bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematopoietic Stem Cell Transplantation (HCST) Is Underutilized in Black Patients with Myeloid Neoplasms. Results from a Retrospective Study at Chicago's Leading Minority-Serving Hospital
Authors: Turk Ekrem , Elsebaie Maha , Deenadayalan Vaishali , Obeidat Khaldun , Nanaa Ahmad , Zia Maryam , Birch Noah 
Published: December 2024

Background: Access to hematopoietic stem cell transplantation (HSCT) is crucial for patients with myeloid neoplasms, yet disparities in its utilization are evident, particularly among ethnically diverse, minority-serving hospitals. These disparities can exacerbate treatment inequities. This study aims to understand how race and ethnicity impact access to and decisions regarding HSCT. Methods: In this retrospective study, we examined patients over 18 with myeloid neoplasms or premalignant conditions, who had undergone genetic profiling. Transplant eligibility was decided through a comprehensive evaluation of patient's risk classification, comorbidities, and donor availability by the leukemia service and transplant referral center. In eligible patients who had an indication for HSCT but did not undergo transplant, we collected information on reasons for non-transplant. Clinical data were presented according to race and ethnicity and compared using Pearson's χ2 or Fisher exact tests.
Results: 94 patients, including 45 females (47.9%) were included. 38 patients (40.4%) identified as Black, 28 (29.8%) as White, and 28 (29.8%) as Other (10.6% Asian, 9.6% Mexican/South American, and 9.6% undetermined). 30 patients (32%) identified as Hispanic and 64 (68%) as non-Hispanic. Diagnoses included Acute myeloid leukemia (AML, 32%), Myelodysplastic syndromes (MDS, 13%), Myeloproliferative neoplasms (MPN, 40%), MDS/MPN overlap syndrome (7%), and Clonal Hematopoiesis of Indeterminate Potential (7%). 27 patients (29%) were deemed eligible for HSCT. 38% of eligible white patients received HSCT compared to none of the black or other race eligible patients (p=0.06). Lack of necessary social support (28.6%) and loss of follow-up (14.3%) were the most common barriers to transplant in eligible Black patients. In contrast, lack of insurance (25%) and patient refusal (25%) were common reasons for non-transplant despite eligibility in white patients. An equal number of Hispanic (18%) and non-Hispanic (18.7%) transplant-eligible patients ended up receiving transplant. Lack of insurance/financial support was common reason for non-transplant despite eligibility (44.4%) in Hispanic compared to non-Hispanic patients (7.6%,P= 0.021).
Conclusions:The study highlights significant racial and ethnic disparities in HSCT use among myeloid neoplasm patients, suggesting systemic healthcare access barriers. Key obstacles for Black patients were insufficient social support and loss of follow-up, whereas Hispanics faced predominantly insurance-related barriers. These findings highlight the urgency of targeted strategies to overcome these disparities and ensure equitable HSCT access for all racial and ethnic groups.
TRIM28 Serves As a Key Regulator of Protein Homeostasis and Mediates Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Fang Teng , Liu Lanting , Sun Hao , Sun Xiyue , Yu Zhen , Qiu Lugui , Hao Mu 
Published: December 2024

