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Tierney, T., and IC Robinson. "Increased lactotrophs despite decreased somatotrophs in the dwarf (dw/dw) rat: a defect in the regulation of lactotroph/somatotroph cell fate?" Journal of Endocrinology 175, no. 2 (November 1, 2002): 435–46. http://dx.doi.org/10.1677/joe.0.1750435.
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The dwarf (dw/dw) rat differs from all other rodent models of GH deficiency in that its pituitary prolactin (PRL) content is normal or even increased. We have now studied this throughout postnatal development, using a combination of immunocytochemistry, RIA and fluorescence-activated cell sorting (FACS) and analysis. Compared with normal Albino Swiss (AS) rats, adult dw/dw rats showed a profound reduction in pituitary GH content accompanied by increased PRL content, significantly so in females (AS vs dw/dw; P<0.01). Somatotroph hypoplasia was evident in the adult dw/dw rats, with most GH(+ve) cells showing weak immunostaining, whereas many more strongly stained PRL cells were evident in pituitary sections from dw/dw rats. Facs analysis confirmed both somatotroph hypoplasia and relative lactotroph hyperplasia in dw/dw rats at all ages studied (9-144 days); the difference in somatotrophs increased with age whereas the difference in lactotrophs declined with age. At 9 days, the percentage of lactotrophs was 10-fold higher in dw/dw rats than in AS rats. Young dw/dw rats also had a higher proportion of mammosomatotrophs than AS rats, although this difference disappeared as the mammosomatotroph proportions increased with age in both strains. GHRH released GH from both dw/dw and as cells maintained in culture for 5 days. The sensitivity to GHRH and the amount of GH released was lower in the dw/dw cultures, mostly explained by their fewer GH cells and lower initial GH content. GHRH increased cAMP in as but not in dw/dw cultures, even when these were greatly enriched for dw/dw somatotrophs by FACS sorting prior to culture. These results suggest that GHRH-induced cAMP stimulation is required for trophic effects on GH synthesis and somatotroph proliferation, but is not required for GHRH-stimulated GH release. The inverse changes in somatotroph and lactotroph numbers suggest that the dw/dw mutation disturbs the mechanism that specifies and retains appropriate numbers of somatotrophs in their differentiated state, and results in a higher proportion of the remaining cells progressing to lactotrophs. The dw/dw phenotype is thus not confined to somatotrophs.
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Fuhrmann, Guy, Dominique di Scala-Guenot, and Alix Ebel. "Hypothalamic and central extrahypothalamic somatostatin levels in the snell dwarf mouse, somatostatin excess as the primary molecular site in the dw/dw mutation." International Journal of Developmental Neuroscience 3, no. 4 (1985): 483. http://dx.doi.org/10.1016/0736-5748(85)90260-6.
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CAMPBELL, T. A. "CHEMICAL MUTAGENESIS IN TWO Cuphea SPECIES." Canadian Journal of Plant Science 67, no. 3 (July 1, 1987): 909–17. http://dx.doi.org/10.4141/cjps87-128.
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Presoaked (24 h at 20 °C) seeds of Cuphea tolucana Peyr. and C. wrightii A. Gray were treated with mutagens at 20 °C in two experiments. Experiment 1 treatments were: distilled water (DW), 0.05 M PO4 buffer (pH 7), 0.01 M ethyl methanesulfonate (EMS) (each applied for 8 h), 0.02 M EMS (applied for 4 h), 0.04 EMS M, 0.08 M EMS, or 0.16 M EMS (each applied for 2 h). Experiment 2 treatments were: DW, 0.1 M PO4 buffer (pH 3), 0.0005 M sodium azide (SA), 0.001 M SA, or 0.002 M SA (each applied for 2 h). None of the treatments had significant effects on emergence and height of M1 plants nor were any macro-mutations noted in the M2 generations. In a third experiment, DW, 0.04 M EMS, or 0.001 M SA were applied for 2 h at 30 °C to presoaked (48 or 72 h at 30 °C) seeds of C. tolucana and C. wrightii. Compared to EMS, SA had deleterious effects on height in the M1, emergence was better for C. tolucana than for C. wrightii, and C. wrightii plants grew taller after a 72-h pre-soak than after a 48-h presoak. M2 progenies were evaluated in the field. None of the presoak-treatment combinations increased variation significantly in several quantitative characters, no macro-mutations were detected in C. wrightii, but a fertile, small-leaved, decumbent mutant with very short internodes was noted in C. tolucana. Mutation rates were greatest for the 72 h presoak-EMS combination.Key words: Cuphea tolucana, Cuphea wrightii, ethyl methanesulfonate, sodium azide, medium-chain triglycerides, lauric acid
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Hollender, Courtney A., Toto Hadiarto, Chinnathambi Srinivasan, Ralph Scorza, and Chris Dardick. "A brachytic dwarfism trait (dw) in peach trees is caused by a nonsense mutation within the gibberellic acid receptorPpeGID1c." New Phytologist 210, no. 1 (December 7, 2015): 227–39. http://dx.doi.org/10.1111/nph.13772.
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Miller, Richard A., Yayi Chang, Andrzej T. Galecki, Khalid Al-Regaiey, John J. Kopchick, and Andrzej Bartke. "Gene Expression Patterns in Calorically Restricted Mice: Partial Overlap with Long-Lived Mutant Mice." Molecular Endocrinology 16, no. 11 (November 1, 2002): 2657–66. http://dx.doi.org/10.1210/me.2002-0142.
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Abstract To gain insight into the pathways by which caloric restriction (CR) slows aging, gene expression levels were assessed for each of 2352 genes in the livers of 9-month-old CR and control mice. A total of 352 genes were found to be significantly increased or decreased by CR. The distribution of affected genes among functional classes was similar to the distribution of genes within the test set. Surprisingly, a disruption or knockout of the gene for the GH receptor (GHR-KO), which also produces life extension, had a much smaller effect on gene expression, with no more than 10 genes meeting the selection criterion. There was, however, an interaction between the GHR-KO mutation and the CR diet: the effects of CR on gene expression were significantly lower in GHR-KO mice than in control mice. Of the 352 genes altered significantly by CR, 29 had shown a significant and parallel alteration in expression in a previous study of liver gene expression that compared mice of the long-lived Snell dwarf stock (dw/dw) to controls. These 29 genes, altered both by CR and in dwarf mice, provide a list of biochemical features common to both models of delayed aging, and thus merit confirmation and more detailed study.
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Polchi, Paola, Rossella Palmieri, Marco Andreani, Javid Gaziev, Cecilia Alfieri, Gioia De Angelis, Cristiano Gallucci, et al. "Bone Marrow Iron Concentration as a Marker of Iron Accumulation and Marrow Expansion in Patients with Beta Thalassemia Major." Blood 112, no. 11 (November 16, 2008): 1852. http://dx.doi.org/10.1182/blood.v112.11.1852.1852.
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Abstract Liver iron concentration (LIC) is a known and accurate marker of iron accumulation and is widely utilized to monitor iron chelation therapy in multiply transfused patients with Beta thalassemia major. Iron concentration in the bone marrow has not been studied and reported before. We utilized atomic absorption spectrophotometry to measure the iron content of marrow biopsy (BIC) in 102 thalassemia patients in various phase of treatment, 74 of them during the course of the disease and 28 patients after successful allogeneic marrow transplant. We observed BIC values below 0.5 mg/g dry weight in 7 healthy donors used as controls. Mean and median BIC were 4.67 and 2.70 (range 0.05 – 59.9) mg/g dw, in 101 valuable patients. Bone Marrow iron concentration (BIC) was calculated at the same time of LIC for each patient and a ratio LIC/BIC was generated. LIC/BIC ratio below 3, ratio between 3 and 10, and above 10 identified three categories of patients each with significant linear correlation between LIC and BIC (0.74; 0.76; 0.81 respectively). Twenty eight patients were in the first category, 48 in the second, and 25 in the third. Mean BIC was 9.47, 3.7, 1.2 mg/g dw and mean LIC was 12.7, 19.6, 22.3 mg/g dw respectively for CAT1, CAT2 and CAT3. Patients were also classified in class of risk for transplant, based on hepatomegaly, presence of liver fibrosis and history of regular or irregular iron chelation. BIC was higher in class 3 patients and in the irregularly chelated patients. Patients in class 1 were prevalently in CAT1 or 2, patients in class 3 were prevalently in CAT2 or 3. BIC value in each of the 3 categories correlated significantly with the whole body iron (WBI) amount, and WBI was significantly different in the three categories being lower in CAT1, that have higher BIC ( 3927 mg; 5894 mg, 7030 mg in CAT1, 2 and 3; p 0.01). Iron chelation quality (regular vs irregular) correlated with BIC value and with BIC category, majority of regularly chelated patients were in the Category 1 vs Category 2 or 3 (p 0.01). Patients before transplant were prevalently in CAT1 and 2, while those post transplant were mostly in CAT3, twelve patients that were studied both before and after transplant, changed from cat 1 to 2 or from cat 2 to 3. Their BIC changed significantly decreasing after BMT (median BIC was 7.8 before transplant and 2.25 after, p=0.002) To investigate the role of genetic hemochromatosis mutations, H63D region and Hamp region in 63 patients were also studied. Mean BIC was 3.08 in 16 patients with H63D mutation compared to 5.59 in those without mutation, and 11/16 had BIC below the median, p=0.03. Significantly more patients with H63D mutation were in CAT3 (p 0.02). Apparently H63D mutation favours accumulation of iron in the body, that was higher in CAT3, but participate also to lowering utilization of introduced iron. In conclusion, patients in category 1 had lower LIC and higher BIC, comprehended 50% of the patients in class 1 of risk, and 45% of the regularly chelated patients. On the contrary, majority of patients post transplant independently of having or not performed an iron removal program were in CAT3. We can draw conclusion that BIC related categories, as described here, give information on the balance between accumulation and utilization of iron. Patients belonging to BIC-Cat 1 correspond to patients that have been treated adequately and with lower iron body burden, better chelation history. They have higher BIC value and lower LIC value. They also are in pre-transplant phase, with active beta-thalassemia, when ineffective erythropoiesis and marrow expansion are more prominent. Further studies will be necessary to confirm the association of marrow iron content with the marrow functionality and expansion.
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Nieves-Martinez, E., W. E. Sonntag, A. Wilson, A. Donahue, D. P. Molina, J. Brunso-Bechtold, and M. M. Nicolle. "Early-onset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation." Journal of Endocrinology 204, no. 1 (October 8, 2009): 31–36. http://dx.doi.org/10.1677/joe-09-0323.
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GH levels increase to high concentrations immediately before puberty then progressively decline with age. GH deficiency (GHD) originating in childhood is treated with GH supplementation to foster somatic development during adolescence. It is not clear if or how early GH replacement affects memory in adulthood, or whether it can prevent the cognitive deficits commonly observed in adults with childhood-onset GHD. Rats homozygous for the Dw-4 mutation (dwarf) do not exhibit the normal increase in GH at 4 weeks of age when GH levels normally rise and are used to model childhood or early-onset GHD (EOGHD). One group of these rats was injected with GH from 4 to 14 weeks of age to model GH supplementation during adolescence with GHD beginning in adulthood (adult-onset GHD; AOGHD). Another group received GH from 4 weeks throughout the lifespan to model normal lifespan GH (GH-replete). Age-matched, Dw-4 heterozygous rats (HZ) do not express the dwarf phenotype and were used as controls. At 8 and 18 months of age, spatial learning in the water maze was assessed. At 8 months of age all experimental groups were equally proficient. However, at 18 months of age, the EOGHD group had poor spatial learning compared to the AOGHD, GH-replete, and HZ groups. Our data indicate that GHD during adolescence has negative effects on learning and memory that emerge by middle-age unless prevented by GH supplementation.
