosis is accompanied by an increase in cytolytic syndrome: patients with severe fibrosis have a 3.3-fold increase in the ALT (p < 0.05) compared to the controls and a 2.1-fold (p < 0.05) compared to that in patients with moderate fibrosis. The AST level is significantly higher — by 4.6 times (p = 0.023) in patients with severe fibrosis than in those with moderate fibrosis. With the progression of liver fibrosis, there is a significant decrease in cellular immunity, an increase in the level of CIC and pro-inflammatory cytokines with a simultaneous decrease in the content of anti-inflammatory cytokines, which is confirmed by correlations between the liver stiffness index according to shear wave elastography data and the level of T-helpers (r = –0.466; p = 0.03), IL-6 (r = 0.364; p = 0.01), IL-10 (r = –0.331; p = 0.039) and CIC (r = 0.381; p = 0.017). Conclusions. Markers of the diagnosis of severe liver fibrosis in patients with TDIH are indicators such as the ratio of IL-6/IL-10 higher than 0.83 (sensitivity 81.8 %, specificity 78.9 %), CIC level more than 4.3 optical density units (sensitivity 77.3 %, specificity 72.2 %), the ratio of T-helpers/T-suppressors is less than or equal to 1.6 (sensitivity 72.7 %, specificity 57.9 %).

Introduction: Multiple myeloma (MM) is the second most common hematological malignancy arising from terminally differentiated plasma cells. The diagnosis of symptomatic ΜΜ is usually based on the presence of end-organ damage, as defined by the CRAB criteria. ΜΜ is part of a spectrum of disorders characterized as monoclonal gammopathies. Smoldering multiple myeloma (SMM) is a plasma cell dyscrasia preceding MM. The risk of sMM progression to active MM is determined by risk stratification models, such as the Mayo Clinic and the Spanish models. The clinical course of MM is quite heterogenous; patients survival is ranging from months to more than a decade. MM risk is determined using the international staging system (ISS) and the revised-ISS (R-ISS), which incorporates LDH and cytogenetics to ISS. tRNA-derived RNA fragments suggest a class of small non-coding RNAs, which derive from either pre- or mature tRNAs. tRNA fragments have only recently emerged and therefore have not been broadly studied. These fragments are not random degradation products, yet occur through specific enzymatic activity. Two large groups of these molecules are currently known and are distinguished based on their length; tiRNAs or tRNA halves consist of 30-50 nucleotides, while tRNA-derived fragments (tRFs) consist of 16-28 nucleotides. Both categories are further subgrouped according to their site of origin, in 5′-, 3′-, and internal fragments. Although their role is still under evaluation, studies have linked them to pathological situations, such as neurodegenerative diseases, various cancer types and hematological malignancies. In this study, the clinical significance of 6 of these fragments was evaluated in MM, and three of them showed interesting results. These molecules are 3′-tRFs or internal tRFs (i-tRFs), which occur from the tRNAs bearing leucine, glutamic acid and proline anticondons, namely 3′-tRF-LeuAAG/TAG, i-tRF-GluCTC, and i-tRF-ProTGG, respectively. Methods: CD138+ plasma cells were collected from 80 patients at the time of diagnosis: 65 with MM and 15 with SMM. Total RNA was extracted from CD138+ cells using TRIzol and thereafter was polyadenylated by Escherichia coli poly(A) polymerase. First-strand cDNA synthesis was performed by MMLV transcriptase, using an oligo-dT-adaptor primer. Subsequently, we used and in-house real-time quantitative PCR assay, based on SYBR Green chemistry, in order to quantify tRFs in all samples. Specific forward primers were designed for all tested molecules, along with a common reverse primer, complementary to the adaptor used during reverse transcription. The small nucleolar RNAs RNU43 and RNU48 were used as reference genes, in order to normalize qPCR data. Biostatistical analysis was carried out to assess these results. Results: Out of 65 MM patients 13 were classified as having ISS I stage, 22 as ISS II stage, and 30 as ISS III stage. Similarly, 13 of them were grouped in R-ISS I stage, 35 as R-ISS II, and 17 as R-ISS III. The Mann Whitney U test revealed that the levels of 3′-tRF-LeuAAG/TAG, itRF-GluCTC, and i-tRF-ProTGG differed significantly between MM and SMM cases (P=0.001, P=0.047 and P=0.033, respectively). Specifically, these molecules had higher levels in the CD138+ cells of the SMM cases. These results were validated by logistic regression analysis, which showed that patients with lower expression levels of these molecules were at a higher risk of suffering from MM (P=0.003 for 3′-tRF-LeuAAG/TAG , P=0.036 for itRF-GluCTC, and P=0.032 for i-tRF-ProTGG). Furthermore, 3′-tRF-LeuAAG/TAG was related with translocation t(4;14). Conclusions: 3′-tRF-LeuAAG/TAG, i-tRF-GluCTC, and i-tRF-ProTGG may represent novel molecular biomarkers for the differential diagnosis of MM from SMM in ambiguous cases, in which the diagnostic work-up does not provide a clear diagnosis. These novel biomarkers could also play a role in the prediction of sMM cases at high risk of evolution to active multiple myeloma given their overexpression in asymptomatic cases. A possible correlation of these biomarkers to prognosis in MM patients may be indicated by their relationship with the t(4;14) translocation. Disclosures Gavriatopoulou: Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Kastritis:Genesis: Honoraria; Prothena: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Terpos:Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Medison: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

Background:Previous studies have suggested similar effectiveness, but longer treatment retention, for tumor necrosis factor inhibitors (TNFi), when used in combination with a conventional synthetic disease modifying anti-rheumatic drug (csDMARD) in psoriatic arthritis (PsA).Objectives:To describe patients with PsA initiating a first TNFi as monotherapy compared to combination therapy, and to explore 1-year treatment retention of TNFi in the two groups.Methods:Patients with PsA starting a first TNFi (2006-2017) were identified in biologics registers of 13 European countries, and data were pooled for analysis. Co-medication with csDMARD was determined at TNFi start.Because of large inter-country variation in TNFi retention, countries were split into two strata, depending on each country’s 1-year retention rate for TNFi being above (stratum A) or below (stratum B) the average 1-year retention rate.TNFi treatment retention was compared through Kaplan-Meier curves; the proportion remaining on the TNFi at one year; and hazard ratios (HR) during the first year: (i) crude; adjusted for (ii) country-strata, and (iii) country-strata, sex, age, calendar year, DAS28 and disease duration. In model (iii) only registers contributing >1000 patients or <33% missing data for DAS28 were included.Results:A total of 14778 patients with PsA starting a first TNFi were included. Baseline disease activity was similar within stratum B, but higher for the combination treatment group in stratum A (table 1).Table 1.Baseline characteristicsCountry strataStratum AStratum BTNFimonotherapyN=2120TNFi/csDMARDcombinationN=2128TNFimonotherapyN=3369TNFi/csDMARDcombinationN=7161Females52%51%53%51%Age, years49.7 (12.2)48.7 (11.8)48.8 (13.0)48.9 (12.2)Disease duration, yrs6.4 (7.0)6.8 (6.8)5.9 (7.5)5.9 (7.1)Tender joints 285.5 (6.3)8.0 (6.3)5.6 (6.0)5.6 (5.7)Swollen joints 282.8 (4.3)5.6 (5.0)3.0 (3.8)3.3 (3.8)VAS pain54 (29)62 (24)59 (23)56 (24)DAPSA-2824.6 (18.6)36.2 (17.6)27.3 (15.6)27.2 (15.2)DAS28 (CRP)3.5 (1.4)4.7 (1.3)4.0 (1.2)4.0 (1.1)Concomitant csDMARDMethotrexate-76%-79%Sulfasalazine-15%-15%Other csDMARD-49%-25%Numbers are means (sd) unless otherwise stated.The Kaplan-Meier curves for the treatment groups were similar within each stratum (fig 1), as were the proportions remaining on TNFi after one year, stratum A: monotherapy 86% (95%CI: 85-88) vs. combination 86% (84-87), stratum B: 71% (69-72) vs. 73% (72-74). The HRs for TNFi discontinuation (ref=TNFi monotherapy) were: (i) 1.06 (0.98-1.13), (ii) 0.94 (0.87-1.01), (iii) 0.89 (0.83-0.96), including 13078 patients (9 countries) for model (iii).Conclusion:In this exploratory study no benefit in TNFi retention was observed for csDMARD combination therapy in crude analyses, while in adjusted analyses an 11% lower risk of TNFi discontinuation was found. These preliminary results offer limited support for use of combination therapy in PsA. Further analyses will explore to what extent the results are affected by inter-country heterogeneity and differences between TNFi.Acknowledgments:UL and DDG contributed equally.Novartis Pharma AG and IQVIA support the EuroSpA collaboration.Disclosure of Interests:Ulf Lindström: None declared, Daniela Di Giuseppe: None declared, Bénédicte Delcoigne: None declared, Bente Glintborg Grant/research support from: Grants from Pfizer, Biogen and Abbvie, Burkhard Moeller: None declared, Manuel Pombo-Suarez Consultant of: Janssen, Lilly, MSD and Sanofi., Speakers bureau: Janssen, Lilly, MSD and Sanofi., Carlos Sánchez-Piedra: None declared, Kari Eklund Consultant of: Celgene, Lilly, Speakers bureau: Pfizer, Roche, Heikki Relas Grant/research support from: Abbvie., Consultant of: Abbvie, Celgene, and Pfizer., Speakers bureau: Abbvie, Celgene, and Pfizer., Björn Gudbjornsson Speakers bureau: Novartis and Amgen, Thorvardur Love: None declared, Gareth T. Jones Grant/research support from: Pfizer, AbbVie, UCB, Celgene and GSK., Adrian Ciurea Consultant of: Consulting and/or speaking fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer., Catalin Codreanu Consultant of: Speaker and consulting fees from AbbVie, Accord Healthcare, Alfasigma, Egis, Eli Lilly, Ewopharma, Genesis, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB, Speakers bureau: Speaker and consulting fees from AbbVie, Accord Healthcare, Alfasigma, Egis, Eli Lilly, Ewopharma, Genesis, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB, Ruxandra Ionescu Consultant of: Consulting fees from Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz, Speakers bureau: Consulting and speaker fees from Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz, Lucie Nekvindova: None declared, Jakub Zavada Speakers bureau: Abbvie, UCB, Sanofi, Elli-Lilly, Novartis, Zentiva, Accord, Nuh Atas: None declared, Servet Yolbaş: None declared, Karen Fagerli: None declared, Brigitte Michelsen Grant/research support from: Research support from Novartis, Consultant of: Consulting fees Novartis, Ziga Rotar Consultant of: Speaker and consulting fees from Abbvie, Amgen, Biogen, Eli Lilly, Medis, MSD, Novartis, Pfizer, Roche, Sanofi., Speakers bureau: Speaker and consulting fees from Abbvie, Amgen, Biogen, Eli Lilly, Medis, MSD, Novartis, Pfizer, Roche, Sanofi., Matija Tomsic: None declared, Florenzo Iannone Consultant of: Speaker and consulting fees from AbbVie, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, MSD, Speakers bureau: Speaker and consulting fees from AbbVie, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, MSD, Maria Jose Santos Speakers bureau: Novartis and Pfizer, Pedro Ávila-Ribeiro Grant/research support from: Novartis, Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Lennart T.H. Jacobsson Consultant of: AbbVie, Eli Lilly, Janssen, Novartis and Pfizer, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma, Michael Nissen Grant/research support from: Abbvie, Consultant of: Novartis, Lilly, Abbvie, Celgene and Pfizer, Speakers bureau: Novartis, Lilly, Abbvie, Celgene and Pfizer

