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1
Davenport, Romola. "Urban Family Reconstitution - a Worked Example." Local Population Studies, no. 96 (June 30, 2016): 28–49. http://dx.doi.org/10.35488/lps96.2016.28.
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Family reconstitutions have been undertaken only rarely in urban settings due to the high mobility of historical urban populations, in both life and death. Recently Gill Newton has outlined a methodology for the reconstitution of urban populations and we applied a modified version of this method to the large Westminster parish of St. Martin in the Fields between 1752 and 1812, a period that posed particular difficulties for family reconstitution because of the rapid lengthening of the interval between birth and baptism. The extraordinary richness of the records for St. Martin in the Fields made it possible to investigate burial and baptismal practices in great detail, and the extent and impact of residential mobility. We found that short-range, inter-parochial movement was so frequent that it was necessary to confine the reconstitution sample to windows in which families registered events at a single street address. Using birth interval analysis and the frequencies of twin births it was possible to demonstrate that the registration of birth events was fairly complete, but that many infant and child burials were missed. These missing burials probably resulted from the unreported export of corpses for burial in other parishes, a phenomenon for which we had considerable evidence. The limitations of family reconstitution in this highly mobile and heterogeneous urban population is discussed and we demonstrate some checks and corrections that can be used to improve the quality of such reconstitutions.
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RUGGLES, STEVEN. "The limitations of English family reconstitution: English population history from family reconstitution 1580–1837." Continuity and Change 14, no. 1 (May 1999): 105–30. http://dx.doi.org/10.1017/s0268416099003288.
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English population history from family reconstitution 1580–1837 (Cambridge, 1997) is an impressive volume. This ambitious study represents the culmination of a quarter-century of laborious research by four of the most accomplished practitioners of English historical demography, E. A. Wrigley, R. S. Davies, J. E. Oeppen, and R. S. Schofield. The sheer volume of information is overwhelming; the book contains 121 tables and 73 graphs, and it weighs in at almost 2½ pounds. The study is a landmark in the field of pre-industrial population history. It contributes important new evidence on long-run trends in fertility, mortality, and marriage behaviour. Even more exciting than the refinement of the aggregate results contained in previous work by the Cambridge Group, however, is the new kinds of analyses made possible by the existence of microdata. The book marshals an array of innovative methods to address a remarkable assortment of demographic issues. The authors address dozens of topics previously hidden from view, ranging from an ingenious analysis of the relative mortality of monozygotic and dyzygotic twins, to an important investigation of lifetime fecundity, to an exhaustive analysis of the seasonality of mortality.
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Menard, Russell R. "Early American Family and Legal History: New Ideas." Journal of Interdisciplinary History 34, no. 3 (January 2004): 435–40. http://dx.doi.org/10.1162/002219504771997917.
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Recent work about the method of family reconstitution and economic history raises serious doubts about the demographic and economic premises that underlie much of the existing scholarship about early American family history. As a result, early American family history—one of the new social history's crowning achievements during the 1960s—is now in disarray. Some scholars see the new microhistorical studies of the colonial family as an effort to sidestep these difficulties by ignoring demographic and materialist perspectives. However, such cultural approaches may well intensify the crisis by challenging the image of the early American family as a loving institution incapable of violent conflict.
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Hall, Jason A., and Ana M. Pajor. "Functional Reconstitution of SdcS, a Na+-Coupled Dicarboxylate Carrier Protein from Staphylococcus aureus." Journal of Bacteriology 189, no. 3 (November 17, 2006): 880–85. http://dx.doi.org/10.1128/jb.01452-06.
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ABSTRACT In Staphylococcus aureus, the transport of dicarboxylates is mediated in part by the Na+-linked carrier protein SdcS. This transporter is a member of the divalent-anion/Na+ symporter (DASS) family, a group that includes the mammalian Na+/dicarboxylate cotransporters NaDC1 and NaDC3. In earlier work, we cloned and expressed SdcS in Escherichia coli and found it to have transport properties similar to those of its eukaryotic counterparts (J. A. Hall and A. M. Pajor, J. Bacteriol. 187:5189-5194, 2005). Here, we report the partial purification and subsequent reconstitution of functional SdcS into liposomes. These proteoliposomes exhibited succinate counterflow activity, as well as Na+ electrochemical-gradient-driven transport. Examination of substrate specificity indicated that the minimal requirement necessary for transport was a four-carbon terminal dicarboxylate backbone and that productive substrate-transporter interaction was sensitive to substitutions at the substrate C-2 and C-3 positions. Further analysis established that SdcS facilitates an electroneutral symport reaction having a 2:1 cation/dicarboxylate ratio. This study represents the first characterization of a reconstituted Na+-coupled DASS family member, thus providing an effective method to evaluate functional, as well as structural, aspects of DASS transporters in a system free of the complexities and constraints associated with native membrane environments.
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Chen, Xiaohua, Gregory A. Hale, Raymond C. Barfield, Ely Benaim, Wing H. Leung, James Knowles, Edwin M. Horwitz, et al. "Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies." Blood 108, no. 11 (November 16, 2006): 5311. http://dx.doi.org/10.1182/blood.v108.11.5311.5311.
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Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.
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Weksberg, David C., Stuart M. Chambers, Nathan C. Boles, and Margaret A. Goodell. "CD150− side population cells represent a functionally distinct population of long-term hematopoietic stem cells." Blood 111, no. 4 (February 15, 2008): 2444–51. http://dx.doi.org/10.1182/blood-2007-09-115006.
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Hematopoietic stem cells (HSCs) are a self-renewing population of bone marrow cells that replenish the cellular elements of blood throughout life. HSCs represent a paradigm for the study of stem-cell biology, because robust methods for prospective isolation of HSCs have facilitated rigorous characterization of these cells. Recently, a new isolation method was reported, using the SLAM family of cell-surface markers, including CD150 (SlamF1), to offer potential advantages over established protocols. We examined the overlap between SLAM family member expression with an established isolation scheme based on Hoechst dye efflux (side population; SP) in conjunction with canonical HSC cell-surface markers (Sca-1, c-Kit, and lineage markers). Importantly, we find that stringent gating of SLAM markers is essential to achieving purity in HSC isolation and that the inclusion of canonical HSC markers in the SLAM scheme can greatly augment HSC purity. Furthermore, we observe that both CD150+ and CD150− cells can be found within the SP population and that both populations can contribute to long-term multilineage reconstitution. Thus, using SLAM family markers to isolate HSCs excludes a substantial fraction of the marrow HSC compartment. Interestingly, these 2 subpopulations are functionally distinct, with respect to lineage output as well as proliferative status.
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Rizzieri, David A., Liang Piu Koh, Gwynn D. Long, Cristina Gasparetto, Keith M. Sullivan, Mitchell Horwitz, John Chute, et al. "Partially Matched, Nonmyeloablative Allogeneic Transplantation: Clinical Outcomes and Immune Reconstitution." Journal of Clinical Oncology 25, no. 6 (February 9, 2007): 690–97. http://dx.doi.org/10.1200/jco.2006.07.0953.
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Purpose Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype. Patients and Methods Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported. Results Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months). Conclusion Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.
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Savona, Michael R., Mark J. Kiel, Andrew D. Leavitt, and Sean J. Morrison. "SLAM-Family Expression on Human Mobilized Peripheral Blood Progenitors." Blood 108, no. 11 (November 16, 2006): 1675. http://dx.doi.org/10.1182/blood.v108.11.1675.1675.
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Abstract Background and significance: A simple but precise method to identify hematopoietic stem cells within mobilized peripheral blood would be useful for transplantation. Our lab has recently identified a family of surface markers whose differential expression distinguishes mouse hematopoietic stem cells from other hematopoietic progenitors. The founding member of the signaling lymphocyte attractant molecule (SLAM) family, CD150, was expressed on all hematopoietic stem cells (HSCs) but not on other hematopoietic progenitors. Other SLAM-family members, including CD244 and CD48, were expressed by non-self-renewing multipotent progenitors and most colony-forming restricted progenitors, respectively. As a result, mouse stem cells can be highly purified as CD150+CD48− cells, dramatically simplifying and improving the purification of mouse HSCs. To begin to test whether SLAM family markers can facilitate the identification and purification of human hematopoietic stem cells, we have assessed the frequency of CD150+CD48− cells in mobilized peripheral blood and compared their distribution to that of CD34+CD38− cells, which are known to be highly enriched for human hematopoietic stem cells. Methods: Mobilized human peripheral blood samples were stained with anti-CD150 (conjugated to the FITC), anti-CD48 (PE), anti-CD41 (PE), anti-CD34 (APC), and anti-CD38 (PE-Cy5) antibodies. Samples were analyzed by flow-cytometry. Results: We have identified a population of CD150+CD48−CD41− cells within human mobilized peripheral blood that is present at a similar frequency as the same population in mobilized mouse peripheral blood (mean 0.039±0.11%). The CD34+CD38− population was similarly infrequent. Interestingly, 16.3±19.5% of CD150+CD48−CD41− cells were also CD34+ whereas only 1.13±3.45% of the CD34+CD38− population was CD150+CD48−CD41− raising the possibility that SLAM-family members may substantially improve the purity of human hematopoietic stem cells. Conclusion: Murine and human hematopoietic tissues have a similar frequency of CD150+CD48−CD41− cells. It is possible that the use of SLAM-family markers might enhance the identification and purification of human hematopoietic stem cells beyond what is possible using CD34 and CD38. We are currently performing reconstitution assays to test this functionally. Peripheral Blood Mononuclear Cells Peripheral Blood Mononuclear Cells
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Fialova, Ludmila, Klara Hulikova Tesarkova, and Barbora Kuprova. "Determinants of the Length of Birth Intervals in the Past and Possibilities for Their Study." Journal of Family History 43, no. 2 (January 11, 2018): 127–56. http://dx.doi.org/10.1177/0363199017746322.
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Knowledge of the length of birth intervals in the past and factors influencing them could help us to reveal many aspects of reproductive behavior at that time. The aim of this article is to describe the reproductive behavior in families from Jablonec (Czech lands) before the onset of the fertility transition using survival analysis and Cox regression based on individual observations acquired from family reconstitution. A usability description of these methods is the methodological aim of this article. The results show that birth intervals were affected, above all, by the survival of the previous child, birth order, and age of mother.
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GAVALAS, VASILIS S. "ISLAND MORTALITY IN THE PAST: SOME EVIDENCE FROM GREECE." Journal of Biosocial Science 40, no. 2 (March 2008): 203–22. http://dx.doi.org/10.1017/s0021932007002246.
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SummaryThis paper explores the course of infant and childhood mortality in the Greek island of Paros from the end of the nineteenth until the mid-twentieth century. For this purpose the method of family reconstitution has been applied to two towns on the island. Official population statistics have been used to derive basic mortality estimates for the Cyclades and Greece as a whole. Reference to other studies concerning island mortality is also made. Hence, there appears the chance to compare insular with mainland mortality and realise that insular mortality presented some distinct features. It is shown that island populations presented lower mortality than the national average until the first decades of the twentieth century. However, by the 1950s Greece’s infant and childhood mortality had dropped to the same or even to lower levels than those of the islands.
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Dodero, Anna, Cristiana Carniti, Anna Raganato, Antonio Vendramin, Simona Di Terlizzi, Lucia Farina, Francesco Spina, et al. "CD8-Depleted Donor Lymphocyte Infusions Can Improve Both T- and B-Cell Reconstitution after Allogeneic Stem Cell Transplantation from Haploidentical Family Donors." Blood 112, no. 11 (November 16, 2008): 354. http://dx.doi.org/10.1182/blood.v112.11.354.354.