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Butylin, Pavel, Natalia Matyuhina, Nadia Siordia, Elza Lomaya, and Andrey Zaritskey. "Rare Case of Alternative Splicing Form Caused By L248V Mutation in CML Patient." Blood 126, no. 23 (December 3, 2015): 5139. http://dx.doi.org/10.1182/blood.v126.23.5139.5139.
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Abstract Clinical data: Subject: Male, 45 years old, diagnosed in 2001 with Ph+ CMLCP (low Sokalrisk).From 2001 to 2005 he was treated with Hydrea and Interferon with low dose Cytarabine. In 2005 he was switched to imatinib 400 mg/day. Due to cytogenetic resistance Imatinib dose was escalated to 600mg/day in 2006 and 800mg/day in 2007. No cytogenetic response was obtained. In 2009 patient was switched to nilotinib. Nilotinib therapy was discontinued in 2012 due to loss of complete hematologic response. Patient refuses unrelated donor allo HSCT. INFa 3000 U/3 times a day was given with prolonged stable complete hematologic response. Myeloid blasts crisis was diagnosed in Jan 2013. (The time patient was hospitalized to Almazov medical research center). Dasatinib 140mg/day was started without rapid blast reduction.The response lost in a few weeks, followed by 2 couses of FLAG regimen. Patient died in Dec 2013. BCR-ABL KD mutations history: 2007- no mutations found; 2009- no mutations found, February 2013 -L248V mutation; July 2013 mutation analysis returns no result due to the poor sequence quality;T315I mutation revealed in samples obtained from October 2013. BCR-ABL mutation analysis: Bcr-Abl analysis performed as described before (Branford et al., 2002). KD sequence was amplified from cDNA using seminested PCR, PCR product extracted from gel and sequenced in the both directions on ABI 3130 genetic analyzer. For confirmation we used genomic DNA extracted from stored peripheral blood samples. Primers specifically amplifying exon 4 and 5 of ABL used for genomic DNA analysis. Analysis of the sequences was done using UGENE software. Results: We analyzed two sets of probes- one dated March 2011 and another dated October 2013. After performing semi-nested PCR on BCR-ABL KD sequence we found at least two bands in each of the samples. Sequencing of this bands revealed 81 bp deletion translated into absence of 27 aa position at 248-274. Genomic DNA analysis confirmed alternative splicing and appearance of the truncated form. We found SNP resulted in T315I mutation presented either in full or in short isoform of BCR-ABL in samples from October 2013. Also we confirmed L248V mutation presented in all analyzed samples. Conclusion: SNP that cause L248V mutation in BCR-ABL transcript known to activate cryptic promotor in ABL exon4 with subsequent appearance of alternative splicing form described before (Gruber et al., 2006). Truncated form known to be kinase dead and have no influence on disease course (Shebenou et al., 2008). On the other hand it disturbs the Sanger sequence quality, masking the appearance of the additional mutations. Extensive attention requires in obtain proper sequence quality: use genomic DNA for Sanger sequencing or alternative sequencing methods, e.g. single-molecule long-read sequencing for revealing mutations in multiple splice isoforms. References: Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571)resistance. Blood. 2002 May 1;99(9):3472-5. Gruber FX, Hjorth-Hansen H, Mikkola I, Stenke L, Johansen T. A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib. Leukemia. 2006 Nov;20(11):2057-60. Sherbenou DW, Hantschel O, Turaga L, Kaupe I, Willis S, Bumm T, Press RD,Superti-Furga G, Druker BJ, Deininger MW. Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia.Leukemia. 2008, Jun;22(6):1184-90. Disclosures Lomaya: Novartis: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy.
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Iqbal, Zafar, Afia Muhammad Akram, Tanveer Akhtar, Aamer Aleem, Muhammad Farooq Sabar, Zeba Aziz, Nadia Sajid, et al. "Brief Research Report: Novel Compound BCR-ABL Mutations in Late Chronic Phase Imatinib Sensitive CML Patients Are Associated with Progression to Advance Disease Phase." Blood 128, no. 22 (December 2, 2016): 3089. http://dx.doi.org/10.1182/blood.v128.22.3089.3089.
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Abstract Introduction: BCR-ABL kinase domain (KD) mutations have well established role in tyrosine kinase inhibitors (TKIs) resistance and disease progression in chronic myeloid leukemia (CML)1. In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib2. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib sensitive CML patients3. Furthermore, BCR-ABL mutation detection is currently recommended only in case of drug resistance and disease progression and clinical significance of BCR-ABL mutation detection in TKI responder chronic phase CML is not well documented4. Therefore, we investigated presence of ABL-KD mutations in chronic phase (CP) and advanced phase imatinib sensitive CML to find out association of BCR-ABL mutations with progression to advanced disease phases in CML patients. . Patients and Methods: Imatinib sensitive CML patients in CP and advanced phases of the disease were included in the study.All CP patients were incomplete hematological, complete cytogenetic and major molecular responses. Due to specific study objectives, patients manifesting drug resistance during follow-up studies were excluded from the study. A total of 90 imatinib sensitive CML patients (CP=41, late CP=33, and accelerated phase=16) were finally available for analysis. All patients as well as 10 healthy controls were investigated for BCR-ABL mutations using Sanger sequencing. All response criteria were per European LeukemiaNet guidelines4. Data was analyzed using SPSS software (version 19). Results: Mean age of the patients was 33 years (Table 1). Eleven out of 33 (33.3%) patients in late-CP CML harbored 24 types of point mutations, out of which eight (72.72%) harbored compound mutated sites (Figure 1, Table 2). E355G (3.33%) was the most prevalent mutant. Five patients (45.45%), all of which had compound mutations, progressed to advanced phases of disease during follow up studies. No BCR-ABL mutation was detected in healthy subjects and in early CP CML patients. Therefore, early CP CML patients served as additional control in this study. BCR-ABL mutations were found in 3 accelerated phase patients as well. Late-CP mutations were associated with elevated platelet count (p= 0.037) and male gender (p= 0.049). The median overall survival and event free survival of CML patients (n=90) was 6.98 and 5.8 years respectively. Seven year survival was found to be 94.2%. Discussion and conclusions: Compound BCR-ABL mutations were associated with progression to advanced disease in imatinib sensitive late-CP CML patients. Although single BCR-ABL mutations have previously been found to cause CML progression5, this is first report of association of compound BCR-ABL mutations with disease progression in stable imatinib responders at late CP. Detection of new mutations can help in defining mechanism of CML progression6. Moreover, BCR-ABL mutation detection in late CP CML patients sensitive to TKI treatment can help in early assessment of risk for disease progression and/or drug resistance and subsequent clinical intervention to delay disease progression which is a major challenge of CML therapy in TKI era7. References: 1. Haznedaroglu IC. Mediterranean journal of hematology and infectious diseases 2015;7. 2. Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, Eide CA, Zabriskie MS, Lange T, Estrada JC. Blood 2013;121:489-98. 3. Deininger MW, Hodgson JG, Shah NP, Cortes JE, Kim DW, Nicolini FE, Talpaz M,Baccarani M, Müller MC, Li J, Parker WT, Lustgarten S, Clackson T, Haluska FG,Guilhot F, Kantarjian HM, Soverini S, Hochhaus A, Hughes TP, Rivera VM, Branford S. Blood. 2016 Feb 11;127(6):703-12.dddd 4. 7. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F. Blood 2013;122:872-84. 5. Carella AM, Garuti A, Cirmena G, Catania G, Rocco I, Palermo C, Pica G, Pierri I, Miglino M, Ballestrero A, Gobbi M, Patrone F. Leukemia & lymphoma 2010;51:275-8. 6. Giotopoulos G, van der Weyden L, Osaki H, Rust AG, Gallipoli P, Meduri E,Horton SJ, Chan WI, Foster D, Prinjha RK, Pimanda JE, Tenen DG, Vassiliou GS,Koschmieder S, Adams DJ, Huntly BJ. J Exp Med. 2015 Sep 21;212(10):1551-69. 7. Mukherjee S, Kalaycio M. Curr Hematol Malig Rep. 2016 Apr;11(2):86-93. Disclosures No relevant conflicts of interest to declare.
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Riley, Paul W., Dharmaraj Samuel, Hong Cheng, Heinrich Roder, and Peter N. Walsh. "NMR Structural Analysis and Folding Studies of the Factor XI Apple 4 Domain as a Model for Factor XI Homodimerization." Blood 106, no. 11 (November 16, 2005): 1958. http://dx.doi.org/10.1182/blood.v106.11.1958.1958.
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Abstract Factor XI (FXI) is a 160kD homodimeric component of the intrinsic pathway of the blood coagulation system. The FXI Apple 4 domain (A4) mediates homodimer formation even when the cysteine responsible for the intermolecular disulfide is mutated to serine (C321S). Preliminary NMR structural studies of the isolated wild type (wt) A4 domain showed a flattened, planar structure (Samuel D, Cheng H, Riley PW, Walsh PN, Roder H. Blood104, 481a, 2004), compared to a more globular structure consisting of two layers of β-sheet and a flanking α-helix that was observed on further analysis of wt and C321S A4. Hydrogen exchange NMR and surface NMR analysis (SEAHSQC), as well as temperature dependent hydrogen exchange NMR showed that in C321S and wt A4, the loop surrounding C321 or S321 is flexible and exposed to the solvent. Thus, the globular structure is the major species in both wt and C321S A4, but the planar structure is present as well. Fluorescence anisotropy studies of C321S A4 yielded a Kd value of ~64 nM (monomeric protein concentration), compared with ~72 nM for a dissociable mutant full-length FXI (G326C) obtained by analytical ultracentrifugation (Sinha D, Marcinkiewicz M, Lear JD, Walsh PN. Biochemistry, in press, 2005), suggesting that only the A4 domain mediates dimer formation in the intact protein. In addition, fluorescence and circular dichroism (CD) studies of the folding equilibrium of C321S A4 indicate that starting from the unfolded monomeric state, partial folding precedes dimerization. This folding mechanism for FXI A4 is consistent with the observed failure of a naturally occurring mutant (FXI F283L) to dimerize intracellularly (Meijers JC, Davie EW, Chung DW. Blood79, 1435–1440, 1992). To determine the structural consequences of the mutation, F283L was introduced into the noncovalent dimer C321S A4, which increased the Kd of the homodimer interaction to ~5 μM, but did not change the secondary structure (from comparison of the CD spectra), or the high degree of thermostability observed for C321S A4. Since the F283 sidechain has been tentatively assigned to the surface of FXI A4 near the interface, the mutation to Leu may significantly alter the interface, thereby raising the Kd but not changing the overall secondary structure significantly. In summary, there appears to be a mechanism by which a conformational change or productive folding process occurs in the monomer state that activates it for native dimer formation. Also, inserting the F283L (type III) patient mutation does affect the dimer stability, but not the overall secondary structure.
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Hermine, Olivier, Maria Domenica Cappellini, Ali T. Taher, Thomas D. Coates, Vip Viprakasit, Ersi Voskaridou, Ashutosh Lal, et al. "Longitudinal Effect of Luspatercept Treatment on Iron Overload and Iron Chelation Therapy (ICT) in Adult Patients (Pts) with β-Thalassemia in the Believe Trial." Blood 136, Supplement 1 (November 5, 2020): 47–48. http://dx.doi.org/10.1182/blood-2020-136517.