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients. Methods: This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled. Results: The current analysis includes 1216 patients; median age of 62.56 years; 58.7% male. The median follow-up from diagnosis for the entire cohort was 51.9 months; 69.1% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.7%), Stage II (34.0%) and Stage III (15.1%), data was missing for the rest. The distribution of concurrent FISH abnormalities included: trisomies (3.5%), del 13q (13.3%), 1q amp (8.8%), and del 17p or monosomy 17 (5.8%). Initial regimen included: 27.2% had an immunomodulatory (IMiD), 45.9% had a proteasome inhibitor (PI), 17.7% had both, and 9.0% had no novel agent. The drug classes by line of therapy are shown in Table 1. An early stem cell transplant (defined as within 12 months of start of first line treatment) was used in 49.4% of patients. The median time to next treatment (TTNT) after starting initial treatment was 26.6 (95% CI: 23.9 to 29.2) months. The median overall survival (OS) from diagnosis for the entire cohort was 95.1 (95% CI: 85.9 to 105.9) months; 4-year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 77.5% and 78.6%, respectively. The median OS for those with any one high risk FISH lesion (del 17p/ 1q amp) was 67.5 (55.2, 97.1) versus 101.7 (89.7, 107.3) months. Patients with early SCT (within 12 months of diagnosis) had better OS: 108.3 (103.8, 133.0) vs. 69.8 (61.5, 80.3) months. Conclusion: Patients with t(11;14) without high risk FISH abnormalities have an excellent survival. Patients receiving a PI + IMiD combination and those receiving autologous SCT as part of initial therapy had best survival. Though numbers are limited, patients in the later lines receiving newer drugs such as venetoclax and daratumumab had high response rates and durable responses. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Bittrich:Celgene: Other: Travel Funding, Research Funding; Else Kröner Fresenius Foundation: Research Funding; Otsuka Pharmaceuticals Europe: Other: N/A; SANOFI Aventis: Membership on an entity's Board of Directors or advisory committees, N/A, Research Funding; University Hospital Wuerzburg: Employment; Bristol Myers Squibb: Research Funding; Pfizer: Other: Travel Funding; AMGEN: Other: Travel Funding; JAZZ Pharmaceuticals: Other: Travel Funding; Wilhelm Sander Foundation: Research Funding; German Research Foundation (DFG): Other: N/A; University of Würzburg: Other: N/A. Goldschmidt:Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; John-Hopkins University: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Janssen: Speakers Bureau; BMS: Speakers Bureau. Mangiacavalli:celgene: Consultancy; Amgen: Consultancy; Janssen cilag: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Yee:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Rosta:Cornerstone Research Group: Employment. Haltner:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Background. This article discusses the features of the program, the origins and symbolism of extra-musical images of the Concerto for Persian Ney and Orchestra “Toward That Endless Plain” by the Iranian-American composer of the XX–XXI centuries Reza Vali. There are also some features of the Concerto’s musical material analyzed: the form, instrumentation, and thematic, as well as the influence of Iranian musical traditions. There are no published scientific musicological materials devoted to the consideration of this Concerto from the point of view the comprehensive analysis. In periodical non-scientific literature, only four publications were found regarding this work. These include the article by the American writer Marakay Rogers, in which she gave a brief overview of the music of the Concerto and expressed her favorable impression of the composition. We also have the short article-annotation of American musicologist Brent Reidy and the article by American writer and journalist Lee Passarella written in connection with the release of the album, and the fragment of the interview by American musicologist Ellen Moysan with Reza Vali, where the composer spoke about the using Persian musical system in the Concerto for Ney and Orchestra. The purpose of this article is to consider the specifics of the Concert for Ney and Orchestra by R. Vali in the aspect of the author’s embodiment of the chosen program, as well as the peculiarities of Iranian traditional culture and music and their influence on professional academic music. Methods. The historical method was used to uncover the genesis of the “Sama” genre, also to study the genre features of the Concerto cycle; for considering the features of the structure and thematism of the Concerto the system-analytical method was used. Research results. The Concerto for Persian Ney and Orchestra “Toward That Endless Plain” was created by Reza Vali in Boston in 2003. In the composer’s legacy, this is the second big work in the concerto genre (for solo instrument and orchestra) and the first his work for an orchestra, which he composed on the base of the Persian traditional musical system. In addition to this Concerto, the composer wrote the Concerto for Flute and Orchestra (1992) and the Concerto for Kamanche and Ney with Orchestra (2009). The peculiarities of the musical material and its development are determined by the composer’s comprehension of the poem “Call of the Beginning” of the 20th century Iranian poet Sohrab Sepehri. Recreating the main images of the poem in the Concerto – the images of a mystic lonely traveler and aggressive surrounding world opposed to him – R. Vali touches on the topics of conflicting relations between an individuality and a society, the tragic panhuman events of our time, and also – of the searches of a lonely person on his spiritual path to God. Understanding the origins of the Concerto’s program and the essence of the images will allow performers and listeners to more deeply penetrate the spirit and idea of the composition. The program of the Concerto is presented as following: the name, epigraph, headings for each part and the author’s notes to the program. The theme, the idea, the content and the images of the Concerto and its connection with the tragic events of the modern world are expressed through the philosophy of Sufism and the symbols contained in it, that was used around 800 years ago by Jalal ad-Din Muhammad Rumi. Reza Vali believes that Sohrab Sepehri contacts the philosophy of ancient poets to the literature of the 20th century. To express the basic musical idea – the search for the path of a human to God and the achievement of unity with him – the composer turns to the solo timbre of the Persian wood wind instrument Ney, which is the bearer of the image of sadness, loneliness, separation from the motherland. The sound of Ney, associated with spiritual search, is presented in Parts I, II and III of the Concerto. In Prelude and Interlude, Ney does not play anything. The theme of the danger is embodied in the Prelude and Interlude through the atonal technique and dissonant sounds of the instruments of the symphony orchestra that associates with the tragic war events that threaten all of humanity and their consequences. R. Vali used both, the European musical (three-part) form and the structures inherent in Iranian music (the mosaic form in Parts I and III based on the classical repertoire of Iranian music (Radif), and the Nobat form in Part II). The structure of the cycle is due to the program concept; its specifics are two additional sections designated as Prelude (before Part I) and Interlude (between Parts II and III). The program led to a change in the sequence of tempo characteristics of the parts in the overall composition of the cycle, which is different from genre customary in a concerto of Western European music. In the R. Vali’s Concert, Parts I and III are slow and Part II is fast. All the headings of the parts correlate with the mystical philosophy of Sufism. The author represents the headings in the score in two languages – Iranian and English that allows a deeper clarification of their semantic characteristics: “Prelude” – “Сhezolm&#225;t” / “The Abyss”; Part I – “Gozar” / “Passage”; Part II – “S&#225;m&#226;” / “Ecstatic Dance”; “Interlude” – “Bargasht” / “Return to the Abyss”; Part III – “Foroud va F&#225;n&#226;” / “Descent and Dissolve”. In figuratively semantic plan, Prelude and Interlude are in opposition to the three main parts of the Concerto. The cruel, destructive images of the material world that presented in Prelude and Interlude are set against the world of concentrated contemplation, the search of spiritual path for a person, recreated in the I, II and III Parts of the cycle. The musical language of the Concerto has roots in the vocal and instrumental Iranian traditional music – the ancient Dastg&#257;h modal system and maqam forms. The medium size of the symphony orchestra is used in the Concerto. The group of brass and percussion instruments is especially important in creating the atmosphere of cruelty and violence and achieving the wild harsh sound. For showing an impending catastrophe, in finish fragment of Prelude, the composer introduces large and small electronic sirens into the orchestra. Conclusions. The extra-musical content and images of the R. Vali’s Concerto for Persian Ney and Orchestra and its connection with the tragic events of the modern world history are expressed through the philosophy of Sufism and its symbols. These philosophical ideas, images and symbols are embodied by the composer on various levels of the work as the structural and artistic integrity: 1) at the level of the structure of the modified three-part cycle; 2) in cycle’s tempo organization; 3) in the use of the system of the traditional Iranian music (dastg&#257;h and maqam) in I, II, III parts; 4) in the use of principally distinct thematism in the Prelude and Interlude in comparison with the main parts; 5) at the level of the timbre and texture organization – in the semantization of the Ney‘s timbre and in multifarious, in terms of imagery, interpretation of the orchestra.

Abstract. In Paper I of four papers, a revised columnar high-order model to investigate gas-aerosol-turbulence interactions in the convective boundary layer (CBL) was proposed. In Paper II, the model capability to predict first-, second- and third-order moments of meteorological variables in the CBL was demonstrated using available observational data. In the present Paper III, the high-order modelling concept is extended to sulphur and ammonia chemistry as well as to aerosol dynamics. Based on the previous CBL simulation, a feasibility study is performed using two "clean air mass" scenarios with an emission source at the ground but low aerosol background concentration. Such scenarios synoptically correspond to the advection of fresh post-frontal air in an anthropogenically influenced region. The aim is to evaluate the time-height evolution of ultrafine condensation nuclei (UCNs) and to elucidate the interactions between meteorological and physicochemical variables in a CBL column. The scenarios differ in the treatment of new particle formation (NPF), whereas homogeneous nucleation according to the classical nucleation theory (CNT) is considered. The first scenario considers nucleation of a binary system consisting of water vapour and sulphuric acid (H2SO4) vapour, the second one nucleation of a ternary system additionally involving ammonia (NH3). Here, the two synthetic scenarios are discussed in detail, whereas special attention is payed to the role of turbulence in the formation of the typical UCN burst behaviour, that can often be observed in the surface layer. The intercomparison of the two scenarios reveals large differences in the evolution of the UCN number concentration in the surface layer as well as in the time-height cross-sections of first-order moments and double correlation terms. Although in both cases the occurrence of NPF bursts could be simulated, the burst characteristics and genesis of the bursts are completely different. It is demonstrated, that observations from the surface layer alone are not conclusive to elucidate the origin of newly formed particles. This is also true with respect to the interpretation of box modelling studies. The binary and ternary NPF bursts observed in the surface layer differ with respect to burst amplitude and phase. New particles simulated in the binary scenario are formed in the forenoon in the upper part of the growing CBL, followed by turbulence-induced top-down transport. Hence, with respect to the burst observation site in the surface layer, new particles are formed ex situ. In opposite to this, the ternary case reveals a much more complex pattern. Here, NPF is initiated in the early morning hours in the surface layer, when temperature (T) is low and relative humidity (RH), sulphur dioxide (SO2) and NH3 concentrations are high, hence new particles are formed in situ. Shortly after that, ex situ NPF in the free troposphere sets in, followed by entrainment and top-down diffusion of newly formed particles into the surface layer. Altogether, these processes mainly contribute to the formation of a strong burst in the morning hours in the ternary scenario. While the time-height cross-section of the binary nucleation rate resembles a "blob"-like evolution pattern, the ternary one resembles a "sucking tube"-like pattern. The time-height cross-sections of the flux pattern and double correlations could be plausibly interpreted in terms of CBL turbulence and entrainment/detrainment processes both in the binary and in the ternary case. Although the present approach is a pure conceptual one, it shows the feasibility to simulate gas-aerosol-turbulence interactions in the CBL. Prior to a dedicated verification/validation study, further attempts are necessary to consider a more advanced description of the formation and activation of thermodynamically stable clusters according to modern concepts proposed by Kulmala et al. (2000), Kulmala (2003) and Kulmala et al. (2004a).