Introduction:
The maintenance of intracellular protein homeostasis is a critical biological process necessary for the survival of multiple myeloma (MM) cells. Tripartite motif (TRIM) proteins, a subfamily of the RING-type E3 ubiquitin ligase family, are integral to protein quality control. In this study, we examined the role of TRIM28, a member of the TRIM family, as a regulator of protein homeostasis in MM.
Methods:
Bioinformatic analysis was utilized to elucidate the association between TRIM28 and genes involved in the proteasome and autophagy mediated protein degradation pathway. ShRNA knockdown (KD) and overexpression (OE) experiments were conducted to investigate the role of TRIM28 in MM pathogenesis. ChIP-seq and IP-MS analyses were performed to identify potential downstream targets of TRIM28.
Results:
Firstly, our survival analysis revealed that MM patients exhibited poor outcomes with high levels of TRIM28 in both the MMRF-CoMMpass and in-house datasets, particularly in the context of bortezomib treatment. Overexpression of TRIM28 promoted cell proliferation and induced drug resistance in MM cell lines, while knock-down of TRIM28 had the opposite effect. Bioinformatic analysis demonstrated a strong correlation between TRIM28 expression and the expression of proteasome subunits and autophagy-related genes in MM datasets. RNA-seq data showed down-regulation of both the proteasome pathway and autophagy pathway after TRIM28 knockdown, leading to decreased proteasome activities and accumulation of ubiquitinated proteins. Immunofluorescence assay confirmed nuclear localization of TRIM28, while ChIP-seq identified its binding to proteasome gene promoters such as PSMB1, PSMD2, and PSMD4. Knock-down of TRIM28 reduced the expression of proteasome subunits, indicating its critical role in transcriptional activation of these genes in MM cells.
Additionally, a decrease in autophagosome formation was observed in TRIM28 KD cells, indicating the involvement of TRIM28 in autophagy activity. Further IP-MS and Co-IP assays demonstrated the interaction between TRIM28 and 14-3-3ζ. A significant reduction in the polyubiquitination level of 14-3-3ζ was noted in TRIM28 KD cells. The 14-3-3ζprotein serves as an adaptor that modulates cellular signaling by binding to a wide array of proteins. Therefore, acting as an E3 ligase, TRIM28 promotes ubiquitin-dependent degradation of 14-3-3ζ, thereby enhancing autophagy activity in MM. These findings underscore the crucial role of TRIM28 in maintaining protein homeostasis by regulating both proteasome and autophagy activities involved in myeloma pathogenesis.
Conclusion:
Our research has provided new and important insights into the crucial role of TRIM28 in maintaining protein homeostasis and its involvement in myeloma pathogenesis. TRIM28 activates the proteasome and autophagy pathways, making it a potential promising therapeutic target in MM.
Donor Neutrophil Subsets in G-CSF Mobilized Peripheral Blood Stem Cell to Predict the Risk of Agvhd
Authors: Zhang Haiyan , Wu Qiaoyuan , Dai Huajuan , Liu Xinyu , Fan Zhiping , Lin Ren , Xu Na , Liu Qianwei , Liu Qifa , Jin Hua 
Published: December 2024

Purpose:
Recently, a few studies began to focus on the role of neutrophil subsets in the immune tolerance; however, the role of these subgroups in acute graft versus host disease (aGVHD) is unclear. In our study, we explore the effect of neutrophil subsets in G-CSF mobilized peripheral blood stem cell transplants on the occurrence of aGVHD and establish a prediction model for the occurrence of II-IV aGVHD within 100 days after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Patients and Methods:
A prospective cohort trial was performed in our hospital from December 2023 to March 2024. The proportion of neutrophil subsets in the donor-derived G-CSF-mobilized peripheral blood stem cell grafts, including: neutrophil progenitor 1 (proNeu1), neutrophil progenitor 2 (proNeu2), neutrophil precursor cells (preNeu), immature neutrophils (immatureNeu), and mature neutrophils (matureNeu), were detected by flow cytometry. Univariate logistic regression and restricted cubic spline (RCS) were used to screen variables related to the onset of aGVHD. A multivariate logistic regression equation was constructed with the screened variables to establish a prediction model, and the prediction performance of the model was evaluated. This trial is registered with ClinicalTrials.gov (NCT 06394895) and is completed.
Results:
A total of 139 patients were enrolled in the study, of which 98 patients were randomly selected as the training cohort and 41 patients as the validation cohort. We found that the matureNeu ratio, proNeu2 ratio, donor type and donor age in the graft were independent influencing factors for II-IV aGVHD. Based on these four variables, we established a prediction model for the risk of II-IV aGVHD.In the prediction model,the area under the receiver operating characteristic (ROC) curve (AUC) of the model was 0.789 and 0.777 in the training set and validation set, respectively. The optimal cutoff value of this prediction scoring system was 0.4. A prediction score greater than 0.4 was defined as a high-risk population for II-IV aGVHD. The 100-day cumulative incidence of grade II-IV aGVHD was 19.1% (95% CI 9.2-27.9%) and 60.6% (95% CI 47.4-70.4%) in the high- and low-risk groups of this cohort, respectively (P &lt; 0.0001).
Conclusion:
The proportion of matureNeu subgroup, proNeu2 subgroup, donor type and donor age in peripheral blood stem cell transplants are independent influencing factors for II-IV aGVHD after allo-HSCT. The prediction model based on these variables has good predictive ability and can intuitively and quickly identify the high-risk population for II-IV aGVHD.
Sintilimab, Rituximab and Lenalidomide (sR2) As First-Line Treatment in Elderly Patients with Diffuse Large B-Cell Lymphoma: A Single-Arm, Open-Label, Phase 2 Trial
Authors: Wei Xiaolei , Guo Xutao , Wei Qi , Wei Yongqiang , Feng Ru 
Published: December 2024