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Introduction: Regular red blood cell (RBC) transfusions are the main supportive treatment for chronic anemia due to β-thalassemia. Transfusion-dependent pts require ICT to prevent iron overload from RBC transfusions, and associated complications. Thus, there is a clinical need to reduce transfusions and iron burden in pts with anemia due to β-thalassemia. Luspatercept, an erythroid maturation agent, is approved by the FDA for treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. The phase 3, double-blind, randomized, placebo (PBO)-controlled BELIEVE study is evaluating the efficacy and safety of luspatercept in adult pts with β-thalassemia requiring regular RBC transfusions (NCT02604433; Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Here we assess the effect of long-term luspatercept use on iron loading and ICT use in the BELIEVE trial. Methods: Pts were ≥ 18 years with β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed) and required regular RBC transfusions (defined as 6-20 RBC units in the 24 wks prior to randomization with no transfusion-free period > 35 days). Pts were randomized 2:1 to luspatercept 1.0 mg/kg (up to 1.25 mg/kg allowed) or PBO subcutaneously every 3 wks for ≥ 48 wks. Pts in both treatment arms continued to receive RBC transfusions to maintain target pretransfusion Hb levels, as well as ICT (deferasirox, deferoxamine, and deferiprone alone or in combination) per product label and physician practice prior to randomization. After study unblinding, pts randomized to PBO were eligible to cross over to luspatercept in an open-label phase. Risk for iron overload-related complications was evaluated by stratifying pts into categories based on serum ferritin (SF) level (< 1,000 μg/L, 1,000 to < 2,500 μg/L, ≥ 2,500 μg/L), liver iron concentration (LIC; ≤ 3 mg/g dw, > 3 mg/g dw), and myocardial iron (by T2* MRI; ≤ 20 ms, > 20 ms). Long-term changes in SF and ICT use were assessed in luspatercept pts remaining on treatment up to data cutoff (July 1, 2019) or study discontinuation, whichever was earlier. Results: Of 336 pts enrolled, 224 were randomized to luspatercept and 112 to PBO. Mean baseline SF, LIC, and myocardial T2* for luspatercept vs PBO arms were 2,097 vs 1,845 μg/L, 12.0 vs 10.1 mg/g dw, and 33.5 vs 34.8 ms, respectively. Overall, 97.3% of pts received ICT at baseline. As of July 1, 2019, 67.9% of pts initially randomized to luspatercept were still receiving treatment at the end of 2 years; 92 (82.1%) PBO pts crossed over to luspatercept after study unblinding. Of 141 luspatercept-treated pts with baseline mean SF ≥ 1,000 μg/L, 24 (17.0%) pts achieved post-baseline mean SF < 1,000 μg/L when assessed over Wks 1−24, vs 3 (5.0%) PBO-treated pts. During Wks 73−96, 26/56 (46.4%) luspatercept pts with baseline mean SF ≥ 1,000 μg/L achieved post-baseline mean SF < 1,000 μg/L (Figure A). At Wks 24 and 48, 5/120 (4.2%) and 13/134 (9.7%) luspatercept pts, respectively, shifted from LIC > 3 mg/g dw at baseline to ≤ 3 mg/g dw, vs 4/61 (6.6%) and 4/68 (5.9%) PBO pts; 15/105 (14.3%) of luspatercept pts shifted from LIC > 3 mg/g dw at baseline to ≤ 3 mg/g dw at Wk 96. 6/30 (20.0%) pts receiving luspatercept shifted from myocardial iron T2* ≤ 20 ms at baseline to > 20 ms at Wk 48 (vs 1/11 [9.1%] PBO pts); at Wk 96, 6/24 (25.0%) luspatercept-treated pts shifted from ≤ 20 ms to > 20 ms. During Wks 1-12, mean daily deferasirox dose in luspatercept pts was 1,477.08 mg (mean change from baseline +136.27 mg) and 1,516.28 mg (mean change from baseline +131.80 mg) in PBO pts. No significant difference was seen between luspatercept and PBO arms during the first 48 weeks, however, the proportion of patients receiving ≥ 1 ICT gradually declined in both luspatercept responders (defined as pts achieving ≥ 33% reduction in transfusion burden from baseline during Wks 13−24) and non-responders over time (Figure B). Both luspatercept responders and non-responders also experienced a gradual decrease in mean daily dose of deferasirox over time (Figure C). Conclusions: Compared with PBO-treated pts, a higher proportion of luspatercept-treated pts shifted to lower SF, LIC, and myocardial iron levels during the first 48 wks, indicative of lower risk of iron overload complications. Long-term luspatercept treatment led to an increasing proportion of patients with SF < 1,000 μg/L and decreasing trends of overall ICT use and deferasirox dosage. Figure 1 Disclosures Hermine: Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Roche: Consultancy; Novartis: Research Funding. Cappellini:CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Taher:Novartis Pharmaceuticals: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ionis Pharmaceuticals: Consultancy; Vifor Pharma: Consultancy, Research Funding; Silence Therapeutics: Consultancy. Coates:Sangamo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios pharma: Consultancy, Honoraria; Celgene, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; apo pharma (Chiesi Pharma): Consultancy, Honoraria; Vifor Pharma: Consultancy, Honoraria. Viprakasit:BMS, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios Pharmaceuticals, Ionis Pharmaceuticals, La Jolla Pharmaceuticals, Protagonist Therapeutics, Vifor Pharma: Consultancy, Research Funding. Voskaridou:ADDMEDICA Company: Consultancy, Research Funding; NOVARTIS Company: Research Funding; GENESIS Company: Consultancy, Research Funding; PROTAGONIST Company: Research Funding; ACCELERON Company: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Lal:Chiesi USA: Consultancy; Novartis: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding; bluebird bio, Inc.: Research Funding; Insight Magnetics: Research Funding; Terumo Corporation: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy. Perrotta:Acceleron Pharma: Research Funding; Celgene, BMS: Honoraria; Novartis: Honoraria, Research Funding. Kattamis:Genesis Pharma SA: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apopharma/Chiesi: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ionis: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:BMS: Current Employment. Tian:BMS: Current Employment. Miteva:BMS: Current Employment. Zinger:Celgene International, A Bristol-Myers Squibb Company: Current Employment. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Backstrom:BMS: Current equity holder in publicly-traded company; Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Porter:Agios Pharmaceuticals: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Protagonist Therapeutics: Honoraria; Silence Therapeutics: Honoraria; La Jolla Pharmaceuticals: Honoraria; Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria.
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Inati, Adlette, Javid Gaziev, Hussein A. Abbas, Serge Korjian, Yazan Daaboul, Mario Kahale, Katia Paciaroni, et al. "Outcome Of Bone Marrow Transplantation In Lebanese Children With β-Thalassemia Major." Blood 122, no. 21 (November 15, 2013): 5505. http://dx.doi.org/10.1182/blood.v122.21.5505.5505.
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Abstract Abstract 5505 Introduction Bone marrow transplantation (BMT) represents the only curative modality for β-Thalassemia Major (β–TM). Best results are achieved in regularly transfused and chelated pediatric patients. Outcome of BMT in 36 Lebanese children who received treatment in the Mediterranean Institute of Hematology (IME) centers in Italy is presented. Methods 36 children with β–TM treated at Chronic Care Center, Lebanon underwent BMT from HLA compatible donors in IME centers. Each was assigned a Pesaro risk category and underwent a percutaneous liver biopsy before BMT. Conditioning regimen consisted of busulfan, cyclophosphamide ± Thiotepa and ATG. GvHD prophylaxis included cyclosporine A, methotrexate and prednisolone. Engraftment was evaluated by fluorescence in situ hybridization. Transplant related mortality (TRM) and other complications were calculated as cumulative incidence. Analyses were performed using R software. Results 36 hepatitis B and C negative children with β –TM (M/F 1:l), median age 8.5 years, underwent BMT from HLA identical donors. The most common β-globin mutation was homozygous IVS1.110 (39.29%). 20.5%, 55.9% and 23.5% had Pesaro risk class 1, 2 and 3, respectively. Mean injected CD34+ cells, total nucleated cells and CD3+ cells/recipient were 10.9x106 /Kg, 8.69x108/Kg and 66.3x106 /Kg. Absolute neutrophil count >0.5 x109 and platelet count >20 x 109 were reached in all patients within a mean of +19.44±4 and +19.15 ±6.5 days. Regular chimerism surveillance showed complete engraftment in 35/36 children (97.3%) up till+ 4.2 years median follow up. 1/36 (2.7%) had partial engraftment but continued to be transfusion independent with a mean Hb of 9g/dcl for +1155 days. Immune reconstitution was seen in all patients by + 12 -18 months. At a median follow up of + 6.20 years, 32/36 (89%) of children are alive and transfusion independent. Among those who died (11%), 1 had multi organ failure, 2 had grade 4 acute GvHD and 1 had fulminant interstitial pneumonitis. 47% had acute GvHD which was not correlated with donor relation, conditioning regimen, and pre-BMT hepatomegaly, splenomegaly and transfusion frequency. 8/36 (22%) had grade 2 to 4 acute GvHD of which 75% resolved on treatment while 25% (all grade 4) were fatal. 9/32 (28%) surviving children had chronic GvHD completely resolved on treatment and not correlated with any recipient, donor or treatment feature. Other transplant related complications included CMV reactivation, sepsis, EBV and candida infections, hemorrhagic cystitis, cerebral toxoplasmosis, tuberculosis and transient cyclosporine related renal and neurotoxicity, all completely resolved on treatment. Late effects of transplant were monitored in 27 children. Iron overload data utilizing magnetic resonance imaging at + 3.1 year median follow up showed that mean baseline LIC for 27 patients was 11.3 mg Fe/g dw but ranged as high as 36.6 mg Fe/g dw. Median serum ferritin was 1255 ng/mL, with a maximum of 5884 ng/mL. 9/27 (33.3%) children had significant iron overload defined as SF >2500 ng/ml, or LIC >15 mg Fe/g dw, or T2* <20 msec, levels known to be associated with increased risk of progressive organ dysfunction and death. Median ejection fraction was 68 % (range 58-75%). Up till + 6.20 years median follow up, serum immunoglobulins, alanine and aspartate aminotransferases, BUN, creatinine and creatinine clearance were normal in all 27 children. Hypothyroidism, growth retardation and diffuse persistent vitiligo were seen in 3/25 (12%), 4/25 (16%) and 1/25 (4%) survivors respectively. Summary Our results reflect an excellent outcome for Lebanese children with β –TM undergoing transplantation. TRM was low and associated complications were transient and manageable. Significant iron overload was, however, noted years after BMT underscoring the need for long term monitoring for iron overload and for iron removal to prevent associated negative outcomes. This study highlights the need for monitoring for late effects for years after transplant. It also demonstrates the effectiveness of international collaboration in facilitating cure for thalassemia in developing countries as Lebanon. Disclosures: No relevant conflicts of interest to declare.
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Beamer, W. G., H. O. Sweet, R. T. Bronson, J. G. M. Shire, D. N. Orth, and M. T. Davisson. "Adrenocortical dysplasia: a mouse model system for adrenocortical insufficiency." Journal of Endocrinology 141, no. 1 (April 1994): 33–43. http://dx.doi.org/10.1677/joe.0.1410033.