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Abstract Purpose: Haploidentical hematopoietic stem cell transplantation (haplo-SCT) provides an option for cancer patients lacking a compatible donor. However, the delayed immune reconstitution increases incidence of opportunistic infections and disease relapse. We conducted a phase I-II prospective trial to evaluate the effect of escalating doses of CD8-depleted (Miltenyi Device) donor lymphocyte infusions (DLIs) following RIC haplo-SCT. Here, we present the data on the immune reconstitution. Patients and Methods: Twenty-eight patients (pts) with advanced lymphoproliferative diseases (n=24) or acute myeloid leukaemia (n=4) were enrolled in this study. Fifteen (54%) of 28 pts had refractory disease. All pts received a thiotepa-fludarabine based RIC regimen, with an ex vivo and in vivo T-cell depletion performed by CD34+ cell selection and alemtuzumab infusion. Fifty-four CD8-depleted DLIs were administered to 23 pts [dose level 1 (n=4): 1×104/kg on days + 45, +75, +105; dose level 2 (n=11): 5×104/kg on days + 45, +75, +105; dose level 3 (n=8): 1×104/kg on day+ 45, 5x104/kg on days +75 and +105]. Results: At a median follow-up of 29 months, 12 pts are alive (n=3 Hodgkin Lymphoma, n=6 Non-Hodgkin Lymphoma, n=1 Multiple Myeloma, n=2 Acute Myeloid Leukemia) and 16 died from any cause [n=6 for non-relapse mortality (NRM), n=10 for disease progression] with a 2-year estimates of overall survival of 39%. The 2-year cumulative incidence of NRM and relapse were 26% and 51%, respectively. Six pts (26%) developed grade II-IV acute graft-versus-host disease (GVHD) (dose level 1: no GVHD; dose level 2: 5 cases; dose level 3: 1 case). Following CD8-depleted DLIs, the major findings were:(i) a significant expansion of memory CD4+ cells and CD19+ cells (median value 107/μL and 135/μL, respectively) at 120 days after haplo-SCT; (ii) de-novo T-cell responses to cytomegalovirus (CMV) peptides performed by activation-induced CD137 expression: the median frequency of CMV-specific CD8+/CD137+ and CD4+/CD137+ cells were 2% and 0.4% at 200 days after haplo-SCT, respectively, as evaluated in a subset of pts at risk for CMV reactivation (R CMVpos/D CMVpos/neg); this frequency was associated to a clearance of CMV antigen; (iii) recovery of thymopoiesis: 10 of 20 (50%) pts showed measurable TREC at 1 year after haplo-SCT; (iv) the increase of CD19+ cells was associated to reconstitution of B lymphocyte repertoire as analysed by Immunoglobulin heavy chain (IgH) CDR3 spectratyping: median number peaks in normal donors and pts, at day 360 after haplo-SCT, were 17 (range, 14–21) versus 12 (range, 7–14), respectively. Conclusions: Our study showed that CD8-depleted DLIs are a feasible procedure with low acute GVHD when using dose level 3. Long-term disease remissions can be observed in advanced lymphoid malignancies. Escalated doses of CD8-depleted DLIs exert complex effects on immune reconstitution: (i) provide help to expansion of CD8 T-cell clones, as suggested by the occurrence of the anti-CMV reactivity; (ii) support B-cell recovery, as demonstrated by a partial recovery of CDR3 polyclonality.
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Bordignon, Claudio, Chiara Bonini, Barbara Sarina, Antonio Lambiase, and Fabio Ciceri. "Randomized phase III trial of haploidentical HCT with or without an add back strategy of HSV-TK donor lymphocytes in patients with high-risk acute leukemia." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 6541. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.6541.
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6541 Background: Suicide gene therapy applied to allogeneic stem cell transplantation has been tested in several trials. When exposed to ganciclovir, donor lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK cells) are selectively eliminated. In a phase I-II trial (Ciceri, Bonini, Lancet Oncology 2009,489-500), TK cells were infused in patients after haploidentical transplantation. Of 50 patients enrolled, 28 received transduced-TK cells and 22 achieved rapid immune reconstitution, with a non-relapse mortality of 14%. GvHD after DLI-TK infusion was reported in 30% of patients and in all cases was fully controlled by ganciclovir treatment. Methods: High risk leukemia patients in first or subsequent complete remission are currently randomized in a 2-arm (3:1 ratio) phase III trial with or without the add-back strategy of HSV-TK donor lymphocytes in patients underwent T-depleted haploidentical stem cell transplant. Primary end point is disease-free survival (DFS), while secondary end points included overall survival, non-relapse mortality, immune reconstitution, acute and chronic GvHD incidence, and relapse incidence. For the primary analysis of DFS 170 patients (127 patients in the experimental group and 43 patients in the control) are required to detect an hazard ratio of 0.55 with at least 80% power for 2-sided 0.05 level test. Patients are eligible for the study if they are older than 18 years-old, absence of timely and suitable HLA matched family or unrelated donor, and have a ECOG performance status < 2. Patients are stratified by state of disease, ECOG PS and country before randomization. Results: Transduced lymphocytes are given to patients between day +21 and day +49 after haploidentical HCT in the absence of spontaneous immune reconstitution and/or development of GvHD. In absence of immune reconstitution and GvHD after the first TK-cells add-back further 3 infusions could be administered 30 days after the last infusion. TK lymphocytes dose is 1 x10^7 CD3/Kg. Conclusions: The study (TK008) is currently open to accrual in EU, US, Israel (clinicaltrials.gov:00914628).
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Ciceri, F., C. Bonini, M. Lupo Stanghellini, A. Santoro, S. Slavin, J. Apperley, P. Bruzzi, et al. "Infusions of HSV-TK genetically modified donor lymphocytes enable a wider use of partially mismatched allogeneic transplantation by reducing infection related mortality and improving survival in high risk acute leukemia." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 6519. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.6519.
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6519 Background: Allogeneic transplantation from a haploidentical family donor (haplo-SCT) represents the ideal solution to offer to every and each patient with high risk leukemia the potential cure of allogeneic adoptive immunotherapy. However, the delayed immune reconstitution compromise haplo-SCT with a high rate of late mortality and relapse. Methods: In a phase II multicenter trial (MM TK007), we explored early add-backs of donor lymphocytes genetically engineered to express the herpes simplex thymidine kinase (TK-DLI) suicide gene after haplo-SCT, in inducing early immune reconstitution and selective control of GvHD by ganciclovir. Results: Thirty-one advanced age pts (median age 51, 17–64) were transplanted for high risk leukemia. No immune reconstitution and no graft versus host disease (GvHD) were observed in absence of TK-DLI. 17 pts received TK-DLI at a median dose of 107/kg with 1st infusion at d +42; 14 pts obtained a prompt and sustained immune reconstitution with CD3+ >100/mcl at a median time of 86 d (57–127) from SCT and 21 d (13–42) from TK-DLI. Six pts developed acute (GvHD), (grade I to IV) that was always completely abrogated by ganciclovir. In patients in remission of leukemia at time of SCT, who were alive at day +42 and received TK-DLI, overall survival was 65% at 2 years (intention-to-treat analysis: 46%).The cumulative incidence of TRM and relapse showed a 40% probability of mortality with a median time of death of 90 days and last event at day +166. The cumulative infectious mortality beyond day 100 post transplant was 12.5% in our population, versus 53% of historical data. These data correlate with rapid development of normalization of the T cell repertoire documented by spectratype, followed by detection of high frequencies of T cells specific for CMV and EBV by gIFN ELISpot. Conclusions: These results indicate that TK-DLI drastically reduces late mortality after CD34+ haplo-SCT in adults. Survival rates in patients treated with TK-DLI were superior to survivals of haploidentical SCT of EBMT registry database. A phase III randomized multicentric study will start in 2006 to validate prospectively the advantage of TK-DLI in haplo-SCT. [Table: see text]
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Rizzieri, David A., Liang Piu Koh, Gwynn D. Long, Cristina Gasparetto, Jerald Z. Gong, Anand S. Lagoo, Donna Niedzwiecki, et al. "Outcome and Immune Reconstitution Following T Cell Depleted Nonmyeloablative Allogeneic Transplantation Using Matched Donors." Blood 106, no. 11 (November 16, 2005): 2036. http://dx.doi.org/10.1182/blood.v106.11.2036.2036.
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Abstract To minimize toxicity and monitor immune recovery without interference of long term use of immunosuppressive agents, we have investigated T-cell depleted, nonmyeloablative allogeneic therapy using matched family member donors. Methods: Seventy five patients who were not candidates for ablative therapy due to age or comorbid diseases received fludarabine 30mg/sq m and cyclophosphamide 500mg/sq m IV qd x 4 with alemtuzumab 20mg IV qd x 5 followed by stem cell infusion. No other post transplant immunomodulation was provided. Results: Patient diagnoses included lymphoma/myeloma (20), leukemias/MDS (30), myelofibrosis/aplasia (7) and metastatic solid tumours (18). The median age was 50 (range 18–17) with a median follow up of 18 months. The median CD34+ cell dose collected was 13.4 x 106/kg. Engraftment occurred in 100% of patients with a median of 97% donor cells responsible for patient hematopoiesis by 3 months. Forty six also had a DLI (range 106–108 CD3+ cells/kg). Overall, Grade III–IV acute GVHD occurred in only 5/75 (7%) and 18 (29%) had grade II–IV. Four patients developed chronic GVHD. The transplant regimen was well tolerated with 4% 100 day treatment related mortality. In those with hematologic malignancies, only 7% started in remission, though 45 (60%) attained a CR. The most common cause of death in this group was progressive disease (28%), followed by infections (5%), and GVHD (5%). A subgroup of 21 of these older, more infirm patients who had high risk AML in 1–2nd CR or PR or ≥2 chronic stable phase CML, partially responding lymphoma, or severe myelofibrosis have been followed for at least 1 year. At 1 year, 13/21 (62%) remain alive and in continuing remission. Phenotypic analysis of lymphocyte subsets (measured by flow) revealed recovery at 6 months. Figure Figure T cell VBeta family recovery (spectratype analysis using PCR) revealed robust recovery by 6 months as well (first figure pre and second is 6 months post transplant), despite T depletion. Figure Figure TRECs analysis reveals little, if any, recovery in these patients for at least 12–18 months. Conclusions: Nonablative allogeneic transplantation using alemtuzumab for T cell depletion results in reliable engraftment with little acute GVHD or TRM. Immune recovery assays reveal that despite T cell purging, T cell subset and VBeta families have significant recovery by 6 months and TRECS results show the recovery is primarily from peripheral expansion of transplanted donor cells, not education of new T cells. These data possibly reflect the advantage of low dose donor lymphocyte boosts without planned long term use of immunosuppressive agents. The future challenge will to be to develop strategies to further improve immune recovery in this setting.
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März, Vincent, and Peter M. Vogt. "Skin Healing of Deep Second Degree Burn Injuries in Four Individuals Sustained in a Boat Explosion—Results after Different Approaches." European Journal of Burn Care 1, no. 1 (September 16, 2020): 191–95. http://dx.doi.org/10.3390/ejbc1010003.
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Intermediate and deep second-degree skin burn injuries are an ongoing challenge for burn surgeons, with the difficult decision regarding whether to handle them with either conservative or operative methods. In this study, the outcome of similar deep second-degree skin burn injuries is shown with the example of four family members. Clinical outcomes of the four family members which were treated at our burn center in 2017 were analyzed. The areas of burned skin (IIa°-IIb°) extended from 14% to 38% of the total burned skin area. Surgical treatment was adjusted to the rate of epithelialization after the first debridement. The excellent cosmetic long-term results of this patient cohort support the importance of stage-related therapy of deep dermal burn injuries. An initial debridement followed by early coverage is the key to early reconstitution of the epidermal barrier. However, with regard to the late effects of skin substitutes, more sensory alterations, dysesthesia, hyperpigmentation and unstable skin areas are still visible after coverage with glycerol conserved skin. The best results were seen after the use of autologous STGS and synthetic skin.
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Dahl, A. Maria, Christoph Klein, Pietro G. Andres, Cheryl A. London, Michael P. Lodge, Richard C. Mulligan, and Abul K. Abbas. "Expression of Bcl-XL Restores Cell Survival, but Not Proliferation and Effector Differentiation, in Cd28-Deficient T Lymphocytes." Journal of Experimental Medicine 191, no. 12 (June 12, 2000): 2031–38. http://dx.doi.org/10.1084/jem.191.12.2031.
