bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Frequency Mutant Genes and Prognosis Value of HIV-Related Diffuse Large B-Cell Lymphoma
Authors: Peng Yu , Ran Longrong , Zhao Mingyu , Yang Zailin , Liu Yao 
Published: December 2023

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype in AIDS-related lymphoma (ARL) in HIV-infected patients, and the probability of DLBCL in HIV-infected patients is up to 17 times higher than that of the healthy population. However, the genetic mutation profile of HIV-associated DLBCL is still controversial, and the gene regulatory mechanism of HIV infection leading to the high incidence of DLBCL is still unclear.
Methods: A total of 12 HIV-positiveDLBCL and 39 HIV-negativeDLBCL patients who treated in Chongqing University Cancer Hospital from March 2022 to October 2022 were enrolled. Tumor tissue samples were selected to detect by second-generation sequencing technology, and gene heat mapping was used to analyze the high-frequency mutant genes in HIV-positive lymphoma patients, comparing the differences mutant genes between HIV-positive and HIV-negative DLBCL patients. The specific mutant genes in HIV-positive DLBCL were screened, and Kaplan-Meier estimate the impact of specific gene changes on disease prognosis in analyze DLBCL lymphoma.
Results Compared with HIV-negative DLBCL patients, 12 patients with HIV-positive DLBCL were mostly male (91.7%), and the disease subtype was mostly germinal center B-cell like(GCB) subtype (75%). HIV-positive DLBCL patients were associated with EBV infection, elevated LDH, increased proportion of CD4 + cells &lt; 200 (cell/ul), and more aggressive. The gene heat mapping results showed that TP53, TBL1XR1 and KMT2D had higher mutations in HIV-positive DLBCL and HIV-negative DLBCL patients. Compared with HIV-positive DLBCL, HIV-negative DLBCL patients were more likely to have gene mutations such as IGLL5, KMT2C, CD79B, BTG1, HIST1H1E, TNFRSF14, B2M. Compared with HIV-negative DLBCL patients, HIV-positive DLBCL patients detected more complex gene mutation sites, and were more common to have gene mutations including TP53, LRP1B, MYC, NOTCH2, SPEN, EP300, SOCS1, TYK2, ARID1A, GNA13, MAP2K1. Among those gene mutations, LRP1B, MYC, TYK2 have a higher probability in HIV-positive DLBCL patients (P&lt;0.05). Compared with HIV-negative DLBCL patients, HIV-positive DLBCL patients have a worse prognosis by Kaplan-Meier analysis, and patients with LRP1B, MYC, TYK2 mutations had a longer time to achieve complete remission.
Conclusion HIV-positive DLBCL patients are more prone to gene mutations, and the mutant genes are more complex and diverse. LRP1B, MYC and TYK2 gene mutations may play an important role in the occurrence and development of HIV-positive DLBCL and affect the prognosis of patients.
Keyword HIV; lymphoma; genetic mutation; prognosis
Transplant Associated Thrombotic Microangiopathy: Acomprehensive Review and Local Experience
Authors: Benkhadra Maria , Gulied Amaal , Mohamed Mohamed Saeed , Mudawi Deena , Gaziev Javid , Al-Khabori Murtadha , Yassin Mohamed A 
Published: December 2023

Introduction
Thrombotic Microangiopathy (TMA) is a rare, life-threatening severe condition characterized by microangiopathic hemolytic anemia, thrombocytopenia and microthrombi in the walls of small blood vessels leading to ischemic organ dysfunction. Transplant-associated TMA (TA-TMA) can occur as a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mechanism of TA-TMA is not fully understood, and conventional treatment options are based on targeting the identified risk factors and hypothesized pathophysiology. This review aimed to compile the information to date about TA-TMA and possible treatment strategies and report successful cases at the National Center for Cancer Care and Research (NCCCR).
Methods
Scientific databases were scoped for reviews on TA-TMA, its pathophysiology, risk factors and therapeutic strategies. Results were compiled to formulate an understanding of TA-TMA. Local cases of TA-TMA at NCCCR were also reported.