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Abstract A spontaneous autosomal recessive mutation causing disordered morphogenesis of the adrenal cortex has been identified in DW/J inbred strain mice and named adrenocortical dysplasia (acd). The acd mutant gene has been mapped just proximal to oligosyndactyly (Os) and esterase-1 (Es-1) in the central region of chromosome 8. Both male and female acd/acd mice are characterized by reduced survival, retarded growth, skin hyperpigmentation, poorly developed pelage and focal ureteral blockage leading to hydronephrosis. Morphometric measurements showed that acd/acd cortical cells and nuclei were increased sevenfold in volume; nuclei often showed a variety of inclusions. Cortical cells of acd/acd mice contained large numbers of mitochondria, smooth endoplasmic reticulum and lipid droplets characterisitic of steroidogenic cells. While cortical X-zones failed to develop in acd/acd adrenals, medullary cells and nuclei were unaffected by mutant gene action. Resting serum corticosterone levels in female, but not male, mutant mice were significantly lower than in +/? normal littermates, whereas ACTH levels were significantly elevated in mutants of both sexes. Serum aldosterone levels were normal in acd/acd mice. Functional studies of adrenals cultured in vitro revealed that acd/acd adrenals secreted reduced amounts of corticosterone per pair of glands under both basal and ACTH-stimulated conditions. However, correction of the corticosterone secretion data to mg cortical mass in culture showed that the mutant cortical tissue secreted the same amount of glucocorticoid as did their +/? normal littermate glands. We conclude that the acd mutant gene acts in an unknown fashion to cause a fundamental defect in cellular proliferation in the adrenal cortex, leading to compensatory marked hypertrophy of cortical cells and grossly enlarged nuclei. The role of acd action in adrenal cortical development remains to be established. Journal of Endocrinology (1994) 141, 33–43
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Nitrini, Ricardo, Renata Areza-Fegyveres, Vilma R. Martins, Rosa Maria R. P. S. Castro, Michele C. Landemberger, Nancy Huang, Luiz A. Bacheschi, et al. "Asymmetric cortical high signal on diffusion weighted-MRI in a case of Creutzfeldt-Jakob disease." Arquivos de Neuro-Psiquiatria 63, no. 2b (June 2005): 519–22. http://dx.doi.org/10.1590/s0004-282x2005000300028.
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High signal in the cerebral cortex and/or basal ganglia on diffusion-weighted magnetic resonance imaging (DW-MRI) has been described as a good diagnostic marker for sporadic Creutzfeldt-Jakob disease (sCJD). We report a case of sCJD with atypical clinical evolution and unusual DW-MRI findings. A 53-year-old man was seen with a 2-year history of a rapidly progressive dementia and cerebellar ataxia. Cerebrospinal fluid analysis, including the test for 14-3-3 protein, was normal. EEG did not show periodic activity. However, DW-MRI showed gyriform hyperintensity involving practically the entire cortical ribbon of the left hemisphere, whilst being limited to the posterior cingulate gyrus in the right hemisphere. DNA analysis showed no mutations or insertions in the prion protein gene, and homozigozity for methionine in codon 129. A subsequent brain biopsy confirmed the diagnosis of CJD. Thus, high signal on DW-MRI may be limited to the cerebral cortex and may present a very asymmetric distribution in sCJD.
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Lu, Meng Yao, Ming Chung Kuo, Shih Chung Wang, Shih Hsiang Chen, Bor Sheng Ko, Cheng-Shyong Chang, and Jih-Luh Tang. "Clinical Features and Morbidities of Hb H Disease in Taiwan." Blood 128, no. 22 (December 2, 2016): 4836. http://dx.doi.org/10.1182/blood.v128.22.4836.4836.
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Abstract Introduction Patients with non-transfusion-dependent thalassemia experience a wide array of clinical complications despite their independence from frequent, regular red blood cell transfusions. They have the higher incidence of osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, cholelithiasis, thromboembolic disease, pulmonary hypertension, silent cerebral ischemia, and leg ulcers. Thalassemia is highly prevalent in Taiwan and Hb H disease is predominant. But limited data are available about clinical features and morbidities. Here, we studied clinical features and morbidities in Taiwanese patients with Hb H disease. Methods & Results We collected 90 patients with Hb H disease in three hospitals since 2014 Nov till 2016 July. Male to female were 43/59. The mean age was 33.1 years ( from 0.5 to 92.3 years). Two cases died of pulmonary hypertension and old age at 31 years old and 87 years old. Alfa-globin gene genotype studies were done in 44 cases. The (- -(SEA)) type of α(0)-thalassemia mutation was detected in all patients. Twenty- four (57.1%) cases were deletional (α(3.7)/ α(4.2)/unknown 19/4/1) and 20 (42.9%) were nondeletional (CS/RS 18/2) type. The mean of Hemoglobin (Hb) and serum ferritin level were 8.7 g/dL and 730 ng/mL. We also revealed the positive correlation between age and serum ferritin level. The liver iron concentration (LIC) were 6.694 mg Fe/g dw (n=35). The Hb, ferritin and LIC level were not different between deletional and non- deletional groups. They received the transfusion management : 1 with regular transfusion ≦ 6 weeks interval, 5 with irregular transfusion ≧ 6 weeks interval, 27 with occasional transfusion and 57 without transfusion. Fifteen cases received splenectomy. There were significantly higher prevalence for transfusion frequency and splenectomy in non-deletional group. The prevalence of morbidities were 16/79 for cholelithiasis, 12/90 for thromboembolic event, 4/90 for heart failure symptoms ( 2 for pulmonary hypertension), 5/90 for arrhythmia, 3/90 for bone fracture, 5/20 for osteoporosis and 0 for renal stone. There were non-significantly higher prevalence for morbidities in non-deletional group. Discussion & Conclusion The study provides the clinical features and the prevalence of morbidities in Hb H disease in Taiwan. Surprisingly, the prevalence of thromboembolic event and pulmonary hypertension are overlooked in our routine Hb H disease care. We need to schedule close and careful clinical follow up of Hb H patients as they get older, they get some morbidities or they are non-deletional genotype. Disclosures No relevant conflicts of interest to declare.
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Tamary, Hannah, Hanna Shalev, Galit Avraham, Meira Zoldan, Itai Levi, Dorine W. Swinkels, Toshihiko Tanno, and Jeffery L. Miller. "High Levels of Growth Differentiation Factor 15 in Patients with Congenital Dyserythtopoietic Anemia Type I." Blood 112, no. 11 (November 16, 2008): 3456. http://dx.doi.org/10.1182/blood.v112.11.3456.3456.
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Abstract Growth differentiation factor 15 (GDF15) is a member of the TGF-beta superfamily of cytokines previously found to suppress hepcidin in primary human hepatocytes. GDF15 is secreted from human erythroblasts, and extremely high serum levels are present in β-thalassemia patients (Tanno et al., Nat. Med. 2007, 13, 1096–1101). To determine if elevated GDF15 levels are unique for thalassemia or more generally associated with iron-loading related to ineffective erythropoiesis, we determined the GDF15 levels, as well as, serum hepcidin (Swinkels DW et al, PLoS ONE PLoS ONE. 2008;3:e2706), ferritin, erythropoietin (EPO) and soluble transferrin receptor (sTfR) in patients with the congenital dyserythropoietic anemia type I (CDA I). Seventeen Israeli Bedouins with CDA I were studied, all homozygous for the founder R1040W mutation in the CDAN1 gene. All of the patients studied were young adults with a mean age of 29 years. Two patients previously underwent splenectomy, and one patient is currently transfusion-dependent. For comparison, ten healthy volunteers (HV) were studied. The mean level of GDF15 in CDA I patients was significantly elevated [10,239 ± 3,049 pg/ml (range 5,530–17,008) compared to 269 ± 238 pg/ml in healthy controls; p = 1.5×10−10]. Consistent with a previous study of dyserythropoietic anemia patients, significantly higher levels of soluble transferrin receptor were detected among the CDA I population (sTfR; CDA I, 86.4 ± 14.0 nmol/L; HV, 21.4 ± 6.2 nmol/L, p = 7.4×10−15). Serum EPO levels were also elevated (EPO; CDA I, 118 ± 59 IU/dL; HV, 2.0 ± 1.5 IU/dL, p = 2.3×10−7). For iron analyses, three patients with extensive transfusion histories were excluded. Among the remaining 14 patients, iron overload was demonstrated by elevated serum ferritin (CDA I, 916 ± 507 ng/ml; HV, 72 ± 60 ng/ml, p = 1.4×10−5). Despite the significant elevation in iron stores, significantly elevated levels of hepcidin 25 (Hep25) were not detected in the CDA I patients. Instead, a minor decrease in serum Hep25 levels were detected (Hep25; CDA I, 3.3 ± 2.8 nM; HV, 4.1 ± 3.0 nM, p = 0.27). Correlation analyses were performed between the iron parameters (Ferritin and Hep25) and GDF15, sTfR, or EPO levels. Only GDF15 demonstrated a significant positive correlation with ferritin and significant inverse correlations with Hep25 and the Hep25/Ferritin ratio. Weaker correlations with EPO were identified. Unexpectedly, the correlation trends for sTfR were opposite those of GDF15 in this group. These results demonstrate that GDF15 is immensely over-expressed in CDA I, and further suggest this cytokine contributes to hepcidin dysregulation and secondary hemochromatosis in humans with ineffective erythropoiesis.
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Cain, Stuart M., Barry Bohnet, Jeffrey LeDue, Andrew C. Yung, Esperanza Garcia, John R. Tyson, Sascha R. A. Alles, et al. "In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures." Proceedings of the National Academy of Sciences 114, no. 9 (February 21, 2017): 2401–6. http://dx.doi.org/10.1073/pnas.1614447114.
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Migraine is characterized by severe headaches that can be preceded by an aura likely caused by cortical spreading depression (SD). The antiepileptic pregabalin (Lyrica) shows clinical promise for migraine therapy, although its efficacy and mechanism of action are unclear. As detected by diffusion-weighted MRI (DW-MRI) in wild-type (WT) mice, the acute systemic administration of pregabalin increased the threshold for SD initiation in vivo. In familial hemiplegic migraine type 1 mutant mice expressing human mutations (R192Q and S218L) in the CaV2.1 (P/Q-type) calcium channel subunit, pregabalin slowed the speed of SD propagation in vivo. Acute systemic administration of pregabalin in vivo also selectively prevented the migration of SD into subcortical striatal and hippocampal regions in the R192Q strain that exhibits a milder phenotype and gain of CaV2.1 channel function. At the cellular level, pregabalin inhibited glutamatergic synaptic transmission differentially in WT, R192Q, and S218L mice. The study describes a DW-MRI analysis method for tracking the progression of SD and provides support and a mechanism of action for pregabalin as a possible effective therapy in the treatment of migraine.
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Wienand, Kirsty, Bjoern Chapuy, Chip Stewart, Andrew Dunford, David Wu, Jaegil Kim, Atanas Kamburov, et al. "Comprehensive Genomic Analysis of Flow-Sorted Hodgkin Reed Sternberg Cells Reveals Additional Genetic Bases of Immune Evasion." Blood 132, Supplement 1 (November 29, 2018): 1559. http://dx.doi.org/10.1182/blood-2018-99-118453.
