Search

Introduction: Indications for HSCT are increasing worldwide, paralleled by a growing demand for donors of therapeutic cells. Methods: Herein, we report our real-world experience of adult HPC donor assessment during a 5-year study period (2018-2023): we have retrospectively revised data of 455 potential related stem cell donors, consecutively evaluated at our center. Donor medical history was assessed by a questionnaire and an interview with a trained physician experienced in donation procedures to evaluate donor fitness and medical history. Pre-existing health disorders were fully investigated. Behavioral risk factors for communicable infectious diseases were also routinely explored. Results and discussion: Overall, 351 donors were finally assessed as eligible for HPC donation, and 233 underwent stem cell collection, 158 through apheresis from mobilized peripheral blood, and 75 through bone marrow harvest. Among them, 27 donors were selected despite the presence of pre-existing health conditions, which would be potential exclusion criteria for unrelated donors: 16 suffered from well-controlled cardiovascular diseases (CVD) and 11 from allergic diathesis. Most of the selected donors with pre-existing disorders were candidates for apheresis HPC collection (21, 77.8%), while only six (22.2%) underwent BM harvest. We then analyzed the data relative to the corresponding 233 allogeneic HSCT to explore if the presence of pre-existing diseases in the donors could show any association with transplant characteristics. Transplants from CVD and allergy donors showed no significant disparities in comparison with those from healthy donors. A significant difference emerged regarding the disease severity, with a higher proportion of patients with high/very high disease risk index (DRI) among those receiving grafts from CVD donors (68.7% in transplants from CVD donors versus 36.0% in transplants from healthy donors, p=0.005). Multivariate analysis confirmed that high/very high DRI patients had an increased probability of receiving donations from CVD donors (OR, 4.89; 95%CI, 1.15-20.86; p=0.031). Among donors with well-controlled pre-existing conditions, no adverse events were recorded during stem cell collection or at follow-up. Our results suggest that in patients at high risk for relapse requiring a prompt allogeneic transplant, a familiar donor might be accepted for HPC apheresis donation on less strict criteria than unrelated donors, without risk for both donor and patient. [ABSTRACT FROM AUTHOR]

Purpose: To explore the mechanism of insulin secretion dysfunction in pancreatic beta cells induced by N-glycosylation mediated by an infection from the hepatitis C virus (HCV). Methods: Min6 cell models infected with HCV and stimulated with glucose were constructed. Meanwhile, an HCV-infected animal model and a type 2 diabetes mellitus (T2DM) rat model were constructed. Glucose uptake in the Min6 cells was detected, and insulin secretion was detected by ELISA. Flow cytometry, immunofluorescence staining, Western blotting, RT-qPCR, and lectin blotting were used to detect the expression levels of related proteins and mRNA, as well as the level of N-glycosylation. HE staining was used to observe the pathological changes in the pancreatic tissue, and an oral glucose tolerance test (OGTT) was used to evaluate the glucose tolerance of the rats. Results: Compared with the NC group, the expression levels of GnT-IVa, GLUT2, galectin-9, and voltage-dependent calcium channel 1.2 (Cav1.2) were significantly downregulated in the HCV-infected group. The ATP-sensitive potassium channel (KATP) component proteins SUR1 and Kir6.2 were significantly upregulated, while intracellular glucose intake and insulin secretion decreased, N-glycosylation levels and ATP levels significantly decreased, and the overexpression of GnT-IVa reversed the effect of the HCV infection. However, treatment with the glycosylation inhibitor kifunensine (KIF) or the KATP channel activator diazine (Dia) reversed the effects of the overexpression of GnT-IVa. In the animal experiments, HE staining revealed serious pathological injuries in the pancreatic tissue of the HCV-infected rats, with decreased glucose tolerance and glycosylation levels, decreased insulin secretion, downregulated expression of GnT-IVa, GLUT2, and Cav1.2, and upregulated expression of SUR1 and Kir6.2. The overexpression treatment of GnT-IVa or the KATP channel antagonist miglinide reversed the effects of HCV. Conclusion: HCV infection inhibits GLUT2 N-glycosylation on the pancreatic β cell surface by downregulating the expression of GnT-IVa and then activates the KATP pathway, which ultimately leads to disturbances in insulin secretion. [ABSTRACT FROM AUTHOR]

Seven groups, each consisting of two to nine unrelated HLA-A, -B, and -DR serologically identical individuals, were analyzed by DNA-restriction fragment length polymorphism (RFLP) and mixed lymphocyte reactions (MLR) in order to evaluate HLA-class II identity between unrelated individuals and to assess the importance of HLA-class II incompatibilities detected by DNA-RFLP in the allogeneic reactions. It is clear that DNA-RFLP represents a powerful typing method for HLA-DR, -DQ, and -DP since the combinations of the RFLP band patterns define all the serological specificities and most of the cellular specificities to give a highly accurate typing. This report shows that an HLA-DP incompatibility induces proliferation in primary mixed lymphocyte culture (MLC) between unrelated HLA-A, -B, -DR, -DQ, and -DW identical individuals, which may suggest the importance of this molecule as a transplantation antigen, especially for unrelated bone marrow transplantations. Still, an isolated HLA-DPw4/HLA-DP a disparity did not induce any proliferation in MLC. Moreover, our results show that DQw7 (w3)/DQw8 (w3) disparity associated with HLA-DR4 represents a nonfunctional incompatibility in MLR. The HLA-Dw subtypes of HLA-DR specificities can induce a high proliferative response in MLC. The HLA-Dw subtypes of HLA-DR specificities can induce a high proliferative response in MLC. Finally, DNA-RFLP typing represents a reliable method for the selection of histocompatible donor-recipient pairs and could potentially reduce many logistic problems and delays in live-donor transplantation, especially for unrelated bone marrow transplantation.