Results
TA-TMA pathophysiology and risk factors are described in Figure 1 and Table 1, respectively. Due to the complexity of the patient cases under investigation, TA-TMA diagnosis is clinical. Proposed diagnostic criteria include anemia, thrombocytopenia, elevated LDH, presence of schistocytes, hypertension, proteinuria, and elevated sC5b-9. Therapeutic approaches start the management of modifiable risk factors such as withdrawal or decreasing the dosage of calcineurin inhibitors (CNIs), control of hypertension and AKI, treatment of active infections and management of graft versus host disease (GvHD). Therapeutic plasma exchange (TPE) may benefit some patients who are positive for factor H autoantibodies. eculizumab, a humanized antibody against complement protein, can be highly effective in patients with TA-TMA. It is recommended for patients with high-risk features such as elevated sC5b-9 and proteinuria and can also be used for patients with organ damage or disseminated disease. Other available treatment options include rituximab and defibrotide. Other therapeutic agents are under clinical trials such as ravulizumab (C5 inhibitor), nomacopan (C5 and leukotriene B4 inhibitor) and narsoplimab (mannan-binding lectin-associated serine protease-2 [MASP-2] inhibitor). Four cases were diagnosed with TA-TMA at NCCCR between September 2017 and February 2023, as described in Figure 2. All cases recovered; however, the challenge remains in the choice of therapy. Thus far, the choice is to individualize therapy according to comorbidities, severity of clinical presentation and availability of the treatment options.
Conclusion
TA-TMA remains a significant clinical challenge for transplant physicians, and more research is needed to improve our understanding of its pathogenesis, diagnosis, and management, particularly in guiding the choice of therapy.
Lenalidomide and Dexamethasone for Patients with Rosai-Dorfman Disease: A Single Arm, Single Center, Prospective Phase 2 Study
Authors: Chang Long , He Lin , Li Jian , Zhou Daobin , Cao Xinxin , Gao Wen 
Published: December 2023

Background
Rosai-Dorfman disease (RDD) is a rare heterogeneous histiocytic disorder. Because of the rarity of RDD and a lack of prospective randomized trials, the treatment strategy for RDD is mostly based on retrospective study. Previous studies showed thalidomide or lenalidomide was effective in recurrent/refractory RDD with skin involvement.
Aims
This study was designed to evaluate the efficacy and safety of lenalidomide and dexamethasone (RD) for Rosai-Dorfman Disease.
Methods
This phase 2, prospective, single-center study enrolled 13 newly diagnosed and 9 recurrent patients with RDD from June 2021 to August 2022 (NCT 04924647). The RD regimen was lenalidomide 25mg d1-21 and dexamethasone 20-40mg d1,8,15,22 for a cycle and 12 cycles in total. The primary endpoint was event-free survival (EFS). Events were defined as a poor response to RD, reactivation after RD therapy or death from any cause. The secondary endpoint was overall response rate (ORR) and overall survival (OS).
Results
The median age was 44 years (range 21-71 years). Fifteen patients were male (68.2%). All the patients were extranodal RDD (2 unifocal, 3 single-system multifocal and 17 multisystem). The most common organ involved was bones (45.5%) and subcutaneous tissue (45.5%), followed by sinus (37.5%). Four patients (18.2%) had central nervous system (CNS) involvement. MAPK pathway alterations were found in 6/15 (20.0%) of the patients. All patients received at least six courses of RD regimen therapy, with median 12 (6-12) courses. Overall, 18 patients (81.8%) completed protocol treatment, and 4 patients (18.2%) went off protocol (3 patients' decision, 1 poor response). The overall response rate was 86.4% (19/22), including 7 patients (31.8%) achieving complete remission and 12 patients (54.5%) achieving partial remission. After a median follow-up of 22 months (range 8-24 months), 3 patients (13.6%) relapsed. No patients died or lost follow-up. The estimated 2-year EFS and OS was 67.8% and 100.0%, respectively. To evaluate the prognostic factors of EFS using univariate analysis, we found that patients with CNS, respiratory system, multi-system involvement and MAPK pathway gene mutations had similar outcomes. No patients had grade 3-4 adverse effects. 8 patients (36.4%) had grade 1 gastrointestinal complications (vomiting, nausea and diarrhea). 6 patients (27.3%) experienced anemia, neutropenia or thrombocytopenia. Only 1 patient (5.6%) had grade 2 neutropenia. 5 patients (22.7%) experienced rash and 5 patients (22.7%) experienced fatigue with grade 1 events. All complications improved with supportive treatment.
Conclusion
Lenalidomide and dexamethasone regimen is an efficient and safe regimen for newly diagnosed and recurrent RDD.
Gene Regulatory Networks Controlling Sinusoidal Hematopoietic Niche Function
Authors: Li Wantong , Faisal Muhammad , Oyman Konur , Blaser Bradley Wayne 
Published: December 2023

The bone marrow sinusoidal vascular niche is important for HSC engraftment and regeneration of hematopoiesis after transplantation, but the epigenetic factors that control these biological functions are undefined. Here, we show that sinusoidal hematopoietic niche functions are controlled by gene regulatory networks (GRNs), involving transcription factors (TFs) that bind to enhancers to regulate corresponding target genes.