Resumen En el presente artículo (i) se desarrolla una crítica al discurso histórico-filosófico de Kant para explicitar sus condiciones de posibilidad, desde lo cual se erige un modelo hermenéutico que (ii) hace inteligible la historia filosofante de la filosofía presente en Los progresos de la metafísica desde los tiempos de Leibniz y Wolff, mostrando cómo las condiciones operan allí y constituyen una determinada narrativa que da cuenta de las perspectivas desde las cuales se ofrece la historia; después (iii) se realiza la interpretación de la historia desde el modelo con el fin de señalar su sostenibilidad; al final, (iv) se vincula la historia filosófica con la propia filosofía trascendental de Kant, legitimando con ello al modelo y señalando cómo el horizonte del proyecto crítico es esa misma historia. Palabras clave Metafísica: Historia; Razón; Teleología; Discurso. Referencias Allison, Henry E., Kant’s Transcendental Idealism. An Interpretation and Defense, USA: Yale University Press, 2004. Allison, H. E., Editor’s Introduction, a What real progress has metaphysics made in Germany since the time of Leibniz and Wolff?, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison, Peter Heath, Cambridge University Press, USA, 2002. Allison, Henry E., “General Introduction”, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison y Peter Heath, USA: Cambridge University Press, 2002. Beiser, Frederick C., “Moral Faith and the Highest Good”, en The Cambridge Companion to Kant and Modern Philosophy, edit. Paul Guyer, USA: Cambridge University Press, 2006. Caimi, Mario, “La metafísica de Kant”, en Kant, Immanuel, Los Progresos de la metafísica desde los tiempos de Leibniz y Wolff, trad. Mario Caimi, México: Fondo de Cultura Económica, UNAM, UAM, 2011. Duque, Félix, “Estudio Introductorio”, en Kant, Immanuel, Los progresos de la metafísica, trad. Félix Duque, Madrid: Tecnos, 1987. Ferrarin, Alberto, The Powers of Reason. Kant and the Idea of Cosmic Philosophy, USA: University of Chicago Press, 2015. Grondin, Jean, Introduction to Metaphysics. From Parmenides to Levinas, trad. Lukas Soderstorm, USA: Columbia University Press, 2012. Guyer, Paul, “The Unity of Nature and Freedom”, en Guyer, Paul, Kant’s System of Nature and Freedom, USA: Oxford University Press, 2005. Heidegger, Martin, Kant y el problema de la metafísica, trad. Gred Ibscher Roth, México: Fondo de Cultura Económica, 1996. Kant, El conflicto de las facultades, trad. Roberto Rodríguez Aramayo, en Immanuel Kant, Kant III, España: Gredos, 2014. Kant, Immanuel, Idea para una historia universal en clave cosmopolita, trad. Roberto Rodríguez Aramayo, en Immanuel Kant, Kant III, España: Gredos, 2014. Kant, Immanuel, Crítica de la razón pura, trad. Mario Caimi, México: FCE, UNAM, UAM, 2011. Kant, Immanuel, Los progresos de la metafísica, trad. Mario Caimi, México: Fondo de Cultura Económica, UNAM, UAM, 2011. Kant, Immanuel, Conjectural beginning of human history, trad. Allen W. Wood, en Immanuel Kant, Anthropology, History and Education, edit. Gunter Zoller, Robert B. Louden, USA: Cambridge University Press, 2007. Kant, Immanuel, On the use of teleological principles in philosophy, trad. Gunter Zoeller, en Kant, Immanuel, Anthropology, History and Education, edit. Gunter Zoller, Robert B. Louden, USA: Cambridge University Press, 2007. Kant, Immanuel, On a recently prominent tone of superiority in philosophy, trad. Peter Heath, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison, Peter Heath, USA: Cambridge University Press, 2002. Kant, Immanuel, Proclamation of the imminent conclusion of a treaty of perpetual peace in philosophy, trad. Peter Heath, en Kant, Immanuel, Theoretical Philosophy after 1781, edit. Henry Allison, Peter Heath, USA: Cambridge University Press, 2002. Kerszberg, Pierre, Critique and Totality, USA State University of New York Press, USA, 1997. Kuhen, Manfred, “Kant’s Critical Philosophy and its Reception –the first five yearse (1781-1786)”, en The Cambridge Companion to Kant and Modern Philosophy, edit. Paul Guyer, USA: Cambridge University Press, 2006. Leibniz, Gottfried, El método verdadero, trad. J. Echeverría, en Leibniz, Leibniz, España: Gredos 2014. Longuenesse, Béatrice, Kant and the Capacity to Judge. Sensibility and Discursivity in the Transcendental Analytic of the Critique of Pure Reason, trad. Charles T. Wolfe, USA: Princeton University Press, 1998. Lyotard, Jean-Francois, Enthusiasm. The Kantian Critique of History, trad. Georges Van Den Abbeele, USA: Standford University Press, 2009. Martínez Marzoa, Felipe, Historia de la filosofía antigua, Madrid: Akal, 1995. Martínez Marzoa, Felipe, Releer a Kant, España: Anthropos, 1989. Platón, Fedón, trad. Carlos García Gual, en Platón, Platón I, España: Gredos, 2014. Platón, Menón, trad. Francisco José Olivieri, en Platón, Platón I, España: Gredos, 2014. Sevilla, Sergio, “Kant: Razón histórica y razón trascendental”, en Kant después de Kant, edit. Javier Muguerza, Roberto Rodríguez Aramayo, Madrid: Tecnos, 1989. Spinoza, Baruch, Ética demostrada según el orden geométrico, trad. Oscar Cohan, México: Fondo de Cultura Económica, 2015. Tugendhat, Ernst, Introducción a la filosofía analítica, trad. José Navarro Pérez, España: Gedisa, 2003. Vieinard-Baron, Jean-Louis, Platón et l’idealisme allemande (1770-1830), Paris: Beauchesne, 1979. Vilar, Gerard, “El concepto del Bien Supremo en Kant”, en Kant después de Kant, edit. Javier Muguerza, Roberto Rodríguez Aramayo, Madrid: Tecnos, 1989. Zammito, John, The Genesis of Kant’s Critique of Judgment, USA: The University of Chicago Press, 1992.

The settlement of the territory of north-eastern Serbia by the representatives of the Co?ofeni culture began during the second half of the IV millennium, probably under the pressure of invading tribes from Euroasian steppe. This territory extended over Transylvania, Banat, Oltenia and Muntenia (Map 2). On the territory of Serbia they settled from the Djrerdap gorge up to the Mlava river to the west, and through Kucajske mountains, Bor, Zajecar and further to the south, up to Nis. Aspecific symbiosis occurred on the territory of Serbia between the Co?ofeni and the Kostolac cultures. According to the results of the latest project of re-identification, the number of Co?ofeni-Kostolac sites and settlements increased to 76. After all the sites were re-identified and georeferenced, with consideration of the surrounding landscape, hydrography, geomorphology of the terrain and the character of the ceramic production finds, we believe that there is a need for re-analyzing specific aspects of the cultural and geographic development not only of settlements, but of the entire Co?ofeni-Kostolac cultural phenomenon. In this paper we considered three archaeological sites in the Nisava valley, given that re-identification work over the past several years yielded new information (Bubanj-Staro Selo, Velika Humska cuka and Donja Vrezina). The topography of Co?ofeni-Kostolac settlements on the territory of north-eastern Serbia, the Serbian part of the Danube valley and its hinterland, is characterized by diversity of position (location above sea level and landscape placement), types of houses and economic survival. In the 70?s of the last century sites were identified that are located in very inaccessible terrain, which in particular cases has an slope incline of 45?, where the number of such settlements in the meantime increased to nine. They are represented by Kulmja Skjopuluji in Klokocevac and Pjatra Kosti in Crnajka (T. I/1-2; Map 1/9), followed by Vratna -Veliki most (T. I/ 7; Map 1/33), Bogovina-above a cave (T. I/ 4; Map 1/8), Jezero (T. I/ 3; Map 1/12), Kljanc (T. I/3; Map 1/11), Turija-Stenje (T. I/ 6; Map 1/22), Mokranjske stene-quarry (T. I/ 5; Map 1/39) and Bolvan (T. I/ 8; Map 1/66). These settlements have several other common elements, the most important being that each one of the elevated settlements is positioned on the rocky peak of a canyon, in places where smaller rivers or brooks flow into a larger river. We can suppose how the selection of such positions was of strategic importance, given that in the mountainous area of north-eastern Serbia the system of waterways and river valleys represents communicational links from prehistory to modern times. The second common characteristic of these settlements is the rocky massif which provided the foundation for their erection. The rock foundation in the majority of cases is of limestone origin and is well suited to artificial nivelation into terraces atop which surface structures could be built using wood covered with mud (Jezero, Kulmja Skjopuluji, Pjatra Kosti, Vratna, Bogovina). The third shared characteristic is that one or more caves are usually located in the immediate vicinity of settlements. An example of the symbiosis of cave and hill fort Co?ofeni-Kostolac settlements is the vicinity of the Zavojsko jezero near Majdanpek. So far two hill fort settlements, Jezero and Kljanc (T. I/3; Map 1/11-12), were identified in this area, built on limestone cliffs above the Mali Pek river. The Rajkova cave (Map 1/14), Paskova cave and Kapetanova cave (Map 1/13) are located in their immediate vicinity, in which the remains of anthropogenic activity were discovered. The Kapetanova cave provides stratigraphy of over 3 m high, which represents a rare case for Co?ofeni-Kostolac cultural sites. This fact does not only indicate its long-term use, but could provide the answer to the genesis and duration of this cultural phenomenon on the territory of the Serbian part of the Djerdap hinterland. The fourth shared characteristic which links these settlements is their dominant position in the landscape. Given that their position and appearance are readily visible from a considerable distance, they probably were not used for hiding, but for making their position prominent. We suppose that pastoral communities emphasized in this manner their control of mountain crosspass and roads, particularly in places where rivers exit narrow canyons in important communications paths to the Crni and Beli Timok, Pek and Danuber rivers. The other Co?ofeni-Kostolac type settlement on the territory of north-eastern Serbia is represented by settlements that are positioned on smaller hills or on gentle slopes that on the average range between 336 and 210 m above sea level. The only fortified hill fort settlement discovered so far, Coka lu Balas near Krivelj (Map 1/3) belongs to this group. The archaeological sites Velika Cuka i Neresnica (Map 1/23), Smiljkova glavica in Stubik (Map 1/31) and Cetace in Kovilovo (Map 1/38) are located on wide and flat, elevated plateaus that dominate up on river valleys. Judging by the considerable surface that they occupy, their position and surroundings for these two settlements, we can suppose that they could have been used for wintering places or points for gathering of flocks and shepherds during pauses between seasonal migrations. They are primarily characterized by the natural surroundings of smaller hills and larger river valleys, as well as the relatively low above sea level elevation on which they are located. Such ?seasonal stations or checkpoints? on which larger groups of shepherds could gather with their flocks during the winter months represented important locations in the lives of pastoral communities. During the warm summer period, homesteads with stable architecture are abandoned because of migrations into mountain areas, where favourable grazing areas area located. Certain groups of shepherds during autumn returned to these settlements en route to lowlands and river terraces, while other groups probably continued their journey to gathering centres in valleys near the Danube and the Timok rivers. The next type of settlement belongs to high, multi-layered settlements (Arija baba-Kosobrdo, Coka Kormaros, Field of Z. Brzanovic, Varzari and Smedovac-Grabar-Svracar) which represent sunbathed dominant positions, with a good view of the surrounding area, well suited to long-term occupation. Settlements on high elevations of this type are usually linked with landscapes that predominate in grazing areas and in which there are no large forests. The last type of Co?ofeni-Kostolac settlement is characteristic of lowland settlements positioned on river terraces. The settlements on the right bank of the Danube, around Kljuc (Kladovo- Brodoimpeks, Mala Vrbica, Zbradila-Fund, Korbovo- Obala, Vajuga-Pesak, Jakomirski potok estuary, Velesnica, Ljubic evac-river bank, Ljubicevac-Island, Brzi prun, Slatinska reka