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Abstract Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. Emerging data suggests that cHLs use multiple genetic mechanisms to evade immune recognition. We previously found that HRS cells exhibit near-universal somatic copy number alterations (SCNAs) involving chromosome 9p24.1/PD-1-L1/PD-L2 and rare chromosomal rearrangements of PD-L1 or PD-L2. The 9p24.1 amplicon also includes JAK2, which increases JAK2 copy numbers, augments JAK2/STAT signaling and further induces PD-1 ligand expression. However, HRS cells also have inactivating mutations of B2M and decreased or absent MHC class I expression. In cHL, clinical responses to PD-1 blockade are unrelated to HRS cell expression of MHC class I but closely associated with HRS cell expression of MHC class II, highlighting the potential role of CD4+ T-cell effectors (J Clin Oncol 2018;36:942-50). To define genetic bases of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole exome sequencing (WES) of HRS cells. We first used a previously described multi-color flow cytometric sorting protocol (Methods 2012; 57:368-75) to obtain highly purified CD30+ HRS cells and normal B cells from the excisional biopsies of 25 newly diagnosed cHLs. The isolated HRS cells and paired normal B cells were then subjected to WES using an optimized workflow for low input samples and an expanded bait set to capture structural variants (SVs). We used established analytical pipelines to identify significantly mutated genes (candidate cancer genes [CCGs], MutSig2CV), SCNAs (GISTIC2.0) and SVs (4 algorithms). With improved methodology and purity (median of 80%) of the isolated HRS cells, we defined 15 significantly mutated CCGs, 21 recurrent SCNAs, including 6 CN gains (4 focal and 2 arm level) and 15 CN losses (14 focal and 1 arm level), and low frequency SVs. We identified 2 cHLs as hypermutators with MSI signatures due to splice site mutations in MSH2 or missense mutations in POLE. Excluding the 2 hypermutators, the analyzed cHLs had a median mutational density of 6.4 mutations/Mb, that falls within the top quartile of reported cancer mutational frequencies (Nature 2013 499:214). We also identified a previously unappreciated high incidence of ARID1A mutations (24%) in cHL. This is noteworthy because ARID1A deficiency increases mutational load and augments the efficacy of PD-1 blockade in murine models (Nature Med 2018;24:556). Together, the observed MSI signatures, relatively high mutational burden and newly identified ARID1A mutations in cHL represent additional potential genetic bases for the efficacy of PD-1 blockade. Notably, these cHLs also exhibited recurrent 9p24.1 copy gain (80%) and multiple genetic bases of enhanced JAK/STAT signaling including JAK2 copy gain (80%), STAT6 mutations (32%) involving known hotspots (D419 and N421) in the DNA-binding domain and frequent inactivating SOCS1 mutations (68%). We also identified multiple genetic bases for immune evasion, including B2M inactivating mutations (36%), HLA-B mutations (16%) and 6p21.32/HLA-B copy loss (28%), copy loss of the larger 6p21.32 region and inactivating CIITA SVs (8%). Additional signaling pathways were perturbed by multiple genetic mechanisms in these cHLs. For example, NF-κB pathway alterations included: TNFAIP3 mutations (24%) and 6q23.2/TNFAIP3 copy loss (56%), 12% biallelic; NFKBIE mutations (24%) and 6q21.32/NFKBIE copy loss (12%); and NFKBIA mutations (16%). The gene encoding the nuclear export protein, XPO1, was perturbed by E571K mutations (24%) and frequent 2p15/XPO1 copy gain (72%). Additionally, GNA13, an activator of RHOA and modifier of PI3K signaling, was mutated in 24% of cases. Of interest, cHL recurrent alterations including B2M, TNFAIP3, STAT6, and GNA13 mutations and 6q23.2 and 9p24.1 SCNAs were also identified in > 20% of examined primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases. In summary, comprehensive genomic analyses of purified HRS cells reveal new genetic bases of immune evasion, potential mechanisms of response and resistance to PD-1 blockade and additional targetable alterations. KW, BC, CS, AD and DW contributed equally. JF, GG and MS contributed equally. Disclosures Rodig: Affimed: Research Funding; KITE: Research Funding; Merck: Research Funding; Bristol Myers Squibb: Research Funding. Shipp:Merck: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria.
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Grossniklaus, Hans E. "Analysis of the ARMD1 locus: Evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Schultz DW, Klein ML, Humpert AJ, Luzier CW, Persun V, Schain M, Mahan A, Runckel C, Cassera M, Vittal V, Doyle TM, Martin TM, Weleber RG, Francis PJ, Francis PJ, Acott TS. Hum Mol Genet 2003;12:3315–3323." American Journal of Ophthalmology 138, no. 6 (December 2004): 1097–98. http://dx.doi.org/10.1016/j.ajo.2004.10.036.
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Meeks, Shannon, Ernest T. Parker, Amy L. Dunn, John F. Healey, and Pete Lollar. "Proteolytically Inactivatable Factor VIII is Less Immunogenic than Factor VIII in a Murine Hemophilia A Model." Blood 114, no. 22 (November 20, 2009): 27. http://dx.doi.org/10.1182/blood.v114.22.27.27.
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Abstract Abstract 27 Patients with hemophilia A have a congenital deficiency of the factor VIII (fVIII) protein due to a mutation in the fVIII gene that frequently leads to absence of detectable expression of fVIII. Accordingly, the therapeutic replacement fVIII protein potentially is recognized as non-self by the immune system. Thirty percent of patients with severe hemophilia A develop detectable inhibitory anti-fVIII antibodies (inhibitors). Additionally, greater than 90 percent of hemophilia A mice treated with human fVIII develop inhibitors using dosing schedule that mimics use in humans. Because fVIII is an immunologically foreign protein, it might be expected that a hemophilia A patient would make a fVIII inhibitor. However, intravenous injection of soluble proteins in either humans or rodents usually results in tolerance rather than a humoral immune response. One major difference between fVIII and other proteins is that it is released from its large carrier protein von Willebrand factor (VWF) and is potentially exposed to the immune system at sites of active hemostasis and inflammation. Heat-inactivated, denatured fVIII, which maintains all T-cell epitopes but lacks several B-cell epitopes, is less immunogenic than native fVIII, suggesting that fVIII-dependent thrombin generation along the intrinsic pathway of blood coagulation may provide co-stimulatory signals necessary for the immune response (Skupsky BS, Zhang A, Scott DW Blood 2008; 112:1220a). We constructed a B domain-deleted human fVIII mutant, designated fVIIIi, which contains alanine substitutions at two critical thrombin cleavage sites, Arg372 and Arg1689, and purified it to homogeneity. FVIIIi does not develop procoagulant activity and is not released from VWF in response to thrombin. Therefore fVIIIi is less likely than wild-type fVIII to be exposed to the immune system at sites of active hemostasis and inflammation. Additionally, VWF binds to the immunodominant fVIII C2 domain and potentially hides part of fVIII from the immune system. FVIIIi was antigenically intact judging from intact binding to a panel of11 mouse anti-fVIII monoclonal antibodies whose epitope specificity was represented by all five domains of BDD fVIII. The immunogenicity of wild-type fVIII and fVIIIi was compared in a murine hemophilia A model in which groups of 25 mice received 8 weekly injections of physiologic doses of fVIII. Plasma was collected weekly for total anti-fVIII antibody titers by ELISA and one week following the last injection for total anti-fVIII antibody titers, inhibitor titers by Bethesda assay and for epitope mapping. Mice treated with fVIIIi had significantly lower levels of inhibitory as well as total anti-fVIII antibodies than mice treated with wild-type fVIII. Domain mapping using single human domain hybrid human/porcine molecules as ELISA antigens revealed that hemophilia A mice broadly recognized all fVIII domains in response to either wild-type or fVIIIi, although fVIIIi produced less anti-light chain antibodies. Mice in both the wild-type fVIII and fVIIIi groups produced antibodies that recognized the phospholipid-binding site of the C2 domain, even though this site overlaps the VWF binding site on fVIII. There was no difference in the isotype spectrum of the antibodies made to fVIII or fVIIIi. This study indicates that inactivatable fVIII is less immunogenic than native fVIII and suggests that the immunogenicity of fVIII is related either to its interaction with VWF or to events triggered by activation of the coagulation mechanism. Disclosures: No relevant conflicts of interest to declare.
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Runquist, David, B�rbel Hahn-H�gerdal, and Maurizio Bettiga. "Increased Ethanol Productivity in Xylose-Utilizing Saccharomyces cerevisiae via a Randomly Mutagenized Xylose Reductase." Applied and Environmental Microbiology 76, no. 23 (October 1, 2010): 7796–802. http://dx.doi.org/10.1128/aem.01505-10.
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ABSTRACT Baker's yeast (Saccharomyces cerevisiae) has been genetically engineered to ferment the pentose sugar xylose present in lignocellulose biomass. One of the reactions controlling the rate of xylose utilization is catalyzed by xylose reductase (XR). In particular, the cofactor specificity of XR is not optimized with respect to the downstream pathway, and the reaction rate is insufficient for high xylose utilization in S. cerevisiae. The current study describes a novel approach to improve XR for ethanol production in S. cerevisiae. The cofactor binding region of XR was mutated by error-prone PCR, and the resulting library was expressed in S. cerevisiae. The S. cerevisiae library expressing the mutant XR was selected in sequential anaerobic batch cultivation. At the end of the selection process, a strain (TMB 3420) harboring the XR mutations N272D and P275Q was enriched from the library. The V max of the mutated enzyme was increased by an order of magnitude compared to that of the native enzyme, and the NADH/NADPH utilization ratio was increased significantly. The ethanol productivity from xylose in TMB 3420 was increased ∼40 times compared to that of the parent strain (0.32 g/g [dry weight {DW}] � h versus 0.007 g/g [DW] � h), and the anaerobic growth rate was increased from ∼0 h−1 to 0.08 h−1. The improved traits of TMB 3420 were readily transferred to the parent strain by reverse engineering of the mutated XR gene. Since integrative vectors were employed in the construction of the library, transfer of the improved phenotype does not require multicopy expression from episomal plasmids.
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Vichinsky, Elliott P., Janet Kwiatkowski, Patricia J. Giardina, Carole Paley, Francis Vekeman, Wendy Y. Cheng, Joseph Damron, et al. "Epidemiologic and Clinical Characteristics of Thalassemia (Thal) Intermedia (TI) in the United States." Blood 126, no. 23 (December 3, 2015): 3279. http://dx.doi.org/10.1182/blood.v126.23.3279.3279.