In a study carried out for patients receiving intrafamilial HLA-A,B,DR identical, MLC negative bone marrow transplants, RFLP profiles of HLA-class II for 27 donor recipient pairs were analyzed. Twenty-four pairs were found HLA-class II identical while three pairs were HLA-DP incompatible. The patients of these three pairs did not reveal any acute GVHD greater than or equal to grade II. The seven cases of acute GVHD greater than or equal to grade II found in our panel were HLA-DR, DQ, and DP compatible. Thus, in practical terms pretransplantation HLA-DP typing does not seem necessary for intrafamilial HLA-identical, MLC negative BMT. On the other hand, this work confirmed that it is possible to type for HLA-DP using molecular biological techniques, and this in itself may have some important implications for unrelated BMT.

From a bank of 50,000 HLA typed French bone marrow donors, 125 transplants have been performed since 1986, with HLA AB and DR--identical MLC--negative donors. The median age was 25 years and the diagnosis was CGL in 59 cases, ALL in 22 cases, AML in 17 cases, SAA in 7 cases, inborn errors in 7 cases and others in 13 cases. Most of the patients received a standard conditioning regimen according to their diagnosis. The prophylaxis of GVHD was methotrexate and cyclosporine A in 77 cases; in addition to this combination 44 patients received an anti-IL2 receptor monoclonal antibody from day +1 to day +28. There was no difference between the two groups as regards the incidence and severity of GVH or survival. The actuarial survival was 36% with a median follow up of 300 days. Unlike matched sibling grafts, the usual prognostic factors such as stage of disease or age were not found to significantly modify the incidence of GVHD, which was 75%. The results of matched unrelated donor transplants are reasonably good, but must be improved by a better selection of donors and better prevention of GVHD.

Race, ethnicity, and ancestry are terms that are often misinterpreted and/or used interchangeably. There is lack of consensus in the scientific literature on the definition of these terms and insufficient guidelines on the proper classification, collection, and application of this data in the scientific community. However, defining groups for human populations is crucial for multiple healthcare applications and clinical research. Some examples impacted by population classification include HLA matching for stem-cell or solid organ transplant, identifying disease associations and/or adverse drug reactions, defining social determinants of health, understanding diverse representation in research studies, and identifying potential biases. This article describes aspects of race, ethnicity and ancestry information that impact the stem-cell or solid organ transplantation field with particular focus on HLA data collected from donors and recipients by donor registries or transplant centers. [ABSTRACT FROM AUTHOR]

Placental neovascularization plays a crucial role in fetomaternal circulation throughout pregnancy and is dysregulated in several pregnancy-related diseases, including preeclampsia, gestational diabetes mellitus, and fetal growth restriction. Endothelial progenitor cells (EPCs) are a heterogeneous population of cells that differentiate into mature endothelial cells, which influence vascular homeostasis, neovascularization, and endothelial repair. Since their discovery in 1997 by Asahara et al., the role of EPCs in vascular biology has garnered a lot of interest. However, although pregnancy-related conditions are associated with changes in the number and function of EPCs, the reported findings are conflicting. This review discusses the discovery, isolation, and classification of EPCs and highlights discrepancies between current studies. Overviews of how various diseases affect the numbers and functions of EPCs, the role of EPCs as biomarkers of pregnancy disorders, and the potential therapeutic applications involving EPCs are also provided. [ABSTRACT FROM AUTHOR]