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Lymphocytes deficient in the T cell costimulatory molecule CD28 exhibit defects in cell survival, clonal expansion, and differentiation into effector cells. It is known that CD28-mediated signaling results in the upregulation of the Bcl family member Bcl-XL. To investigate the role that Bcl-XL plays in the various functions of CD28, we expressed Bcl-XL in CD28-deficient primary T lymphocytes using retrovirus-mediated gene transfer. T cells were activated in vitro and infected with Bcl-XL or control retroviruses; this method allows gene expression in activated, cycling cells. Expression of Bcl-XL in naive T cells was achieved by reconstitution of the immune system of lethally irradiated recipient mice with retrovirus-infected purified bone marrow stem cells from CD28−/− or wild-type donor mice. Our studies demonstrate that Bcl-XL prolongs the survival of CD28−/− T cells but does not restore normal proliferation or effector cell development. These results indicate that the various functions of CD28 can be dissociated, and provide an experimental approach for testing the roles of downstream signals in the functions of cellular receptors such as CD28.
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Stanghellini, Maria Teresa Lupo, Fabio Ciceri, Chiara Bonini, Attilio Bondanza, Catia Traversari, Monica Salomoni, Lucia Turchetto, et al. "Early and Effective Immune-Recovery by Gene-Engineered Lymphocytes after Haploidentical Transplantation for Leukemia Abate Late Transplant Mortality." Blood 112, no. 11 (November 16, 2008): 353. http://dx.doi.org/10.1182/blood.v112.11.353.353.
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Abstract Background. Haploidentical family donors represent the ideal solution to offer to every patient with high risk leukemia the potential cure of hematopoietic stem cell transplantation. Extensive application of haploidentical transplantation (haplo-SCT) has been limited by high rate of late transplant related mortality (TRM) and relapse associated with the delayed immune reconstitution (IR) secondary to the procedures of profound T-cell depletion required for severe graft-vs-host-disease (GvHD) prevention. Methods. In a haplo-SCT phase I-II multicenter, open, non-randomized trial sponsored by MolMed SpA, we infused donor lymphocytes genetically engineered to express the suicide gene herpes simplex thymidine kinase (TK-DLI) to induce early IR, while selectively controlling GvHD. We enrolled 54 patients (pts) -median age 51- with high-risk hematologic malignancies. Thirty-two patients were in remission at transplantation. Results. After myeloablative conditioning regimen, 50 pts received a median 11×10^6/ kg CD34+ and 1.1×10^4/kg CD3+ after Clinimacs CD34+ selection. Median time to engraftment of neutrophils > 1.0 ×10^9/L and platelets > 50 ×10^9/L was 14 days. TK cells could always be prepared in the appropriate timeframe, and no drop out secondary to inadequate cell manipulation occurred. Twenty-eight pts received TK-DLI at a dose of CD3+ cells of 0.9–40 ×10^6/kg: 22 pts obtained prompt IR with CD3+>100/mcl at day +75 (median) from haplo-SCT and day +23 from TK-DLI. Eleven pts developed GvHD (10 acute GvHD grade I-IV and 1 chronic GvHD) that was always abrogated by the suicide gene induction; no progression from acute GvHD to chronic GvHD and no GvHD-related death or long-term complication occurred. No acute or chronic adverse event related to the gene transfer procedure was observed during extended follow-up. With a median follow-up of 178 days (range 2–1821), the 3-year TRM in intention to-treat (ITT) analysis was 40% with last mortality event at d+166. Significantly, the cumulative infectious mortality was 10% in TK-treated immune-reconstituted patients. Immune reconstitution obtained with TK-cells infusion correlated with rapid development of a wide T-cell repertoire and detection of high frequencies of T-cells specific for opportunistic pathogens. Initially, TK-cells represented the predominant T cell component in reconstituting patients and showed a effector memory phenotype, an oligoclonal repertoire and a persistent ganciclovir sensitivity. At later times, untransduced cells progressively expanded and became the prevalent circulating lymphocyte population. This reconstitution kinetic was observed only in patients with TK-cell engraftment, suggesting a critical homeostatic contribution of TK-cells early after transplant. One year after TK cells infusion the repertoire and distribution of T cell subsets completely normalized. In ITT, the median leukemia-free survival (LFS) for patients transplanted with advanced chemoresistant disease was at d+169, while patients in remission at the time of transplantation showed an overall survival in ITT of 51% at 1 year. Conclusions. This multicenter trial confirm the safety and potential benefit in improving survival of the gene transfer technology integrated with a standard therapeutic procedure such as allogeneic SCT. The conditional benefit for patients treated with TK cells was remarkable as indicated by a complete abrogation of late infectious mortality provided by the fast and effective immune reconstitution. In the future, this technology based on genetic engineering of activated donor lymphocytes with higher allo-reactive potentialwill potentially impact also the transplant outcome of patients with refractory disease.
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Munneke, J. Marius, Jenny M. Mjösberg, Jochem H. J. Bernink, Cynthia Huisman, Hergen Spits, and Mette D. Hazenberg. "Reconstitution of Innate Lymphoid Cells After Hematopoietic Stem Cell Transplantation." Blood 120, no. 21 (November 16, 2012): 4104. http://dx.doi.org/10.1182/blood.v120.21.4104.4104.
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Abstract Abstract 4104 Introduction Patients undergoing hematopoietic stem cell transplantation (HSCT) are at increased risk of developing (severe) opportunistic infections, which can be attributed to the combination of a decimated immune system and disrupted epithelial barriers. Innate lymphoid cells (ILCs) represent a novel family of regulator and effector cells that share phenotypic and functional characteristics with both NK cells and T lymphocytes, but are non-cytotoxic and lack antigen specific receptors. ILCs serve important roles in the maintenance of epithelial integrity and - as part of the first line of defence - in protection against microbes. ILCs are mainly tissue-resident and can be identified by the absence of lineage markers (Lin-) and bright expression of the alpha chain of the IL-7 receptor (CD127). Extensive research has been carried out focussing on the relative contribution of different immune cells to immune deficiency and graft-versus-host disease (GvHD) following HSCT. However, little is known about ILCs in this context. We studied reconstitution dynamics of ILCs in order to explore their function in tissue repair and mucosal immunity following HSCT. Methods Blood samples of adult patients (n=15) receiving an allogeneic HSCT after reduced-intensity conditioning (RIC) for acute myeloid leukemia (AML) were obtained at sequential time points during induction, consolidation and conditioning chemotherapy, at the day of HSCT and up to 6 months following HSCT. Peripheral blood ILCs were analyzed using flow cytometry and defined as Lin-CD127hi. The ILC population was further divided into various subpopulations using the markers NKp44, CRTH2 and CXCR3. Results Induction and consolidation chemotherapy led to a significant decline in the number of circulating ILCs. Recovery of ILCs in between chemotherapy cycles was partial as ILC numbers improved without returning to healthy control values (n=10; reference values defined as upper and lower boundaries of 95% CI), in contrast to other innate cells such as neutrophils and NK cells. Following allogeneic HSCT, recovery dynamics of ILCs parallelled those of adaptive immune cells, rather than of innate cells: recovery was relatively slow, as normal numbers of circulating ILCs had not been reached 6 months after HSCT. In addition, we observed enrichment of a particular ILC subset, defined as Lin-CD127hiCD117+NKp44+ cells, in subgroups of patients after chemotherapy and HSCT. These RORγt-dependent ILCs have been found to comprise an important innate source of IL-22 (hence referred to as ILC22s), a cytokine crucial for epithelial homeostasis and induction of epithelial antimicrobial peptides. Discussion and conclusion Our observation of a relatively slow reconstitution of ILCs is notable since innate immune cells are generally known to recover within weeks to months after HSCT. In fact, ILC reconstitution following HSCT bears resemblance to post-transplantation adaptive lymphocyte recovery dynamics. Fitting with this notion, there is a certain degree of analogy between ILCs and T helper cells as ILCs with cytokine profiles resembling those of the various T helper subsets are found, i.e. ILCs producing mainly IL-13/5, IL-22, IL-17 or IFN-γ. Furthermore, proliferation and differentiation of the ILC subpopulations stands under the control of transcription factors known to be master regulators of the different T helper subsets (i.e. GATA3, Tbet, RORγt and AHR). Hence, our data show that the analogy between the ILC and T helper systems in terms of factors that control differentiation and function is matched by their similarities in reconstitution dynamics following chemotherapy and HSCT. Interestingly, following chemotherapy and allogeneic HSCT, ILC22s, known to be primarily dedicated to the maintenance of epithelial homeostasis, were found to be enriched in subgroups of patients. Damage to mucous membranes lining the gastrointestinal tract, due to chemotherapy-induced mucositis, conditioning radiotherapy or graft-versus-host disease, is a common problem that constitutes a significant limiting factor in HSCT. Therefore, improvements in the prevention or management of such epithelial damage are eagerly awaited. Our data suggest that ILCs may be involved in protection against and/or recovery of epithelial damage in patients with a hematological malignancy receiving chemotherapy and HSCT. Disclosures: No relevant conflicts of interest to declare.
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Canty, John T., Ruensern Tan, Emre Kusakci, Jonathan Fernandes, and Ahmet Yildiz. "Structure and Mechanics of Dynein Motors." Annual Review of Biophysics 50, no. 1 (May 6, 2021): 549–74. http://dx.doi.org/10.1146/annurev-biophys-111020-101511.
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Dyneins make up a family of AAA+ motors that move toward the minus end of microtubules. Cytoplasmic dynein is responsible for transporting intracellular cargos in interphase cells and mediating spindle assembly and chromosome positioning during cell division. Other dynein isoforms transport cargos in cilia and power ciliary beating. Dyneins were the least studied of the cytoskeletal motors due to challenges in the reconstitution of active dynein complexes in vitro and the scarcity of high-resolution methods for in-depth structural and biophysical characterization of these motors. These challenges have been recently addressed, and there have been major advances in our understanding of the activation, mechanism, and regulation of dyneins. This review synthesizes the results of structural and biophysical studies for each class of dynein motors. We highlight several outstanding questions about the regulation of bidirectional transport along microtubules and the mechanisms that sustain self-coordinated oscillations within motile cilia.
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Dominietto, Alida, Anna Maria Raiola, Barbara Bruno, Maria Teresa van Lint, Francesco Frassoni, Carmen Di Grazia, Francesca Gualandi, et al. "Rapid Immune Reconstitution Following Unmanipulated Haploidentical BMT with Post-Transplant High Dose Cyclophosphamide." Blood 118, no. 21 (November 18, 2011): 3050. http://dx.doi.org/10.1182/blood.v118.21.3050.3050.
