bluuebunny/crossref_metadata_2025_split huggingface dataset:
Graft-Versus-Host Disease Prophylaxis with Post-Transplant Cyclophosphamide Better Preserves Regulatory T Cell
Authors: Koh Jeong Suk , Heo Buyeon , Lee Seul Bi , Choi Su-Young , Pham Thi Thuy Duong , Lee Sang-Woo , Park Jung-Hyun , Jang Yunseon , Seo Wonhyoung , Lee Myung-Won , Jo Deog-Yeon , Kwon Jaeyul , Song Ik Chan 
Published: December 2024

Background: Antithymocytic globulin (ATG) and post-transplant cyclophosphamide (PTCy) are the most commonly used regimens for graft-versus-host disease (GVHD) prophylaxis. However, there is lack of data about the difference of regulatory T cell (Treg) subpopulation between these two regimens.
Method: We collected peripheral blood sample at day+21 after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). We analyzed Treg subpopulation by flow-cytometer and classified Treg into 3 subgroups: naïve, effector and non-suppressive Treg. And we compared overall survival (OS), the cumulative incidence of acute and chronic GVHD, relapse rate between 3 group: ATG, PTCy and ATG plus PTCy group.
Results: We enrolled 68 patients (28 in ATG, 17 in PTCy and 23 in ATG plus PTCy) in total. In ATG group, all patients received human leukocyte antigen (HLA) matched-donor HSCT, whereas in the PTCy group, 12 (70.6%) patients received haplo-identical HSCT, and in ATG plus PTCy group, all patients received haplo-identical HSCT (p&lt;0.001). The conventional CD25+FOXP3+Treg count of CD4+T cell was 6.14% in ATG, 12.96% in PTCy and 14.48% in ATG plus PTCy group, respectively (ATG vs PTCy, p=0.0020/ ATG vs ATG plus PTCy, p&lt;0.0001). The naïve Treg count of CD4+T cell was 5.22% in ATG, 5.64% in PTCy, and 6.17% in ATG plus PTCy group (p=0.4643). The effector Treg count of CD4+T cell was 4.13% in ATG, 5.57% in PTCy, and 5.85% in ATG plus PTCy group (p=0.2816). The non-suppressive Treg count of CD4+T cell was 23.75% in ATG, 19.82% in PTCy, and 21.37% in ATG plus PTCy group (p=0.3767). The cumulative incidence of Grade 2 to 4 acute GVHD was 18.3% in ATG, 38.1% in PTCy, and 4.8% in ATG plus PTCy group (p=0.032). And extensive chronic GVHD was 19.4% in ATG, 28% in PTCy, and 21% in ATG plus PTCy group (p=0.615). OS and relapse rate were not statistically different between three group.
Conclusion: There were more conventional CD25+FOXP3+Tregs in PTCy-containing group than in ATG alone group, which was a result of the fact that there were more naïve and effector Treg in PTCy-containing group. ATG plus PTCy showed better outcomes for acute GVHD. Therefore, ATG plus PTCy is more recommended for the prevention of acute GVHD in haplo-identical HSCT.
Gaps in Access to Diagnostic Studies and Treatments for Patients with Lymphoproliferative Diseases in Chile
Authors: León Pilar , Flores Angulo Carlos , Roa Macarena , Vergara Carmen , Espinoza Marcela 
Published: December 2024

Introduction: Chile is a country in Latin America that is classified as high-income by the World Bank Group. However, there are significant wage differences, with half of the country's population concentrated in the lowest income brackets (Fonasa A and B) of the public welfare system, which has coverage for approximately 80% of the population. Additionally, geographical characteristics can lead to the concentration of specialized services in large cities. For these reasons, the study aims to determine the gaps in access to diagnostic studies and treatment for patients with lymphoproliferative diseases in Chile.
Methods: We conducted a cross-sectional study by sending a survey to hematologists in Chile between October and December 2023. The survey included questions about the type of work activity (public or private) and the characteristics of health centers. It consisted of 9 questions related to access to diagnostic studies, staging, and treatment response, and 30 items on access to treatment. We used a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= almost always, 5= always) and dichotomized the answers into low access (1-3) and greater access (4 and 5). Consistency was evaluated using Cronbach's alpha, with values between 0.7 and 0.9 considered optimal. Single and multiple logistic regression analyses were performed, considering the location and type of health center as explanatory variables. Statistical analysis was conducted using the glm function and the psych library in R software.