estuary, Knjepiste, Ruzenjka, Kusjak-Bordjej, Kusjak-Motel, Kusjak-Vrkalj), represented points at which shepherd?s flocks could remain for longer periods, waiting for favourable conditions for crossing to the other side of the river. This assumption is based on old maps predating the construction of the accumulation lake. These maps indicate that in the immediate vicinity of these settlements were located small sand islands linked to the river bank, pointing to shallows and crossing points. These sections of the river bank, during prolonged droughts or during cold winters, when ice was formed, could have been places where the river was crossed from one side to the other. Residential architecture cannot be precisely defined, given that the discovered remains of houses are very meagre and lack sufficient elements for reconstruction. The most recent excavations on the Bubanj-Staro Selo settlemant at Nis, indicate an identical type of architectural construction as discovered at Gomolava and Bordjej which represents structures that are characteristic for lowland areas. Houses in hill fort settlements built on artificial terraces have been mostly devastated by erosion, so that judging by the impressions of wooden structures and wattle and daub, as well as the remains of hearths, it can be asserted that these were residential structures. Numerous studies so far noted that based on the stylistic and typological characteristics of ceramics on archaeological sites in Timocka Krajina it is possible to distinguish between two phases of the Co?ofeni group, where the first is dominated by ornamental techniques of carving that are characteristic of the Co?ofeni group, and a later phase in which this style is mixed with the furchenstich, as well as other Kostolac cultural elements (furchenstich, certain types of ceramics, etc.). The fact is that the majority of Co?ofeni-Kostolac group sites in eastern Serbia have not been excavated, or have only been partially excavated, and that no vertical stratigraphy had been observed, where no stratigraphic relationship between stylistic-topological characteristics of older ceramics (Co?ofeni) and the more recent phase (Co?ofeni-Kostolac) have been established. These are mostly settlements in which ceramics were observed with elements both of the Kostolac and the Co?ofeni group, or only with elements of the Co?ofeni group, while settlements with only Kostolac ceramics have not been identified. Therefore, in Serbia it is only possible to distinguish between sites where furchenstich ornamentation has been observed and those where this type of ornamentation still has not been observed. Still, it is unclear whether this distinction can be applied to period assignment, or whether it is in fact caused by settlement of different populations in different regions of Eastern Serbia - the Kostolac region from the west and the Co?ofeni group from the East. In Romania, however, vertical stratigraphy was observed at several settlements where development phases were observed of the Co?ofeni group, so that based on the stratigraphy at those sites, with certain caution, it is possible to draw conclusions about the development of the Co?ofeni-Kostolac group in eastern Serbia. Settlements without any furchenstich ornamentation would be assigned to the older phase (Co?ofeni group) where ceramics characteristic of the Co?ofeni group have been observed, although observed shapes and ornaments are usually associated with the furchenstich technique and the more recent phase of the group. The most frequent type of vessels at sites in eastern Serbia are amphorae with extended funnel shaped necks, ornamented below the neck with carved lines or with stamped ornamentation (fig. 6, 21, 38, 64, 71, 89, 98-100, 104, 109, 115, 116, 134), fishbone shape impressions (fig. 4, 28), and in the more recent period furchenstich ornamentation or point impressions (fig. 9, 20, 25, 140), with a tongue shaped or vertically perforated handle, tunnel shaped or horse-shoe shaped handle below the rim (fig. 6, 9, 20, 21, 51, 63, 100, 126, 134, 88, 115 ). The second characteristic type of vessel are semi-spherical bowls with deeper recipients, with flat rims (fig. 11, 12, 23, 27, 29, 52-54, 57, 59-60, 74, 79, 81, 82, 90, 91, 95, 113, 124, 125, 131 and 145), or with shallower recipients, with a slanted, triangular rim or T-shaped profiled rim (14, 19, 133 and 146). Such vessels are characteristic for both phases, because they are ornamented, besides vertical ribs, with carves, and with furchenstich ornamentation (fig. 23, 68, 81 and 82). The third type of vessels are semi-spherical bowls with contracted rims creating a nearly spherical shape. They can be ornamented with vertical ribs on rims (fig. 148) in combination with pinholes (fig. 17), carves (fig. 61, 84, 85) or line impressions (fig. 132). Less frequent vessels on the territory of northeastern Serbia are biconical or spherical goblets, followed by pare-shaped goblets with a single handle, larger pare-shaped amphorae with an extended or conical neck, with small handles below the rim, ornamented with a series of carves (fig. 39, 86), as well as barrel or spherical pots ornamented with carves, horizontal tapes or circular impressions (fig. 45-47, 141, 142). The appearance of ropeshape ornaments is very significant, given that they appear in Rumanian finds in the second phase of the Co?ofeni group, and most frequently in the third phase. This ornament was sporadically observed in the far south, on the Dikili Tas site on the northern shore of the Aegean sea, in level 6, which according to the author belongs chronologically to the Bubanj-Hum II group and the Kostolac group. Its presence at sites in eastern Serbia can be linked to the older phase at the majority of settlements, except in the case of Grabar-Svracar, as these ceramics were not found alongside ceramics with furchenstich. The largest number of sites with only Co?ofeni elements on ceramics have been observed (34), but it is indicative that only a few have been excavated. 28 sites with Kostolac group elements were noted, while 17 unspecified sites in which the period cannot be precisely defined have been identified. According to the stratigraphy of several of the mentioned sites in western Bulgaria, in the Morava valley and in southern Romania it can be concluded that the Co?ofeni group (northeastern Serbia and Romania) and the Co?ofeni-Kostolac group (Morava valley and western Bulgaria), in all of the mentioned regions, was preceded by the Cernavoda III group, and was superseded by the Vucedol culture and the Bubanj-Hum II group in the Morava valle and the Struma valley, and the Glina II-Schnekenber group in Oltenija and the territory of Transylvania and the southern Carpathians. Analysis of the distribution of settlements and stylistictopological characteristics of ceramics from all of the settlements led to the conclusion that the oldest settlements, without ceramics with furchenstich ornamentation, were established in Kljuc in Negotinska Krajina, leading to the assumption that the representatives of the Co?ofeni group came from Oltenia and from the southern Carpathians. A large number fo sites west of Kljuc, along the Danube, at which ceramics with furchenstich ornamentation were noted, point to the direction of expansion of Kostolac elements, from Banat, Branicevo and Stig. The influence of the Kostolac group was very strong starting in the Co?ofeni II phase, even in Romanian sites, given that in Transylvania and in the southern Carpathians a large number of ceramic finds were found with furchenstich ornamentation, while it is interesting that only sporadic appearances were noted in Oltenia. It is clear that Co?ofeni group settlements represented a certain barrier to the expansion of these elements to the east. With the formation of the Co?ofeni-Kostolac group which was created through contacts between representatives of the Co?ofeni to the east and the representatives of the Kostolac group to the west and north-west a short period of coexistence occurred on this territory. Absolute dating of the chronological framework of the Co?ofeni-Kostolac group in the Danube valley and in eastern Serbia can only be assigned indirectly, as there is no carbon dating available from these sites. According to J. Bojacijev, phase II-III of the Co?ofeni group (4400-4300 bp) can be assigned chronologically approximately to the same period as the Kostolac group (4500-4100 bp), and if we suppose that the Co?ofeni-Kostolac group occurred a little while after the occurrence of the Kostolac group, it can be concluded that the Co?ofeni-Kostolac group existed at the end of the IV and the first half of the III millennium BC, although it is possible that it continued even later in particular regions. The results for the oldest and the middle phase of the Kostolac cultural group at Gomolava range between 3038-2903 BC and 3108-2877 BC, while the Kostolac culture at the Streim and Vucedol sits was dated 3310-2920 BC, as is the approximate dating of settlements of this group in Pivnica (3042-2857 BC). All the dating of Kostolac group sites indicate that this cultural group occurred and developed in the period of the last quarter of the IV and the first half of the III millennium BC, which would chronologically assign the Co?ofeni-Kostolac group in the Morava valley and Timocka Krajina to the end of the IV and the start of the III millennium BC, and to the ensuing period.

Abstract Introduction VMP is a standard of care (SOC) for transplant ineligible NDMM. Daratumumab (D), a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and multifaceted immunomodulatory mechanism of action significantly improves PFS and depth of response in combination with SOC in relapsed MM. Treatment-naïve pts may benefit greatly with the addition of D to SOC regimens. Here we report the results from the ALCYONE study, where D is added to VMP in transplant ineligible NDMM. Methods Pts ≥65 years or otherwise ineligible for high-dose chemotherapy with autologous stem cell transplantation were randomized 1:1 to VMP ± D and stratified by International Staging System (ISS [I, II, III]), region (Europe vs other) and age (&lt;75 vs ≥75 years). All pts received up to a maximum of nine 6-week cycles of VMP. V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, 32 (Cycle 1) and Days 1, 8, 22, and 29 (Cycles 2-9); M: 9 mg/m2 PO and P: 60 mg/m2 PO on Days 1-4 (Cycles 1-9). In the D-VMP arm, D was given at 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ (post VMP-treatment phase) until disease progression. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, minimal residual disease (MRD)-negativity rate (10-5 threshold, Adaptive clonoSEQ® Assay), overall survival (OS), and safety. Results Of 706 pts randomized (350 D-VMP; 356 VMP), median (range) age was 71 (40-93) years; 29.9% were ≥75 years; 46.3% were male. 74.9% of pts had ECOG scores ≥1, and 19.3%, 42.4%, and 38.4% were ISS stage I, II, and III, respectively. Of 616 pts evaluable for FISH/karyotyping cytogenetic analysis, 84.1% and 15.9% were standard and high risk (positive for del17p, t[14;16], t[4;14]), respectively. At the timepoint of the prespecified analysis after 231 PFS events on 12 June 2017, pts had received a median (range) of 12 (1-24) vs 9 (1-9) treatment cycles for D-VMP vs VMP, respectively. 