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Abstract Abstract 3050 Background. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for the majority of hematological malignancies. Early and successful immunologic reconstitution after HSCT reduces morbidity and mortality due to infection complications and improves survival. Aim of the study. We analyzed immune recovery after HSCT in 444 patients according to donor source. Patients and Methods. From January 2005 to June 2011 176 patients were grafted from HLA identical siblings (MSD), 125 from alternative donors (1 antigen mismatched family or unrelated donors) (ALT), 103 from unrelated cord blood grafted intra bone (CBIB) and 40 from haplo-identical mismatched family donors (HAPLO). All patients received unmanipulated bone marrow: 283 after a myeloablative (MA) conditioning regimen (CY-TBI or BU-CY) and 161 after a fludarabine based reduced intensity regimen (RIC). Graft versus host disease (GvHD) prophylaxis was cyclosporin methotrexate (CyA+MTX) for all patients except for CBIB (CyA and mycophenolate, MMF) and for HAPLO transplants which consisted of CyA+MMF and post-transplant high dose cyclophosphamide (HDCY) according to the Baltimore protocol (Lutznik et al BBMT 2008). Anti-thymocyte globulin (ATG) was used only for ALT transplants. Results. We compared immune reconstitution in MA and RIC transplants according to donor type at different time points post BMT. CD3+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 477, 565, 700; in ALT donors were 146, 404, 470; in CBIB were 30, 57, 196; for HAPLO transplants they were 195, 182, 499. CD3+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 301, 660, 700; in ALT donors were 506, 186, 721; in CBIB 234, 399, 522; in HAPLO were 178, 276, 1300. CD4+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 166, 170, 198; in ALT donors were 36, 86, 111; in CBIB 7, 36, 106; for HAPLO transplants they were 45, 127, 211. CD4+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 89, 189, 274; in ALT donors were 131, 210, 220; in CBIB 52, 110, 130; for HAPLO transplants they were 41, 205, 385. CD8+ absolute median counts/μl in MA conditioning on day+30, +90, +180 were respectively in MSD 280, 389, 500; in ALT donors were 102, 278, 413; in CBIB 42, 16, 51; in HAPLO transplants were 73, 424, 408. CD8+ absolute median counts/μl in RIC conditioning on day+30, +90, +180 were respectively in MSD 196, 432, 300; in ALT donors were 366, 65, 494; in CBIB 71, 167, 199; for HAPLO transplants they were 137, 129, 900. CD3, CD8, and CD4 counts in HAPLO transplants were not statistically different from MSD with the only exception of day +30, both for MA and RIC conditioning. Platelet median counts/μl on day+30, +90, +180 in MA conditioning were in MSD 142, 129, 180, in ALT 75, 101, 147, in CBIB were 19, 77, 128 and for HAPLO transplants were 67, 126, 128; in RIC conditioning platelets counts were in MSD 137, 156, 168, in ALT 33, 134, 142, in HAPLO were 77, 95, 188. Acute GvHD II-IV developed in 29% (MSD) 38% (ALT) 16% (CBIB) and 12% (HAPLO) (p=0.004) in MA conditioning and 40% (MSD) 18% (ALT) 25% (CBIB) and 10% (HAPLO) (p=0.07). Overall Cumulative Incidence of Non-Relapse Mortality (CI-NRM) was respectively 18% (MSD), 35% (ALT), 34% (CBIB), 22% (HAPLO) (p=0.02) in MA conditioning (p=0.02) and was 30% (MSD), 33% (ALT), 45% (CBIB), 0% (HAPLO) (p=0.02) in RIC conditioning (p=0.02). Day+100 CI-NRM was respectively 10% (MSD), 21% (ALT), 19% (CBIB), 12% (HAPLO) in MA conditioning (p=0.01) and 11% (MSD), 19% (ALT), 26% (CBIB), 0% (HAPLO) in RIC conditioning (p=0.02). Death due to infections were respectively 6% (MSD), 26% (ALT), 30% (IBCB), 17% (HAPLO) in MA conditioning and for RIC were 15 (MSD), 36% (ALT), 32% (IBCB), 0% (HAPLO). Conclusions. HAPLO transplant with HDCY post transplant as proposed by the Baltimore group, is associated with (1) rapid immunologic (CD3, CD4, CD8) recovery (2) low infectious death rate, (3) low overall and Day+100 CI-NRM, (4) rapid hematologic recovery. These results are comparable with those achieved with MSD and warrant further studies with HDCY post transplant as a GvHD prophylaxis. Figure: absolute CD4+ counts/μl on day+30, +90, +180, according to donor type in MA conditioning regimen. Disclosures: No relevant conflicts of interest to declare.
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de Jong, Jill L. O., Caroline E. Burns, Aye Tinmaung, Emily Pugach, Elizabeth Mayhall, Alexandra C. H. Smith, Henry A. Feldman, Yi Zhou, and Leonard I. Zon. "Development of a Limiting Dilution Assay and MHC-Matched Transplantation Model to Detect Hematopoietic Stem Cell Activity in Zebrafish." Blood 112, no. 11 (November 16, 2008): 3489. http://dx.doi.org/10.1182/blood.v112.11.3489.3489.
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Abstract The zebrafish is a powerful model for the discovery of novel genetic mechanisms through large scale forward and reverse screening methodologies, and has been used prominently for the study of hematopoiesis. Methodologies capable of assessing hematopoietic stem cell (HSC) activity, however, are largely undeveloped. Here, we created a long-term limit dilution hematopoietic reconstitution assay in adult zebrafish, defined zebrafish haplotypes at the proposed core Major Histocompatibility Complex (MHC) locus, and tested their functional significance by performing the first matched and unmatched transplants. We identified a sublethal radiation dose of 25Gy which was optimal for hematopoietic reconstitution while minimizing mortality presumably due to radiation damage of other organs. Our method detects multi-lineage repopulation in primary and secondary recipients. Using Poisson statistics, our limit dilution analyses suggest that at least 1 in 65,000 nucleated marrow cells in zebrafish contain repopulating activity, consistent with mammalian marrow HSC frequency. Finally, we characterized the genes in the proposed MHC core locus on chromosome 19 for one family used for sibling marrow transplantations. We were able to identify the four parental MHC haplotypes by sequencing PCR products amplified for specific MHC Class I genes: mhc1uea, mhc1ufa, mhc1uda, mhc1uba, mhc1uca, loc751750, and mhc1uxa2. F1 generation siblings were subsequently typed, and we demonstrated that matching the donor and recipient MHC haplotypes at this chromosome 19 locus dramatically increases engraftment and percentage of donor chimerism in recipients compared to MHC-mismatched donors and recipients. At 15 weeks post-transplant, MHC-matched recipients showed engraftment in 4 of 5 surviving fish with mean donor chimerism of 59.15% +/− 25.1% for myeloid cells and 8.26% +/− 6.2% for lymphoid cells. Those animals receiving MHC-mismatched donor marrow had only 3.92% +/− 2.1% myeloid donor chimerism and 0.97% +/− 0.5% lymphoid donor chimerism. These data represent the first assay allowing long term HSCs to be distinguished from other hematopoietic progenitor fates and provides the first functional test of MHC genes between zebrafish haplotypes. This method opens the door to MHC-matched long-term transplantation experiments in zebrafish that have previously not been possible, including competitive transplantation experiments with zebrafish mutants already identified in prior genetic screens, and long-term tumor transplantation assays. By harnessing the unique genetic and screening advantages of the zebrafish model, such experiments may provide critical insight into mammalian transplantation biology.
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Wiegering, Verena A., Matthias Eyrich, Paul G. Schlegel, and Beate Winkler. "Differences in Immune Reconstitution and Cytokine Production in Children with Sibling Donor BMT Versus T-Cell Depleted PBSCT from Unrelated or Mismatched Family Donors." Blood 108, no. 11 (November 16, 2006): 2916. http://dx.doi.org/10.1182/blood.v108.11.2916.2916.
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Abstract Introduction: Transplantation of haematopoietic stem cell (HSCT) from human leucocyte antigen (HLA)-disparate parental donors presents an approach for the treatment of patients lacking an HLA-matched donor, but little is known about differences in immune reconstitution as compared to conventional BMT. We prospectively compared paediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated or HLA-mismatched donors vs. recipients of unmanipulated bone marrow from matched sibling donors. Patients: Immune reconstitution was studied in 20 children (20 transplants [5 sibling, vs. 8 UD, 7 haplo]; median age was 9,6 years; range 7m-26y; 7 female, 13 male). Blood samples were drawn before allo-HSCT, on days 14 (take), 30, 60, 100, 200 and 365 and >15months after SCT. Methods: We analyzed lymphocyte subpopulations using flow cytometry. Cytokines (IFNg, IL2, TNFa, IL4, IL5, IL10) were determined by FACS after in vitro stimulation with PMA, ionomycin and brefeldin for 24h. Additionally, we measured IL2, IL7, IL13, IL15, IFNg and TGFb in unstimulated sera by ELISA. Further more, we studied TREC values and did spectratype analysis by real time-PCR and gel electrophoresis. Results: After allo-HSCT, NK-cells were the cells, which regenerated first. In T-cells, decreased absolute counts could be detected as well as an inverted CD4-CD8-ratio during the first year after SCT. In CD4+ T-cells, the memory phenotype (CD45RO+) predominated. Sibling recipients show a faster T-cell regeneration than recipients of UD or mismatched family donors (MM). As to cytokine levels in unstimulated sera, IFNg levels remained stable, while we saw high level of IL4 shortly after allo-HSCT; IL4 levels decreased during the first year after SCT. TGFb showed increased levels post-transplantation for up to two years. In stimulated T-cells, we measured a rise in Th2-cytokines (IL4, IL5, IL10) until d60 and a decrease of IFNg/TNFa. Th2-cytokines returned to pre-transplantation levels until d200, whereas Th1-cytokines rise to higher level than before transplantation. We could find that IL2 was produced predominantly by CD4+ / IFNg+ cells and by CD8+cells. Patients who received T-cell depleted stem cell preparations show lower IFNg and TNFa values and higher Th2-cytokine levels than patients who received bone marrow. TREC counts appear earlier in sib HSCT (median d60) than in MM-transplant (median d200). As to spectratype values, we found a distribution of the 24Vb gene families of 4,18% per Vb-family with clonal expansion, especially in the first months after HSCT, of BV6b>BV23>BV1>BV16.
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Bogdanov, Rashit, Saskia Leserer, Evren Bayraktar, Nikolaos Tsachakis-Mück, Lara Kasperidus, Markus Ditschkowski, Dietrich W. Beelen, and Amin T. Turki. "Immune Reconstitution after Allogeneic Hematopoietic Cell Transplantation: Comparing Post-Transplant Cyclophosphamide Versus Anti-T-Lymphocyte Globulin As Graft-Versus-Host Disease Prophylaxis in a Retrospective Cohort Study." Blood 134, Supplement_1 (November 13, 2019): 3289. http://dx.doi.org/10.1182/blood-2019-130623.
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Introduction: Both post-transplant cyclophosphamide (PT-Cy) and anti-T-lymphocyte globulin (ATLG) eliminate proliferating allo-reactive T cells after allogeneic hematopoietic cell transplantation (HCT) and therefore contribute to reduce the incidence of graft-versus-host disease (GVHD). Exposure to ATLG has been previously associated with delayed T cell reconstitution (Gooptu et al. BBMT 2018). Yet, no study has compared PT-Cy to ATLG for its effect on cellular immune reconstitution and only one small study compared it to anti-thymocyte globulin (Retiere et al. Oncotarget 2018). Hence, we analyzed the dynamics of immune reconstitution after HCT in patients that received either PT-Cy or ATLG as additional GVHD prophylaxis. Methods: We retrospectively analyzed 247 patients (138 male, 109 female) from a single-center, who received HCT from HLA-identical siblings (n=29), haploidentical family donors (n=21), or matched unrelated donors (n=197) between January 2017 and December 2018. All patients were transplanted for hematologic malignancies (49% acute myeloid leukemia). Median age was 56 (range, 18-76) years. Myeloablative conditioning regimen was performed in 119 patients and reduced intensity conditioning in 128 patients. PT-Cy (n=59) was dosed 50 mg/kg/day intravenously (i.v.) on days HCT +3 and +4, followed by tacrolimus in combination with mycophenolate mofetil from day +5. In 188 patients, ATLG was administered at 10 mg/kg bodyweight i.v. on days -3, -2 and -1 in combination with cyclosporine 3 mg/kg i.v. from day -1 and methotrexate (15 mg/m2 on day +1 and 10mg/m2 on days +3, +6, and +11 i.v.). All patients received HCT using peripheral blood stem cells with amedian dose of 6.3x106CD34+ cells/kg (range, 1.3 to 25). Blood samples were collected on days +30, +90, +180, +270 and +365 and analyzed by multiparametric flow cytometry for the following cell subsets: T lymphocytes (CD3+), T helper cells (CD3+/CD4+); cytotoxic T cells (CD3+/CD8+), regulatory T cells (CD3+/CD4+/CD25+/CD127+), T cell receptor αβ(CD3+/TCRαβ), T cell receptor γδ(CD3+/TCRγδ), NK T-cells (CD3+/CD16+/CD56+), NK-cells (CD3-/CD16+/CD56+), naïve helper T cell (CD4+/CD45RA), memory helper T cells (CD4+/CD45RO) and B cells (CD19+). Results: Immune cell reconstitution differed significantly between the PT-Cy and the ATLG cohorts. The use of PT-Cy associated with significantly higher median counts of helper T cells during the first 6 months after HCT (p<0.0001, Fig. 1A). In particular, naïve helper T cells (Fig. 1B; median absolute (abs.) cell counts of PT-Cy versus (vs) ATLG cohort: month 1, 15 cells/µL vs 12 cells/µL , p<0.0001; month 3, 13 vs 3 cells/µL, p<0.0001; month 6, 25 vs 4 cells/µL, p<0.0001) and memory helper T cells (median abs. counts month 1, 94 vs 3 cells/µL, p<0.0001; month 3, 116 vs 64 cells/µL, p<0.0001; month 6, 189 vs 89 cells/µL, p =0.004) were significantly higher in the PT-Cy cohort. Cytotoxic T cells (Fig. 1C) and NK cells did not differ between PT-Cy and ATLG cohorts. Interestingly, γδ T cells were significantly higher in the ATLG cohort (Fig. 1D; median abs. counts month 1, 14 cells/µL vs 3 cells/µL; p =0.019). For B cells or NKT cells the use of PT-Cy associated with earlier immune reconstitution with significant differences only at month 1 after HCT (median abs. cell counts 10 cells/µL vs 1 cell/µL, p=0.007 and 11 vs 2 cells/µL, p=0.03, respectively), regulatory T cells differed significantly in months 3 and 6 (median abs. count 9 vs 2 cells/µL, p<0.0001; 10 vs 4 cells/µL, p<0.0001). The incidence of grade II to IV acute GVHD was significantly lower in the PT-Cy cohort as compared to the ATLG cohort (Hazard ratio 0.48, 95% Confidence interval, 0.30-0.78, p=0.003). Within a median follow up of 11 months, no significant differences in overall survival, relapse incidence and non-relapse mortality were observed between the PT-Cy and ATLG cohorts. Conclusions: Our data suggest that the choice of the additional T cell depleting regimen using either ATLG or PT-Cy significantly affects immune reconstitution after HCT. Knowledge of the distinct immune reconstitution profiles should assist clinical decision-making and help optimizing GVHD prophylaxis. Disclosures Bogdanov: Jazz Pharmaceuticals, MSD.: Other: Travel subsidies. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Turki:Jazz Pharmaceuticals, CSL Behring, MSD.: Consultancy; Neovii Biotech, all outside the submitted work: Other: Travel subsidies.
