bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Tsrna Can be Used As a Biomarker of the Activation States of T Cells for Early Detection of GvHD after Allogeneic Stem Cell Transplantation
Authors: Xia Lin , Xu Wei , Tang Shuhan , Yao Han , Zhao Lu , Liu Yuqing , Chen Ting , Tang Jie , Chen Xiaoli , Wang Li , Yang Shijie , Feng Yimei , Zhang Xi 
Published: December 2024

Background
Allogeneic hematopoietic cell transplantation is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. However, as a common complication after transplantation, GvHD remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. tRNA-derived small non-coding RNA (tsRNA) is a class of newly identified small noncoding RNA (sncRNA), usually ~30 nucleotides (nt) in length. tsRNA was found to be highly enriched in vertebrate serum as remarkably stable forms, suggesting a promising role of serum tsRNAs as diagnostic biomarkers for human diseases and actively involved in starvation, oxidative stress, hypoxia, and other adverse conditions. Here, by employing small non-coding RNA sequencing on serum of patients who underwent HSCT, we presented the landscape of tsRNA profiles and showed the difference in patients with GvHD and non-GvHD, which can be further used as fingerprints for early detection of GvHD after allo-HSCT.
Methods
In this retrospective cohort study, two cohorts were incorporated and serum samples were prospectively collected before drug treatment (-7 day), before stem cell transfusion after drug treatment (-1 day), the 7th day after stem cell transfusion (+7 day), the 14th day after stem cell transfusion (+14 day), and the 28th day after stem cell transfusion (+28 day) if possible, namely 1) the auto-transplantation cohort: 50 serum samples in total, including 10 patients undergoing the auto-transplantation.2) the allogeneic transplantation cohort: 149 serum samples in total, including 35 patients undergoing the auto-transplantation. Serum RNA was extracted and measured by small noncoding RNA sequencing, RT-qPCR, and northern blot.
Results
By employing small RNA sequencing, we found significant differences in tsRNA after hematopoietic stem cell transplantation, especially in GvHD and non-GvHD groups. In the non-GvHD group, tsRNA usually goes through a low (+7d) - high (+14d) - low (+28d) express pattern. However, in the GvHD group, tsRNA still maintains high-level expression at +28d of allo-HSCT, which presents a low (+7d) - high (+14d) - high (+28d) express pattern. Additionally, by simulating T cells in vitro, we found that T cells secrete a large amount of functionally tsRNA into the extracellular space after activation and those tsRNAs can induce cell apoptosis. Taken together, It suggests that tsRNA-mediated epigenetic information may be involved in regulating the occurrence and development of GvHD after allo-HSCT, and can serve as specific diagnostic markers.
Conclusions
The express pattern of serum tsRNA at 14d to 28d after allogeneic stem cell transplantation could represent the activation states of T cells and can be fingerprinted for early detection of GvHD after allo-HSCT.
Efficacy and Safety of Bendamustine, Pomalidomide, Sintilimab in Patients with Recurrent or Refractory Diffuse Large B-Cell Lymphoma: A Retrospective Study
Authors: Yang Haiyan , Zhou Shengsheng , Huang Fengxiang , Li Meiwei , Bao Wenguang , Wang Man , Lan Dong , Peng Zhigang 
Published: December 2024

Background:
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately 40% of patients develop recurrent or refractory (R/R) diseases after frontline chemoimmunotherapy. The patients with R/R DLBCL after at least 2 lines of therapy have unsatisfactory outcome and are always encouraged to participate in clinical trials. More effective therapeutic approaches are urgently needed. Here, we conducted a study to evaluate the efficacy and safety of bendamustine in combination with pomalidomide and sintilimab for these R/R DLBCL patients.
Methods:
We retrospectively analyzed the data of R/R DLBCL patients, who had received 2-6 cycles BPD regimen: bendamustine 70mg/m2, d1-2, pomalidomide (POM) 4mg, day 1-14, sintilimab, 200mg, day 2, 21 days/cycle. After 4-6 cycles therapy, patients that achieve PR or CR would continue receive pomalidomide (POM) and sintilimab as maintenance therapy for one year. The primary endpoint was objective response (ORR).