80% of pts in the D-VMP arm completed 9 treatment cycles of VMP vs 62% of pts in the VMP arm. Median (range) cumulative bortezomib doses were 46.9 (1.3-55.3) mg/m2 vs 42.2 (2.6-55.0) mg/m2 for D-VMP vs VMP, respectively. At a median follow-up of 16.5 months, the hazard ratio for PFS (D-VMP vs VMP) was 0.50 (95% confidence interval, 0.38-0.65, P &lt;0.0001), representing a 50% reduction in the risk of progression or death in pts treated with D-VMP (Figure). Median PFS was not reached vs 18.1 months for D-VMP vs VMP. The PFS treatment benefit of D-VMP vs VMP was consistent across all pre-specified subgroups, including age ≥75 years, ISS stage III, and high-risk cytogenetics. ORR (90.9% vs 73.9%), ≥VGPR (71.1% vs 49.7%), ≥CR (42.6% vs 24.4%) and MRD-negativity rate (22.3% vs 6.2%) were significantly higher for D-VMP vs VMP (all P &lt; 0.0001; Table). OS data were immature after 93 deaths (45 vs 48 deaths for D-VMP vs VMP). The most common (≥20%) all-grade treatment emergent adverse events (TEAE; D-VMP/VMP) were neutropenia (49.7%/52.5%), thrombocytopenia (48.8%/53.7%), anemia (28.0%/37.6%), peripheral sensory neuropathy (28.3%/34.2%), upper respiratory tract infection (26.3%/13.8%), diarrhea (23.7%/24.6%), pyrexia (23.1%/20.9%), and nausea (20.8%/21.5%). Most common (≥10%) grade 3/4 TEAEs (D-VMP/VMP) were neutropenia (39.9%/38.7%), thrombocytopenia (34.4%/37.6%), anemia (15.9%/19.8%), and pneumonia (11.3%/4.0%). Only 1 pt in each arm discontinued treatment due to pneumonia. The rates of grade 3/4 infections were 23.1% vs 14.7% and treatment discontinuations due to infections were 0.9% vs 1.4% for D-VMP vs VMP. D-associated infusion-related reactions (27.7%) mostly were grade 1/2 (grade 3/4, 4.3%/0.6%) and most (92.7%) occurred during the first infusion. Tumor lysis syndrome occurred in &lt;1% of pts in each arm. Second primary malignancy occurred in 2.3% vs 2.5% pts in D-VMP vs VMP. Conclusion The combination of D with VMP in transplant ineligible NDMM pts doubled the PFS (HR 0.50), which was driven by more pts achieving deep responses, including significantly higher ≥CR rate and tripling of the MRD-negativity rate. No new safety signals were observed when combining D with VMP. Three phase 3 studies have now demonstrated a consistent doubling of PFS and more than threefold increase in MRD-negativity rate when combining D with SOC regimens. These results support the use of a D-based combination, D-VMP, in transplant ineligible NDMM. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology. Cavo:Celgene:: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria. Suzuki:Bristol Myers Squibb: Honoraria; Novarltis: Honoraria; Celgene: Honoraria; Ono Pharmaceuticals: Honoraria; Fujimoto: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Jakubowiak:Amgen Inc., BMS, Celgene, Janssen, Karypharm, Millennium-Takeda, Sanofi, SkylineDX: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Chicago: Employment. Knop:Bristol-Myers Squibb Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Janssen Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Germany: Honoraria, Membership on an entity's Board of Directors or advisory committees. Doyen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lucio:Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy. Cook:Amgen: Honoraria, Other: Travel support; Takeda: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria; Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding. Garg:Janssen: Other: travel support, Research Funding, Speakers Bureau; Takeda: Other: travel support; Novartis: Other: travel support, Research Funding. Chiu:Janssen: Employment. Wang:Janssen: Employment. Carson:Janssen: Employment. Crist:Janssen: Employment. Deraedt:Janssen: Employment. Nguyen:Janssen: Employment. Qi:Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. San-Miguel:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cilag: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Immunogenetic analysis of MM has proven instrumental in elucidating disease ontogeny e.g. by revealing the clonal relationship between switch variants expressed by the bone marrow plasma cells and myeloma progenitors in the marrow and blood; demonstrating the marked under-representation of the inherently autoreactive IGHV4-34 gene; and, identifying patterns of somatic hypermutation (SHM) indicative of post-germinal center derivation. Yet, limited information exists about the composition of the immunoglobulin (IG) gene repertoire in MM cases expressing different heavy chain isotype, in particular A versus G. This is relevant in light of studies showing an overall higher SHM impact in CD27+IgA+ compared to CD27+IgG+ normal memory B cells, perhaps reflecting a distinct location of the immune response, especially considering that IgA class switching mostly occurs in mucosa-associated lymphoid tissues. From a clinical perspective, it is also relevant to note that IgA patients exhibit a higher incidence of the t(4;14) translocation, shorter progression-free survival and worse median overall survival compared to IgG patients. Here, we explored potential differences in the immunoprofiles of IgA versus IgG MM focusing on IG gene repertoire and SHM characteristics. In total, 428 patients with a diagnosis of MM following the IMWG criteria from collaborating institutions in Greece, Italy and Spain (n=355) or retrieved from the LIGM-DB (n=73) were included in the study. Of these, 135 and 293 belonged to IgA and IgG MM groups, respectively. Amongst the evaluated productive IG rearrangements, IGHV3 subgroup genes predominated in both groups (IgA: 58.5%; IgG: 52.2%). However, at the individual gene level, major asymmetries were noted, since only 7 IGHV genes accounted for 41.6% of the IgA and 46.7% of the IgG cases, respectively. Of these, 3 genes were shared between IgA and IgG MM cases: IGHV3-30 (IgA: 11.9% - IgG: 13.3%), IGHV3-23 (IgA: 5.2% - IgG: 6.8%) and IGHV3-9 (IgA: 6.7% - IgG: 4.4%), whereas the remaining 4 of the 7 most frequent genes were specific for each group with significant (p<0.05) differences regarding the IGHV3-7 (5.2% in IgA versus 1.7% in IgG) and IGHV3-21 gene (0.7% in IgA 4.1% in IgG). IGHD3 predominated in both groups (IgA: 37% - IgG: 39.6%) followed by IGHD2 in IgG MM (18.4%) and IGHD6 in IgA MM (20.7%). IGHJ4 and IGHJ6 were the most frequent IGHJ genes with no significant differences in relative frequency. Searching for restricted IGHV-IGHJ combinations, we noted that the IGHV3-9 gene preferentially paired with the IGHJ6 gene in IgA MM versus the IGHJ4 gene in IgG MM (66.7% and 46.2% of all IGHV3-9 rearrangements, respectively). The median complementarity-determining region 3 (CDR3) length was identical in both IgA and IgG MM (15 amino acids, aa), yet differences were identified for specific CDR3 lengths as in the case of 19 aa, concerning 10.4% of all IgA versus 4.8% of all IgG rearrangements (p<0.05). Turning to SHM, the vast majority of rearrangements (IgA: 90.4%, IgG: 85%) were heavily mutated (IGHV germline identity (GI) <95%) with median GI of 91.8% for IgA and 92.2% for IgG. To study the topology of SHM, we compared the ratios of replacement (R) to silent (S) mutations in the framework (FR) and complementarity determining regions (CDRs) in cases expressing common frequent IGHV genes, namely IGHV3-23, IGHV3-30 and IGHV3-9 and identified distinct SHM patterns in all 3 instances: (i) IGHV3-23: the highest R/S ratios in IgA versus IgG MM were observed in FR2 (3.88) and CDR1 (3.9), respectively; (ii) IGHV3-30: overall "normal" SHM topology with higher R/S in CDRs rather than FRs, however, compared to IgG, IgA cases also showed a very high R/S in FR2 (5.3 versus 1.4); and, (iii) IGHV3-9: significantly (p<0.05) higher R/S ratios in CDR1 and CDR2 in IgG versus IgA cases (10.2 and 8.3 versus 1 and 2.9, respectively). Overall, in-depth immunogenetic analysis in the largest to-date series of IgA MM and IgG MM patients reveals differences regarding IGH gene repertoires, CDR3 characteristics and the topology of SHM. These findings suggest distinct antigen exposure histories and/or affinity maturation processes for IgA versus IgG MM, further highlighting the importance of microenvironmental stimuli in disease pathogenesis. Disclosures Terpos: Celgene: Honoraria; Novartis: Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Stamatopoulos:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding.

Introduction Immunomodulatory drug (IMiD)-based regimens are a standard of care (SOC) for RRMM. Daratumumab (DARA) is a CD38-targeted mAb approved for treatment of pts with RRMM. The subcutaneous (SC) formulation of DARA has a similar safety profile as intravenous DARA, with a statistically significant reduction in infusion-related reaction (IRR) rates and a considerably shorter administration duration of 5 mins. DARA SC is approved for use in the US, EU, Canada, and Korea. In the phase 1b study of DARA plus the IMiD pomalidomide, D-Pd induced deep responses and was well tolerated in pts with heavily pretreated RRMM, including those with prior lenalidomide (len) treatment. D-Pd is approved in the US for RRMM pts with ≥2 prior lines of therapy, including len and a proteasome inhibitor (PI). APOLLO (NCT03180736) is a phase 3 study conducted in collaboration between European Myeloma Network investigators and Janssen to evaluate DARA SC plus Pd vs Pd alone in RRMM pts who had received ≥1 prior line of therapy including len and a PI. We report the primary analysis of APOLLO. Methods In this open-label, multicenter study, eligible pts had RRMM and received ≥1 prior line of therapy including len and a PI, had responded to prior treatment and progressed on or after their last regimen; pts with only 1 prior line of therapy (1PL) were required to be refractory to len. Prior anti-CD38 or pomalidomide was not permitted. Pts were randomized 1:1 to Pd ± DARA SC. Stratification was based on International Staging System (ISS) disease stage (I, II, III) and number of lines of prior therapy (1, 2-3, ≥4). All pts received 28-day treatment cycles (C). P: 4 mg (PO) QD on Days 1-21; d: 40 mg (PO) on Days 1, 8, 15 and 22 (20 mg for pts ≥75 years of age). For D-Pd pts, DARA was given QW for C 1-2, Q2W for C 3-6, and Q4W thereafter. Prior to protocol amendment, pts received DARA IV 16 mg/kg (n=7); after protocol amendment, all pts received DARA SC 1,800 mg co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.). All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Major secondary endpoints included overall response rate, rates of very good partial response or better and complete response or better, MRD-negativity rate, overall survival (OS), and safety. Results A total of 304 pts from 12 European countries were randomized (151 D-Pd; 153 Pd). The median (range) age was 67 (35-90) years, and 45%/33%/22% pts were ISS stage I/II/III. 35% had high cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). 11% of pts had received 1PL (median [range] prior lines of therapy = 2 [1-5]). 82% of pts were refractory to len, 68% of pts were refractory to a PI, and 63% of pts were refractory to both. Median duration of treatment was 11.5 months with D-Pd vs 6.6 months with Pd. The primary analysis was performed after 190 PFS events. The study met its primary endpoint of improved PFS; the hazard ratio (HR) was 0.63 (95% CI, 0.47-0.85; P=0.0018), representing a 37% reduction in the risk of progression or death in pts treated with D-Pd. The median PFS for the D-Pd vs Pd arms was 12.4 vs 6.9 months, respectively. With a median follow-up of 16.9 months, 99 pts (33%) have died; the HR for OS was 0.91 (95% CI, 0.61-1.35); survival data are immature and follow-up is ongoing. ≥CR rates for D-Pd vs Pd were 24.5% vs 3.9%; ≥VGPR rates were 51.0% vs 19.6%. The most common grade 3/4 adverse events with a &gt;5% difference between D-Pd vs Pd were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), and pneumonia (13% vs 7%). The rate of IRRs with DARA SC was low (6%, all grade 1/2), and 2% of pts had local injection-site reactions (all grade 1). Median duration of injection was 5 mins. Rates of study treatment discontinuation due to TEAEs were similar for D-Pd vs Pd (2% vs 3%). The safety profile of D-Pd is consistent with known profiles of DARA SC and Pd. Conclusion In this phase 3 study evaluating DARA SC plus Pd, D-Pd significantly reduced the risk of progression or death by 37% in pts with RRMM who had received ≥1 prior line of therapy vs Pd alone. No new safety concerns were observed. The IRR rate was very low and administration duration short, thus increasing convenience for pts and decreasing treatment burden. Collectively, these data show that D-Pd is an effective and convenient treatment for pts with RRMM who received ≥1 prior therapy, including len and a PI. Disclosures Dimopoulos: Beigene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Terpos:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Beksac:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou:Theagenion Cancer Hospital: Current Employment; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Symeonidis:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Celgene/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Mateos:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Orfanidis:Health Data Specialists: Current Employment, Current equity holder in private company. Ahmadi:Genmab: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Kampfenkel:Janssen: Current Employment. Schecter:Janssen: Current Employment, Current equity holder in publicly-traded company. Qiu:Janssen: Current Employment. Amin:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Sonneveld:Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding.