Results: The survey was answered by 47 hematologists from 14 out of 16 regions, providing information from 59 centers (68% public and 32% private), of which 34% were located in the Metropolitan Region. In the crude models, we found significantly greater access in the Metropolitan Region to PET-CT, tissue flow cytometry, and new drugs compared to other regions. We determined that access in the public system (adjusted for the location of the center) was significantly lower than in the private system for PET-CT at diagnosis (OR 0.12; 95% CI 0.02, 0.52) and interim (OR 0.17; 95% CI 0.02, 0.71). Additionally, we evidenced a 94% and 90% reduction in the chance of access to nivolumab/pembrolizumab (p=0.001) and brentuximab (p=0.001), respectively, in the second line of treatment for patients with Hodgkin's lymphoma, as well as for Bruton's tyrosine kinase inhibitors for patients with chronic lymphocytic leukemia (OR 0.06, p&lt;0.001). The results regarding access to specific treatments for patients with follicular, mantle, and T-cell aggressive lymphomas were similar.
Conclusions: We demonstrate reduced access to diagnostic studies and specific treatments in health centers outside the Metropolitan Region and public hospitals. Identifying these gaps can contribute to developing public policies that reduce these disparities, resulting in better health outcomes.
Protein Language Model-Based Intra-Gene Disparity of Donor HLA Alleles Informs Prognostic Risk in Hematologic Malignancy Patients Undergoing Haplo-Identical HSCT: A Combined Xinqiao-CIBMTR Analysis
Authors: Feng Yimei , Wang Yijie , Li Xiaobo , Di Da , Liu Xiangjun , Zhang Xi 
Published: December 2024

It has been suggested that the intra-gene disparity in human leukocyte antigen (HLA) within a donor or recipient may play an important immunological role in haplo-identical hematopoietic stem cell transplantation (haplo-HSCT). Current methods to estimate HLA disparity primarily rely on epitope analysis and amino acid index scores. Recently, AlphaFold and emerging protein language models (PLMs) have highlighted the potential of large-scale deep learning techniques for predicting protein structures and functions. In this study, we utilized the newly proposed Protein-Vec PLM (PMID: 38045331) to extract functional embedding vectors from the amino acid sequences encoded by HLA alleles. With these vectors, we defined a novel PLM-based measure of intra-gene disparity for any allele pair of the same HLA gene within an individual and explored its prognostic value in haplo-HSCT.
We collected data from 425 hematologic malignancy (HM) patients undergoing haplo-HSCT between 2015 and 2022 at Xinqiao Hospital in Chongqing, China. We analyzed the association of PLM-based intra-gene HLA disparity (HLA-A/B/C/DRB1/DQB1) in a donor or recipient with overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse. We validated our results by using a publicly available dataset from CIBMTR IB20-02 (PMID: 34774819), which included 985 HM patients who underwent haplo-HSCT between 2013 and 2017.
Using Cox regression to calculate proportional hazard ratios (HR), with p&lt;0.01 as the threshold for statistical significance, our analysis of the Xinqiao dataset showed that higher disparity of donor HLA-B alleles was significantly associated with worse OS (HR=2.0, 95%CI 1.34-3.0, p=0.0007), worse DFS (HR=1.78, 95%CI 1.27-2.49, p=0.0008), higher NRM (HR=1.77, 95%CI 1.1-2.86, p=0.019), and higher relapse risk (HR=1.78, 95%CI 1.11-2.86, p=0.017). The result was further verified by the CIBMTR dataset, where higher disparity of donor HLA-B alleles was associated with worse OS (HR=1.3, 95%CI 1.09-1.57, p=0.0046), worse DFS (HR=1.20, 95%CI 1.02-1.42, p=0.03), higher NRM (HR=1.33, 95%CI 1.0-1.78, p=0.053), higher relapse risk (HR=1.14, 95%CI 0.93-1.40, p=0.2). Multivariate analysis demonstrated that PLM-based disparity of donor HLA-B alleles was an independent prognostic factor for OS in both Xinqiao and CIBMTR dataset. In contrast, we did not find significant results for intra-gene disparity of HLA-A/C/DRB1/DQB1 alleles in either donors or recipients.