Results:
From May 2022 to July 2024, a total of 13 patients who were not eligible for transplant or CART were included. Key baseline characteristics included: Median age, 62 years (range 45-77), 76.9% IPI score 2-5, 76.9% Ann Arbor stage III-IV, 84.6% non-GCB, 46.2% dual expression, 100% EBER-negative. Patients were heavily pretreated, with a median of 3 (range 2-6) previous lines of systemic therapy. All patients were treated with RCHOP as the first line and platinum-based chemotherapy as a second line. Of these patients, 12 patients had refractory disease or early recurrence, and one experienced relapse＞12 months after the last treatment. Out of the 13 evaluable patients, the disease control rate (DCR) was 92.3%, with an overall response rate (ORR) of 11 cases (84.6%). Among them, stable disease (SD) was observed in 1/13 (7.7%) patients. Complete response (CR) was achieved in 2/13 (15.4%) cases, while partial response (PR) was seen in 9/13 (69.2%) patients. Tumor volume reduction ranged from 40% to 100%. With a median follow-up of 24 months, the median progression-free survival (PFS) was 7 months.
The most common adverse events of any grade were hemocytopenia (50.0%), infection (33.3%), digestive symptoms (16.7%). Grade 3-4 adverse events occurred in 3/13 (23.1%) patients, including neutropenia (15.4%), thrombocytopenia (15.4%), anemia (15.4%), nausea (15.4%), decreased appetite (15.4%), pneumonia (15.4%), herpes virus (7.7%). No treatment-associated death was observed.
Conclusions：
These data supported that bendamustine in combination with pomalidomide and sintilimab had promising anti-tumor activity and manageable safety profile in R/R DLBCL. Currently, a phase II, prospective study is ongoing to further investigate the efficacy and safety of this regimen (ChiCTR 2400084099).
Adsl, As a Hub for Amino Acid Metabolism and Glucose Metabolism, Promotes the Development of Multiple Myeloma
Authors: Zhong Ling , Xiao Jialing , Luo Ji , Wu Yajie , Yi Qing , Gong Bo 
Published: December 2024

Multiple myeloma (MM) is the second most common hematological malignancy, with its global incidence on the rise. Despite significant improvements in the survival rate of MM patients, there is still considerable variation in prognosis, with some patients experiencing rapid progression and short survival periods. Therefore, identifying specific markers for highly malignant plasma cell subgroups with poor prognosis is crucial.
To address this, we conducted single-cell transcriptome sequencing across the entire disease progression spectrum, including MGUS, MGRS, SMM, and MM. We identified highly malignant plasma cell subgroups (clusters 5 and 17) based on copy number variations and malignant plasma cell subgroup (MPCS) scores. Using a malignant metabolic pathway scoring method (MPAS), we discovered that abnormalities in the alanine, aspartate, and glutamate metabolic pathways significantly impacted the poor prognosis of patients in these subgroups. Notably, within these pathways, adenylosuccinase (Adsl) was significantly overexpressed. Data from the GEO (GSE6477) and MMRF databases revealed that Adsl was significantly associated with poor clinical stages (R-ISS) and survival prognosis of patients. Knockdown of Adsl significantly promoted apoptosis and reduced the proliferation index, as evidenced by TUNEL, cell cycle assay and expression levels of classic apoptotic proteins (cleaved Caspase-3 and cleaved PARP). Further research showed that Adsl knockdown led to a significant reduction in AMP production, which was the main downstream product of Adsl. This reduction inhibited AMP from directly binding to the γ subunit of AMPK, thereby inhibiting phosphorylation at the Thr172 site and suppressing AMPK pathway activation. Mitochondrial fission factor (MFF), a core member of the mitochondrial fission process, is a phosphorylation substrate of AMPK at Ser172. After Adsl knockdown, MFF Ser172 phosphorylation was significantly reduced, leading to decreased mitochondrial fission. Reduced mitochondrial fission weakened glycolysis, enhanced oxidative phosphorylation, and increased ROS production. Consequently, increased ROS inhibited myeloma cell proliferation and promoted apoptosis.
In summary, Adsl acts as a bridge linking amino acid metabolism and glucose metabolism and serves as a specific marker for highly malignant plasma cell subgroups. This finding provides a novel therapeutic target for improving the prognosis of MM patients.
Clinical Analysis of Sequential CAR-T Therapy Combined with Demethylating Agents and Personalized Targeted Drugs in 18 Elderly Patients with Relapsed/Refractory Acute B-Lymphoblastic Leukemia
Authors: Li Biyi , Yan Hong , Zheng Ruyue , Liu Shuangyou , Lin Yuehui , An Lihong , Deng Biping , Zheng Qinlong , Tong Chunrong , Wu Tong , Zhao Defeng 
Published: December 2024

Background: CAR-T therapy is a crucial method for treating relapsed/refractory acute B-lymphoblastic leukemia (ALL). Elderly patients often have poor treatment tolerance and limited treatment options.