Abstract Background The introduction of multiple novel agents and regimens for NDMM and relapsed/refractory MM (RRMM) has improved outcomes while increasing the complexity of treatment selection and disease management. The real-world effectiveness of many novel-agent-based regimens remains to be elucidated. INSIGHT MM (NCT02761187) is the largest global, prospective, observational MM study to date. It aims to understand global NDMM/RRMM disease and pt characteristics, treatment patterns, and clinical outcomes, as well as regional variations. Here we report data for 1056 NDMM pts enrolled from July 1, 2016 to April 27, 2018. Methods INSIGHT MM is enrolling ~4200 adult pts with NDMM/RRMM (1-3 prior therapies) from 15 countries; 9 in Europe (EU), 3 in Latin America (LA), the United States (US), and 2 in Asia. Pts will be followed prospectively for ≥5 yrs. Data are collected from hospital/clinic records at baseline (MM-specific disease characteristics, prior therapies) and every 3 mos (disease management, effectiveness, safety). Results At data cut-off, 1056 NDMM pts had been enrolled from 14 countries, including 495 (47%) from EU, 361 (34%) from the US, 112 (11%) from LA, and 88 (8%) from Taiwan. Median age at enrollment was 64 (range 32-89) yrs and 139 (13%) pts were aged >75 yrs (14%/12%/11%/13% in EU/US/Taiwan/LA); 57% of pts were male (60%/58%/61%/39% in EU/US/Taiwan/LA); 72%, 13%, and 8% were White/Caucasian, Asian, and Black/African American, respectively. Overall, 62% of pts were treated at academic centers and 38% in community settings. Based on accrual at data cut-off, regional differences were observed, with more pts treated at academic centers in EU/Taiwan (88%/91%) vs the US/LA (30%/25%). 87% of pts were treated outside of clinical trials (88%/82%/95%/98% in EU/US/Taiwan/LA). Bone pain (32%, including 33%/28%/40%/37% in EU/US/Taiwan/LA), weakness/fatigue (anemia; 11%, including 12%/10%/6%/18% in EU/US/Taiwan/LA), and kidney problems (5%, including 3%/3%/17%/2% in EU/US/Taiwan/LA) were the most common reasons for pts seeking care; 32% (36%/32%/22%/24% in EU/US/Taiwan/LA) were asymptomatic at diagnosis. At diagnosis, 27%/26%/31% of pts had physician-reported ISS Stage I/II/III MM, and 88% had ECOG PS 0-1; 8% of pts had hypercalcemia, 34% creatinine clearance <60 ml/min, 56% anemia, and 30% >3 bone lesions. The most common reasons for initiating therapy were the presence of CRAB criteria, e.g. bone involvement (54%) and anemia (37%). At start of treatment, fixed-duration therapy, treat-to-best-response, and treat-to-progression approaches were planned for 38%, 29%, and 31% of pts, respectively. The most frequently administered regimens are shown in the Table; 20%/66% of pts received a doublet/triplet. V-based regimens were the most frequently used. Regional differences in regimen selection are emerging: among IMiDs, T is most commonly prescribed in EU, Taiwan, and LA; R is more common in the US. After a median follow-up of 9.3 mos, 72 (7%) pts had discontinued the study, most often due to death (57%), consent withdrawal (14%), or change of treatment provider (11%). At data cut-off, data for 236 (22%) pts who received 1st-line ASCT were available (median age 60 yrs; 12%/63%/25% of pts aged <50/50-65/>65 yrs). Of these, 64% received ASCT at academic centers; 42% of pts each in EU and the US received ASCT vs 11% in Taiwan and 4% in LA. The most frequently administered regimens in ASCT-eligible (n=429) vs ASCT-ineligible (n=571) pts were VC±d (21% vs 21%), VR±d (19% vs 17%) and VT±d (17% vs 10%). At data cut-off, 115 NDMM pts had progressed to 2nd-line therapy; 99 pts received a PI with 1st-line therapy, of whom 33 (33%) then received a PI-based regimen in 2nd line; 61 pts received an IMiD with 1st-line therapy, of whom 35 (57%) then received an IMiD-based regimen in 2nd line. Among 1st/2nd-line pts, 2%/12% received monoclonal antibody therapy. Conclusions PIs and IMiDs remain the global backbones of MM therapy, with V-based regimens most commonly used in NDMM pts, regardless of intended transplant status. These data from INSIGHT MM are beginning to elucidate regional differences in disease presentation and treatment selection, including higher numbers of pts receiving ASCT in the US/EU vs Taiwan/LA, which are likely reflective of differences in healthcare systems and access to MM treatments in the participating countries. Future studies will evaluate the impact of these regional variations on outcomes. Table. Table. Disclosures Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Hungria:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Leleu:Karyopharm: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; BMS: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Davies:Abbvie: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; ASH: Honoraria; MMRF: Honoraria. Costello:Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Rifkin:Takeda: Consultancy; EMD Serono: Consultancy; McKesson: Equity Ownership; Celgene: Consultancy; Amgen: Consultancy; Sandoz: Consultancy; Boehringer Ingelheim: Consultancy. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Chari:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; The Binding Site: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Berdeja:Teva: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Zonder:Takeda: Honoraria; Coelum: Honoraria; BMS: Research Funding; Celgene: Consultancy, Honoraria; Alnylam: Honoraria; Janssen: Honoraria; Pharmacyclics: Other: DSMC. Abonour:Prothena: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Omel:Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Demers:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Ren:Takeda Pharmaceuticals International Co.: Employment. Skacel:Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Terpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding.

In the Brioude-Massiac district (French Massif Central), a network of W-As-Bi-Au quartz veins constitutes the Bonnac deposit, where tungsten is the major economic element, together with high-grade gold (up to 15 g/t Au). The evolution of this mineralization has been divided into 3 stages: i) an early deep-seated wolframite-lollingite stage formed between 12 to 9 km, at up to 400°C, ii) a ductile/brittle deformation stage associated with scheelite and arsenopyrite deposition, with an estimated temperature of 430-380 °C; iii) a late stage controlled by fluid-overpressure at a depth of 7 to 5 Km and a temperature between 266 to 240 °C, marked by micro-fracturing, infilled by native bismuth, bismuthinite, hedleyite, electrum, pyrite and base-metals. Structural analysis, and apatite LA-ICP-MS U/Pb dating, demonstrate a spatial and temporal link between the emplacement of the peraluminous leucogranitic dykes and the Bonnac mineralization. In more details, the mineralization was deposited between 321-316 Ma, during or just after the emplacement of the peraluminous dykes emplaced around 329-315 Ma, suggesting a magmatic-hydrothermal transition for the ore-forming process. In the proposed model, the cooling of a hidden two-mica granitic pluton could have generated a magmatic fluid, and acted as the heat source responsible for fluid flow towards inherited permeability zones. The magmatic fluid was then re-equilibrated at high temperature by fluid-rocks interaction. The sharp changes in temperature, pressure, and sulfide-fugacity generated by a late input of meteoric fluid were responsible for the deposition of the late gold-stage. At the regional scale, the tungsten-gold event is ascribed to an early hydrothermal stage, dissociated from the formation of the antimony event in the district. The leucogranitic dykes and Bonnac quartz veins are controlled by a NW-SE stretching direction, interpreted as an expression of the Serpukhovian-Bashkirian syn-orogenic extension (D4 event of the French Massif Central). These new data provide evidence for an early tungsten and gold metallogenic event in the FMC, prior the “Or300” event. The genetic classification of the Bonnac mineralization is equivocal. The W-As-Bi-Au-quartz veins exhibit the features of both an “orogenic gold” deposit at a relatively deep emplacement level, and an Intrusion-Related-Gold-Deposit (IRGD) type with a spatial-temporal link with the peraluminous intrusion emplacement. We propose that the Bonnac deposits represent an intermediate type between a typical orogenic-gold deposit and an IRGD. We argue that the presence of this type of mineralization, and more generally the IRGD deposits, have been underestimated in the Variscan French Massif Central.

Objectives: This research is aimed to evaluate plasma free amino acid in gastric cancer patients without metastasis (early gastric cancer post gastrectomy) and with metastasis (advanced gastric cancer). Amino acids level of postoperative gastric cancer (M0) patients are compared with metastatic gastric cancer (M1) patients in search of biomarker which can predict the metastasis of gastric cancer. We have made clinical correlation of patients’ vital signs, respiratory rate, pulse rate, blood pressure, body temperature, disease stages, chief complaints, complications and survival curve within light of metastatic and nonmetastatic domain. Background: Majority of cancer patients are diagnosed after seeding of metastatic cells to adjacent organs and distant sites. At this point, treatment is palliative and supportive. The cellular propagation of cancer cells and tumor micro-environment plays vital role in genesis of gastric cancer. Genetic alteration leading to faulty nucleotides to amino acids, then to protein, and finally formation of tumor is the natural sequence of pathogenesis of gastric cancer. Prediction of metastasis by use of plasma free amino acid profile may be of great significance because it will help to tailor the patient specific cancer treatment. Plasma Amino acids are ideal for being developed as tool for prediction of metastasis as they are affordable, less expensive and convenient. Method: This study includes total 54 patients, among which 27 had metastasis of Gastric cancer and rest 27 had undergone gastric surgery at early stage with no recurrence at the time of the study. Twenty-three amino acids were studied. Student’s t test was performed to find out statistically significant values of amino acids. The p value of ≤ 0.05 was considered statistically significant. Amino acids with significant p values were investigated with multivariate logistic regression. Partial Least Squares Discriminant Analysis (PLS DA) was done using Microsoft SPSS 23 version software®. Variable Importance of Projection (VIP) was estimated, values ≥ 1 was considered statistically significant. Result: Performance Score (PS) (p= 0.004) and Body Mass Index (BMI) (p= 0.035) were statistically significant between M0 and M1 groups. Staging (I, II vs. III, IV) (p< 0.001) was significant. Seven amino acids, Asp, Cys, Hcy, His, Leu, Orn and Ser were significant between M0 and M1 in first month evaluation. Eight amino acids, Cys, Hcy, His, Leu, Met, Thr, Trp and Tyr were significant between M0 and M1 in sixth month evaluation. PLS DA regression analysis, VIP test showed Cys, Ser, Hcy, Thr, His, Met, Tyr, Trp to be more important amino acids of significance. Kaplan Meier Overall Survival (OS) = 34.979 months. Mean survival time in M0 was 43.53± 1.741 months. Mean survival in M1 was 26.29± 2.635 months. Conclusion: We found BMI and PS as most important variables in defining and determining the disease status of gastric cancer patients. Nutrition and physical activity is very much characteristic of disease outcome from a physician’s perspective. This study propounds amino acids can be valuable biomarkers of predictive and prognostic importance in metastasis in gastric cancer patients.

“K29.” One day it will be me (oh please let it be so). When I’m K29, it will mean that my book is on the shelf of a library which has a collection large enough to employ the Cutter-Sanborn Three Figure Author Table so that it might translate “Kelly” to code. K29 grates a little, sure—I’d prefer the visually softer, assonantal, sonorous J88 for Joy, or the zippiness of Laâbi’s L111—but that’s just a personal preference. K29, J88, L111: divested of their link to authors’ surnames, it can be argued that Cutter-Sanborn numbers have a particular relationship to the practice of “scanning” as a mode of reading. These numbers are available to two types of scanning (in fact, they are perhaps available only to scanning and not “reading”). On a superficial level, they promote the scan which is purely pragmatic: the brief glimpse or glance, a looking which does not know or care what the number represents. Or they may be subject to the analytical scan which is an act of scrutiny, or interrogation. That is to say, while the Cutter-Sanborn number is open to decipherment, it is constitutionally affective (“sonorous”, “zippy”) and effective (as a library tool) for everyone, even those disinterested in its deeper codified meaning. This essay considers what a superficial scan of the Cutter-Sanborn number could signify for all who encounter it, and offers an idiosyncratic account of the possibilities of deeper, scrutinising signification, in particular its ramifications for the author it contracts. The author number is the heart of the book number, and the Cutter-Sanborn number is a particular type—indeed a paradigm—of the author number. It is used especially by libraries employing Dewey Decimal Classification (Lehnus 76). The book number is designed to sub-arrange books which share the same classification number, and is thus formed by those letters and figures which follow the classification number. Abdellatif Laâbi’s L’arbre de fer fleurit, for example, is represented by the call number 848.9964 L111 E 1 at the University of Sydney Library: 848.9964 is a subdivision within the Dewey class of 848 for French miscellaneous writings; L111 E 1 is the book number, broadly conceived. Accordingly, the overall call number structure is worldly, then parochial. Book numbers thus create and express the singularity of books within an institution which, through classification, create and range a community of books. Book numbers are assigned on the basis of the library’s extant collection: new acquisitions are inserted around those numbers already bestowed. Lisa Zhao writes “We have to accept the shelflist (sic.) we have” (116), and thus numbers may vary for the same books at different libraries. Book numbers, it may be seen, are designations of philosophical, textual, and bibliographic consequence. The Cutter-Sanborn number is derived from a table that numerates letter combinations in order to maintain an alphabetical arrangement on the shelves. Charles Cutter printed the first of several versions of his author number scheme in 1880; Kate Emery Sanborn later revised it to produce the Table’s most popular edition (Lehnus 18, 37-42). The Cutter-Sanborn number’s familiar contemporary form is a first initial followed by two, three, or more digits. No matter what a patron knows about the Cutter-Sanborn number, it will be impossible to miss the number’s recurring formal feature of lopsidedness. The mnemonic initial is consistently overpowered by a splatter of integers. Numbers appear as the furthered refinement. The single letter becomes almost incidental—a blunted, rudimentary, and superseded signifier—against a run of figures which seem more attenuating, demanding, or sophisticated. The Cutter-Sanborn