The chemo-free combination of rituximab and lenalidomide (R2) has been showed activity in a significant proportion of older patients with diffuse large B-cell lymphoma (DLBCL). Lenalidomide could enhance the cytotoxicity induced by checkpoint blockade in vitro. Herein, we did a phase 2 trial of sintilimab, rituximab, and lenalidomide (sR2) to evaluate the efficacy and safety in older patients with de novo DLBCL.
Eligible patients were aged older than70 years or older than 60 years with ECOG PS ≥ 2, newly diagnosed DLBCL. Patients were administered a maximum of 8 28-day cycles of 10 mg oral lenalidomide from days 1 to 21, IV rituximab 375 mg/m2 and sintilimab 200mg on day 1, with response assessment after cycles 4 and 8. Patients with partial response or complete response (CR) at cycle 8 were administered lenalidomide 10 mg/d from days 1 to 21 for every 28 cycles for a total of 2 years or until progression or unacceptable toxicity. The primary endpoint in this study was complete response rate (CRR) after 8 cycles or at the end of the induction treatment. The secondary end point was 2-year overall survival, progression-free survival, overall response rate (ORR) and treatment-emergent adverse events.
Until April 9, 2024, A total of 18 older DLBCL patients were enrolled and 14 of them was evaluated. The median age of the patients in this study was 75 years old (range 68-70) and 2 (11.1%) patients had a poor performance status with an ECOG score of 2 or greater. 12 (85.7%) patients achieved an overall response at the end of the induction treatment, with 11 (78.6%) achieving a complete response. With a median follow up of 8.9 months, the 1-year progression-free survival and overall survival were 80.8% and 92.9%, respectively. Common grade 3-4 adverse events were hematological toxicities (neutropenia in 4 patients (28.6%), thrombocytopenia in 3 patients (21.4%), anemia in 3 (21.4%). No treatment-related deaths were reported.
A chemotherapy-free sR2 regimen is clinically effective and safe and warrants further investigation in older patients with DLBCL.
Vincristine Overcomes Cytarabine Resistance in Acute Myeloid Leukemia By Suppression of ARHGAP18-Mediated Cellular Senescence
Authors: Ren Xiyang , Yan Haotian , Zhou Mei , Wu Fan , Zhang Qing , Ding Yangyang , Li Qian , Wang Huiping , Xu Caixian , Wang Jiyu , Li Cong , Zhang Wanqiu , Liu Linlin , Chen Ruotong , Dong Yi , Dai Wenjie , Zhai Zhimin , Tao Qianshan 
Published: December 2024

Background : Cytarabine is the cornerstone of chemotherapy in patients with acute myeloid leukemia (AML), yet the outcomes remain unsatisfactory because of resistance. Cellular senescence is a novel mode of cytarabine resistance in AML, but its mechanism of action and solution strategy remain unclear.
Methods : We observed the proportion of cellular senescence and the expression level of ARHGAP18 in relapsed and refractory AML patients after treatment with cytarabine. In vitro, we established stable AML cell lines with knockdown and overexpression of ARHGAP18 gene using lentiviral transduction. In vivo, we developed an mouse xenograft model to explore the role of ARHGAP18 gene in the process of cytarabine resistance. Additionally, we used the microtubule inhibitor targeting ARHGAP18 protein to evaluate the potential applicability of overcoming cytarabine resistance in AML.
Results: In this study, we demonstrated that cellular senescence primarily occurred in leukemia cell subsets in AML patients resistant to cytarabine, accompanied by high expression of ARHGAP18gene and ARHGAP18 protein. Cellular senescence (including cellular senescence specific staining, cell cycle arrest, and cellular senescence related secretory phenotypes) was rare in ARHGAP18 gene wild-type and knockdown leukemia cells but frequent in ARHGAP18 gene overexpressed leukemia cells. Under the stress of cytarabine, both in vitro and in vivo, ARHGAP18 gene knockdown significantly decreased the incidence of cellular senescence and increased chemotherapy sensitivity compared to the wild-type ARHGAP18gene. Conversely, ARHGAP18 gene overexpression significantly increased the incidence of cellular senescence, chemoresistance, the ability to resume proliferation, and extramedullary invasion, and resulted in shorter survival times. Mechanistically, the p16/Rb and p53/p21 signaling pathways were involved in ARHGAP18-mediated cellular senescence. Importantly, given previous research indicates that the ARHGAP18 is located on microtubules, we found that the microtubule protein inhibitor vincristine significantly disrupted the ARHGAP18 protein, reduced cellular senescence, and increased chemotherapy sensitivity.
Conclusions: ARHGAP18 induces cellular senescence via the p16/Rb and p53/p21 signaling pathways, mediating cytarabine resistance in AML. However, vincristine overcomes cytarabine resistance by suppression of ARHGAP18-mediated cellular senescence.
Early Responders (Time to Best Response ≤3 months) Predicts Functional High-Risk Multiple Myeloma
Authors: Xu Yang , Fan Yili , Wang Luyao , Zhang Jiawei , Chen Boxiao , Yang Luyu , Zhang Xuzhao 
Published: December 2024