Introduction: The large HLA diversity in worldwide populations is a major challenge for matched unrelated haematopoietic stem cell (HSC) donor searches. The impact of regional diversity on the effective HSC donor selection has not been documented so far for national registries. Methods: The aim of the study was to analyse the 532 consecutive work-up (WU) requests received by Swiss Blood Stem Cells (SBSC), over a 9-year period (2011–2019) with respect to criteria including the geographical origin of the donors as derived from the postal codes, countries requesting SBSC donors, HLA-matching parameters, and patients' HLA haplotype frequencies. Results: Highly matched donors (10/10) represented 73.5% of the WU, whereas 8–9/10 mismatched donors accounted for 24.0%. The remaining donors were 7–8/8 matched (1.7%) or had an unknown matching grade (0.8%). Among the 10/10 matched patient/donor pairs with full HLA-DPB1 typing information, the rate of 11–12/12 matched donors was 73.3%. Of the 532 WU requests, 47.6% were for patients of the four neighbouring countries and for national patients. The ratio of WU requests was directly proportional to the total number of donors registered in each region (Pearson's r = 0.977). However, for two regions (lemanic and north-eastern areas of Switzerland (CH)), the proportion of selected donors was slightly above the min-max ratio of registered donors throughout the study period. The number of WU requests differed between countries when considering donors from the northern and southern parts of the country delineated by the alpine barrier. Conclusion: This study shows the value of the SBSC registry for both national and international patients. Two countries (USA and Germany) which operate the two worldwide largest registries (>19 million donors) requested 30% of SBSC registered donors, while the Swiss transplant centres accounted for 13% of the WU requests. When considering the geographic origin of SBSC donors, we observe a correlation of WU requests with the total number of registered donors in each subregion. This finding thus supports recruitment efforts throughout all regions. Interestingly, donors from three regions (lemanic area, Zurich and Ticino) are slightly over-represented, which is possibly related to higher HLA haplotypic diversity. A focus on planning recruitment in these regions might contribute to more successful donor searches. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) is a universally prevalent pathogen and a major cause of liver-related morbidity and mortality worldwide. The evolution of antiviral therapy for HCV has rapidly progressed from interferon (IFN)-based therapies to IFN-free combinations of direct-acting antivirals (DAAs). Aims: This study aims to assess the response of DAAs in chronic hepatitis C (CHC) patients and to study the various factors affecting the response of DAAs in CHC. Settings and Design: This longitudinal observational study spanning over a year was conducted in the Medicine department of a tertiary care teaching hospital. Materials and Methods: The study was conducted on 400 adult CHC patients, diagnosed by a positive anti-HCV antibody test and a detectable viral load (HCV RNA) by real time polymerase chain reaction (RT-PCR), registered for treatment with DAAs. The first 400 patients satisfying the eligibility criteria were enrolled by non-probability consecutive sampling. All the participants were treated as per the National Viral Hepatitis Control Programme (NVHCP) guidelines. Repeat HCV viral load was done at or after 12 weeks of completion of anti-viral therapy to ascertain sustained virological response (SVR). Various factors which might predict treatment response were analyzed. Statistical Analysis Used: The continuous variables were expressed as mean and standard deviation, while the categorical variables were summarized as frequencies and percentages. The Student's independent t-test was employed for the comparison of continuous variables. The Chi-square or Fisher's exact test, whichever is appropriate, was employed for the comparison of categorical variables. Multivariate Logistic Regression was used to identify the independent predictors of treatment nonresponse. A P < 0.05 was considered statistically significant. Results: The mean age of the subjects was 42.3 ± 15.23 years with a male-to-female ratio of 1.96:1. Most of the patients (80.5%) were non-cirrhotic; among 19.5% cirrhotic, 13% were compensated while 6.5% were decompensated cirrhotic. The overall SVR done at or after 12 weeks of completion of treatment was 88.75%. Age, gender distribution, occupation, socioeconomic status, educational status, body mass index, treatment regimen, duration of treatment, and baseline viral load did not alter the treatment response. Among comorbidities, only diabetes mellitus (DM) and human immunodeficiency virus (HIV) co-infection adversely affected the treatment response (P = 0.009 and P < 0.001, respectively). Intravenous (IV) drug abuse was significantly associated with treatment failure (P < 0.001). The presence of liver cirrhosis (P < 0.001), thrombocytopenia (P < 0.001), elevated transaminases (alanine transaminase: P = 0.021, aspartate transaminase: P < 0.001), and previous treatment experience (P = 0.038) were other significant predictors of treatment failure. Conclusions: DAAs are highly efficacious drugs in the treatment of CHC with a high rate of treatment response. Significant predictors of CHC treatment failure included comorbidities especially DM and HIV co-infection, IV drug abuse, presence of liver cirrhosis, thrombocytopenia, elevated transaminases, and previous treatment experience. However, independent predictors of treatment nonresponse observed in this study were thrombocytopenia, IV drug abuse, and liver cirrhosis. Résumé Contexte: Le virus de l'hépatite C (VHC) est un agent pathogène universellement répandu et une cause majeure de morbidité et de mortalité liées au foie dans le monde. L'évolution de la thérapie antivirale pour le VHC a rapidement progressé des thérapies à base d'interféron (IFN) à des combinaisons sans IFN de médicaments à action directe antiviraux (AAD). Objectifs: Cette étude vise à évaluer la réponse des AAD chez les patients atteints d'hépatite C chronique (HCC) et à étudier les différents facteurs affectant la réponse des AAD dans les CHC. Cadres et conception : Cette étude observationnelle longitudinale s'étalant sur un an a été menée dans le département de médecine d'un hôpital universitaire de soins tertiaires. Matériels et méthodes: L'étude a été menée sur 400 patients adultes atteints d'HCC, diagnostiqués par un test d'anticorps anti-VHC positif et une charge virale détectable (ARN du VHC) par réaction en chaîne par polymérase en temps réel, inscrit pour le traitement par DAA. Les 400 premiers patients répondant aux critères d'éligibilité ont été enrôlés par échantillonnage consécutif non probabiliste. Tous les participants étaient traités conformément aux directives du programme national de contrôle de l'hépatite virale. La charge virale répétée du VHC a été effectuée à ou après 12 semaines d'achèvement traitement antiviral pour déterminer la réponse virologique soutenue (RVS). Divers facteurs susceptibles de prédire la réponse au traitement ont été analysés. Analyse statistique utilisée: les variables continues ont été exprimées sous forme de moyenne et d'écart-type, tandis que les variables catégorielles ont été résumés sous forme de fréquences et de pourcentages. Le test t indépendant de Student a été utilisé pour la comparaison des variables continues. Le chi carré ou Le test exact de Fisher, selon le cas, a été utilisé pour la comparaison des variables catégorielles. La régression logistique multivariée a été utilisée identifier les prédicteurs indépendants de la non-réponse au traitement. A P < 0.05 était considéré comme statistiquement significatif. Résultats: L'âge moyen des sujets était de 42.3 ± 15.23 ans avec un ratio hommes-femmes de 1.96:1. La plupart des patients (80.5%) étaient non cirrhotiques ; parmi 19.5% de cirrhose, 13% étaient compensés alors que 6.5% étaient cirrhotiques décompensés. La RVS globale effectuée à 12 semaines ou après la fin du traitement était 88.75%. Âge, répartition par sexe, profession, statut socio-économique, niveau d'instruction, indice de masse corporelle, schéma thérapeutique, durée du traitement, et la charge virale de base n'a pas modifié la réponse au traitement. Parmi les comorbidités, seuls le diabète sucré (DM) et l'immunodéficience humaine la co-infection par le virus (VIH) a affecté négativement la réponse au traitement (P = 0.009 et P < 0.001, respectivement). L'abus de drogues par voie intraveineuse (IV) a été significativement associée à l'échec du traitement (P < 0.001). La présence de cirrhose du foie (P < 0.001), thrombocytopénie (P < 0.001), élévation les transaminases (alanine transaminase: P = 0.021, aspartate aminotransférase: P < 0.001) et l'expérience de traitement antérieure (P = 0.038) étaient d'autres facteurs prédictifs significatifs d'échec thérapeutique. Conclusions: les AAD sont des médicaments très efficaces dans le traitement de l'HCC avec un taux de traitement élevé réponse. Les facteurs prédictifs significatifs d'échec du traitement des CHC comprenaient les comorbidités, en particulier la co-infection par le diabète et le VIH, l'abus de drogues par voie intraveineuse, la presence de cirrhose du foie, de thrombocytopénie, d'élévation des transaminases et d'antécédents de traitement. Cependant, des prédicteurs indépendants du traitement les non-réponses observées dans cette étude étaient la thrombocytopénie, l'abus de drogues intraveineuses et la cirrhose du foie. Mots-clés: Cirrhose, antiviraux à action directe, virus de l'hépatite C, toxicomanie par voie intraveineuse, réponse virologique soutenue, thrombocytopénie [ABSTRACT FROM AUTHOR]