To characterize sinusoidal niche specific transcriptional and chromatin accessibility states, we performed multimodal single nuclei RNA and ATAC-seq analysis on unsorted zebrafish embryos. We identified 4 niche clusters, including mesenchymal stem cells, fibroblasts, osteoblasts and sinusoidal endothelial cells. Differential RNA transcriptome analysis confirmed the identity of each niche cluster with canonical gene markers for each niche cluster. To examine differential transcriptional accessibility in zebrafish niche clusters, we aggregated co-accessible regions in cells from these clusters. Each cluster demonstrated a unique chromatin accessibility profile with differentially accessible regions. Differential motif activity based on chromatin accessibility analysis further exhibited unique TF motifs activity in sinusoidal endothelial cells.
To identify potential regulatory TFs in sinusoidal vascular niche, we predicted TFs based on the TF binding sites accessibility and TF expression. Thus, we identified 3 specific expressed and enriched TFs for sinusoidal vascular niche, including Fli1 (Friend leukemia integration 1), Mef2a (Myocyte enhancer factor 2A) and Mef2c. Next, to investigate genomic regulatory regions that interact with TFs, in which control the transcription of their target genes, we performed random forests and regression trees machine learning methods to infer GRNs. We observed multiple active GRNs in sinusoidal vascular niche, which were predicted to essential for regulating hematopoietic niche development and HSC maintenance, including klf12, egfl7, ebf3 and ldb2.
Finally, we examined whether these putative gene regulatory networks were conserved across species and tissue types. We used same approach (single-cell multiome sequencing) on E4-HUVEC cells, a transduced human umbilical vein endothelial cells (HUVEC) with the adenovirus E4ORF1 gene, which was a well-defined model of the human sinusoidal vascular niche. We likewise observed regulatory networks in HUVEC cells. As in zebrafish, GRNs in human sinusoidal cluster consisted of FLI1 and MEF2 family, regulatory regions and their target genes. Our findings reveal that unique sinusoidal vascular niche specific gene regulatory networks, including TFs, regulatory regions and target genes indicate the treatments targeting GRNs may help to facilitate reprogramming of sinusoidal endothelial niche to support HSC homing and regeneration after transplantation.
Safety and Efficacy of a-319 (a CD3xCD19 T cell engager) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Liu Wei Ping , Jiang Bo , Shuang Yue Rong , Zhao Xing , Zhong Xuan Fan , Tan Ying , Yu Guo Jian , Xue Sheng Jie , Shen Wu Zhong , Tu Gui Yun , Yang Zheng , Chen Han Yang , Xu Jason , Liu Shui , Yan Xiao Qiang Qiang , Zhu Jun , Song Yu Qin 
Published: December 2023

Background: A-319 is a CD19 x CD3 bispecific T cell engager to treat B-cell non-Hodgkin Lymphoma (B-NHL). A-319 contains a scFV domain derived from SP34 CD3 antibody and a CD19 binding domain in a Fab format without Fc. A-319 has the same mechanism of action as that of blinatumomab, and may benefit B-NHL patients. We report the phase I study results of A-319 in patients with relapsed/refractory B-NHL.
Methods: The current study is a multi-center, open-label, dose-escalation phase I clinical study. The primary endpoint was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of A-319. The secondary endpoints were to evaluate the pharmacokinetics (PK) and efficacy.
During dose escalation stage, one treatment cycle contains one week of A-319 priming doses and three weeks of treatment doses. During priming doses, A-319 was administered three times per week (day 1, day 3 and day 5) at dose level of 0.05 ug/kg/day by 24 hr IV infusion. Dose escalation started at week two at dose level of 0.05, 0.15, 0.3, 0.6, 1.2, 1.8 and 2.4 ug/kg/day, respectively, by 6 hr IV infusion three times per week. The study was registered at ClinicalTrials.gov (NCT04056975).