number seems to suggest that the numbers enhance the letters, but it is an enhancement which denies the patron easy intelligibility. It substitutes a number for a name it still hints at with a first initial, and the precision of this former device creates a designation that looks like a measure of the book. This conception is facilitated by the everyday scanning eye undertaking a traversing kind of interpretation, not a probing one. Why should the critic probe any deeper than this: why disturb the Cutter-Sanborn number beyond remarking on its simple utility and its affective scientism? Because of the Cutter-Sanborn number’s own pretensions. Conceived by Charles Cutter, the Cutter number was instrumental in the book number’s task of ensuring that “every volume has its own mark, shared with no other volume, its proper name, by which it is absolutely identified” (quoted in Lehnus, 9). The discourse surrounding the genesis of Cutter numbers was thus one of radical individuality. In spite of not being easily legible, the Cutter number hoped to be a kind of translation: Melvil Dewey, for instance, claimed that author numbers “are significant like our class numbers, and translate themselves into the name” (quoted in Lehnus, 27). The Cutter number is historically implicated by its optimistic aspirations of absolute identification, translation, and comprehensibility. This optimism has served it well—a Library Journal editorial blithely suggested that a new innovation “may be the best idea since Cutter numbers” (Berry III, 96)—but it has also obscured investigation of the way in which the Cutter-Sanborn number functions by presupposing its own adequacy. ‘Cuttered’, the author mark holds that said author may be satisfactorily equated with their name, which may be satisfactorily equated with a number. The author has their proper name converted for and contributed to another “proper name” (Cutter’s exact words), that of the volume. This latter proper name is claimed to be superior: “more exact,” suggests Dewey, “than a full written title, as it specifies the identical copy” (Dewey, 296). It is a proper name, then, which is motivated by a blinkered allegiance to the limitable unit and presence of the book. Jacques Derrida, in explaining the replacement of the proper name of a particular author with the designation “Sarl”—an acronym of Société à responsabilité limitée (Society with Limited Responsibility), bestowed so as to acknowledge all the named and unnamed signatures bearing upon the article under question—declares “I hope that the bearers of proper names will not be wounded by this technical or scientific device” (36). I would like to suggest that this is a sentiment that may also be applicable for book authors whose names have been “translated” into Cutter numbers, albeit that the library is more insouciant in expressing any repentance for its actions. The Cutter number format accounts for the book in particular standardising ways, which authors’ names have connotative apparatus (biography, contingency, etymology) to prevent. Derrida recognises his renaming may affront the author, but does not try in any way to mitigate this indignity. He does no more than express the hope that if he did in fact wound the author, that this wasn’t the case. The corollary of this position is that any injury is worthwhile, or has been compensated for elsewhere. The author number’s result is nothing less than an expression of confidence in the viability of transacting a human proper name. A “transaction” concludes something: that something would be concluded was inevitable from the moment that Cutter’s words “by which [the volume] is absolutely identified” established the book number’s precept of satisfaction. The Cutter-Sanborn number concludes a care for human susceptibility: the wound Derrida excises is an ego celebrated in paragraph one and now (I wish to say fully) relinquished. In these very particular book number places—on the shelf-marker, on the spine, and on the sticker—a reduced human authority is proposed. The Cutter-Sanborn number is a text with the express purpose to create an author who has limited ability to claim, and limited ability to connote. In the Cutter-Sanborn number, the book’s author is only just present. They may be able to be traced, but I would like to suggest that in the Cutter number the author is presented without spoil (that is, presented without the rot or reward attendant upon the contingencies and connotations of a human proper name). Consider, furthermore, the genesis of individual Cutter-Sanborn numbers themselves. Any Cutter-Sanborn number has Cutter and Sanborn as ur-authors, but individual authors—working in libraries everywhere—have no means of claiming the number they allocate as their own. The Cutter-Sanborn number simultaneously proposes reduced individual authority and enacts reduced individual authority. The Cutter-Sanborn number is thus available for use by critical textual practices sincerely and self-reflexively, both as an alternative authorial designation (traceable, connotative but standardising, international but relative), and as a model in the task of re-imagining authorship. There is, however, a complicating factor. The Cutter-Sanborn number has proven bibliographically mobile. Its form of an initial followed by digits has been adapted to denote not only authors but titles, topics, subjects, place names, and even publication dates. For example, in the call number of a book entitled Power Sales Presentations: Complete Sales Dialogues for Each Critical Step of the Sales Cycle, a Cutter number P74 stands for the topic “Presentations” (O’Neill). The Cutter-Sanborn number format assimilates book features, it is slippery. In these assorted adaptations, the Cutter-Sanborn number manifests bibliographic features indiscriminately. However incomprehensible the number may appear at each individual occurrence, as a fabrication it does indeed always broadcast various measures of the book. The author’s proper name is thus potentially reduced to just one factor among many: other factors may be given equal leverage. (It is only now that the full consequence of the Cutter-Sanborn number’s sophistication is becoming evident: for devotees of these factors, in particular the author, its totalising representation veers towards sophistry.) A single initial followed by a splatter of integers, which could refer to any bibliographic thing? The Cutter-Sanborn number is an agitator: imprecise in its target, but utterly confident in the genius of its own designative force. The Cutter-Sanborn number does not encourage the scanning, probing eye to look closely, but upon investigation one can discern its paradoxical attempt to challenge author authority while trying to cement its own. Subject to two different types of scanning eye, the Cutter-Sanborn number and its wider contextual environment of the book number destabilise and reconfigure ideas of authorship, simultaneously reducing and promoting it. These doubly scannable codes—these eminent library figures—have implications for the reading of books themselves. In textualising and deprioritising the author, in varying according to location, and in mitigating the grand narratives of classification, the book number has a stake in postmodern expression. And so this essay has been cautionary: it is wary of claiming or promoting book number literacy because of these very evidences of decentralisation. But this relativity is not a problem, as the book number is a thing so saturated in code that a degree of unintelligibility is in fact integral to its message. Unintelligibility need not be white noise. The book number is available to be read impressionistically—that is, available to be read in a manner somewhere between the two paradigmatic scanning cases of those indifferent and those intrigued. A fiction book from a scholarly archive stamped and stickered 853.91 C168 J8 T 1—the example is Italo Calvino’s If on a Winter’s Night a Traveller—is a different text to the version marked F-CAL from a local library. The first example’s complex denotation and brute extent does not so well accommodate the accessible and leisured reading suggested by the second. Calvino from the local is on my time, and its direct address—F-CAL, Fiction: Calvino—is integral in facilitating this. This observation reveals that book number analysis cannot be trusted for any reason, other than that of the Cutter-Sanborn number’s refusal to coalesce adequately across libraries and submit to investigation. Book number analysis is suspect too because, in explaining parts of the book number’s code, analysis pollutes the same experience’s affective value. The loss is significant, as innocence or ignorance is not easily regained. It is ironic that this essay—itself a measured study—must in the final analysis refuse the polarity of the two modes of scan initially posited as exemplary for encountering book numbers (the unaffected glance; the probing need to intuit and ramify), in order to reinstitute and advocate a mode of experience that the book number, within its stipulated self, excludes: susceptibility, a mere responsiveness to presence. References Berry III, John N. “Certification: Is It Worth the Price?” Editorial. Library Journal 15 Feb. 2001: 96. Cutter-Sanborn Three-Figure Author Table: Swanson-Swift Revision, 1969. Chicopee, Ma: H. R. Huntting, 1969. Derrida, Jacques. “Limited Inc a b c…” Trans. Samuel Weber. Glyph 2 (1977). Rpt. in Limited Inc. By Derrida. Evanston, Il: Northwestern UP, 1988. Dewey, Melvil. “Eclectic Book-Numbers.” Library Journal 11 (1886): 296-301. Laâbi, Abdellatif. L’arbre de fer fleurit: Poémes (1972). Paris: Oswald, 1974. Lehnus, Donald J. Book Numbers: History, Principles, and Application. Chicago: ALA, 1980. O’Neill, Edward T. “Cuttering for the Library of Congress Classification.” Annual Review of OCLC Research 1994 1 Jul. 2005. http://digitalarchive.oclc.org/da/ViewObject.jsp? fileid=0000002650:000000058648&reqid=701>. Zhao, Lisa. “Save Space for ‘Newcomers’ – Analyzing Problems in Book Number Assignment under the LCC System.” Cataloging & Classification Quarterly 38.1 (2004): 105-19. Citation reference for this article MLA Style Kelly, Michelle. "Eminent Library Figures: A Reader." M/C Journal 8.4 (2005). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0508/07-kelly.php>. APA Style Kelly, M. (Aug. 2005) "Eminent Library Figures: A Reader," M/C Journal, 8(4). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0508/07-kelly.php>.

Introduction Cookbooks are an exceptional written record of what is largely an oral tradition. They have been described as “magician’s hats” due to their ability to reveal much more than they seem to contain (Wheaton, “Finding”). The first book printed in Germany was the Guttenberg Bible in 1456 but, by 1490, printing was introduced into almost every European country (Tierney). The spread of literacy between 1500 and 1800, and the rise in silent reading, helped to create a new private sphere into which the individual could retreat, seeking refuge from the community (Chartier). This new technology had its effects in the world of cookery as in so many spheres of culture (Mennell, All Manners). Trubek notes that cookbooks are the texts most often used by culinary historians, since they usually contain all the requisite materials for analysing a cuisine: ingredients, method, technique, and presentation. Printed cookbooks, beginning in the early modern period, provide culinary historians with sources of evidence of the culinary past. Historians have argued that social differences can be expressed by the way and type of food we consume. Cookbooks are now widely accepted as valid socio-cultural and historic documents (Folch, Sherman), and indeed the link between literacy levels and the protestant tradition has been expressed through the study of Danish cookbooks (Gold). From Apicius, Taillevent, La Varenne, and Menon to Bradley, Smith, Raffald, Acton, and Beeton, how can both manuscript and printed cookbooks be analysed as historic documents? What is the difference between a manuscript and a printed cookbook? Barbara Ketchum Wheaton, who has been studying cookbooks for over half a century and is honorary curator of the culinary collection in Harvard’s Schlesinger Library, has developed a methodology to read historic cookbooks using a structured approach. For a number of years she has been giving seminars to scholars from multidisciplinary fields on how to read historic cookbooks. This paper draws on the author’s experiences attending Wheaton’s seminar in Harvard, and on supervising the use of this methodology at both Masters and Doctoral level (Cashman; Mac Con Iomaire, and Cashman). Manuscripts versus Printed Cookbooks A fundamental difference exists between manuscript and printed cookbooks in their relationship with the public and private domain. Manuscript cookbooks are by their very essence intimate, relatively unedited and written with an eye to private circulation. Culinary manuscripts follow the diurnal and annual tasks of the household. They contain recipes for cures and restoratives, recipes for cleansing products for the house and the body, as well as the expected recipes for cooking and preserving all manners of food. Whether manuscript or printed cookbook, the recipes contained within often act as a reminder of how laborious the production of food could be in the pre-industrialised world (White). Printed cookbooks draw oxygen from the very fact of being public. They assume a “literate population with sufficient discretionary income to invest in texts that commodify knowledge” (Folch). This process of commoditisation brings knowledge from the private to the public sphere. There exists a subset of cookbooks that straddle this divide, for example, Mrs. Rundell’s A New System of Domestic Cookery (1806), which brought to the public domain her distillation of a lifetime of domestic experience. Originally intended for her daughters alone, Rundell’s book was reprinted regularly during the nineteenth century with the last edition printed in 1893, when Mrs. Beeton had been enormously popular for over thirty years (Mac Con Iomaire, and Cashman). Barbara Ketchum Wheaton’s Structured Approach Cookbooks can be rewarding, surprising and illuminating when read carefully with due effort in understanding them as cultural artefacts. However, Wheaton notes that: “One may read a single old cookbook and find it immensely entertaining. One may read two and begin to find intriguing similarities and differences. When the third cookbook is read, one’s mind begins to blur, and one begins to sense the need for some sort of method in approaching these documents” (“Finding”). Following decades of studying cookbooks from both sides of the Atlantic and writing a seminal text on the French at table from 1300-1789 (Wheaton, Savouring the Past), this combined experience negotiating cookbooks as historical documents was codified, and a structured approach gradually articulated and shared within a week long seminar format. In studying any cookbook, regardless of era or country of origin, the text is broken down into five different groupings, to wit: ingredients; equipment or facilities; the meal; the book as a whole; and, finally, the worldview. A particular strength of Wheaton’s seminars is the multidisciplinary nature of the approaches of students who attend, which throws the study of cookbooks open to wide ranging techniques. Students