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Moyle, Helen. "Tracking Couples who leave the Study Location in Historical Studies of Fertility: an Australian Example." Historical Life Course Studies 3 (June 9, 2016): 32–42. http://dx.doi.org/10.51964/hlcs9352.
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The paper describes the methods used to create a database to study the fall of fertility in Tasmania, a colony of Australia, in the late 19th and early 20th centuries. The database was initially created from digitised Tasmanian vital registration data using techniques of family reconstitution. However, because of the high mobility in Australia in the 19th and early 20th centuries, couples who moved out of the colony were tracked to other places, and births and deaths that took place in other Australian colonies and other countries, such as New Zealand and England, were included in the database. A wide variety of data sources were used for this task, most of which are available on the internet. The results presented in the paper show that including families who moved outside Tasmania, either temporarily or permanently, produced a database that was more representative of the study population and provided more accurate birth histories for couples who at first glance appeared to have spent their married lives within the colony.
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Schofield, Roger. "Automatic Family Reconstitution." Historical Methods: A Journal of Quantitative and Interdisciplinary History 25, no. 2 (April 1992): 75–79. http://dx.doi.org/10.1080/01615440.1992.9956345.
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Sheih, Alyssa, Jonathan L. Golob, Abir Bhattacharyya, Michael C. Wu, Aesha Vakil, Sujatha Srinivasan, Steven A. Pergam, David N. Fredricks, and Cameron J. Turtle. "Impact of Intestinal Microbiota on Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Stem Cell Transplantation." Blood 132, Supplement 1 (November 29, 2018): 3393. http://dx.doi.org/10.1182/blood-2018-99-115158.
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Abstract INTRODUCTION: Mucosal-associated invariant T (MAIT) cells are innate-like T cells that express a semi-invariant T cell receptor (TCR) consisting of a Vα7.2 chain paired with a restricted repertoire of Vβ chains. The MAIT cell TCR recognizes riboflavin metabolites, and potentially other ligands produced by distinct bacterial and fungal species and presented in the context of the MHC class I-related molecule (MR1). MAIT cells are abundant in humans, comprising up to 10% of T cells in the peripheral blood, and are enriched in the gastrointestinal (GI) mucosa and liver. The GI localization of MAIT cells and their activation by microbial metabolites raises the possibility of a role in acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT) when the GI mucosal barrier is compromised. Indeed, we found an increased risk of severe aGVHD in patients with low MAIT cell counts in the blood after HCT (Bhattacharyya, BBMT 2018). The impact of alterations in the GI microbiota on reconstitution and function of MAIT cells in HCT recipients remains unknown. METHODS: Paired blood and stool samples were collected from allogeneic HCT recipients prior to conditioning, and on days 0, 10, 20, 30, 60, and 100 after HCT. MAIT cells were identified as CD3+/CD161hi/Vα7.2+ cells by flow cytometry and absolute counts in the peripheral blood were determined in conjunction with a complete blood count. The bacterial composition of the stool was characterized by broad-range 16S ribosomal RNA gene PCR and high-throughput sequencing followed by placement into a maximum-likelihood phylogeny via pplacer against a custom reference package. A linear mixed model with random intercept was used to estimate the correlation between absolute MAIT cell count in the blood and relative abundance of bacterial species in the stool. RESULTS: We analyzed 302 paired blood and stool samples from 78 allogeneic HCT recipients. MAIT cells declined from pre-conditioning levels to a nadir on the day of stem cell infusion, followed by an increase to a plateau between day 30 and 100 after HCT. Microbial diversity was low prior to HCT and further decreased in the first 20 days after HCT, followed by an increase between days 30 and 100 to pre-HCT levels. MAIT cell counts in the blood correlated with stool microbial diversity and the relative abundance of individual bacterial species. We found a direct correlation between the abundance of bacterial species belonging to the Lachnospiraceae family (including distinct Blautia and Clostridium spp.) and an inverse correlation between the relative abundance of oral and perineal bacteria in the stool with absolute MAIT cell counts in blood (Table 1). Consistent with our findings and a possible protective role for MAIT cells in the pathogenesis of aGVHD (Varelias, JCI 2018), decreased Blautia abundance in stool has been associated with increased risk of death from aGVHD (Jenq, BBMT 2015) and increased abundance of oral and perineal bacteria in stool has been associated with aGVHD (Golob, CID 2017). CONCLUSION: In this study, we identified bacterial species whose relative abundance directly or inversely correlated with the absolute number of MAIT cells in blood after HCT. This observation is consistent with a mechanism in which a gut microbiome that is deficient in bacteria in the Lachnospiraceae family (capable of generating riboflavin metabolites for MAIT cell activation) is associated with poor MAIT cell recovery and potentially an increased risk of aGVHD. Disclosures Turtle: Caribou Biosciences: Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno/Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
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Vicente, Fátima de la Cruz, Omar BenMarzouk-Hidalgo, Irene Gracia-Ahufinger, Raul García-Lozano, Manuela Aguilar-Guisado, Jose Miguel Cisneros-Herreros, Alvaro Urbano-Ispizua, Pilar Perez-Romero, and Ildefonso Espigado. "Risk Factors for Mortality In Cytomegalovirus Infection After Hematopoietic Stem Cell Transplantation." Blood 116, no. 21 (November 19, 2010): 4539. http://dx.doi.org/10.1182/blood.v116.21.4539.4539.
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Abstract Abstract 4539 BACKGROUND: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). Described risk factors for CMV infection are pretransplant CMV seropositive status of the recipient, non related donor or umbilical cord transplant, depleted lymphocyte graft, high intensity conditioning regimen, severe graft versus host disease (GVHD), CD34+ selection of the graft and delayed CMV specific immune reconstitution. OBJETIVES: To identify different profiles of allogeneic stem cell recipients based on their previously described risk factors for CMV infection and its association with their clinical outcomes. PATIENTS AND METHODS: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Patients were sequentially monitored both clinically and analytically. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry. Non-normal distribution data were expressed as median values (range). Chi-square test or Fisher exact test were used to compare differences between groups of categorical data. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). RESULTS: Twenty-six patients were included with a median age of 33 years (range:15-61). The donor was an identical sibling in 42.3%, unrelated donor in 53.8% and a mismatched family member in 3.8%. The source was peripheral blood 76.9%, cord blood 15.4% and bone marrow in 7.7%. Previous positive serostatus for CMV was 76.9% in recipients, and 53.8% in donors. The conditioning regimen was myeloablative in 57.7% and reduced-intensity in 42.3%. Graf versus host disease (GvHD) prophylaxis was cyclosporine (CsA) plus methotrexate (MTX) in 57.7% and CsA plus mycophenolate mofetil (MMF) in 42.3%. The incidence of acute GvHD was 76.9% and chronic GvHD was 53.8%. Treatment of GVHD was steroids plus CsA or tacrolimus and/or MMF in 76.9% of acute and 46.2% of chronic GvHD. Previously described risk factors for developing CMV infection were compared between patients developing (n=18) and non-developing (n=8) CMV infection. A higher risk for developing CMV infection was associated with previous CMV positive serostatus of the recipient (84% in viremic patients vs. 16% in non-viremic patients; p=0.01) and CsA plus MMF as GvHD prophylaxis (90.9% vs. 9.1%; p=0.04). We analyzed whether having several risk factors for developing CMV infection has an effect on the risk for developing CMV replication after the transplant. Patients that presented four or more risk factors, developed viral replication more frequently than patients having less than four risk factors (91.6% vs. 8.3%; p=0.02). Patients who acquired an earlier specific CMV immune reconstitution did not developed CMV replication, opposite to those with later immune reconstitution (week 2 vs. week 8, p= 0.01). Overall survival at one year was of 44.4% in the group with viral replication, and 100% in the group with no viral replication, p=0.014 (Figure 1). CONCLUSIONS: Patients that did not developed episodes of CMV replication after the transplant presented less than four risk factors for developing CMV infection, developed an early T-cell mediated CMV immune response and had better overall survival. The development of CMV specific immunity able to control CMV replication may be considered as a paradigm of post-transplant immune reconstitution with potential influence on overall survival. Disclosures: No relevant conflicts of interest to declare.
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Kennedy, Gregory M. W. "Pushing Family Reconstitution Further." Journal of Family History 37, no. 3 (June 20, 2012): 303–18. http://dx.doi.org/10.1177/0363199012439153.
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Rohlwink, Ursula, Naomi Walker, Alvaro Ordonez, Yifan Li, Elizabeth Tucker, Paul Elkington, Robert Wilkinson, and Katalin Wilkinson. "Matrix Metalloproteinases in Pulmonary and Central Nervous System Tuberculosis—A Review." International Journal of Molecular Sciences 20, no. 6 (March 18, 2019): 1350. http://dx.doi.org/10.3390/ijms20061350.
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Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.
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Wainwright, Richard, and Shannon Stevens. "MashUp at the Vancouver Art Gallery: “In Review” [onto]Riffologically." Art/Research International: A Transdisciplinary Journal 2, no. 1 (March 22, 2017): 166. http://dx.doi.org/10.18432/r2g04t.
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@font-face { font-family: "Arial"; }@font-face { font-family: "Arial"; }p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 0cm 0cm 0.0001pt; line-height: 115%; font-size: 11pt; font-family: Arial; color: black; }p.normal, li.normal, div.normal { margin: 0cm 0cm 0.0001pt; line-height: 115%; font-size: 11pt; font-family: Arial; color: black; }.MsoChpDefault { font-size: 11pt; font-family: Arial; color: black; }.MsoPapDefault { line-height: 115%; }div.WordSection1 { }Abstract: [onto]Riffology, a “plug in and play” method of inquiry that riffs across technological platforms and with all manner of material, finds easy resonance in mashup and remix, and we turn our riffological sights to the Vancouver Art Gallery which hosted MashUp[1] from February 20th through June 12th, 2016. Creative and combinatorial, mashup is identifiable in popular discourse as fundamentally humanist and epistemological in nature; however, as an interdisciplinary, ontological practise of repurposing and reconstituting, acts of mashup also exist in geological activity, far outside of humanity, and here we apply ontological focus through riffological measures. We are interested not in seeing merely what is being exhibited, but deterritorializing what is being curated. Our emergent senses of new materialisms inform our riffology here as we ceaselessly (re)encounter the exhibition; experienced as a riff arcade of dream like experience that one mayn’t exit; like the arcades of Benjamin’s mammoth project of 1927 to 1940.[1] "Vancouver Art Gallery: The Making Of Mashup", YouTube, accessed February 8, 2017, https://www.youtube.com/watch?v=DjFPesKTa5Q&t=2s.
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Caffrey, Martin. "A comprehensive review of the lipid cubic phase orin mesomethod for crystallizing membrane and soluble proteins and complexes." Acta Crystallographica Section F Structural Biology Communications 71, no. 1 (January 1, 2015): 3–18. http://dx.doi.org/10.1107/s2053230x14026843.