In summary, PLM-based disparity of donor HLA-B alleles might be a potential prognostic factor in haplo-HSCT, and might be used as a novel tool assisting donor selection.
Generation of Hypoimmunogenic Hematopoietic Stem Cells and Their Potential Application in HSCT
Authors: Han Yiwen , Hao Sha , Hu Linping , Rao Shuquan , Hou Zhaoyi , Cheng Tao 
Published: December 2024

The mismatch of human leukocyte antigens (HLA) significantly limits the availability of suitable donors, primarily due to the risk of immune rejection in allogeneic hematopoietic stem cell transplantation (allo-HSCT). To improve donor-host matching, we performed precise depletion of HLA gene on human hematopoietic stem cells (HSCs) via CRISPR-Cas9 system. Combining with umbilical cord blood, one of the best optional sources for HSCs, we attempt to create off-the-shelf HSCs that are more accessible and available.
To identify the highly efficient guide RNAs (sgRNAs) capable of addressing the genetic diversity of the Chinese population，we firstly designed a library of sgRNAs targeting HLA-A and HLA-B genes. Finally,screened sgRNAs were found up to 60% HLA-A/B protein knock-down efficiency in HEK293T cell line.
To determine the knock-down efficiency of screened sgRNAs in human HSCs, CD34+ HSPCs from umbilical cord blood were obtained and then transduced with RNP by electroporation. The expression of HLA-A/B was detected by flow cytometry after 3 days' ex vivo culture. The knock-down efficiency of HLA-A/B proteins in CD34+ hematopoietic stem and progenitor cells (HSPCs) achieved up to 90%.
To investigate whether the functions of HSPCs with HLA-A/B knocked out(KO-HSPCs) were impaired in vitro, Colony forming cell (CFC) and multi-lineage differentiation assay were performed and the results. confirmed that the abilities of colony forming, self-renewal and lineage differentiation were well retained. To assess their engraftment and reconstruction potential in vivo, we transplanted both KO-HSPCs and non-edited HSPCs into NOG mice via tail vein injection. Transplantation studies in NOG mice showed higher engraftment with KO-HSPCs compared with non-edited ones in peripheral blood, BM and spleen, respectively. To examine the immunogenicity of KO-HSPCs, we performed CFSE-labeled T cell proliferation assay and CD107a assay. These results indicated that KO-HSPCs did not activateNK cells but effectively dampened the response of CD8+ T cells. Finally, the off-target detection assay was performed to investigate the safety by deep sequencing. All potential off-target sites were considered safety.
Our data demonstrate the feasibility of generating hypoimmunogenic HSCs by precisely editing HLA alleles in cord blood stem cells, thereby increasing accessibility and availability for patients in need of HSCT.
Predictive Value of Maximum Tumor Dissemination (Dmax) in Lymphoma Patients Treated with CD19 Specific CAR T-Cell Therapy
Authors: Kunz Wolfgang G , Blumenberg Viktoria , Rejeski Kai , Sheik Gabriel , Brendel Matthias , Von Bergwelt Michael , Subklewe Marion , Winkelmann Michael 
Published: December 2024

CD19 specific chimeric antigen receptor T-cell therapy (CART) has emerged as an effective treatment for relapsed or refractory (r/r) lymphoma. Imaging biomarkers are becoming increasingly important in risk assessment. The maximum distance (Dmax) of lymphoma lesions across the body holds potential as prognostic imaging biomarker in lymphoma treated with conventional therapies but has not been studied in context of CART. We evaluated Dmax at baseline imaging as a prognostic tool for assessment of metabolic and overall response, progression-free survival (PFS) and overall survival (OS).
Consecutive r/r lymphoma patients with PET/CT or CT imaging at baseline (BL) and PET/CT at 3 months follow-up (FU) after CAR T-cell transfusion were included. Dmax was measured in cm at BL. Patients were divided into three equal risk groups according to Dmax: low, intermediate, and high. Ann Arbor stages were calculated as baseline for comparison. The sum of product diameters (SPD) in mm2 of up to 6 target lesions was used to represent tumor burden (TB). Overall response according to Lugano criteria and the Deauville score were determined in FU PET/CT imaging.