Despite over 41 million registered potential volunteer stem cell donors worldwide, many patients in need of a transplant do not find an HLA-matched unrelated donor or cord blood units, with the respective odds differing significantly between various populations. In this study, we analysed data of 2205 unsuccessful real-life donor searches sent to the DKMS Registry to identify populations in which further donor recruitment would be associated with particularly large patient benefits. For that purpose, we estimated haplotype frequencies of 67 donor populations at various sample sizes and entered them into two different mathematical models. These models assessed patient benefits from population-specific donor recruitment, operationalised by the number of originally unsuccessful searches that may become successful due to new donors. Consistently, across the different mathematical models and sample sizes, we obtained several countries from East and Southeast Asia (Thailand, Vietnam, China, and the Philippines) and the population of Asians in the USA as countries/populations where donor recruitment activities would be particularly beneficial for patients. We also identified various countries in Southeast and Central Europe as possible target regions for donor recruitment with above-average patient benefits. The results presented are registry-specific in the sense that they were obtained by optimising unsuccessful searches that had been sent to the DKMS Registry. Therefore, it would be desirable to apply the presented methods to a global data set that includes all unsuccessful stem cell donor searches worldwide and uses population-specific haplotype frequencies based on all donors available in the WMDA Search & Match Service., (© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

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1. Beneficial effect of HLA matching is observed mainly among sensitized recipients. 2. Two DR and at least 1A and 1B antigen shared between donor and recipient significantly improve the results at 5 years.

This is the first time a study has been undertaken on the HLA profile of the Martinican population, a population which is essentially the product of intermixture between African-Negroes and French Caucasians. Two hundred and thirty-eight nonrelated subjects were typed for the A and B loci, 158 subjects for C locus and 128 for DR locus. After analysis of our parameters (antigen and gene frequencies, linkage disequilibria, etc.) and their comparison to those found in the Black and Caucasian control populations, we came to the conclusion that our racially-mixed population is closer to the African-Negro population than to the French Caucasian. A study of the average gene flow enabled us to evaluate the Caucasian contribution as being about 30%. This figure is subject to change inasmuch as racial intermixture continues. Socio-cultural variables are assumed to play a minimal role, given the high rate of illegitimacy.

The outcome of 893 prospectively typed (HLA-A, B, and DR) and matched cadaveric kidney transplants--all first grafts, with patients being transfused before transplantation--was studied using actuarial survival methods. The effect of HLA-A, B and DR matching was only found to be significantly beneficial to graft survival in the group of 289 presensitized recipients: 70% and 43% graft survival at two years in the case of best-matched (4-6 HLA-A, B, and DR) identities versus mismatched (0 and 1 HLA-A, B, and DR) identities, respectively (P = 0.05). Although a cumulative effect of matching for antigens belonging to the 3 HLA-A, B, and DR series was observed among the group of preimmunized recipients, a trend arose in favor of the prominent role of the HLA-B alleles. No significant difference related to HLA matching was observed in the group of nonsensitized recipients. These results confirm previous observations and support efforts to give priority for matched kidneys to preimmunized patients.

HLA antigens (27 HLA alleles of the A and B loci) were determined in 20 subjects of the same family, covering three generations; 6 of them were suffering from hereditary hemorrhagic telangiectasia. The haplotype HLA A2, Bw17 was found in all the sufferers. The same haplotype was not found in clinically health members except two of the generation III, but a visceral angiomatosis without clinical evidence cannot be excluded. An association of hereditary hemorrhagic telangiectasia with the haplotype HLA A2, Bw17 can be suspected in this family.

To study the HLA-B7 and HLA-B27 antigenic determinants, hybrid genes between these two alleles were constructed by in vivo recombination in Escherichia coli. After transfection of these genes into P815 (high transfection efficiency recipient) murine cells, the bindings of Bw6, HLA-B7, and HLA-B27 allele-specific mAb were studied, as well as that of human anti-HLA-B7 and anti-HLA-B27 monospecific alloantisera. Most of the HLA-B7 antigenic determinants were assigned to the first external domain of the molecule. Four different epitopic areas could be defined: the Bw6 epitope was associated with residues 82 and 83; the BB7.1 epitope to amino acids 63, 67, and 70; the MB40.2 and MB40.3 epitope to amino acid sequence 177-180, and human alloantisera identified as an epitope associated with residue 9. HLA-B27 antigenicity studied by TM-1 mAb was found to involve residues 77 and 80 in the alpha-1 domain. Results obtained with human monospecific alloantisera allowed the definition of an additional allospecific site associated with the NH2 terminal part on the alpha-1 domain of HLA-B27. Epitope mapping fits with data obtained by sequence comparisons and is discussed with reference to the crystallographic three-dimensional structure of the HLA-A2 molecule.

Our recent segregation analysis, carried out on 27 large pedigrees from a Caribbean island (Desirade), has shown the presence of recessive major gene(s) controlling susceptibility to leprosy per se and nonlepromatous leprosy, respectively. Linkage analysis was performed between each of these two detected genes and each of five markers typed in the Desirade population: HLA, ABO, Rhesus, Gm and Km. No positive significant lod score was observed. However, for leprosy per se close linkage was excluded with Rhesus and Gm (and also with ABO and HLA, considering a lower value for the frequency of the gene controlling susceptibility to leprosy per se). The highest lod score, although not significant, was obtained between the gene for nonlepromatous leprosy and ABO. Our overall results, joined with previous studies and experimental data, suggest that the gene controlling susceptibility to leprosy per se and that controlling susceptibility to nonlepromatous leprosy might be different, acting at successive stages of the immune response to infection with Mycobacterium leprae.