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The lipid cubic phase orin mesomethod is a robust approach for crystallizing membrane proteins for structure determination. The uptake of the method is such that it is experiencing what can only be described as explosive growth. This timely, comprehensive and up-to-date review introduces the reader to the practice ofin mesocrystallogenesis, to the associated challenges and to their solutions. A model of how crystallization comes about mechanistically is presented for a more rational approach to crystallization. The possible involvement of the lamellar and inverted hexagonal phases in crystallogenesis and the application of the method to water-soluble, monotopic and lipid-anchored proteins are addressed. How to set up trials manually and automatically with a robot is introduced with reference to open-access online videos that provide a practical guide to all aspects of the method. These range from protein reconstitution to crystal harvesting from the hosting mesophase, which is noted for its viscosity and stickiness. The sponge phase, as an alternative medium in which to perform crystallization, is described. The compatibility of the method with additive lipids, detergents, precipitant-screen components and materials carried along with the protein such as denaturants and reducing agents is considered. The powerful host and additive lipid-screening strategies are described along with how samples that have low protein concentration and cell-free expressed protein can be used. Assaying the protein reconstituted in the bilayer of the cubic phase for function is an important element of quality control and is detailed. Host lipid design for crystallization at low temperatures and for large proteins and complexes is outlined. Experimental phasing by heavy-atom derivatization, soaking or co-crystallization is routine and the approaches that have been implemented to date are described. An overview and a breakdown by family and function of the close to 200 published structures that have been obtained usingin meso-grown crystals are given. Recommendations for conducting the screening process to give a more productive outcome are summarized. The fact that thein mesomethod also works with soluble proteins should not be overlooked. Recent applications of the method forin situserial crystallography at X-ray free-electron lasers and synchrotrons are described. The review ends with a view to the future and to the bright prospects for the method, which continues to contribute to our understanding of the molecular mechanisms of some of nature's most valued proteinaceous robots.
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de Jong, Jill, Caroline Erter Burns, Aye Chen, Emily Pugach, Elizabeth Mayhall, Alexandra Smith, Henry A. Feldman, Yi Zhou, and Leonard I. Zon. "Long-Term Hematopoietic Transplantation in Zebrafish Using Immune-Matched Marrow Cells." Blood 114, no. 22 (November 20, 2009): 3535. http://dx.doi.org/10.1182/blood.v114.22.3535.3535.
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Abstract Abstract 3535 Poster Board III-472 Transplantation of hematopoietic cells, tumors or any allogeneic tissue has been hindered in the zebrafish due to poor understanding of the functional major histocompatibility complex (MHC) genes and inability to immune-match donors and recipients. Despite this, the zebrafish has been used prominently for the study of hematopoiesis, due to the advantages of large scale forward and reverse genetic and chemical screening methodologies leading to the discovery of novel genetic mechanisms. We created a quantitative long-term hematopoietic reconstitution assay to assess hematopoietic stem cell (HSC) function in adult zebrafish. We identified a sublethal radiation dose of 25Gy which was optimal for hematopoietic reconstitution while minimizing the mortality presumably due to radiation damage of other organs. At 3 months post-transplant, primary and secondary recipients showed multi-lineage engraftment, as measured by flow cytometric analysis of GFP-expressing donor cells. Statistical analyses of limiting dilution data suggest that at least 1 out of 65,000 nucleated zebrafish marrow cells contain repopulating activity, consistent with mammalian HSC frequencies. We defined zebrafish haplotypes at the proposed core MHC locus on chromosome 19, testing the functional significance of these haplotypes by performing matched and mismatched hematopoietic transplants. Utilizing a single family for subsequent experiments, we identified the four parental MHC haplotypes by sequencing PCR products amplified for specific MHC genes. MHC-typed recipient fish were transplanted with whole kidney marrow cells from sibling donors, demonstrating that matching the donor and recipient MHC haplotypes at the chromosome 19 locus increases engraftment and percentage of donor chimerism in recipients compared to MHC-mismatched donors and recipients. At 3 months post-transplant, MHC-matched recipients had multilineage engraftment in 13 of 15 fish with mean donor chimerism of 47.86% (range 5.56- 93.44%) for myeloid cells and 10.51% (range 0.92-77.57%) for lymphoid cells. Engrafted animals receiving MHC-mismatched donor marrow (n= 4 of 6) had only 6.45% mean myeloid donor chimerism (range 4.58 to 8.58%) and 1.28% mean lymphoid donor chimerism (range 0.83 to 1.41%). This new assay allows long term HSCs to be distinguished from other hematopoietic progenitor cells and provides the first functional test of zebrafish MHC genes. Our data indicate the zebrafish MHC locus at chromosome 19 is functionally important for immune matching in the setting of transplantation. This method will facilitate MHC-matched long-term transplantation experiments in zebrafish that have previously not been possible, including competitive transplantation experiments with zebrafish mutants already identified in prior genetic screens, and long-term tumor transplantation assays. Note: The first two authors contributed equally to this work. Disclosures: Zon: Stemgent: Consultancy; FATE Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Ramjeesingh, Mohabir, Canhui Li, Yi-Min She, and Christine E. Bear. "Evaluation of the membrane-spanning domain of ClC-2." Biochemical Journal 396, no. 3 (May 29, 2006): 449–60. http://dx.doi.org/10.1042/bj20060043.
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The ClC family of chloride channels and transporters includes several members in which mutations have been associated with human disease. An understanding of the structure–function relationships of these proteins is essential for defining the molecular mechanisms underlying pathogenesis. To date, the X-ray crystal structures of prokaryotic ClC transporter proteins have been used to model the membrane domains of eukaryotic ClC channel-forming proteins. Clearly, the fidelity of these models must be evaluated empirically. In the present study, biochemical tools were used to define the membrane domain boundaries of the eukaryotic protein, ClC-2, a chloride channel mutated in cases of idiopathic epilepsy. The membrane domain boundaries of purified ClC-2 and accessible cysteine residues were determined after its functional reconstitution into proteoliposomes, labelling using a thiol reagent and proteolytic digestion. Subsequently, the lipid-embedded and soluble fragments generated by trypsin-mediated proteolysis were studied by MS and coverage of approx. 71% of the full-length protein was determined. Analysis of these results revealed that the membrane-delimited boundaries of the N- and C-termini of ClC-2 and the position of several extramembrane loops determined by these methods are largely similar to those predicted on the basis of the prokaryotic protein [ecClC (Escherichia coli ClC)] structures. These studies provide direct biochemical evidence supporting the relevance of the prokaryotic ClC protein structures towards understanding the structure of mammalian ClC channel-forming proteins.
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Clancy, Cornelius J., Palash Samanta, Shaoji Cheng, Kevin Squires, and Minh-Hong Nguyen. "1726. Candida albicans Virulence Genes Induced During Intra-abdominal Candidiasis (IAC) in the Absence of Antifungal Exposure Mediate Echinocandin Resistance." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S633. http://dx.doi.org/10.1093/ofid/ofz360.1589.
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Abstract Background We developed and validated a mouse model of C. albicans IAC that mimics peritonitis and abscesses (IAA) in humans, and that is amenable to temporal–spatial transcriptional profiling and virulence studies. Methods We measured C. albicans SC5314 gene expression by RNA-Seq (RiboPure extraction; Illumina MiSeq) in triplicate during early peritonitis (within 30 minutes of infection), late peritonitis (24 hours) and IAA (48 hours). Differential expression was defined by ≥2-fold differences at false discovery rate ≤0.01. Results ≥7 million C. albicans reads were detected in each experiment. 67% of C. albicans reads mapped to coding sequences, covering 93% of open reading frames. The 50 C. albicans genes most highly expressed during early peritonitis were associated with pH (including RIM101 and PHR1) and oxidative stress responses, and adhesion/hyphal growth (e.g., ALS3, HWP1, ECM331, SAP6). The corresponding 50 C. albicans late peritonitis genes were associated with neutrophil/macrophage responses and nutrient acquisition (glyoxylate cycle, fatty acid β-oxidation, iron homeostasis). Responses within IAA included DNA damage and iron metabolism, reflecting stress response and nutrient/metal limitation. The top 50 core gene responses for all stages were associated with adhesion, stress response, and glucose transport. Among the most up-regulated genes in late peritonitis and IAA compared with early peritonitis were those involved antifungal drug resistance (CDR family, MDR1, FLU1, and ERG family), although mice were not exposed to antifungals. Null and reconstitution mutants for genes involved in adhesion (ALS3), copper transport (CCC2), DNA (DDI1) and cell wall damage responses (DAP1 homologs), and glycerol biosynthesis (RHR2) were attenuated for virulence in temporal-spatial fashion during peritonitis and IAA, and/or hyper-susceptible to phagocytosis and echinocandins (table). Conclusion C. albicans relies upon diverse biologic processes to cause peritonitis and IAA. Multiple genes induced in response to stress during IAC mediate virulence, phagocyte, and echinocandin resistance. Therefore, pathogenic strategies used by C. albicans during IAC may lessen responses to echinocandin treatment, even in the absence of drug exposure or FKS mutations. Disclosures All authors: No reported disclosures.
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Cooke, Kenneth, Jonathan Bradshaw, Dorothy Lawton, and Richard Brewer. "CHILD DISABLEMENT, FAMILY DISSOLUTION AND RECONSTITUTION." Developmental Medicine & Child Neurology 28, no. 5 (November 12, 2008): 610–16. http://dx.doi.org/10.1111/j.1469-8749.1986.tb03903.x.
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Schlumbohm, Jürgen. "Family reconstitution before family reconstitution: Historical demography in the context of racial science and racial policy." Annales de démographie historique 136, no. 2 (2018): 213. http://dx.doi.org/10.3917/adh.136.0213.
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Herlin, Troels, Sofie E. Jørgensen, Christian Høst, Patrick S. Mitchell, Maria Hønholt Christensen, Mira Laustsen, Dorthe A. Larsen, Florian I. Schmidt, Mette Christiansen, and Trine H. Mogensen. "Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant." Rheumatology 59, no. 9 (December 24, 2019): 2334–39. http://dx.doi.org/10.1093/rheumatology/kez612.
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Abstract Objectives Here we investigated a patient with inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, tooth abnormalities and, eczema to uncover the genetic and immunological basis of the disease. Methods On suspicion of an autoinflammatory condition, Sanger sequencing of nucleotide-binding oligomerization domain-like, leucine-rich repeat pyrin domain containing 1 (NLRP1) was performed and combined with an in vitro inflammasome reconstitution assay to measure caspase-1-mediated IL-1β cleavage, stimulation of patient peripheral blood mononuclear cells (PBMCs) and whole blood to measure IL-1β, IL-18 production and quantification of apoptosis-associated speck-like protein containing CARD (ASC) speck formation as a measure of inflammasome activation by flow cytometry. Results Sanger sequencing revealed a novel mutation (c.175G>C, p.A59P; NM_33004.4) in the inflammasome molecule NLRP1 segregating with disease, although with incomplete penetrance, in three generations. We found that patient PBMCs produced increased IL-1β in response to inflammatory stimuli, as well as increased constitutive levels of IL-18. Moreover, we demonstrate that expression of the identified NLRP1 A59P variant caused spontaneous IL-1β cleavage to mature IL-1β. In addition, patient PBMCs responded to NLRP1 stimulation with increased ASC speck formation as a reflection of elevated inflammasome activity. Conclusion We demonstrate that this novel NLRP1 A59P variant caused increased activation of the NLRP1 inflammasome, resulting in constitutively and inducibly elevated IL-1β and IL-18 synthesis. We suggest the NLRP1 mutation underlies the pathogenesis of this rare autoinflammatory dyskeratotic disease inherited in an autosomal dominant manner with incomplete penetrance in the patient and within the family for several generations.
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Noviello, Maddalena, Elena Tassi, Pantaleo De Simone, Francesca Serio, Maria Teresa Lupo Stanghellini, Giacomo Oliveira, Sara Racca, et al. "CMV-Specific T Cells Restricted By Shared and Donor, but Not By Host HLA Molecules Reconstitute in the First 180 Days after Allogeneic HSCT and Protect from CMV Reactivation: Results of a Prospective Observational Study." Blood 134, Supplement_1 (November 13, 2019): 4536. http://dx.doi.org/10.1182/blood-2019-129779.