Objective: To observe the efficacy of sequential CAR-T therapy combined with demethylating agents and personalized targeted drugs in elderly patients with relapsed/refractory acute B-lymphoblastic leukemia (B-ALL).
Methods: This study included data from 18 patients treated at Beijing Boren Hospital between June 2018 and March 2023, with follow-up until June 20, 2024. All patients were over 50 years old, diagnosed with relapsed/refractory acute B-ALL. All patients relapsed after chemotherapy or allo-HSCT and received two different antigen-targeted sequential CAR-T therapies, followed by maintenance therapy with BCL2 inhibitors, demethylating agents, and specific targeted drugs. The cohort consisted of 5 males and 13 females, with an age range of 53 to 74 years (median age: 60.5 years). Four patients (22.2%) were Ph+, one patient (5.56%) had undergone allo-HSCT before CAR-T therapy, and four patients (22.2%) underwent allo-HSCT after CAR-T therapy.
Results: All 18 elderly patients achieved MRD-negative remission by flow cytometry after the first CAR-T therapy and then received a second sequential CAR-T therapy targeting different antigens. One-year continuous remission was achieved in 12 patients (66.7%), and two-year continuous remission in 6 patients (33.3%). Progression-free survival (PFS) after sequential CAR-T therapy ranged from 2 months to 39 months (as of June 20, 2024). The two-year event-free survival (EFS) rate was 65.81% (95% CI: 39.06%~83.01%), and the three-year EFS rate was 29.25% (95% CI: 7.7%~55.34%), with a median EFS of 849 days. The two-year overall survival (OS) rate was 79.91% (95% CI: 49.31%~93.13%), and the three-year OS rate was 59.94% (95% CI: 27.34%~81.7%), with the median OS not reached. During the first CAR-T therapy, the probability of CRS was 66.7%, with 11 patients (61.1%) experiencing grade 1 CRS, 1 patient (5.6%) experiencing grade 2 CRS, and no patients experiencing grade 3 or higher CRS or ICANS. Only one patient experienced grade 1 CRS during the second CAR-T therapy.
Conclusion: CAR-T therapy in elderly patients with relapsed/refractory B-ALL shows high remission rates, minimal side effects, and high safety, effectively prolonging disease-free survival and overall survival.For elderly patients with relapsed/refractory B-ALL, sequential CAR-T therapy combined with BCL2 inhibitors and demethylating agents (decitabine or azacitidine) as part of maintenance therapy can effectively extend remission duration, providing a new treatment option for these patients.
Clinical Analysis of CAR-T Cell Therapy in Patients with Relapsed Acute B-Lymphoblastic Leukemia after Second Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Yan Hong , Li Biyi , Zheng Ruyue , Lin Yuehui , An Lihong , Deng Biping , Tong Chunrong , Wu Tong , Zhao Defeng 
Published: December 2024

**Background:** Patients with relapsed acute B-lymphoblastic leukemia (B-ALL) after a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) have limited treatment options and low remission rates. This study explores the efficacy of CAR-T cell immunotherapy in these patients.
**Objective:** To observe the efficacy of CAR-T therapy in patients with relapsed B-ALL after a second allo-HSCT and to evaluate the effect of maintenance therapy with demethylating agents and targeted drugs in patients who achieve remission after CAR-T therapy.
**Methods:** The study included eight patients treated at Beijing Boren Hospital from February 2021 to July 2024. Follow-up continued until July 16, 2024. All patients had relapsed after a second allo-HSCT and received CAR-T therapy. Patients who achieved remission after CAR-T therapy received sequential CAR-T treatment and maintenance therapy with targeted drugs.
The cohort consisted of four males and four females, aged between 5 and 58 years, with a median age of 29 years. Two patients did not respond to CAR-T therapy, while the remaining six achieved varying degrees of remission. The shortest remission duration was 1.3 months, and the longest was 20 months (as of July 16, 2024), with a median remission duration of 9.5 months.