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Abstract Introduction TI is increasingly prevalent in the US due to changing immigration patterns. It is underdiagnosed, leading to inadequate or delayed management. This study reviewed the prevalence, epidemiology, and clinical characteristics of TI in patients (pts) in the US. Methods Medical records from 1/1997- 4/2014 at 4 US hematology centers were reviewed. Index date was the 1st TI visit at a center on or after 1/1/1997. Eligible pts had a TI diagnosis (≤8 mean packed red blood cell transfusions per year (yr) over a ≥3-y period after index date) and ≥12 months of follow-up. Data spanned from index date to death or last record. Descriptive analyses of demographic and clinical data were done by TI subtype. Results Of 138 pts enrolled, 84 had α-thal, 39 had β-thal, and 15 had E/β-thal. 74% of α-thal pts had deletional (del) Hb H, and 26% had non-deletional (ndel) Hb H. 59% of β-thal pts had homozygous or compound heterozygous β-globin mutations (8% with α deletion, 51% without), 20% had a single β mutation with α-gene triplication, 13% had autosomal dominant β thal, and 8% had other β-globin mutations. Of the E/β-thal pts, 80% had E/β0 and 20% had E/β+. Median age at index date was 2.3 yr (1.64 del; 6.1 ndel) in the α-thal group, 9.2 yr in the β-thal group, and 2.2 yr in the E/β-thal group. Most α-thal (77%) and E/β-thal (87%) pts were Asian; most β-thal pts were White (46%) or African-American (36%). Most α-thal (56%) and E/β-thal (53%) pts were of Southeast Asian origin; most β-thal pts were of Mediterranean (31%) or African (21%) origin. 21%, 10%, and 20% of α, β, and E/β-thal pts, respectively, were foreign-born, and 5%, 3% and 7%, respectively, were transfused outside of the US. Observation length was similar across subtypes (median: 5.3 yr). Clinical comorbidities are shown in Table 1. 22% of pts received ≥1 transfusion, while 7% of pts received ≥8 transfusions in any 1 yr to treat anemia, acute hemolysis, or cardiac abnormality; increased transfusions were initiated due to growth failure, acute hemolysis, or unspecified reasons. β-thal pts had a higher mean number of transfusions per pt per yr (PPPY) (α: 0.4 (0.0 del; 1.5 ndel), β: 0.9, E/β: 0.2) and higher mean serum ferritin (ng/mL) (204.3; 511.7; 362.4), and more often had iron chelation therapy (ICT) (11%; 28%; 7%). There was an association between higher serum ferritin, more frequent transfusions, and older age. In pts <10 yr, mean number of transfusions PPPY for regularly and ever transfused was 4.0 and 2.1, and serum ferritin for regularly, ever, and never transfused was 723.7, 438.0, and 146.4 ng/mL. In pts >18 yr, these values were 9.8 and 4.6 transfusions PPPY and 1166.8, 1042.2, and 521.4 ng/mL. An association also existed between ICT and higher mean serum ferritin (ICT: 769.9; no ICT: 463.7 ng/mL). 22% of pts had ≥1 liver iron test, and 18% had ≥1 cardiac iron test. Tested pts were older than those not tested (median yr, liver iron: 26.1 vs 7.4; cardiac: 20.1 vs 4.6). Among tested pts, 78% (25/32) had abnormal liver iron results. Median (range) LIC based on R2 or SQUID was 10.8 (2.5-18.2) mg/g dw, with corresponding within-12-month serum ferritin of 494 (127-1770) ng/mL. 49% (17/35) of pts tested had abnormal cardiac results based on electrocardiogram or echocardiogram. Table 1. Clinical comorbidities All α-thal α-thal del α-thal ndel β-thal E/β-thal N=138 N=84 N=62 N=22 N=39 N=15 Splenomegaly 54% 55% 39% 100% 51% 60% Extramedullary hematopoiesis 28% 24% 13% 55% 36% 33% Growth retardation 21% 23% 18% 36% 13% 33% Hepatomegaly 21% 24% 13% 55% 15% 20% Infections needing hospitalization/IV antibiotics 21% 25% 19% 41% 15% 13% Hypoparathyroidism/hypocalcemia 15% 17% 8% 41% 10% 20% Osteopenia/osteoporosis 13% 11% 5% 27% 21% 7% Bone deformities 9% 6% 5% 9% 21% 0% Splenectomy and/or cholecystectomy 9% 5% 2% 14% 21% 0% Cardiomegaly 4% 6% 2% 18% 0% 7% Conclusion TI in the US affects a diverse population. Our data showed a higher prevalence in African-Americans than previously documented. Rates of comorbidity and transfusion frequency increased with age. 18% and 4% of pts were born and transfused outside of the US, potentially leading to additional transfusion-related morbidity. Consistent with extant data, serum ferritin in TI often underestimated actual LIC, rendering more pts potentially eligible for ICT than observed. Morbidities observed in this study underscore the need for better and earlier diagnosis, substantiating the need for nationwide TI screening/surveillance to optimize management. Disclosures Vichinsky: Novartis: Research Funding. Kwiatkowski:Novartis: Research Funding; Sideris Pharmaceuticals: Consultancy; Shire Pharmaceuticals and Sideris Pharmaceuticals: Consultancy; ISIS: Membership on an entity's Board of Directors or advisory committees. Paley:Novartis: Employment. Vekeman:Novartis: Research Funding. Cheng:Novartis: Research Funding. Damron:Novartis: Research Funding. McCormick:Novartis: Research Funding. Sasane:Novartis: Employment. Qiu:Novartis: Employment. Duh:Novartis: Research Funding. Thompson:Bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Mast: Research Funding; Apopharma: Consultancy; Baxter: Consultancy, Research Funding.
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Stagos, Dimitrios, Dimitrios Balabanos, Salomi Savva, Zoi Skaperda, Alexandros Priftis, Efthalia Kerasioti, Eleni V. Mikropoulou, et al. "Extracts from the Mediterranean Food Plants Carthamus lanatus, Cichorium intybus, and Cichorium spinosum Enhanced GSH Levels and Increased Nrf2 Expression in Human Endothelial Cells." Oxidative Medicine and Cellular Longevity 2018 (November 15, 2018): 1–14. http://dx.doi.org/10.1155/2018/6594101.
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The Mediterranean diet is considered to prevent several diseases. In the present study, the antioxidant properties of six extracts from Mediterranean plant foods were assessed. The extracts’ chemical composition analysis showed that the total polyphenolic content ranged from 56 to 408 GAE mg/g dw of extract. The major polyphenols identified in the extracts were quercetin, luteolin, caftaric acid, caffeoylquinic acid isomers, and cichoric acid. The extracts showed in vitro high scavenging potency against ABTS•+ and O2•− radicals and reducing power activity. Also, the extracts inhibited peroxyl radical-induced cleavage of DNA plasmids. The three most potent extracts, Cichorium intybus, Carthamus lanatus, and Cichorium spinosum, inhibited OH•-induced mutations in Salmonella typhimurium TA102 cells. Moreover, C. intybus, C. lanatus, and C. spinosum extracts increased the antioxidant molecule glutathione (GSH) by 33.4, 21.5, and 10.5% at 50 μg/ml, respectively, in human endothelial EA.hy926 cells. C. intybus extract was also shown to induce in endothelial cells the transcriptional expression of Nrf2 (the major transcription factor of antioxidant genes), as well as of antioxidant genes GCLC, GSR, NQO1, and HMOX1. In conclusion, the results suggested that extracts from edible plants may prevent diseases associated especially with endothelium damage.
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Bando, Hironori, Michelle Brinkmeier, Peter Gergics, Qing Fang, Amanda Helen Mortensen, Ayse Bilge Ozel, Qianyi Ma, et al. "SIX3 Variant Causes Pituitary Stalk Interruption Syndrome and Combined Pituitary Hormone Deficiency." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A530. http://dx.doi.org/10.1210/jendso/bvab048.1079.
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Abstract The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over 30 causal genes have been identified. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified two children with neonatal GH and TSH deficiency and stalk interruption who were doubly heterozygous for rare, likely deleterious variants in SIX3 and POU1F1. Functional studies demonstrated that both variants are disruptive. We used Six3 and Pou1f1 loss of function mice to assess the genetic interaction between Six3 and Pou1f1. Six3 heterozygotes have variable pituitary gland dysmorphology, while Pou1f1 heterozygotes are normal. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease. To understand the role of SIX3 in pituitary and hypothalamic development, we used Prop1-cre and Nkx2.1-cre to delete Six3. Disruption of Six3 expression in Rathke’s pouch caused poor activation of Lhx3 expression and arrested anterior pituitary development. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination and failed to induce FGF and BMP signaling, which normally drive expansion of Rathke’s pouch. By E11.5 cells in Rathke’s pouch underwent apoptosis. The Nkx2.1-cre, Six3flox/flox embryos failed to activate expression of Lhx2 and Tbx3 in the neural ectoderm. These embryos had elevated CCND1, MYCN, and Axin2 expression in the area of the presumptive infundibulum. This indicates that SIX3 is necessary to repress cell proliferation and Wnt/beta-catenin signals to promote formation of the pituitary stalk. Thus, Six3 has essential roles in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities or PSIS.
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Barcellini, Wilma, Anna Ines Gregorini, Giulia Soverini, Anna Zaninoni, Juri A. Giannotta, Cristina Vercellati, Valeria Ferri, Paola Bianchi, Agostino Cortelezzi, and Maria Domenica Cappellini. "Iron Overload and Cytokine Serum Levels in Congenital Hemolytic Anemias." Blood 128, no. 22 (December 2, 2016): 2458. http://dx.doi.org/10.1182/blood.v128.22.2458.2458.
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Abstract Background: Congenital hemolytic anemias (CHAs) are a heterogeneous group of inherited RBC disorders including membrane and enzyme defects and dyserythropoietic anemias. Iron overload is a well recognized complication of hereditary hemoglobinopathies, both in transfusion-dependent and independent cases. However, little is known in congenital hemolytic anemias, with the exception of anecdotic reports in pyruvate kinase deficiency and dyserythropoietic anemias. Aim: to describe the clinical and hematological features at diagnosis and enrolment, to investigate iron overload by hepatic and cardiac T2* MRI, and to study inflammatory/regulatory cytokine profiles (IL-6, TNF-alpha, IFN-gamma, IL-10, IL-17) and hepcidin levels in patients with CHAs. Confounding factors such as hemocromatosis genotyping, metabolic syndrome, and hepatic viral profile were also considered. Methods: Between July 2015 and April 2016, 38 patients were enrolled (13 hereditary spherocytosis -HS, 3 hereditary stomatocytosis - HSt, 8 congenital dyserythropoietic anemia type II - CDAII, 13 pyruvate kinase deficiency - PKD, 1 glucose-phosphate isomerase deficiency). HS cases were enrolled on the basis of ferritin >300 ng/mL at diagnosis. Cytokine levels were detected in serum by ELISA. Comparisons were made by Students T test (continuous) and Fisher's exact test (categorical), and correlations by Pearson's linear coefficient. Results: The main clinical and hematological findings are shown in table. Median Hb values progressively decreased in the 4 groups considered, being close to normal in HS and moderately reduced in CDAII patients, whereas hemolytic parameters were comparable among groups. Consistently with clinical severity, ferritin values were particularly high in CDAII (together with transferrin saturation-TfS) and PKD patients, notwithstanding chelation in about half cases of both groups. Of note, only 2 PKD patients were transfusion-dependent, suggesting that other factors are involved in iron overload. Splenectomy had been performed in 17/38 (44.7%), mainly CDAII. Liver iron concentration (LIC) showed a great heterogeneity in all groups, with a trend towards higher values in CDAII; 16/36 (44%) patients had a LIC>4 mg/g DW (23%, 33%, 38% and 88% in HS, HSt, PKD and CDAII, respectively). Cardiac T2* value was normal in all subjects, with the exception of a HS and a CDAII case. Regarding possible cofactors, 12/16 displayed at least one of the following: 1 homozygous for HFE C282Y and 1 for H63D mutations, 3 HCV+, 4 BMI>25, 2 alcohol abuse, 3 heterozygous for HFE mutations. The following positive correlations were observed at enrolment: LIC and ferritin (r=0.68, p<0.05), LIC and TfS (r=0.34, p=0.05), and cardiac T2* and TfS (r=0.34, p<0.05). Moreover Hb values at diagnosis negatively correlated with LIC (r=0.37, p<0.05). Interestingly, among the 28 cases with ferritin <800 ng/mL, 10 (36%) displayed liver iron overload (LIC>4), of whom 5 with the above listed cofactors. As regards cytokine levels, IL-10 was significantly increased in HS, PKD and CDAII groups compared with normal cases; TNF-alpha was decreased in HS and PKD, and IFN-gamma increased in HS and CDAII. Ferritin values were positively correlated with IL-6 and IFN-gamma, and TfS negatively with IL-6 (r= -0.38, p<0.05). Hepcidin values were slightly increased in CHAs compared with normal controls, and correlated positively with ferritin (r=0.33; p<0.05), and negatively with TfS (r= -0.56; p<0.001). Finally, hepcidin levels were positively correlated with IL-6 (r=0.62; p<0.001), and negatively with IFN-gamma (r=0.3; p<0.05). Conclusion: Iron overload is highly prevalent in CHAs, particularly in PKD and CDAII, is independent from transfusion support, and is also observed in cases with ferritin <800 ng/mL. T2* MRI is the gold standard approach to evaluate iron overload in CHAs (as in other congenital anemias) and its use is advisable, particularly in the presence of cofactors, for early chelation. Cytokine studies suggest the existence of a positive loop among ferritin, hepcidin, and inflammatory cytokines such as IL-6 and IFN-gamma, and of a negative loop among TfS, hepcidin, and the same inflammatory cytokines. These findings disclose important hints to understand the multiple biological mechanisms of iron overload, and support the rationale for new emerging therapies. Table Table. Disclosures Barcellini: Agios: Consultancy.
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Ishii, Kazusa, Haneen Shalabi, Bonnie Yates, Cindy Delbrook, Crystal L. Mackall, Terry J. Fry, and Nirali N. Shah. "Tocilizumab-Refractory Cytokine Release Syndrome (CRS) Triggered By Chimeric Antigen Receptor (CAR)-Transduced T Cells May Have Distinct Cytokine Profiles Compared to Typical CRS." Blood 128, no. 22 (December 2, 2016): 3358. http://dx.doi.org/10.1182/blood.v128.22.3358.3358.