Results: A total of 21 B-NHL patients (CD19+) were treated with A-319 for at least 1 cycle. Eighteen (85.7%) patients experienced adverse events and 12 (57.1%) patients experienced treatment-related adverse events (TRAEs). The most common TRAE was cytokine release syndrome (CRS, 23.8%, n=5), followed by fever (66.7%, n=14) and decreased immunoglobulin (23.8%, n=5). Most of the reported adverse events were CTCAE Grade I-II. Five patients experienced CRS (Grade I-II, n=5；≥Grade III, n=0). Six patients experienced immune effector cell-associated neurotoxicity syndrome (Grade I-II, n=6；Grade III, n=2). The serious adverse events were reported in 3 patients, which included lung infection (Grade III, n=1), interstitial pneumonia (Grade I, n=1), and pulmonary embolism (Grade III, n=1). There was no reported DLT. No fatal cases were reported during treatment. The preliminary pharmacokinetic (PK) results showed that A-319 has linear PK properties with an estimated T 1/2 of 6-10 hrs. Preliminary responses were reported that one patient achieved complete remission (CR), 3 achieved partial remission (PR), and 7 achieved stable disease (SD) after one cycle of treatment. In the 5 th cohort (at the dose level of 1.2 ug/kg/day), one patient with diffuse large B cell lymphoma (DLBCL) achieved CR, one with follicular lymphoma (FL) achieved PR and on with DLBCL achieved SD.
Conclusions: A-319 was well tolerated in relapsed/refractory B-NHL. A-319 at the dose level of 1.2 ug/kg/day showed encouraging disease control and warranted further clinical investigation.
Is Short-Course Antibiotic Therapy Suitable for Pseudomonas Aeruginosa Bloodstream Infections in Onco-Hematology Patients with Febrile Neutropenia? Results of a Multi-Institutional Analysis
Authors: Feng Xiaomeng , Jiang Erlie , Feng Sizhou 
Published: December 2023

Background. Several studies have suggested that short-course antibiotic therapy does not increase infection recurrence or mortality in immunocompetent patients. While similar studies in patients with hematological malignancies were rare.
Methods. This cohort included onco-hematology patients with Pseudomonas aeruginosa (PA) bloodstream infections (BSI). These patients had undergone chemotherapy or hematopoietic stem cell transplantation (HSCT) and experienced febrile neutropenia. Inverse probability of treatment weighting was used to balance the confounding factors.
Results. 434 patients met eligibility criteria (short-course, 7-11 days, n=229; prolonged therapy, 12-21 days, n=205). In the weighted cohort, after multivariate analysis, the recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group ( p = 0.926), the recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group ( p =0.276), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group ( p = 0.980). While multidrug-resistant PA, relapsed/refractory hematological malignancies and perianal mucositis were the key determinants of infection recurrence/mortality other than the short course of antibiotic treatment (p&lt;0.05 for all). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital ( p&lt;0.001).
Conclusions. We found that onco-hematology patients with PA BSI who received approximately 8 days of antibiotics had similar clinical outcomes to those who received a prolonged-course therapy, with the potential added benefit of earlier hospital discharge.
Checkpoint Inhibitor PD-1H/VISTA Affects Myeloma Bone Disease By Osteoclast Cytoskeleton Remodeling
Authors: Fu Jing , Li Shirong , MA Huihui , Brown Lewis M , Mapara Markus , Lentzsch Suzanne 
Published: December 2023

Introduction
We have recently described the critical role of checkpoint inhibitor PD-1H/VISTA in osteoclast activation and multiple myeloma bone disease. Highly expressed in osteoclast precursors and mature osteoclasts, PD-1H functions as the receptor for osteoclastogenic factor MMP-13 and mediates MMP-13 induced osteoclast activation and myeloma bone disease ( Nat Commun14, 4271 (2023)). Despite the extensive functional study of PD-1H in immune disease models, the PD-1H interacting cellular complex is yet to be defined. Here we report how PD-1H interacts with cytoskeleton proteins contributing to osteoclast remodeling in multiple myeloma bone disease.