Of 103 patients with baseline imaging and measurable Dmax, 63 had a PET/CT after 3 months. Median Dmax was 40.0 cm (IQR: 16.4 - 70.3 cm) at BL. TB decreased in the median from BL with 4,095 mm2 to 770 mm2 at FU imaging. Median TB was significantly higher in the intermediate and high-risk group compared to the low-risk group (p=0.005) with 7,222 mm2 (IQR: 3,355 - 11,941 mm2), 4,649 mm2 (IQR: 2,376 - 10,406 mm2) and 1,739 mm2 (IQR: 715 - 7,402 mm2), respectively. Intermediate and high-risk groups showed significantly higher Ann Arbor stages (p&lt;0.001). The survival analysis revealed a significantly (p=0.030) shorter PFS in the high-risk group compared to the other patients (91 vs 364 days), but no relevant differences in OS (p=0.151), which is comparable to the analysis by grouping according to Ann Arbor stage. In addition, no significant differences in Deauville score and ORR were detected.
Patients with high Dmax showed a shorter PFS, but no significant differences in OS. In addition, there was no superiority over the Ann Arbor stages for risk assessment. Nevertheless, Dmax as an interval-scaled parameter represents a useful alternative to the latter. Dmax in the context of CART as an interval-scaled parameter could be used in multiparametric scores to guide and improve patient care.
APRIL CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma: A Phase I Clinical Trial
Authors: Li Wenxiao , Hu Yongxian , Zhang Mingming , Lai Xinyi , Zhao Mengyu , Fu Shan , Hong Ruimin , Chang Alex H. , Huang He 
Published: December 2024

Background: Chimeric antigen receptor T (CAR-T) cell therapy targeting B cell maturation antigen (BCMA) is an effective treatment for relapsed/refractory multiple myeloma (r/r MM). However, antigen escape-mediated relapse often occurs. CARs simultaneously targeting two antigens may overcome this limitation. Therefore, we used A proliferation inducing ligand (APRIL) to construct a ligand-base CAR that allows for bispecific targeting of BCMA and transmembrane activator and CAML interactor (TACI) as a novel therapy for r/r MM.
Methods: The APRIL CAR-T was evaluated in a Phase 1 clinical trial (NCT04657861) in patients with BCMA/TACI positive relapsed/refractory multiple myeloma. Safety, efficacy, and APRIL CAR-T cellular kinetics were evaluated.
Results: 9 patients received APRIL CAR-T infusions following a conditioning regimen of cyclophosphamide and fludarabine. The treatment was generally well tolerated, with 6 patients experiencing grade 1 cytokine release syndrome (CRS) and 1 patient experiencing grade 2 CRS, no patient had grades 3-4 CRS , no GvHD and immune effector cell-associated neurotoxicity were observed. The overall response rate was 88.8% (8/9), including 2 (22.2%) with complete remission (CR), 4 (44.4%) with very good partial remission (VGPR), and 2 (22.2%) with partial remission (PR).After a median follow-up of 6.63 months (range, 0.50-13.90 months), 1 patients remained in complete remission,and 1 patient died of a cerebrovascular accident. The median overall survival and relapse-free survival for the patients treated with APRIL CAR-T cells was 8.31 months (95% confidence interval [CI], 0.50-13.90 months) and 2.80 months (95% CI, 0.50-6.63 months), respectively.
Conclusions: The APRIL CAR-T cell-based therapy appeared to be a promising therapeutic approach in r/r MM, based on its antitumor effects and manageable side effects, meanwhile additional strategies are required to sustain the therapeutic response.
Successful Cohorting Strategy in CRE-Positive Hospitalized Patients: A Single Center Experience
Authors: Stagno Fabio , Mirabile Giuseppe , Penna Giuseppa , Cancemi Gabriella , Nasso Maria Elisa , Russo Sabina , Allegra Alessandro 
Published: December 2024

Introduction: Patients (pts) with Carbapenem-Resistant Enterobacteriaceae (CRE) colonization have at least a two-fold increased risk of infection than non-CRE colonized pts. Further, CRE colonization is also one of the main sources of CRE transmission in hospitals and communities and pts with hematological malignancies are particularly vulnerable to infections with CRE. In this view we started to screen for CRE colonization every pt who required hospitalization to our Hematology Section by executing a cohorting strategy.