HLA-A,B,C, and DR frequencies have been determined in 34 Coloured Martinican IDDM patients to establish the HLA and IDDM associations. HLA A3, B15, B18, Cw3 and DR4 antigens associations with IDDM are confirmed by this study. We found an increase of B21 similar to that found in Asiatic Indians. As in some African Black populations and in Cape coloured people, A1, B8, and DR3 are not increased in our population. We should point out that our patients' ages of onset were low, and that some studies have found DR4 association in young patients and DR3 in older ones. The protective role of DR2 is confirmed here. B35 and Cw4 negative associations have been found. We have observed that the antigens associated with IDDM are decreased in our control population, except DR4, and that the negative associated DR/ and Cw4 antigens are increased compared to the Continental French population. This corresponds with the low IDDM incidence in Blacks and Coloured people.

A program to obtain volunteer bone marrow donors has been developed. A total of 33.000 HLA-A, B typings were performed. A search for 527 patients has been initiated. Among these, 44% are suffering from chronic myelogenous leukemia. For 23% of the patients no HLA-A, B identical donor has been identified. Out of the 401 patients who had HLA-A, B identical donor 35% (139/401) had one or more HLA-A, B, DR identical donors. In one of the transplant center, when the mixed lymphocyte culture (MLR) was carried out between 219 donors and 79 patients, a transplantation for 20/79 patients has been proposed. Up to now, transplantation has been carried out in 31 patients whom donor searches were initiated.

Thirty members of Family C, which included cases of alkaptonuria and ochronosis, were investigated by means of HLA typing and homogentistic acid determination. The antigen HLA B27 was found in one of the two members of the first generation, in all eight members of the second generation, and in 15 of the 21 members of the third generation. Eight of 10 subjects suffering from alkaptonuria, with or without ochronotic arthropathy or spondylosis, had B27. The gene for B27 is not the gene determining homogentisic acid oxydase synthesis but this study suggests that it may be associated or linked to it.

The effector cell populations in human peripheral blood responsible for antibody-dependent cellular cytotoxicity against allogenic cells coated with HLA polyspecific antibodies were investigated using several separation techniques including preparative electrophoresis. Electrophoresis produced a marked effector cells enrichment in a range of 2--5 fractions which exhibited an intermediary electrophoretic mobility. Monocytic cells do not contribute an effector mechanism but minor subsets of polymorphonuclear cells and nylon wool non-adherent non-phagocytic lymphocytes displayed ADCC. Both effector cell populations were found to exhibit a similar electrical charge of cell surface centered around -1.05 micrometer . sec-1 V-1 cm. These observations provided a precise biophysical basis for the identification of effector cells in ADCC.

Thirty-seven patients with chronic granulocytic leukemia have been treated with supralethal chemoradiotherapy followed by transplantation of bone marrow from HLA-identical donors. All patients showed engraftment, and the Philadelphia chromosome (PH1) disappeared in each case. Four patients had syngeneic grafts before blast crisis and are still alive; 2 are in remission not maintained by therapy, and 2 others are receiving chemotherapy after having relapsed in the chronic phase. Thirty-three patients had allogeneic grafts; only 2 received the grafts during blast crisis, and neither is a long-term survivor. Of the 13 patients who had grafts in the accelerated phase, 6 died of complications related to the transplantation, and 1 died after a myeloblastic relapse. Thus 6 patients are in unmaintained remission with a median follow-up of 13 months. Eighteen patients received grafts in the chronic phase. All 10 survivors are in unmaintained remission with a median follow-up of 14 months; in this group, no patient has relapsed. The granulocytic hyperplasia of the chronic phase can be more effectively ablated than established blastic leukemia. The mortality rate of transplant-related complications must be weighted against the typical rate of progression of chronic granulocytic leukemia. Although a longer follow-up period is needed for full evaluation, bone marrow transplantation may now be offered to patients in the chronic phase in an attempt to achieve long-term survival or cure of more than one-half of these patients.

In a young girl with a severe combined immunodeficiency, the presence of circulating maternal T lymphocytes was proven by HLA typing. Manifestations of skin graft vs host disease were associated with the persistence of maternal cells. The patient received an HLA identical bone marrow transplantation from her brother without any conditioning. The bone marrow transplantation was quickly followed by a transient and dramatic increase in skin lesions associated with fever and the finding of a high number of circulating lymphocytes and eosinophils. Lymphocytes were shown to be of donor origin and exerted a spontaneous cytotoxic activity toward maternal cells. This activity progressively disappeared within 90 days, whereas maternal cells were no longer detected in patient's blood, and skin graft vs host disease was resolved within 8 wk. Cytotoxic activity was proven to be mediated by donor T lymphocytes specific for the mother's HLA antigens. The cytotoxic activity was demonstrated to be specific for the HLA class I molecules of the mother not shared with her daughter (HLA A1, B17) as shown by the use of a series of HLA typed cells as targets. In addition, cold K562 target cells did not block the cytotoxic activity, and the kinetics of the cytotoxic activity did not correlate with that of natural killer activity emergence after the bone marrow transplantation. Patient's serum did not contain antibodies toward maternal specific HLA class I antigen. Cytotoxic activity was totally blocked by anti-T3 monoclonal antibodies and partially by anti-T8 and anti-T4. It is thus likely that donor origin cytotoxic T lymphocytes were promptly activated after bone marrow transplantation and provoked the elimination of the maternal graft after a transient exacerbation of graft vs host disease manifestations. This observation represents one of the first examples of the possible role in vivo of allogeneic cytotoxic lymphocytes in humans.