Methods and Results
To identify interacting proteins of PD-1H, PD-1H-His 6 recombinant protein was overexpressed in mouse mononuclear BMCs, and PD-1H-His 6 binding protein complex was pulled down by Ni-NTA agarose beads followed by mass spectrum analysis (Figure A). LIM and SH3 domain protein 1 (LASP1) was one of the most abundant cytoskeleton proteins identified in the PD-1H complex. We therefore first confirmed its binding to PD-1H by two-way co-IP assays (Figure B and C). Co-localization of LASP1 and PD-1H were further confirmed by immunofluorescence assay when co-expressed in HEK293 cells (Figure D). LASP1 is an F-actin-binding protein that stabilizes F-actin bundles and is involved in podosome regulation in macrophages (PLoS ONE 7(4): e35340). It has four domains: LIM, two nebulin-like repeats (N1 and N2) and SH3 domains. While nebulin-like repeats mediate binding to F-actin, SH3 domain is the major protein-protein binding site (PLoS ONE 7(4): e35340). In co-IP assay using PD-1H and domain deleted LASP1, deletion of LIM (△LIM) or either one or both nebulin-like repeats (△N1, △N2 and △N1/2) did not affect the binding to PD-1H. Instead, deletion of SH3 (△SH3) in LASP1 lead to loss of PD-1H binding, demonstrating that PD-1H binds to LASP1 at the SH3 domain (Figure E). Next, the association of LASP1 and PD-1H in the osteoclast cytoskeleton was demonstrated by confocal immunofluorescence microscopy. LASP1 co-localized with F-actin (Figure F) and PD-1H (Figure G) at the sealing ring in mature osteoclasts. Interestingly, although MMP-13 stimulation increased the size of osteoclasts and the sealing ring, MMP-13 did not change the co-localization pattern of LASP1 with PD-1H or F-actin.
Conclusions
Taken together, this study reveals the novel mechanism of PD-1H regulation of osteoclasts cytoskeleton reorganization, which is critical for osteoclast bone resorption activity. PD-1H directly associates with LASP1 at its C-terminal SH3 domain. Although LASP1 was reported to regulates podosomes function in macrophages, its role in osteoclast cytoskeletons remain largely obscure. The future study will be focused on delineating the role of LASP1 in osteoclast function, and its role in MMP-13/PD-1H signaling regulated myeloma bone disease.
Correlation of TCR Repertoire Diversity with Myeloid Gene Mutations in Chronic and Advanced Phase Myeloproliferative Neoplasms
Authors: Piris-Villaespesa Miguel , Marquet Juan , Fernandez-Lanza Val , García Gutiérrez Valentín , Jimenez Carlos , del Castillo Francisco J , Muñoz Gloria , López Javier 
Published: December 2023

Introduction: Myeloproliferative neoplasms (MPN) are characterized by a chronic phase (CP), with indolent clinical behavior and, in 10-30% of cases, progression to advanced phases (AP), with aggressive behavior and compromised prognosis. Numerous factors have been associated with progression to AP, including the acquisition of mutations in recurrently mutated myeloid genes (1,2). On the other hand, decreased diversity in the T-cell receptor (TCR) repertoire has been associated with worse prognosis in solid tumors. The purpose of this work is to study the correlation between the acquisition of mutations in myeloid genes and the diversity of the TCR repertoire in chronic and advanced myeloproliferative neoplasms.
Methods: Patients with chronic CP and AP myeloproliferative neoplasms were selected. The selected patients underwent an NGS panel of 48 myeloid genes. Only pathogenic (P) or likely pathogenic (LP) variants were considered. In parallel, the study of the TCR repertoire by NGS with the panel “AmpliSeq for Illumina Immune Repertoire Plus, TCR beta Panel” (Illumina™) was performed on the available samples. Finally, the obtained data were correlated. The study was approved by the local ethics committee.
Results: A total of 22 patients were selected, 10 in CP and 12 in AP. Regarding diagnosis, 8 were polycythemia vera (PV), 4 essential thrombocythemia (ET), 6 secondary myelofibrosis (MFS) (1 to PV and 5 to ET), 2 systemic mastocytosis (MS) and 1 primary myelofibrosis (MFP). Eighty percent were male and the mean age was 68 years. The AP patients were significantly older (74 vs. 62 years of age, p&lt;0,001). Regarding the myeloid NGS panel result, 41 mutations were found in 19 patients. Fourteen percent of the patients had no mutation, 36% had an isolated driver mutation and 50% had additional mutations. Of these, 9% were in CP and 81% were in AP. The most recurrently mutated genes were JAK2 (45.4%), CALR (18.2%), ASXL1, IDH2, SRSF2, IDH2 (all 13.6%), MPL and KIT (both 9.1%). Regarding the results of the TCR repertoire, it was possible to perform the study in 11 patients, 4 in CP and 7 in AP. Only 6/11 had results of sufficient quality to allow analysis. Of these 6 patients, 3 were in CP and 3 in AP. As can be seen in Figure 1, the diversity of the TCR between CP patients and PC patients was different. Thus, while the pattern of diversity in the CP phase shows the expected distribution, the diversity in AP shows a characteristic pattern.
Conclusions: APs of MPNs show an abnormal TCR diversity pattern. This pattern may be related to the acquisition of myeloid gene mutations in AP. To our knowledge, this is the first study demonstrating an alteration in TCR diversity in AP and opens the door to future fields of research.