**Results:** Among the eight patients, six achieved minimal residual disease (MRD)-negative remission (75%) after CAR-T therapy, while two did not respond (25%). The overall survival (OS) ranged from 1.3 months to 20 months (as of July 16, 2024). Among the six patients who achieved remission, one received two different CAR-T treatments, one received four different CAR-T treatments, and the remaining four received one CAR-T treatment each. During the first CAR-T treatment, all patients experienced cytokine release syndrome (CRS) with a 100% incidence rate. Five patients had grade 1 CRS (62.5%), and one patient had grade 3 CRS (37.5%). No patients experienced grade 3 or higher CRS or ICANS (immune effector cell-associated neurotoxicity syndrome).
**Conclusion:** CAR-T therapy shows a significant remission rate, minimal side effects, and high safety in patients with relapsed B-ALL after a second allo-HSCT, effectively prolonging disease-free survival.Combining CAR-T therapy with BCL2 inhibitors and demethylating agents may improve patient outcomes and extend survival, providing a new treatment approach for patients with relapsed/refractory B-ALL after a second allo-HSCT.
Wogonin Induces Apoptosis of Acute Myeloid Leukemia Cells through PI3K/Akt Pathway and Synergies with Venetoclax
Authors: Jiang Xia , Li Youhong , Jiang Lei , Pei Renzhi , Jin Jie , Lu Ying 
Published: December 2024

Background:Acute myeloid leukemia (AML) is a highly aggressive and heterogeneous hematological malignancy. Although 80% of patients with AML achieve complete remission after receiving standard chemotherapy, most relapse or die from treatment-related complications, and the overall prognosis remains less than 30%. Wogonin is a kind of natural flavonoid with anti-inflammatory, anti-tumor and other biological activities which could kill tumor cells by inducing cell cycle arrest. Venetoclax is a highly selective BCL-2 inhibitor that is currently approved for the treatment of chronic lymphocytic leukemia. Although venetoclax combined with demethylated drugs or low-dose cytarabine has become a first-line treatment option in elderly AML patients who were unable to tolerate high-intensity chemotherapy, resistance remained unavoidable, suggesting the need for more venetoclax-based combination regimenes. However, it was unclear whether Wogonin could promote the anti-AML effects of venetoclax.
Objective: To explore whether Wogonin combined with venetoclax has synergistic effect in the treatment of acute myeloid leukemia and the potential synergistic mechanism.
Methods: After treatment with Wogonin alone or combined with venetoclax, the viability of AML cell lines and primary AML cells was detected by cell proliferation assay, and the combined index of the two drugs was calculated by Compusyn software to evaluate the synergy effect. Apoptosis and cell cycle changes were detected by flow cytometry. The enrichment of differentially expressed genes and related signaling pathways in different drug treatment groups were analyzed by RNA sequencing. The expression levels of apoptosis-related proteins, BCL-2 family proteins, and the activation levels of PI3K/Akt signal related molecules were detected by western blot.
Results: In AML cell lines and patient-derived primary tumor cells, Wogonin combined with venetoclax significantly inhibited cell viability, and the inhibitory effect on AML was stronger than that of the two drugs alone. Flow cytometry detected that Wogonin promoted apoptosis of AML cells in a dose-dependent manner and blocked the cells in the G0/G1 phase. Western blot verified that Wogonin promoted the cleavage of apoptotic proteins such as caspase3 and PARP, affected the expression of BCL-2 family proteins, such as down-regulating MCL-1 and BCL-xL, inactivating the PI3K/Akt/GSK3β signaling pathway, and further inducing the death of AML cells.
Conclusion: Wogonin combined with venetoclax has a synergistic anti-AML effect, providing scientific basis for preclinical and clinical trials, and a potential combination strategy for the clinical treatment of AML.
Bone Marrow Impairment in Patients with Adenosine Deaminase 2 Deficiency
Authors: Miano Maurizio , Lupia Michela , Schena Francesca , Caorsi Roberta , Barzaghi Federica , Giarratana Mariacarla , Corcione Anna , Terranova Paola , Aiuti Alessandro , Mortellaro Alessandra , Cafaro Alessia , Palmisani Elena , Cangemi Giuliana , Barco Sebastiano , Dell'Orso Gianluca , Arcuri Luca , Grossi Alice , Traggiai Elisabetta , Ceccherini Isabella , Gattorno Marco , Dufour Carlo 
Published: December 2024

Introduction
Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory syndrome caused by biallelic mutations in the ADA2 gene characterized by early-onset inflammatory vasculopathy, strokes and immunodeficiency. Haematologic manifestations include lymphopenia, and bone marrow failure (BMF) mainly pure red cell aplasia. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. TNFα inhibitors control inflammatory symptoms whereas hematopoietic stem cell transplant may be needed to treat refractory cytopenia.