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Abstract Background: Cytokine release syndrome (CRS) in the setting of CAR T cell therapy manifests as a wide constellation of symptoms with multi-organ involvement. CRS can vary from a mild, self-limited course to a life-threatening systemic inflammatory response which, in severe cases, may be associated with manifestations similar to those seen in hemophagocytic lymphohistiocytosis (HLH). Tocilizumab, an anti-human IL-6 receptor antibody, has become a widely accepted pharmacologic intervention of first choice in severe CRS based on the observation of elevated levels of inflammatory cytokines, most notably interleukin (IL)-6 and interferon (IFN)-γ. Indeed, following administration of tocilizumab, most patients show rapid signs of improvement. However, in rare circumstances, CRS may be refractory to tocilizumab, and repeat administration or institution of additional immunosuppression is needed. Here we summarize cytokine profiles and CRS seen in patients treated with anti-CD22-CAR T cells and propose tocilizumab-refractory CRS as a potentially distinct pathophysiological entity from typical CRS that may merit alternative immunosuppressive interventions other than tocilizumab. Methods: Children and young adults with relapsed/refractory CD22+ ALL were treated with anti-CD22 CAR T cells. Serial samples for serum cytokine levels (IFN-γ, IL-6, IL-2, IL-10, IL-12p70, IL-1β, IL-15, IL-13, IL-4, IL-8, TNF-α, GM-CSF, MIP1-α) were obtained at pre-specified time points (0, 12, 24, 48, 72 hours, then daily on days 4 - 14 and 28 following CAR T cell infusion). Transduced CAR T cell dosage ranged from 3x10e5 cells/kg (dose level [DL] 1), 1x10e6 cells/kg (DL2), and 3x10e6 cells/kg (DL3). CRS severity was determined according to recently proposed grading system (Lee DW et al., Blood. 2014). Disease burden was assessed using standard morphology and flow cytometry analysis of bone marrow and peripheral blood samples. Results: Cytokine profiles are available on 10 patients treated: first 9 patients enrolled in our phase I trial (NCT02315612), and the tenth patient was treated off-protocol on an emergency investigational new drug protocol given lack of alternative treatment option for rapidly progressing disease. All subjects, median age 20 years (range, 6-22 years), had a diagnosis of multiply relapsed ALL. Seven of 10 subjects developed CRS. Five subjects with CRS were complete responders to CAR therapy (Table). The median time to the onset of CRS was 9 days (range, 7-12 days) post-infusion and resolved within 1 week with supportive care alone except in one patient who received pharmacologic intervention for grade 4 CRS. Rise in C-reactive protein (CRP) tended to correlate with clinical severity of CRS. Chronological changes in the level of IFN-γ, IL-6, IL-1β, IL-8, TNF-α, and MIP1-α generally mirrored the CRP trend, typically preceding CRP change by 1-2 days. In contrast to the CRS (maximum grade 2) seen in the first 9 patients, the 10th patient treated at DL3 developed grade 4 CRS with manifestations characteristic of HLH unresponsive to tocilizumab. Cytokine profile for this patient, compared to those of other CRS patients, was notable for a substantially higher serum IL-2 (35 pg/mL vs median 6.1 (range, 1.2-13.5)) and GM-CSF level (28 pg/mL vs median 1.0 (range, 0-6.1)) at 12 hours post infusion. Subsequent CRP elevation was not initially accompanied by a rise in IL-6 as in other patients, which may have explained the lack of response to tocilizumab (Figure). Evaluation for a genetic cause of HLH did not reveal any mutations (PRF1, MUNC13-4, RAB27A, STX11, STXBP2). Although this patient was a complete responder to therapy, the clinical course was complicated by pre-existing respiratory compromise and bacteremia, which may have contributed to increased CAR toxicity with variability in the cytokine profile. Conclusion: Based on our early experience, we postulate that patients with an early increase in GM-CSF and IL-2 may potentially experience more atypical and severe CRS, which without a concomitant rise in IL-6, may not respond to tocilizumab and thus early intervention with other immunosuppression may be indicated. Analysis of larger numbers of patients is required to better delineate clinical confounders and to develop rational pharmacological approach to CAR-mediated inflammatory responses. Ongoing efforts are underway to further analyze clinical samples for biomarkers. Disclosures Mackall: NCI: Patents & Royalties: B7H3 CAR.
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van Beers, Eduard J., Wilma Barcellini, Stefan W. Eber, Janet L. Kwiatkowski, Jennifer A. Rothman, Ellis J. Neufeld, Mukta Sharma, et al. "Iron Overload Is Highly Prevalent in All Disease Severity States in Pyruvate Kinase Deficiency (PKD)." Blood 128, no. 22 (December 2, 2016): 2430. http://dx.doi.org/10.1182/blood.v128.22.2430.2430.
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Abstract Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children < 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was >1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) >3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values <0.05 were considered statistically significant. Results: Of the 194 patients, 111 (57%) were adults ≥18 years and 83 (43%) were children. The median age of enrollment was 20.6 y (range: 1.3-69.9). Splenectomy had been performed in 65% (126/194). Screening ferritin levels were available for 72% (140/194) and LIC for 32% (62/194). At enrollment, 48% (70/147) had iron overload as defined by ferritin and/or current chelation. Using the LIC criterion, iron overload had been present at some point in 86% (95/110) of patients. Ferritin positively correlated with LIC (n=45); r=0.62, p<0.0001. However, of 29 patients with an LIC measurement and a mean ferritin <1000 ng/mL, 15 (52%) had a LIC >3 mg/g DW. Baseline characteristics in patients with and without iron overload are shown in the Table. Notably, even in patients that were never regularly transfused and had a hemoglobin (Hb) >8.7 g/dl, the prevalence of iron overload was 26% (8/31). The frequency of iron overload was significantly higher in patients who had a prior splenectomy (p<0.0001), even after controlling for transfusion history (p<0.0001). Age was associated with iron overload (p=0.046); although, the age range of patients with iron overload was broad (1.3-69.9 years). The frequency of iron overload was significantly higher in those with a lower baselineHb(p=0.004) and higher bilirubin (p=0.03). Data on cardiac iron status was available for 66 patients.Only 2 had cardiac iron overload (defined as T2*<20ms); they were age 5 (T2* 17.8ms, LIC 5 mg/g) and 22 years (T2* 19.7ms, LIC 14 mg/g) at the time of the MRI. Of the 194 patients, 52 (27%) were from the Pennsylvania Amish community. These patients were managed differently than the non-Amish, in that only 2% of the Amish patients were on iron chelation therapy in the 12 months prior to enrollment compared with 43% among the non-Amish cohort. In addition, the Amish had a significant higher prevalence of splenectomy (96% vs 52%, p<0.0001) and proportion who had been historically transfused (79% vs 32%, p<0.0001). Despite these differences, the Amish patients had a lower prevalence of iron overload (34% vs. 51%). There was no significant difference inHbor enrollment age between the Amish and non-Amish cohorts. Conclusion: Iron overload is a common, serious complication in PKD, regardless of age, disease severity, or transfusion status. Although ferritin correlates with LIC for the PKD population overall, at the individual patient level, ferritin is not a good predictor of LIC and a ferritin <1000 ng/ml does not exclude hepatic iron overload. Therefore, we recommend that all patients with PKD starting at age 1 year should be screened annually for iron overload using ferritin and, at least once, using MRI. Disclosures Barcellini: Agios: Consultancy. Neufeld:Novartis: Consultancy. Morton:Agios Pharmaceuticals: Research Funding. Yaish:Octapharma: Other: Study investigator. Kuo:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: unrestricted educational grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:bluebird bio: Consultancy, Research Funding; Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Amgen: Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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"Recognition of the HLA class II-peptide complex by T-cell receptor: reversal of major histocompatibility complex restriction of a T-cell clone by a point mutation in the peptide determinant." Philosophical Transactions of the Royal Society of London. B, Biological Sciences 323, no. 1217 (June 12, 1989): 553–64. http://dx.doi.org/10.1098/rstb.1989.0035.
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Recognition of the HLA DR-peptide complex by an influenza haemagglutinin-specific T-cell clone was examined by assaying a variety of peptide analogues for their ability to be recognized. Consistent with earlier experiments arguing that the peptide blinds the restriction element in a helical conformation, acetylation of the amino terminus and amidation of the carboxy terminus of the natural determinant (residues 307-319) resulted in a peptide that exhibited both greater propensity to form a helix, as judged by circular dichroism, and the ability to stimulate the clone at concentrations approximately two orders of magnitude lower than the native sequence. The peptide was modelled into the potential antigen-combining site of HLA class II based on the ability of analogues containing point mutations to stimulate the T-cell clone. The working model was initially tested by examining the ability of Epstein-Barr-transformed B-cell lines expressing in different DR4 subtypes to present the native haemagglutinin sequence and analogues to the clone. The different alleles could be categorized as high, intermediate, or low responders based on the resulting proliferation. DR4 dw 15 was a high-responding allele, dw 4, 13, and 14 were intermediate-responding alleles, whereas dw 10 was a low responder. Mutation of Gin to Arg at 312 in the haemagglutim n sequence converted the high and intermediate responders to non-responders, while turning the low-responding allele into an intermediate responder. Potential explanations for these effects are discussed in the context of the model of the complex between peptide and the major histocompatibility complex.
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Cao, Chenxiang, Xueyao Han, Yumin Ma, Victor Joseph Bernet, and Jianzhong Xiao. "MON-LB120 MODY3 With Insulin Coding Gene Mutation and Craniofacial Microsomia: A Case Report." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.2136.
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Abstract Background: Maturity onset diabetes in young 3 (MODY 3) is caused by mutation of the hepatic nuclear factor 1 alpha (HNF-1A) gene. Craniofacial macrosomia (CFM) is associated with an abnormal development of craniofacial structures during the embryonic period. Maternal diabetes and genetic predisposition have been associated with CFM1. There are rare reports about an association of MODY 3 and CFM. Clinical case: An 11-year-old male patient presented with right side CFM (mild mandibular hypoplasia, internal auditory canal absence, severe pinna hypoplasia, abnormal orbital size and location, O3.M0.E3.N0.S02) noted at 8 months of age. Preoperative examination revealed A1c at 10.9%. After short term intensive insulin therapy, he had standard bread meal test: fasting glucose 8.11 mmol/L, insulin 13.9 mIU/L (3-25), C-peptide 1.25 ng/ml (0.81-3.85); 1 hour glucose 10.05 mmol/L, insulin 27 mIU/L, C-peptide 2.42 ng/ml; 2 hour glucose 8.17 mmol/L, insulin 16.09 mIU/L, C-peptide 2.11 ng/ml. GADA, IAA and ICA were negative. The mother was diagnosed diabetes at age 27years, when the patient was 8-month-old, and received insulin therapy. The mother was blind by age 35years due to diabetic retinopathy and died of DKA at 38-years-old. The patient’s 16-year-old brother had left side CFM (O2.M1.E2.N0.S0) and his OGTT was normal. The father was diagnosed with impaired glucose tolerance. The family had whole genome sequencing by Sanger technique, and resequenced the mutation with side primers. The CGA to CAA mutation was present at the 686 loci of exon 3 of HNF1A gene in the patient and mother. The HNF1A exon 3 mutation of CGA to CAA resulted in the change of arginine to glutamine which by the HGMA database is recognized as a reported MODY3 gene mutation. There was a mutation of G to A in the 4 loci of exon 1 of the insulin coding region in chromosome 11 in both the patient and elder brother. Neither elder brother nor father had the CGA mutation of HNF1A. Conclusion: There has not been a previous report of a relationship between HNF1A and CFM. In this case, the elder brother had CFM without a HNF1A mutation which does not support a connection between CFM and HNF1A. The two brothers both had CFM and insulin coding gene mutations which would represent a new association not previously described. Further testing is needed to confirm a relationship between the two. Reference: 1. Chen Q, Zhao Y, Shen G, Dai J. Etiology and Pathogenesis of Hemifacial Microsomia. J Dent Res 2018; 97(12): 1297-305. 2. Gougoutas AJ, Singh DJ, Low DW, Bartlett SP. Hemifacial microsomia: clinical features and pictographic representations of the OMENS classification system. Plast Reconstr Surg 2007; 120(7): 112e-20e.