with a purely scientific training unearth interesting patterns by developing databases of the frequency of ingredients or techniques, and cross referencing them with other books from similar or different timelines or geographical regions. Patterns are displayed in graphs or charts. Linguists offer their own unique lens to study cookbooks, whereas anthropologists and historians ask what these objects can tell us about how our ancestors lived and drew meaning from life. This process is continuously refined, and each grouping is discussed below. Ingredients The geographic origins of the ingredients are of interest, as is the seasonality and the cost of the foodstuffs within the scope of each cookbook, as well as the sensory quality both separately and combined within different recipes. In the medieval period, the use of spices and large joints of butchers meat and game were symbols of wealth and status. However, when the discovery of sea routes to the New World and to the Far East made spices more available and affordable to the middle classes, the upper classes spurned them. Evidence from culinary manuscripts in Georgian Ireland, for example, suggests that galangal was more easily available in Dublin during the eighteenth century than in the mid-twentieth century. A new aesthetic, articulated by La Varenne in his Le Cuisinier Francois (1651), heralded that food should taste of itself, and so exotic ingredients such as cinnamon, nutmeg, and ginger were replaced by the local bouquet garni, and stocks and sauces became the foundations of French haute cuisine (Mac Con Iomaire). Some combinations of flavours and ingredients were based on humoral physiology, a long held belief system based on the writings of Hippocrates and Galen, now discredited by modern scientific understanding. The four humors are blood, yellow bile, black bile, and phlegm. It was believed that each of these humors would wax and wane in the body, depending on diet and activity. Galen (131-201 AD) believed that warm food produced yellow bile and that cold food produced phlegm. It is difficult to fathom some combinations of ingredients or the manner of service without comprehending the contemporary context within they were consumeSome ingredients found in Roman cookbooks, such as “garum” or “silphium” are no longer available. It is suggested that the nearest substitute for garum also known as “liquamen”—a fermented fish sauce—would be Naam Plaa, or Thai fish sauce (Grainger). Ingredients such as tea and white bread, moved from the prerogative of the wealthy over time to become the staple of the urban poor. These ingredients, therefore, symbolise radically differing contexts during the seventeenth century than in the early twentieth century. Indeed, there are other ingredients such as hominy (dried maize kernel treated with alkali) or grahams (crackers made from graham flour) found in American cookbooks that require translation to the unacquainted non-American reader. There has been a growing number of food encyclopaedias published in recent years that assist scholars in identifying such commodities (Smith, Katz, Davidson). The Cook’s Workplace, Techniques, and Equipment It is important to be aware of the type of kitchen equipment used, the management of heat and cold within the kitchen, and also the gradual spread of the industrial revolution into the domestic sphere. Visits to historic castles such as Hampton Court Palace where nowadays archaeologists re-enact life below stairs in Tudor times give a glimpse as to how difficult and labour intensive food production was. Meat was spit-roasted in front of huge fires by spit boys. Forcemeats and purees were manually pulped using mortar and pestles. Various technological developments including spit-dogs, and mechanised pulleys, replaced the spit boys, the most up to date being the mechanised rotisserie. The technological advancements of two hundred years can be seen in the Royal Pavilion in Brighton where Marie-Antoinin Carême worked for the Prince Regent in 1816 (Brighton Pavilion), but despite the gleaming copper pans and high ceilings for ventilation, the work was still back breaking. Carême died aged forty-nine, “burnt out by the flame of his genius and the fumes of his ovens” (Ackerman 90). Mennell points out that his fame outlived him, resting on his books: Le Pâtissier Royal Parisien (1815); Le Pâtissier Pittoresque (1815); Le Maître d’Hôtel Français (1822); Le Cuisinier Parisien (1828); and, finally, L’Art de la Cuisine Française au Dix-Neuvième Siècle (1833–5), which was finished posthumously by his student Pluméry (All Manners). Mennell suggests that these books embody the first paradigm of professional French cuisine (in Kuhn’s terminology), pointing out that “no previous work had so comprehensively codified the field nor established its dominance as a point of reference for the whole profession in the way that Carême did” (All Manners 149). The most dramatic technological changes came after the industrial revolution. Although there were built up ovens available in bakeries and in large Norman households, the period of general acceptance of new cooking equipment that enclosed fire (such as the Aga stove) is from c.1860 to 1910, with gas ovens following in c.1910 to the 1920s) and Electricity from c.1930. New food processing techniques dates are as follows: canning (1860s), cooling and freezing (1880s), freeze drying (1950s), and motorised delivery vans with cooking (1920s–1950s) (den Hartog). It must also be noted that the supply of fresh food, and fish particularly, radically improved following the birth, and expansion of, the railways. To understand the context of the cookbook, one needs to be aware of the limits of the technology available to the users of those cookbooks. For many lower to middle class families during the twentieth century, the first cookbook they would possess came with their gas or electrical oven. Meals One can follow cooked dishes from the kitchen to the eating place, observing food presentation, carving, sequencing, and serving of the meal and table etiquette. Meal times and structure changed over time. During the Middle Ages, people usually ate two meals a day: a substantial dinner around noon and a light supper in the evening (Adamson). Some of the most important factors to consider are the manner in which meals were served: either à la française or à la russe. One of the main changes that occurred during the nineteenth century was the slow but gradual transfer from service à la française to service à la russe. From medieval times to the middle of the nineteenth century the structure of a formal meal was not by “courses”—as the term is now understood—but by “services”. Each service could comprise of a choice of dishes—both sweet and savoury—from which each guest could select what appealed to him or her most (Davidson). The philosophy behind this form of service was the forementioned humoral physiology— where each diner chose food based on the four humours of blood, yellow bile, black bile, or phlegm. Also known as le grand couvert, the à la française method made it impossible for the diners to eat anything that was beyond arm’s length (Blake, and Crewe). Smooth service, however, was the key to an effective à la russe dinner since servants controlled the flow of food (Eatwell). The taste and temperature of food took centre stage with the à la russe dinner as each course came in sequence. Many historic cookbooks offer table plans illustrating the suggested arrangement of dishes on a table for the à la française style of service. Many of these dishes might be re-used in later meals, and some dishes such as hashes and rissoles often utilised left over components of previous meals. There is a whole genre of cookbooks informing the middle class cooks how to be frugal and also how to emulate haute cuisine using cheaper or ersatz ingredients. The number dining and the manner in which they dined also changed dramatically over time. From medieval to Tudor times, there might be hundreds dining in large banqueting halls. By the Elizabethan age, a small intimate room where master and family dined alone replaced the old dining hall where master, servants, guests, and travellers had previously dined together (Spencer). Dining tables remained portable until the 1780s when tables with removable leaves were devised. By this time, the bread trencher had been replaced by one made of wood, or plate of pewter or precious metal in wealthier houses. Hosts began providing knives and spoons for their guests by the seventeenth century, with forks also appearing but not fully accepted until the eighteenth century (Mason). These silver utensils were usually marked with the owner’s initials to prevent their theft (Flandrin). Cookbooks as Objects and the World of Publishing A thorough examination of the manuscript or printed cookbook can reveal their physical qualities, including indications of post-publication history, the recipes and other matter in them, as well as the language, organization, and other individual qualities. What can the quality of the paper tell us about the book? Is there a frontispiece? Is the book dedicated to an employer or a patron? Does the author note previous employment history in the introduction? In his Court Cookery, Robert Smith, for example, not only mentions a number of his previous employers, but also outlines that he was eight years working with Patrick Lamb in the Court of King William, before revealing that several dishes published in Lamb’s Royal Cookery (1710) “were never made or practis’d (sic) by him and others are extreme defective and imperfect and made up of dishes unknown to him; and several of them more calculated at the purses than the Gôut of the guests”. Both Lamb and Smith worked for the English monarchy, nobility, and gentry, but produced French cuisine. Not all Britons were enamoured with France, however, with, for example Hannah Glasse asserting “if gentlemen will have French cooks, they must pay for French tricks” (4), and “So much is the blind folly of this age, that they would rather be imposed on by a French Booby, than give encouragement to an good English cook” (ctd. in Trubek 60). Spencer contextualises Glasse’s culinary Francophobia, explaining that whilst she was writing the book, the Jacobite army were only a few days march from London, threatening to cut short the Hanoverian lineage. However, Lehmann points out that whilst Glasse was overtly hostile to French cuisine, she simultaneously plagiarised its receipts. Based on this trickling down of French influences, Mennell argues that “there is really no such thing as a pure-bred English cookery book” (All Manners 98), but that within the assimilation and simplification, a recognisable English style was discernable. Mennell also asserts that Glasse and her fellow women writers had an enormous role in the social history of cooking despite their lack of technical originality (“Plagiarism”). It is also important to consider the place of cookbooks within the history of publishing. Albala provides an overview of the immense outpouring of dietary literature from the printing presses from the 1470s. He divides the Renaissance into three periods: Period I Courtly Dietaries (1470–1530)—targeted at the courtiers with advice to those attending banquets with many courses and lots of wine; Period II The Galenic Revival (1530–1570)—with a deeper appreciation, and sometimes adulation, of Galen, and when scholarship took centre stage over practical use. Finally Period III The Breakdown of Orthodoxy (1570–1650)—when, due to the ambiguities and disagreements within and between authoritative texts, authors were freer to pick the ideas that best suited their own. Nutrition guides were consistent bestsellers, and ranged from small handbooks written in the vernacular for lay audiences, to massive Latin tomes intended for practicing physicians. Albala adds that “anyone with an interest in food appears to have felt qualified to pen his own nutritional guide” (1). Would we have heard about Mrs. Beeton if her husband had not been a publisher? How could a twenty-five year old amass such a wealth of experience in household management? What role has plagiarism played in the history of cookbooks? It is interesting to note that a well worn copy of her book (Beeton) was found in the studio of Francis Bacon and it is suggested that he drew inspiration for a number of his paintings from the colour plates of animal carcasses and butcher’s meat (Dawson). Analysing the post-publication usage of cookbooks is valuable to see the most popular recipes, the annotations left by the owner(s) or user(s), and also if any letters, handwritten recipes, or newspaper clippings are stored within the leaves of the cookbook. The Reader, the Cook, the Eater The physical and inner lives and needs and skills of the individuals who used cookbooks and who ate their meals merit consideration. Books by their nature imply literacy. Who is the book’s audience? Is it the cook or is it the lady of the house who will dictate instructions to the cook? Numeracy and measurement is also important. Where clocks or pocket watches were not widely available, authors such as seventeenth century recipe writer Sir Kenelm Digby would time his cooking by the recitation of the Lord’s Prayer. Literacy amongst protestant women to enable them to read the Bible, also enabled them to read cookbooks (Gold). How did the reader or eater’s religion affect the food practices? Were there fast days? Were there substitute foods for fast days? What about special occasions? Do historic cookbooks only tell us about the food of the middle and upper classes? It is widely accepted today that certain cookbook authors appeal to confident cooks, while others appeal to competent cooks, and others still to more cautious cooks (Bilton). This has always been the case, as has the differentiation between the cookbook aimed at the professional cook rather than the amateur. Historically, male cookbook authors such as Patrick Lamb (1650–1709) and Robert Smith targeted the professional cook market and the nobility and gentry, whereas female authors such as Eliza Acton (1799–1859) and Isabella Beeton (1836–1865) often targeted the middle class market that aspired to emulate their superiors’ fashions in food and dining. How about Tavern or Restaurant cooks? When did they start to put pen to paper, and did what they wrote reflect the food they produced in public eateries? Conclusions This paper has offered an overview of Barbara Ketchum Wheaton’s methodology for reading historic cookbooks using a structured approach. It has highlighted some of the questions scholars and researchers might ask when faced with an old cookbook, regardless of era or geographical location. By systematically examining the book under the headings of ingredients; the cook’s workplace, techniques and equipment; the meals; cookbooks as objects and the world of publishing; and reader, cook and eater, the scholar can perform magic and extract much more from the cookbook than seems to be there on first appearance. References Ackerman, Roy. The Chef's Apprentice. London: Headline, 1988. Adamson, Melitta Weiss. Food in Medieval Times. Westport, Connecticut: Greenwood P, 2004. Albala, Ken. Eating Right in the Renaissance. Ed. Darra Goldstein. Berkeley: U of California P, 2002. Beeton, Isabella. Beeton's Book of Household Management. London: S. Beeton, 1861. 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