Objectives
The aim of this study is to characterize the mechanisms of bone marrow damage in DADA2 patients.
Methods
Bone marrow(BM) samples from DADA2 patients and healthy donors (HD) were analyzed for different in-vitro assays to test in vitro potential therapeutic agents. In-vitro colony forming unit assay were performed from fresh bone marrow mononuclear cells (BMMNCs) in presence of anti-TNFα, human recombinant ADA2 or Eltrombopag. After 14 days CFU colonies were scored. Pro-inflammatory cytokines in the BM plasma were also measured by flow cytometry bead array.
Results
Fourteen patients (median age 17yo) were studied. Eight /14 (57%) showed reduced erythroid (CFU-E 0.5, normal range 27-81/2 × 104) and myeloid (CFU-GM 3.5, normal range 33-100/2 ×104) progenitor cell growth; The addition of anti-TNFα and eltrombopag 1 ug/ml, had a statistically significant stimulatory effect on the growth of myeloid progenitors (p=0.01 and p= 0.05, respectively). The addition of ADA2 (1 ug/ml and 10 ug/ml) had a stimulatory effect on myeloid progenitors, although not statistically significant. TNFα marrow plasma levels were higher in 4/9 patients (44 %) compared to 1/6 (17%) of healthy controls (p=0,002). No differences were noted in marrow plasma IFNγ levels.
Conclusion
Our study shows that the bone marrow of DADA2 patients is characterized by an inflammatory milieu and by a reduced growth of marrow progenitor cells, partially rescued in vitro by anti-TNFα and Eltrombopag.
Further studies are needed to better understand the mechanisms of BM damage and to develop novel potential therapeutic approaches.
Daratumumab Overcome Platelet Transfusion Refractoriness in Patients with Aplastic Anemia: A Pilot Trail
Authors: Gao Zhen , Pan Hong , Huang Jinbo , Zhao Xin , Zhang Lele , Li Weiwang , Li Jianping , Nie Neng , Zhao Jingyu , Li Liyun , Xu Jing , Yu Xiao , Kuang Zhexiang , Ge Meili , Fang Liwei , Shi Jun 
Published: December 2024

Introduction
Platelet transfusion refractoriness (PTR) represents a significant clinical challenge, markedly elevating the risk of hemorrhagic mortality in some patients with transfusion-dependent aplastic anemia. There is an urgent need for effective therapeutic strategies to enhance platelet transfusion responsiveness, beyond the administration of repeated platelet transfusions.
Methods
We conducted a single-arm, single-center, prospective pilot study involving patients with aplastic anemia who exhibited platelet transfusion refractoriness, as evidenced by a decrease in the corrected count increment (CCI) on at least two occasions (1-hour CCI &lt; 7500 or 24-hour CCI &lt; 4500 post-transfusion). Daratumumab was administered intravenously at a dose of 8 mg per kilogram of body weight once weekly for four consecutive weeks. The primary endpoints were adverse events and overall response rate (ORR), defined as the percentage of patients achieving at least two effective platelet transfusions, followed by a 12-week follow-up.
Results
A total of 10 patients were recruited with 8 reaching the 12-week primary endpoint. Within this subset, one patient was administered daratumumab monotherapy, six received a combination therapy with cyclosporine, and one was treated with a regimen including tacrolimus and danazol. The median baseline platelet count was 2.5×109 per liter (range, 1 to 13). The ORR at 12 weeks was 87.5% (7 out of 8 patients), with a median time to response of 3 weeks (range, 1 to 6). The most frequently observed adverse events were grade 1-2 electrolyte imbalances (75%) and grade 1 general symptoms (62.5%), such as fatigue, headache, and insomnia. Throughout the study, a total of 38 transfusions were administered, with transfusion reactions occurring in 4 cases (10.5%). The infection rate during the 12-week follow-up period was 50% (4 out of 8 participants), with infections classified as severity grade 2-3. Importantly, no fatalities were reported during the study period.
Conclusion
Anti-CD38 targeted therapy demonstrates promising preliminary efficacy in addressing platelet transfusion refractoriness, while exhibiting mild and tolerable adverse reactions in patients with aplastic anemia. (Funded by the National Clinical Research Center for Blood Diseases Fund for Clinical Research; ClinicalTrial.gov ID: NCT05832216).
Keywords: Aplastic anemia, Platelet transfusion refractoriness, CD38 monoclonal antibodies