Patients and methods: From January 2024 to July 2024 164 pts were screened at hospitalization. They were 77 males and 87 females; median age was 68.8 years. Hematological malignancies were as follow: MM 34, NHL 42, CLL 23, AML 16, ALL 9, MDS 11, CML 4, HD 5, MPN 12, ITP 5, sickle cell anemia 1, anemia from solid cancer 2.
Results: Median duration of hospitalization days for the all the 164 investigated patients was 9 days. Median white blood cell count was 7,3x103/L, median neutrophil count was 4,0x103/L, median lymphocyte count was 2,0x103/L and median neutrophil to lymphocyte (N/L) ratio was 1.7. Thirty-eight out of 164 pts (23.1%) resulted positive for CRE and were all cohorted. Overall, 43/164 (26.2%) received chemotherapy (CHT) regimens while CHT was administered in 10 CRE positive pts. Fever events (FUO) were 33 out of 164 (20.1%), 25/126 (19.8%) occurred in CRE negative pts whereas 8/38 (21.0%) in CRE positive (p=1.0). No statistical differences were observed between CRE positive and negative pts as for WBC counts (p=0.4) neutrophil count (p=0.5) lymphocyte counts(p=0.07) and N/L ratio (p=0.7). Interestingly, because of the cohorting strategy, median duration of hospitalization days for CRE positive and CRE negative pts was the same (9 days).
Conclusions: Pts with hematological malignancies, because of the underlying disease, the necessary treatment and the frequent use of antibacterial drugs are at risk of CRE infections. Our internal policy of both screening and cohortization strategy allowed us to both minimize FUO events and hospitalization days in CRE positive pts. Further, screening for CRE colonization, although cost-effective, revealed to be cost saving,
Validating Laboratory Accuracy of the Next Generation Sequencing (NGS) Technology As a Newborn Screening Tool for Hemoglobinopathies and Thalassemia in Southeast Asian Population
Authors: Suksangpleng Thidarat , Ekwattanakit Supachai , Riolueang Suchada , Viprakasit Vip 
Published: December 2024

Background
Thalassemia and hemoglobinopathies are one of the most important health burden to Thailand and several Southeast Asian countries due to a very high frequency of carriers of these globin disorders in the region. Although, Thailand as one of the leading countries on thalassemia research has established a national program for prevent and control of severe thalassemia syndrome at ante-natal screening follows by prenatal diagnosis in pregnant women. However, such program has several limitations due to a late antenatal care and a lack of public awareness. Early screening at neonatal levels together with data incorporated within our Thailand's national health care database (eGovernment) can improve the national thalassemia control program in a long-term run.
Aims
To evaluate the efficacy and accuracy of using next generation sequencing (NGS) technology as a fast, high through-put and scalable method for thalassemia screening in Southeast Asian setting.
Methods
Newborn peripheral blood (heel prick) were collected for hematologic testing including complete blood count and hemoglobin (Hb) typing. Also, genomic DNA (gDNA) was extracted and then analyzed using conventional multiplex PCR methods including α-GAP multiplex PCR, α-ARMS multiplex PCR and β-ARMS multiplex PCR, which covered &gt; 95% of common mutations of globin genes found in the Thai population. All samples were then analyzed for sequences of α-globin (HBA1 and HBA2) and β-globin (HBB) genes using NGS technology and the combinatorial probe-anchor synthesis sequencing method (BGI VISTATM Thalassemia-Seq panel) and detection by software provided by BGI Biotechnology, Wuhan.
Results
Based on the comparative analysis of α-globin and β-globin gene mutations. The 352 neonatal gDNA samples by multiplex PCR methods and combinatorial probe-anchor synthesis sequencing methods, 335 samples (95%) showed identical results on globin gene mutations. However, the NGS approach has a superior on identification several rare but possible clinical significance variants such as Hb Westmead (2.6%), α-triplication (αααanti3.7, 0.3%) and αααanti3.7/–SEA (0.3%) that were missed using the conventional methods.
Conclusion
Application of NGS technology to detect globin gene mutations that causes thalassemia and hemoglobinopathies showed a promising accurate technology for the future newborn screening program in Thailand and other Southeast Asian countries.