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Introduction: Cytomegalovirus (CMV) reactivation and disease are important risk factors after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and strongly affect morbidity and mortality after transplant. CMV-specific T cell reconstitution controls CMV reactivation and protects against serious adverse events but a protective level of CMV-specific T cell response or standardized method for its monitoring have not been yet determined. Methods: We designed a prospective, single-center observational study to assess if the kinetic and quality of CMV specific T-cell reconstitution impact the incidence and severity of CMV reactivations. We have enrolled 84 consecutive patients affected by hematological malignancies receiving allo-HSCT followed by Cyclophosphamide and Rapamycin between December 2017 and February 2019. Here we report preliminary data on the first 61 patients. Patients received allo-HSCT from family (siblings=10; HLA haploidentical=24), unrelated HLA-matched (n= 24) donors or cord blood (CB, n=3). The CMV serostatus of host (H) and donor (D) pairs was: H+/D+(n=40, 65%), H+/D-(n=20, 33%) and H-/D+ (n=1, 2%); H-/D-(7% of the overall transplanted population at our center) were excluded. CMV DNAemia was assessed weekly in whole blood (WB). Absolute numbers of polyclonal and CMV-specific T cells were quantified by flow cytometry using Troucount™Tubes (BD) and Dextramer®CMV-Kit (Immudex), respectively, in the graft and fresh WB at days -7, +30, +45, +60, +90, +120, +150, +180 and +360. Dextramer CMV kit includes reagents for the identification of CMV-specific lymphocytes restricted for several HLA class I molecules: A*01:01/*02:01/*03:01/*24:02 and B*07:02/*08:01/*35:01. These alleles allowed the longitudinal evaluation of 54 out of 61 (89%) patients. Results: At a median follow-up of 226 days post-HSCT, 31 (57%) patients experienced a CMV-related clinically relevant event (CRE, median +63 days), including 8 patients (15%) with CMV disease (median +59 days). Univariate analyses showed that the incidence of CMV clinically-relevant reactivation (CRE) was influenced by H/D CMV serostatus (0.90 in H+/D- versus 0.44 in H+/D+pairs, p=0.015) and by previous acute Graft-versus-Host Disease (aGvHD) requiring systemic immunosuppression (0.82 in aGvHD grade II-IV versus 0.52 in aGvHD grade 0-I, p=0.051). The disease status at transplant, the donor type (HLA-matched versus HLA-haploidentical/CB donors), donor's or host's age did not significantly affect the probability to develop CRE. For each time-point, we compared the absolute number of CMV-specific lymphocytes in patients experiencing or not a subsequent CRE. Our data demonstrate that higher levels of CMV-specific CD8+T cells in the donor apheresis and at +45 days after allo-HSCT are associated with reduced risk of subsequent CRE (median CMV-specific CD8+cells/kg in the apheresis=5x103in CRE-positive patients (CRE+) and 5x105in CRE-negative patients (CRE-), p=0.012; median CMV-specific CD8+at +45 days=0.14 cells/μL in CRE+and 1.21 cells/μL in CRE-, p=0.034). Furthermore, patients with any Dextramer positivity at +45 days displayed a lower incidence of CRE compared with subjects who were negative (CRE probability: 0.5 vs 1.0, p=0.003). Conversely, the absolute number of neither polyclonal CD3+CD8+T lymphocytes nor total CD3+T cells correlate with subsequent CRE. Taking advantage of the HLA mismatched-HSCT setting, we then dissected CMV-specific T-cell response according to HLA restriction elements (H/D=shared n=45, D-restricted n=14, H-restricted n=11). In H+/D+pairs, we observed a fast and similar kinetic of reconstitution of CMV-specific lymphocytes restricted by H/D and D HLAs. Conversely, in H+/D-pairs, we detected only CMV-specific CD8+lymphocytes restricted for H/D haplotypes. Host-restricted cells remained undetectable for the first 180 days after HSCT. Conclusion: Early after allo-HSCT and in the donor apheresis, the level of CMV-specific CD8+T cells measured by Dextramer staining differs in patients experiencing or not subsequent CRE. Furthermore, our findings indicate that CMV reactivations can prime H/D-restricted T cells presumably educated in the donor thymus; conversely, D- and H-restricted donor-derived lymphocytes have not yet undergone neither cross-priming nor thymic education respectively. Disclosures Brix: Immudex: Employment. Bonini:Kite/Gilead: Consultancy; Intellia Therapeutics: Consultancy; Intellia Therapeutics: Research Funding; Novartis: Consultancy; GSK: Consultancy; Allogene: Consultancy; Molmed: Consultancy; TxCell: Consultancy; -: Patents & Royalties: Adoptive T cell therapy field.
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Chen, Jichun, Stephanie O. Omokaro, Keyvan Keyvanfar, and Neal S. Young. "Enrichment of Hematopoietic Stem Cells from Normal and Trp53 Null Mice Using SLAM Receptor CD150 as a Positive Selection Marker." Blood 110, no. 11 (November 16, 2007): 2235. http://dx.doi.org/10.1182/blood.v110.11.2235.2235.
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Abstract CD150 is a member of the signaling lymphocyte activation molecule (SLAM) family of receptors which can be used as a positive selection marker for hematopoietic stem cells (HSCs) from mouse bone marrow (BM) and fetal liver (Kiel et al., Cell 2005; Yilmaz et al., Blood 2006; Kim et al., Blood 2006). In the current study, we combined CD150 with a set of lineage-specific markers to enrich HSCs, comparing normal C57BL/6 (B6) mice with B6-Trp53-deficient (Trp53 null) mice which were previously shown to have elevated HSC activity. Using an anti-mouse CD150 antibody (Clone TC 15-12F 12.2, BioLegend), we defined a population of Lin−CD41−CD48−CD150+(SLAM) cells that is 0.0078 ± 0.0010% and 0.0135 ± 0.0010% of total BM cells from B6 and Trp53 null mice. The size of the SLAM cell fraction was strongly correlated (R2= 0.7116, P<0.0013) to the population of well defined Lin−Sca1+CD117+ (LSK) cells (at 0.0165 ± 0.0036% and 0.0276 ± 0.0036% respectively) for the same B6 and Trp53 null mice we have tested (results consistent with previous findings indicating that the HSC pool is larger in Trp53 null mice than in B6 mice). To test HSC function in vivo, we sorted SLAM cells and Lin−CD41−CD48−CD150+ (SLAM−) cells from B6 and Trp53 null donors and transplanted them into lethally irradiated (11 Gys) B6 recipients. In a day 12 colony forming unit-spleen (CFU-S) assay, both SLAM and SLAM−cells formed colonies but the SLAM cells contained 12–15 fold higher day 12 CFU-S than did SLAM−cells. In a competitive repopulation assay, when donor SLAM and SLAM−cells were mixed with fresh B6-CD45.1 BM cells and engrafted into lethally-irradiated B6 recipients for six months, the density of repopulating units (RUs) was 22.48 ± 12.05 and 11.06 ± 8.78 per thousand SLAM cells from B6 and Trp53 null donors, dramatically higher than the RU density of 0.43 ± 0.09 and 0.55 ± 0.43 per thousand SLAM−cells from the same B6 and Trp53 null donors. When BM cells from the competitive repopulation recipients were serially-transplanted into secondary recipients, the SLAM donor cell contribution increased while the SLAM−donor cell contribution decreased with time when measured at two, six and fourteen weeks in the secondary recipients, indicating that SLAM cells were the primitive HSCs that sustained hematopoiesis long-term. No recipient that received Try53 null SLAM or SLAM−cells died, significantly different from our previous observation that whole BM cells from Trp53 null donors yielded high donor reconstitution in a competitive repopulation assay but 56% recipient died within five months after reconstitution (TeKippe et al., Exp Hematol 2003). SLAM markers may have enriched HSCs by excluding any Try53 null BM cell responsible for early recipient death. Analysis of intracellular reactive oxygen species (ROS) revealed higher proportions of ROS−cells in the CD150+ than in the CD150− BM cell fraction in both B6 and Trp53 null mice, consistent with the hypothesis that HSCs are metabolically inactive and therefore contain lower level of ROS. While SLAM− cells may still contain some residual HSC activity, results from the present study are in strong support of utilization of SLAM receptor CD150 as a positive selection marker for HSCs. The Lin− CD41−CD48−CD150+SLAM combination provides a simple and effective method for HSC enrichment.
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Lang, Peter, Tobias Feuchtinger, Heiko-Manuel Teltschik, Michael Schumm, Patrick Schlegel, Matthias Pfeiffer, Martin Ebinger, Carl-Philipp Schwarze, and Rupert Handgretinger. "Transplantation Of TcRαβ/CD19 Depleted Stem Cells From Haploidentical Donors In Children: Current Results." Blood 122, no. 21 (November 15, 2013): 692. http://dx.doi.org/10.1182/blood.v122.21.692.692.
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Abstract T-cell depletion of the graft is an effective method to prevent or completely avoid Graft-versus-Host Disease (GvHD) in haploidentical stem cell transplantation. In order to increase the T-cell depletion efficacy while maintaining the anti-tumor and anti-infectious properties of the graft, we have investigated a new T-cell depletion method which removes αβ+ T-lymphocytes via a biotinylated anti-TcRαβ antibody followed by an anti-biotin antibody conjugated to magnetic microbeads while retaining γδ+ T-lymphocytes, Natural killer (NK) cells and other cells in the graft. In addition, CD19+ B-lymphocytes were concomitantly depleted for the prevention of posttransplant EBV-associated lymphoproliferative disease. The CliniMACS system was used for manipulation of peripheral stem cell grafts from full haplotype mismatched family donors in 35 patients. Results The overall depletion of αβ+ T-cells was highly effective with 4.6 log (range 3.8–5.0). Patients received a median number of only 14 x 103/kg residual αβ+ T-cells. Recovery of CD34+ stem cells was 72%, and the median number of infused CD34+ stem cells was 12 x 106/kg (range 5-38 x 106/kg). Additionally, the patients received 2 types of potential antileukemic effector cells: 107 x 106/kg (range 35 -192 x 106/kg) CD56+ NK-cells and 11 x 106/kg (range 5–30 x 106/kg) γδ+ T-lymphocytes. Diagnoses were ALL (n=20), AML/MDS/JMML (n=9), nonmalignant diseases (n=4), solid tumors (n=2); disease status: CR2-CR6 (n=17), active disease (n=18). 23 patients received a second or third SCT (65%). A toxicity reduced conditioning regimen (fludarabin 40mg/m² or clofarabin 50mg/m² (day -8 to d -5), thiotepa 10mg/kg (d -4), melphalan 70mg/m² (d -3 and d -2) was used. The anti CD3 specific OKT3 antibody was used as rejection prophylaxis from day -8 to day -1 without affecting cotransfused effector cells because of its short half-life period in the first 7 patients. However, due to its restricted availability, the substance was substituted since 2011 by a reduced ATG-F dose (15mg/kg) given at start of the conditioning regimen in order not to impair NK and γδ+ T-cells of the grafts (1 mg/kg d -12, 4 mg/kg d -11, 5 mg/kg d -10 and -9; n=28 patients). Short course MMF (until day +30) was given in 25 patients. Graft rejection occurred in 14% of the patients. However, after reconditioning and second stem cell donation, final engraftment was achieved in all patients. The median time to reach neutrophil and platelet recovery in patients with primary engraftment was 10 and 11 days respectively. All patients showed a rapid immune reconstitution with 250 (OKT3 conditioning) and 273 (ATG conditioning) CD3+ T-cells/µl, 30 (OKT3) and 47 (ATG) CD3+4+/µl and 300 (OKT3) and 382 (ATG) CD56+ NK-cells/µl at day +30 posttransplant. γδ+ T-cells started to expand faster than αβ+ T-cells in the early post-transplant period (156 vs. 82 cells/µl at day +30) whereas at day +90, αβ+ T-cells were predominant (170 vs. 134 cells/µl). Acute GvHD grade 0-I occurred in 25 patients (71%); 6 patients had GvHD II (17%), 3 patients had GvHD III (9%) and one patients experienced GvHD grade IV (3%). 3 patients experienced chronic GvHD (8%). Incidence of acute GvHD was not influenced by the number of residual T cells or by the type of serotherapy. 1 year EFS for patients with acute leukemias was 66% (any CR) and 14% (active disease).TRM at 1 year was 20%. Conclusions These data indicate that transplantation of TcR αβ+/CD19 depleted cells from a haploidentical donor results in sustained engraftment, remarkably fast immune reconstitution and low incidence of both acute and chronic GvHD. OKT3 could be substituted by ATG without negative effects. The anti-leukemic efficacy of this approach in comparison to other methods of T-cell depletion needs to be evaluated with a longer patient follow-up. Disclosures: No relevant conflicts of interest to declare.