Background: Human leukocyte antigen (HLA)‐matched unrelated donors are not available for some patients considered for allogeneic hematopoietic cell transplantation, particularly among certain ethnic groups. Simulated recruitment modeling can inform efforts to find new matches for more patients. Methods: Simulated recruits were generated by assigning a pair of donor HLA haplotypes from historical data files and matched against HLA data of patient searches in the Canadian Blood Services Stem Cell Registry. Recruitment cohorts reflected the proportion of five specific ethnic groups in the 2016 Canadian census data. Results: Novel 8/8 HLA matches between simulated recruits and patients increased linearly with larger recruitment cohorts. The proportion of novel 8/8 HLA matches from Caucasian, Hispanic, and Native American/First Nations recruits was equal to or greater than their relative proportion in the recruited cohort (match to: recruit ratio (MRR) ≥ 1). In contrast, African American and Asian & Pacific Islander recruits represented a smaller proportion of novel matches relative to their percentage of the recruited cohort (MRR <1). The proportion of novel 7/8 HLA‐matches from each ethnic group was approximately the same as their proportion in the recruited cohort (MRR ~ 1) and high rates of 7/8 HLA‐matching already exist within the Canadian Blood Services registry for all ethnic groups. Conclusion: Continued large recruitment cohorts are needed to add new 8/8 HLA matches to registry inventories. Likelihoods of novel HLA matches varied across ethnic groups, reflecting varied HLA haplotype frequencies across groups. Simulated cohort modeling can inform recruitment strategies that will generate new donor options for patients. [ABSTRACT FROM AUTHOR]

Donor screening has nearly eliminated the risk of hepatitis C virus post-transfusion transmission in resource-rich settings. Moreover, the use of direct antiviral agents made it possible to treat the majority of patients with thalassemia and hepatitis C. However, this achievement, while extremely significant, does not erase the effects of the virus in terms of fibrogenesis and mutagenic risk, and adult patients with thalassemia are facing the long-term consequences of the chronic infection both on the liver and extrahepatically. As in the general population, it is in mainly patients with cirrhosis who are increasing in age, even though they are now HCV RNA-negative, who are at risk of hepatocellular carcinoma, which continues to be statistically much more frequent in individuals with than without thalassemia. In certain resource-limited settings, the World Health Organization has estimated that up to 25 percent of blood donations do not undergo screening. It is therefore not surprising that hepatitis virus infection is still the most prevalent in patients with thalassemia worldwide. [ABSTRACT FROM AUTHOR]

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor–suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type. Probing p53 mutations: p53 is a tumor suppressor that is variably mutated across many cancer types and represents an ideal target for therapeutic rescue. Although each of these mutations inactivates p53, they do so through diverse mechanisms, making each mutation rescuable to a different degree, which has not been studied. To elucidate this, Song et al. have evaluated the 800 most frequent p53 mutations for their ability to be rescued by aresenic trioxide (ATO). They found that solvent accessibility and temperature sensitivity were key determinants of the rescue potential of mutant p53 by ATO and created a classification for p53 mutations that may benefit from this therapy. —DH [ABSTRACT FROM AUTHOR]

Human leukocyte antigens (HLA) represent one of the most polymorphic systems in humans, responsible for the identification of foreign antigens and the presentation of immune responses. Therefore, HLA is considered to play a major role in human disorders, donor-recipient matching and transplantation outcomes. This study aimed to determine the HLA class I and II alleles and haplotypes in the Greek population. Moreover, a comparative analysis of HLA alleles and haplotype frequencies found in Greek and pooled European populations was also performed to acquire a better knowledge about the HLA alleles distribution. A total number of 1896 healthy individuals were typed for their HLA alleles in the National Tissue Typing Center of Greece. High-resolution HLA typing for the HLA-A, -B, -C and -DR, -DQ, -DP with the use of the next-generation sequencing analysis was performed, followed by data analysis for establishing the HLA allele and haplotype differences. The results of this study showed that the most frequent alleles for the HLA-A were the A*02:01:01 (27.1%), *24:02:01 (14.4%), *01:01:01 (9.3%), for the HLA-B were the B*51:01:01 (15.3%), *18:01:01 (9.7%), *35:01:01 (6.8%) and for the HLA-C were the C*04:01:01 (15.4%), *07:01:01 (13.1%), *12:03:01 (9.6%). For the HLA class II, the most frequent alleles for the HLA-DRB1 were the DRB1*11:04:01 (16.4%), *16:01:01 (11.3%), *11:01:01 (9.5%), for the HLA-DQB1 were the DQB1*03:01:01 (30.5%), *05:02:01 (15.1%), *05:01:01 (10.6%) and for the HLA-DPB1 were the DPB1*04:01:01 (34.8%), *02:01:01 (11.6%), *04:02:01 (7.3%). Additionally, the most frequent haplotypes were the A*02:01:01∼C*07:01:01-B*18:01:01∼DRB1*11:04:01 (2.3%), followed by the A*01:01:01∼C*07:01:01∼B*08:01:01∼DRB1*03:01:01 (2.2%), A*24:02:01∼C*04:01:01∼B*35:02:01∼DRB1*11:04:01 (1.4%) and A*02:01:01∼C*04:01:01∼B*35:01:01-DRB1*14:01:01 (1.2%). The results herein were comparable to those obtained from the pooled European populations. Moreover, these results can be used for the improvement of the donor-recipient matching procedure and to understand better the disease association in Greece., (© 2024 John Wiley & Sons Ltd.)