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Brinkmeier, Michelle, and Sally Ann Camper. "SAT-288 Pituitary Developmental Defects Caused by Haploinsufficiency for the Transcription Factor SIX3 Are Worsened by POU1F1 Deficiency." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.634.
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Abstract Advances in genomic technologies are revolutionizing the practice of medicine by delivering molecular diagnoses that can be informative for prognosis and treatment of genetic disorders. Most of the known genetic causes of multiple pituitary hormone deficiency have been investigated as monogenic disorders. It can be challenging to predict clinical features from genetic data, as loss of function mutations in some genes can present with a spectrum of phenotypes ranging from craniofacial abnormalities, intellectual disability, and neurosensory and neuroendocrine defects to pituitary hormone deficiency with no other abnormalities. Although maternal exposures could be contributing factors, the contribution of rare, deleterious variation in other genes is a likely contributor. In humans, loss of function mutations in the transcription factor SIX3 cause variable, autosomal dominant holoprosencephaly with incomplete penetrance, and mouse models recapitulate some of the clinical features. Because Six3 and Pou1f1 gene expression patterns overlap in pituitary development, we hypothesized that doubly heterozygous mice (Six3+/-; Pou1f1+/dw) might have pituitary anomalies not present in singly heterozygous mice. We intercrossed Six3+/- and Pou1f1+/dw mice to produce doubly heterozygous animals. At e11.5, both Six3+/- and Six3+/-; Pou1f1+/dw exhibited abnormal morphology of the developing infundibulum and Rathke’s pouch, although ventral diencephalon expression of Tle4, Fgf10, and Nkx2.1 appeared normal. Both newborn Six3+/- and Six3+/-; Pou1f1+/dw littermates had abnormal pituitary gland morphology that resembled that of Aes-/-. AES is a co-repressor that interacts with SIX3. Specification of vasopressin neurons and anterior lobe hormone cell types appeared normal. Mice of all genotypes were born in expected Mendelian ratios (N=144, p=0.49), and there were no significant differences in body weight at 3 wks. A portion of the Six3+/- and doubly heterozygous mice developed hydrocephalus, exhibited failure to thrive, and died (6-9% of N=82, 85, respectively). At 6 wks, 25% (N=61) of the Six3+/-; Pou1f1+/dw animals exhibited striking pituitary dysmorphology in which the rostral aspect of the pituitary penetrated the palate. This was not observed in single heterozygotes. These results reveal that haploinsufficiency for Six3 affects Rathke’s pouch formation, resulting in pituitary gland dysmorphology in and around the stem cell niche. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease and highlighting phenotypic variability. Genetically engineered mice provide an excellent tool for assessing the possibility of gene-gene interactions that could enhance the severity of hypopituitarism and associated craniofacial development.
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"Errata." Journal of VitreoRetinal Diseases 1, no. 5 (September 2017): 352–53. http://dx.doi.org/10.1177/2474126417732356.
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An Ethical Approval Statement and/or Statement of Informed Consent should have been included for the articles listed below. Their corresponding statements are presented following the article information: Emerson GG, Kim JE, Packo KH, Flynn HW Jr. Guidelines for intraoperative time-out before corneal scraping and before fluid–air exchange. J Vitreoretin Dis. 2017;1(1):79-80. (Original DOI: 10.1177/2474126416680932) Ethical Approval: Ethical approval was not sought for the present study because no identifiable images or information were used and because this was a special correspondence. Statement of Informed Consent: Informed consent was not sought for the present study because no identifiable images were used. Ryder SJ, Tutiven JL, Gayer S, Miller D, Flynn HW Jr, Townsend JH. Retinal detachment repair in a patient with active Zika virus infection. J Vitreoretin Dis. 2017;1(1):81-83. (Original DOI: 10.1177/2474126416685495) Statement of Informed Consent: Informed consent was not sought for this case report because no identifiable images were used. Dubey N, Minija CK, Shanmugam MP. Intravitreal dexamethasone implant in a case of recurrent posterior scleritis. J Vitreoretin Dis. 2017;1(1):84-87. (Original DOI: 10.1177/2474126416681324) Statement of Informed Consent: Written informed consent was obtained from the patient to perform the procedure and have photographs taken. Kim H, Wang A, Mititelu M. Case series of anti-vascular endothelial growth factor and photodynamic therapy in the treatment of circumscribed choroidal hemangiomas. J Vitreoretin Dis. 2017;1(2):133-137. (Original DOI: 10.1177/2474126416687424) Statement of Informed Consent: Informed consent was not sought for the present study because no identifiable images were used. Cunningham WJ, Michael E, Welch S, Crosby N, Host B, Polkinghorne P. The Auckland Endophthalmitis Study: the incidence and management of endophthalmitis following intravitreal bevacizumab. J Vitreoretin Dis. 2017;1(3):175-180. (Original DOI: 10.1177/2474126417690987) Ethical Approval: Ethical approval for this study was waived by the Health and Disabilities Ethics Committees of New Zealand because the details of our study were such that ethics approval was not required. Statement of Informed Consent: Not applicable. Lee AC, Opremcak EM, Hunt C, et al. Severe corneal complications associated with corneal lubricant used during surgery. J Vitreoretin Dis. 2017;1(3):187-190. (Original DOI: 10.1177/2474126417698880) Ethical Approval: Ethical approval was not sought for the present study because it was a retrospective report and no identifiable data were included in the study. Statement of Informed Consent: Informed consent was not sought for the present study images because no identifiable images were used. Chen Y, Shah V, Jeroudi AM, Blinder KJ, Shah GK. Surgical detachment of the anterior hyaloid membrane from the posterior lens capsule: two techniques. J Vitreoretin Dis. 2017;1(3):214-217. (Original DOI: 10.1177/2474126417698873) Statement of Informed Consent: Informed consent was not sought for the present study because no identifiable images or data were used. Yau GL, Chin EK, Parke DW III, Bennett SR, Almeida DRP. West Nile virus chorioretinitis with foveal involvement: evolution of lesions on optical coherence tomography. J Vitreoretin Dis. 2017;1(3):218-221. (Original DOI: 10.1177/2474126417697593) Statement of Informed Consent: Informed consent was not sought for the present study because no identifiable images were used. Rahman R, Khan K, Stephenson J, Amjad M. Nonposturing surgery for persistent macular hole using heavy silicone oil (Oxane HD) endotamponade. J Vitreoretin Dis. 2017;1(4):246-250. (Original DOI: 10.1177/2474126417712645) Ethical Approval: Ethical approval was not sought for the present study because of the following reasons: The basis for this decision was made on the fact that there would be no change to the standard of care for patients studied and we were evaluating our service for failed macular holes treatment offered to patients. Statement of Informed Consent: Informed consent was not sought for the present study because it was not required as no identifiable images were used. Sundy M, Malihi M, Chang EY, et al. Retinal artery occlusions in healthy children. J Vitreoretin Dis. 2017;1(4):257-260. (Original DOI: 10.1177/2474126417710138) Statement of Informed Consent: Informed consent was not obtained for this multicenter retrospective case series because no identifiable images were used. Oellers P, Eliott D. Good visual outcome following vitrectomy for epiretinal membrane with foveal tissue herniation. J Vitreoretin Dis. 2017;1(4):278-280. (Original DOI: 10.1177/2474126417709382) Statement of Informed Consent: Informed consent was not sought for the present study because no identifiable images were used. Kovach JL. Persistent placoid maculopathy treatment response imaged with OCT angiography. J Vitreoretin Dis. 2017;1(4):281-283. (Original DOI: 10.1177/2474126417712646) Statement of Informed Consent: Informed consent was not sought for the present study because no identifiable images were used. Reyes-Capó D, Ventura CV, Tekin M, Lam BL, Berrocal AM. ABCA4 mutation in a patient with juvenile neuronal ceroid lipofuscinosis. J Vitreoretin Dis. 2017;1(4):284-286. (Original DOI: 10.1177/2474126417714136) Statement of Informed Consent: Written informed consent was obtained from the subject for the use of photographs for professional publication.
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"Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Percin EF, Ploder LA, Yu JJ, Arici K, Horsford DJ, Rutherford A, Bapat B, Cox DW, Duncan AMV, Kalnins VI, Kocak-Altintas A, Sowden JC, Trabousli E, Sarfarazi M, McInnes RR.∗1 Nat Gen 2000;25:397–401." American Journal of Ophthalmology 131, no. 1 (January 2001): 156–57. http://dx.doi.org/10.1016/s0002-9394(00)00921-1.
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Silva, Diego Romário, Rafaela Durrer Parolina Carvalho, Ana Caroline Rodrigues, Kaiane Tavares Pontes, and Andréa Cristina Barbosa da Silva. "Os produtos naturais são uma alternativa para o tratamento da candidose oral? Uma revisão de ensaios clínicos." ARCHIVES OF HEALTH INVESTIGATION 7, no. 12 (March 20, 2019). http://dx.doi.org/10.21270/archi.v7i12.3054.
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Introdução: a candidose oral é uma doença oportunista que acomete principalmente pacientes imunossuprimidos e usuários de prótese dentária total. Apesar da eficácia terapêutica dos antifúngicos utilizados atualmente para o tratamento desta doença, essas drogas apresentam muitos efeitos adversos relacionados à dose. Além disso, tem-se observado um aumento da resistência microbiana para esses agentes. Baseado nisso, uma fonte de busca promissora de princípios ativos alternativos para o tratamento da candidose oral são os produtos naturais. Objetivo: revisar a literatura sobre ensaios clínicos com produtos naturais para o tratamento da candidose oral, a fim de responder se existe evidência que os produtos naturais podem ser utilizados como tratamento alternativo para esta doença. Material e método: foi realizada uma síntese de todos os ensaios clínicos com produtos naturais para tratamento da candidose indexados banco de dados Pubmed. Resultado: seguindo os critérios de inclusão e exclusão entraram nesta revisão 6 estudos. Os estudos avaliaram a eficácia dos produtos naturais quanto aos parâmetros clínicos e micológicos e grau de satisfação do paciente. Conclusão: apesar da pouca quantidade de ensaios clínicos nesta temática, há evidência de que os produtos naturais podem ser usdos para tratar a candidose oral, especialmente alho, mamona, româ e melaleuca.Descritores: Produtos Biológicos; Candida; Imunidade.ReferênciasHani U, Shivakumar HG, Vaghela R, Osmani RAM, Shrivastava A. Candidiasis: A fungal infection- current challenges and progress in prevention and treatment. Infect Disorders Drug Targets. 2015;15(1):42-52.Pereira CA, Domingues N, Araújo MI, Junqueira JC, Back-Brito GN, Jorge AO. Production of virulence factors in Candida strains isolated from patients with denture stomatitis and control individuals. Diagn Microbiol Infect Dis. 2016;85(1):66-72.Patil S, Rao RS, Majumdar B, Anil S. 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Intensive Care Med. 2014; 40(9):1241-55.Alexander BD, Johnson MD, Pfeiffer CD, Jiménez-Ortigosa C, Catania J, Booker R et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56(12):1724-32.Shields RK, Nguyen MH, Press EG, Updike CL, Clancy CJ. Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob Agents Chemother. 2013;57(8):3528-35.