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Choudhury, Aniruddha, Katja Derkow, Eva Mikaelsson, Parviz Kokhaei, Anders Österborg, Hodjattallah Rabbani, and Håkan Mellstedt. "Downregulating the Fibromodulin Gene by Short Interfering RNA Causes B-CLL Cell Death." Blood 104, no. 11 (November 16, 2004): 176. http://dx.doi.org/10.1182/blood.v104.11.176.176.
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Abstract Development of targeted therapies against B-CLL is dependent on the identification of molecules that are essential for the proliferation and survival of the leukemic cells. One such molecule investigated by us as a putative leukemia-associated target is Fibromodulin (FIM). FIM is an extracellular matrix molecule belonging to the leucin-rich proteoglycan family. Our laboratory studies have verified that expression of FIM is upregulated in B-CLL cells. Moreover, this molecule is specifically overexpressed in B-CLL cells and not on normal peripheral blood mononuclear cells. Analysis of FIM expression on various other hematological tumor cells have revealed that with the exception of mantle cell lymphoma, FIM is not expressed in other hematological malignancies. RNAi technology has recently emerged as a powerful method to specifically silence the expression of a gene. We have generated three siRNA against various segments of FIM and tested the effects of these siRNA on B-CLL cells. Transfection of B-CLL cells with these siRNA significantly diminished, or completely abrogated the expression of FIM mRNA as detected by RT-PCR. The figure below shows silencing of the FIM gene following siRNA transfection, as assayed by RT-PCR. “Untrans” and “ctrl” represents untransfected and control siRNA-transfected B-CLL cells respectively. As noted, transfection with each of the three siRNA against FIM completely abrogated the expression of FIM siRNA. 24–48 hours after siRNA transfection, a substantial fraction (30–70%) of the B-CLL cells, compared to cells transfected with control non-silencing siRNA, went into apoptosis as assayed by Annexin-V-propidium iodide staining. Time kinetic studies revealed that siRNA mediated silencing and apoptosis occurred between 18 and 48 hours. No such effect was noted when peripheral blood mononuclear cells of healthy donors or FIM-positive fibroblast cell lines were transfected with siRNA. In reconstitution experiments, siRNA treated B-CLL cells were co-cultured with various numbers of FIM-positive fibroblasts. The presence of these fibroblasts greatly diminished the apoptosis of B-CLL cells induced after siRNA treatment. Our results indicate that overexpression of FIM in B-CLL cells are critical for their survival and FIM may serve as a leukemia-specific target for B-CLL therapy. Figure Figure
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Kolb, Hans-Jochem, Iris Bigalke, Belinda Simoes, Christine Falk, Johanna Tischer, Wolfgang Hill, and Georg Ledderose. "CD6-Depleted Mobilized Stem Cells for Modification of HVG and GVH Reactions after HLA-Haploidentical Marrow Transplantation." Blood 104, no. 11 (November 16, 2004): 978. http://dx.doi.org/10.1182/blood.v104.11.978.978.
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Abstract Allogeneic stem cell transplantation is limited to patients with a histocompatible donor, but for patients with advanced acute leukemia and high-grade lymphoma HLA-haploidentical transplantation may be considered. Rejection of the transplant and graft-versus-host disease are major obstacles and T-cell depletion eliminates the graft-versus-leukemia effect and causes prolonged immune deficiency. Here we studied the use of CD6-depleted G-CSF mobilized blood cells (mbc) 6 days after transplantation of unmodified marrow in order to suppress host-versus-graft and graft-versus-host reactions (GVHD) retaining a graft-versus-leukemia effect and the capacity to reconstitute the immune system. CD6-depleted mbc contain a large proportion of NK and NK-T cells. 63 patients with advanced disease (AML 32, ALL 15, NHL 11, CLL 2, CML 2, SAA 1) were transplanted with marrow from family donors sharing one HLA-haplotype and differing in 0 – 4 HLA-antigens of the second haplotype. Conditioning consisted of total body irradiation (TBI), antithymocyte globulin (ATG) and cyclophosphamide (CY), post-grafting immunosuppression of cyclosporin A (CSA) and a short course of methotrexate (sMTX). A transfusion of donor leukocytes was given prior to CY. Complete engraftment was observed in 34 evaluable patients given 12 Gy TBI. The dose of TBI could be reduced to 4 Gy without rejection in 25 evaluable patients. GVHD was severe (grade III and IV) in 12 of 48 evaluable patients. An improved method of CD6-depletion was administered to mbc in 9 patients and severe GVHD did not develop. GVHD responded to corticosteroids in most patients. 15 patients survive disease free up to 6 years (median 784 days). Recurrent infections including PTLD were the major cause of transplant-related mortality. Absolute counts of lymphocytes, CD4 and CD8 subpopulations were not different from those of a contemporary group of 46 patients in advanced disease given HLA-identical sibling transplants. However naïve CD4 cells and TRECs were low. Rejection, GVHD and GVL have been controlled by this regimen, but immune reconstitution remains a problem that may be solved by early discontinuation of immunosuppression in this regimen.
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Machneva, E. B., A. V. Mezentseva, L. V. Olkhova, E. A. Pristanskova, A. E. Burya, V. V. Konstantinova, O. A. Filina, et al. "BCG vaccine–related complications in patients with primary immunodeficiencies after allogeneic hematopoietic stem cell transplantation." Pediatric Hematology/Oncology and Immunopathology 20, no. 2 (May 22, 2021): 133–42. http://dx.doi.org/10.24287/1726-1708-2021-20-2-133-142.
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BCG (Bacillus Calmette–Guérin) vaccine is widely used for the vaccination of newborns within the first few days of life to prevent mycobacterial infections. However, complications occurring after BCG vaccination in patients with primary immunodeficiencies (PIDs) can lead to serious consequences for their health and life. BCG vaccine-related complications occurring in patients with severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD) after hematopoietic stem cell transplantation (HSCT) constitute an important problem. The article presents a retrospective observational analysis of 45 patients with SCID and CGD who received BCG vaccination and underwent HSCT. In the post-transplant period, 33 (73.3%) patients had BCG-related complications, either localized or generalized. The presence of BCG vaccine-related complications in the pre-transplant period was a significant predictor of the development of post-transplant complications. The most severe and long-term BCG vaccine-related complications were observed in the patients with SCID: the median time to the resolution of symptoms of BCG infection was 30 days and 100 days in the CGD patients and the SCID patients, respectively (p< 0.001). The severity of BCG vaccine-related complications, the nature of the primary disease and the presence of pre-transplant BCG vaccine-related complications did not affect the overall survival (OS) of the patients: OS for the entire study group was 79.5 ± 6.6%. Non-compliance with antimycobacterial prophylaxis prior to HSCT resulted in severe infections in a number of patients. The treatment of BCG vaccine-related complications included a combination of several antimycobacterial agents, and anti-inflammatory drugs (such as glucocorticoids, interleukin-1 and 6 receptor antagonists) in cases of immune reconstitution inflammatory syndrome (n= 18). The only effective method of prophylaxis of BCG-related infections in patients with SCID and CGD in the pre- and post-transplant period is the exemption of newborns from BCG vaccination based on their family history. Uninterrupted antimycobacterial prophylaxis in vaccinated patients in the pre- and post-transplant period is also important. Furthermore, an effective uniform strategy for the prevention and treatment of BCG vaccine-related complications in PID patients both before and after HSCT is needed.
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Minkyung Lee. "Identity reconstitution of children from international marriage family." Korean journal of sociology of education 26, no. 1 (March 2016): 101–20. http://dx.doi.org/10.32465/ksocio.2016.26.1.005.
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Rabb, Theodore K., and E. A. Wrigley. "English Population History from Family Reconstitution, 1580-1837." American Historical Review 104, no. 3 (June 1999): 990. http://dx.doi.org/10.2307/2651124.
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Ittman, Karl, E. A. Wrigley, R. S. Davies, J. E. Oeppen, and R. S. Schofield. "English Population History from Family Reconstitution, 1580-1837." Albion: A Quarterly Journal Concerned with British Studies 31, no. 1 (1999): 104. http://dx.doi.org/10.2307/4052836.
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Benakli, Malek, Rose-Marie Hamladji, Redhouane Ahmednacer, Amina Talbi, Farih Mehdid, Rachida Belhadj, Mounira Baazizi, Nadia Rahmoune, Farida Harieche, and Fatiha Zerhouni. "Second Allogeneic Stem Cell Transplantation as Treatment for Chronic Myeloid Leukemia Relapse Following a First Reduced Intensity Conditioning Allograft." Blood 112, no. 11 (November 16, 2008): 4313. http://dx.doi.org/10.1182/blood.v112.11.4313.4313.
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Abstract Background: Relapsed chronic myeloid leukemia (CML) is a possible complication after allogeneic stem cells transplantation (SCT). Treatment options for relapse include chemotherapy, Donor lymphocyte Infusion (DLI) and second SCT. In such treatments, second SCT is the only potentially curative therapy. We report the results of myeloablative transplantation as second SCT in 7 adults patients (pts) with CML relapsed after first reduced intensity conditioning (RIC) allo-SCT. Patients and methods: Between April 2001 and December 2006, 154 CML pts treated with RIC allo-SCT from an HLA-identical family donor. First RIC-SCT following conditioning using Fludarabine 150 mg/m2 and oral Busulfan 8 mg/m2. GVHD prophylaxis consisted of association Ciclosporine and Mycophenolate (6 pts), one patient received an additional prophylaxis with ATG. Twenty four pts (16%) relapsed, of whom 7 underwent second conventional allograft. The median time between first and second SCT was 11 (range, 3–24) months. As second SCT, the median age was 34 (range, 23–46) years and gender: 3 male, 4 female. Six pts were in second chronic phase and one pt in accelerated phase. In all cases, myeloablative conditioning consisted of Busulfan (8 mg/kg), Etoposide (30 mg/kg) and Cyclophosphamid (120 mg/kg). Second SCT used with another HLA-identical sibling donor in 4 cases. All received G-CSF mobilized peripheral blood stem cells, with median CD34+: 5,85 106/kg (range,3,28–9,34). GVHD prophylaxis was consisted of Ciclosporine-Methotrexate. Results: All pts had myeloid reconstitution and the median time to achieve 0,5 109/l neutrophils count was 25 (range,15–57) days. One pt needed a boost 40 days after allograft. The median time of aplasia was 20 (range,10–52) days. No acute GVHD noticed. Four pts had chronic GVHD, of whom 3 with extensive form. Although 3 pts died of relapse on 2, 3 and 20 months. Four pts are alive and free of disease on 24, 48, 55 and 55 months respectively after second SCT with complete chimerism of donor origin and negative minimal residual disease, of whom 3 had second allo-SCT with another family donor. Conclusion: This study suggests that second SCT for CML relapse after RIC-SCT can result in long-term survival for some of pts without lethal treatment related toxicity. Another HLA-identical sibling donor is favourite in this case. Further follow-up and more pts are necessary to validate this series.
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Jonsson, Jan O., and Michael Gahler. "Family Dissolution, Family Reconstitution, and Children's Educational Careers: Recent Evidence for Sweden." Demography 34, no. 2 (May 1997): 277. http://dx.doi.org/10.2307/2061705.
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Voland, Eckart. "Contributions of family reconstitution studies to evolutionary reproductive ecology." Evolutionary Anthropology: Issues, News, and Reviews 9, no. 3 (2000): 134–46. http://dx.doi.org/10.1002/1520-6505(2000)9:3<134::aid-evan3>3.0.co;2-m.
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Ovadia, Adi, Vy Hong-Diep Kim, Brenda Reid, Harjit Dadi, Anne Pham-Huy, and Chaim M. Roifman. "Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A." LymphoSign Journal 6, no. 2 (June 1, 2019): 52–60. http://dx.doi.org/10.14785/lymphosign-2019-0004.
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Introduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency. Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency. Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT. Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution. Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient. Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.