Simple Summary: Hepatitis C is a liver infection caused by the hepatitis C virus and is a major health problem that contributes to the global burden of chronic disease. Chronic infection can lead to liver cancer and death from end-organ damage. Despite the introduction of novel anti-viral therapy, the disease burden is still high. This review focuses on the various extrahepatic manifestations of the hepatitis C virus, including frequency, mechanism, and outcomes. Despite the introduction of direct-acting antiviral drugs which have more than a 90% rate of sustained virologic responses, about one-third of patients with chronic HCV infections still develop at least one extrahepatic manifestation. Hepatitis C virus (HCV) is a significant cause of chronic liver diseases worldwide and is associated with negative consequences, including cirrhosis, hepatic decompensation, hepatocellular carcinoma, and increased risk of mortality. In addition to liver-related morbidities, HCV is also associated with several extrahepatic manifestations, including mixed cryoglobulinemia, diabetes mellitus, cardiocerebrovascular disease, lymphoma, and autoimmune diseases. These non-liver-related complications of HCV increase the complexity of this disease and can contribute to the economic burden, morbidity, quality of life, and mortality throughout the world. Therefore, understanding how this virus can contribute to each extrahepatic manifestation is worth investigating. Currently, the advancement of HCV treatment with the advent of direct-acting anti-viral agents (DAAs) has led to a high cure rate as a result of sustained virologic response and tremendously reduced the burden of extrahepatic complications. However, HCV-associated extrahepatic manifestations remain a relevant concern, and this review aims to give an updated highlight of the prevalence, risk factors, associated burdens, and treatment options for these conditions. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation (SCT) offers a potential cure for some hematological malignancies. For those patients without a family donor, unrelated donor (MUD) registries serve for identifying the best donor. In the present study, we aimed to give a cross-sectional report of our registry's activity and experience as the first established national MUD registry in the country. The study is retrospective and covers the period of 2016 to 2019. A total of 1855 donor searches were performed, and 642 were included in the study. All data were electronically obtained from the institutional database system. All SCTs were either 10/10 or 9/10 HLA matched and originated from an international registry. The most preferred stem cell source was peripheral blood (70.2%). A quarter of transplants were performed using bone marrow, and cord blood was used with a rate of 1.4%. The pandemic-related problems were similar for the other two national registries. During the pandemic, 71 of 432 patients who were searched for donors underwent stem cell transplant(SCT). The low number was related mostly with postponing of SCTs and/also difficulties in continuing of volunteering and in achievement of stem cells from international registry. During the Covid19 pandemic, the SCT activity of centers decreased according to the national, and international guidelines. The study revealed an organized, and multidirectional capacity of the registry and also the adaptation to unpredicted conditions such as pandemic. On the other hand, there is a need for more effective strategies for donor recruitment and retention programme. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRSs) are being constructed for many diseases and are presented today as a promising avenue in the field of human genetics. These scores aim at predicting the risk of developing a disease by leveraging the many genome-wide association studies (GWAS) conducted during the two last decades. Important investments are being made to improve score estimates by increasing GWAS sample sizes, by developing more sophisticated methods, and by proposing different corrections for potential biases. PRSs have entered the market with direct-to-consumer companies proposing to compute them from saliva samples and even recently to help parents select the healthiest embryos. In this paper, we recall how PRSs arose and question the credit they are given by revisiting underlying assumptions in light of the history of human genetics and by comparing them with estimated breeding values (EBVs) used for selection in livestock. [ABSTRACT FROM AUTHOR]

Objective: Otosclerosis affects women twice as often as men, especially during fertile age. A role of female hormones has been claimed, but controversy still exists regarding the influence of pregnancy. The purpose of this research was to analyse the role of pregnancy on the course of otosclerosis. Method: PubMed was searched in May 2019 using the terms 'otosclerosis AND pregnancy', 'otosclerosis AND pregnant', 'otosclerosis AND parous', 'otosclerosis AND parity', and 'otosclerosis AND puerperium'. Age at diagnosis, number of pregnancies and the temporal relationship of the disease with childbearing were considered. Results: From 65 articles, 11 were chosen for review. They described 2323 women affected by otosclerosis: 1805 had at least 1 pregnancy, while 518 did not. During childbearing, otosclerosis began in 1 per cent of pregnant women, worsened in 21 per cent and worsened during puerperium in 4 per cent. Often, the authors reported hearing change with pregnancy without details, so a further group has been considered composed of women belonging to any of the groups just mentioned or to another group of women not further characterised. Overall, hearing change occurred during pregnancy in 44 per cent. A statistically significant correlation emerged between hearing change and number of pregnancies (p = 0.003). Conclusion: Because of wide data heterogeneity and the difficulty in analysing a single factor, absolute statements could not be formulated. According to this review, pregnancy seems to have a worsening effect on the course of otosclerosis. [ABSTRACT FROM AUTHOR]

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Haematopoietic progenitor cell donation from bone marrow and mobilised peripheral blood obtained from related and unrelated donors is an established procedure. The donation process in general has proven to be safe, but in rare cases severe and even fatal events have been reported. The present study aimed at providing a description of the current situation of donor protection measures in Council of Europe member States. A specific questionnaire was developed to compile information on donation activities, graft sources, legal frameworks, donor protection measures, collection of donor outcome data, and long-term follow-up of paediatric and adult related and unrelated donors. The outcome of this survey served as a basis for elaborating the Recommendation CM/Rec(2020)6 of the Committee of Ministers to member States on establishing harmonised measures for the protection of haematopoietic progenitor cell donors., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Autoimmune diseases (ADs) could occur due to infectious diseases and vaccination programs. Since millions of people are expected to be infected with SARS-CoV-2 and vaccinated against it, autoimmune consequences seem inevitable. Therefore, we have investigated the whole proteome of the SARS-CoV-2 for its ability to trigger ADs. In this regard, the entire proteome of the SARS-CoV-2 was chopped into more than 48000 peptides. The produced peptides were searched against the entire human proteome to find shared peptides with similar experimentally confirmed T-cell and B-cell epitopes. The obtained peptides were checked for their ability to bind to HLA molecules. The possible population coverage was calculated for the most potent peptides. The obtained results indicated that the SARS-CoV-2 and human proteomes share 23 peptides originated from ORF1ab polyprotein, nonstructural protein NS7a, Surface glycoprotein, and Envelope protein of SARS-CoV-2. Among these peptides, 21 peptides had experimentally confirmed equivalent epitopes. Amongst, only nine peptides were predicted to bind to HLAs with known global allele frequency data, and three peptides were able to bind to experimentally confirmed HLAs of equivalent epitopes. Given the HLAs which have already been reported to be associated with ADs, the ESGLKTIL, RYPANSIV, NVAITRAK, and RRARSVAS were determined to be the most harmful peptides of the SARS-CoV-2 proteome. It would be expected that the COVID-19 pandemic and the vaccination against this pathogen could significantly increase the ADs incidences, especially in populations harboring HLA-B*08:01, HLA-A*024:02, HLA-A*11:01 and HLA-B*27:05. The Southeast Asia, East Asia, and Oceania are at higher risk of AD development. [ABSTRACT FROM AUTHOR]

Objective: To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans. Background: Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort. Design/methods: The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational "Be the Match" registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms. Results: Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)–similar to that observed in the WTCCC (OR = 3.25; p<10−168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)–again, similar to the WTCCC (OR = 2.2; p<10−38). Moreover, four African haplotypes were "protective" relative to a neutral reference, to three European CEHs, and also to the five other African CEHs. Conclusions: The common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were "protective"–perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans. [ABSTRACT FROM AUTHOR]

Background: To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC "risk-haplotypes" nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. Methods: The SNP-data from the WTCCC was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01 ~ DQB1*06:02 ~ a1)-containing (H +); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different "risk-combinations" at the MHC and other non-MHC "risk-loci" and the appropriateness of additive and multiplicative risk-accumulation models were assessed. Results: Different combinations of "risk-haplotypes" produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H +)-haplotypes had greater impact when combined with (0)-haplotypes than with (H +)-haplotypes, whereas, (H +)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H +), (c1,H +), (H + ,H +) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H +) and (AP,c1) were unaffected. Conclusions: Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual's particular combination of "risk-haplotypes" and how these loci interact. [ABSTRACT FROM AUTHOR]

Prekallikrein (PK) deficiency, also known as Fletcher factor deficiency, is a very rare disorder inherited as an autosomal recessive trait. It is usually identified incidentally in asymptomatic patients with a prolonged activated partial thromboplastin time (aPTT). In this article, we present the case of a 52-year-old woman, with no prior personal or family history of thrombotic or hemorrhagic disorders, who was noted to have substantial protracted aPTT through the routine coagulation assessment before a kidney biopsy. The patient had an uneventful biopsy course after receiving fresh frozen plasma (FFP). Laboratory investigations performed before the biopsy indicated normal activity for factors VIII, IX, XI, XII, and von Willebrand factor (vWF) as well as negative lupus anticoagulant (LA) screen. The plasma PK assay revealed low activity at 15% consistent with mild PK deficiency. The deficit of PK is characterized by a severely prolonged aPTT and normal prothrombin time (PT) in the absence of bleeding tendency. PK plays a role in the contact-activated coagulation pathway and the inflammatory response. Thus, other differential diagnoses of isolated prolonged aPTT include intrinsic pathway factor deficiencies and nonspecific inhibitors such as LA. We concluded that the initial evaluation of a prolonged aPTT with normal PT should appraise the measurement of contact activation factors and factor inhibitors. PK deficiency should be considered in asymptomatic patients with isolated aPTT prolongation, which corrects on incubation, with normal levels of the contact activation factors and factor inhibitors. [ABSTRACT FROM AUTHOR]

The aggregation of specific proteins and their amyloid deposition in affected tissue in disease has been studied for decades assuming a sole pathogenic role of amyloids. It is now clear that amyloids can also encode important cellular functions, one of which involves the interaction potential of amyloids with microbial pathogens, including viruses. Human expressed amyloids have been shown to act both as innate restriction molecules against viruses as well as promoting agents for viral infectivity. The underlying molecular driving forces of such amyloid–virus interactions are not completely understood. Starting from the well-described molecular mechanisms underlying amyloid formation, we here summarize three non-mutually exclusive hypotheses that have been proposed to drive amyloid–virus interactions. Viruses can indirectly drive amyloid depositions by affecting upstream molecular pathways or induce amyloid formation by a direct interaction with the viral surface or specific viral proteins. Finally, we highlight the potential of therapeutic interventions using the sequence specificity of amyloid interactions to drive viral interference. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response. [ABSTRACT FROM AUTHOR]

Purpose: Programmed death ligand-1 (PD-L1) is the main ligand for programmed death-1 (PD-1), and is one of the major targets for cancer immunotherapy. Only a few studies are available for the clinical significance of PD-1/PD-L1 in nasopharyngeal carcinoma (NPC). There is a controversial association between PD-L1 expression and survival in NPC. This study aimed at defining any potential association between PD-L1 expression in tumor cells (TCs) and prognosis in NPC.Patients and Methods: A total of seventy NPC patients treated between January 2008 and December 2016 were included in the study. PD-L1 expression was assessed by immunohistochemistry (IHC) in tumor specimens. The IHC assay was considered positive if ≥5% of TCs are stained. Clinicopathological variables were documented. Variables included in the analysis were PD-L1 expression, clinicopathological characteristics, and prognosis.Results: The estimated 5-year overall survival (OS) rate was 62%. Nearly 55.7% (n = 39) of the TCs tested positive for PD-L1 expression. No associations were found between the level of PD-L1 in TCs and clinicopathological characteristics. Comparisons between patients with PD-L1-positive tumors and PD-L1-negative tumors revealed that OS was statistically significantly longer in patients with PD-L1-positive tumors as assessed by the univariate Cox regression analysis (hazard ratio [HR], 0.378; 95% confidence interval, 0.158-0.905; P = 0.029) and Kaplan-Meier curves (P = 0.023).Conclusion: PD-L1 expression is an important prognostic factor in NPC. PD-L1 expression positively correlates with survival. [ABSTRACT FROM AUTHOR]