Introduction: Despite advancements in risk evaluation and management of multiple myeloma (MM), functional high-risk (FHR) MM often shows a suboptimal response to induction therapy or relapses early after initial treatment. Early recognition of FHRMM may help to tailor treatment approaches and improve survival outcomes. However, the characteristics of FHRMM is not fully understood, and the impact of current treatment on FHRMM remains unclear. Our objective is to identify baseline risk factors and treatment response kinetics associated with FHRMM.
Method: The patients with newly diagnosed multiple myeloma (NDMM) between January 2017 and December 2022 were included. The patients' characteristics, treatment protocols, best responses, and survival data were collected and analyzed. High-risk factors were defined based on the NCCN MM guideline 2024v4, which includes various cytogenetic abnormalities and disease characteristics (R-ISS III, extramedullary disease, circulating plasma cells, and cytogenetic abnormalities including Del(1p32), t(4;14), t(14;16), t(14;20), Del17p, 1q21 gain/1q21 amp, and MYC translocation). Among MM without baseline risk factors, those progressed or relapsed ≤18 months after treatment initiation were considered FHR, while those progressed or relapsed &gt;18 months were classified as standard risk (SR). Cox regression analysis was used to assess the impact of multiple variables on prognosis, and log-rank test was performed to explore risk factors for FHRMM.
Results: Among 211 NDMM patients, there were 30 patients (14.2%) in the FHR group, 119 (56.4%) in the SR group, and 62 (29.4%) in the high-risk (HR) group. With a median follow-up of 44.0 months, the progression-free survival (PFS) and overall survival (OS) for FHR group were 14.0 months and 39.0 months, respectively. Notably, the FHR group had a significantly higher proportion of patients with time to best response (TBR) ≤3 months compared to the SR group, P=0.039. Furthermore, among non-HR groups stratified by TBR, there were significant differences in PFS and OS between TBR ≤3 months and TBR &gt;3 months, with median PFS of 30.0 months and 56.0 months, and median OS of 58.0 months and 94.0 months, respectively, both P&lt;0.001. Autologous stem cell transplantation (ASCT) significantly improved the PFS of FHRMM patients, P=0.033.
Conclusions: At present, it is not easy to differentiate FHR from SR patients based on the baseline characteristics of NDMM. Nevertheless, the analysis of response kinetics suggests that TBR ≤3 months could be a feasible indicator for early identification of FHRMM. ASCT has been found to improve the prognosis of FHRMM.
A Novel Approach Combining Type II JAK Inhibitor Chz-868 with Nutrient Restriction to Augment Cell Death in Philadelphia like Acute Lymphoblastic Leukemia
Authors: Alhaddad Muneera , Buono Roberta , Huynh Van Thu , Tasian Sarah K. , Fruman David A 
Published: December 2024

Background: There is an urgent clinical need to improve therapeutic outcomes in Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). Approximately 60% of Ph-like cases harbor rearrangements in the CRLF2 locus, often with accompanying mutations in JAK kinases. Current clinical trials are assessing whether ruxolitinib, a type I JAK inhibitor, can enhance responses to chemotherapy in CRLF2-r acute leukemias. Notably, preclinical studies have shown that type II JAK inhibitors provide greater anti-leukemic effects than ruxolitinib. Other work has demonstrated promising ability of nutrient limitation to enhance the efficacy of tyrosine kinase inhibitors (TKIs) in solid tumors and chemotherapy in hematologic malignancies. Indeed, there is growing excitement for short-term application of fasting-mimicking diet (FMD), since clinical studies have shown promising therapeutic efficacy with higher compliance rates than other dietary interventions. The objectives of this study were to compare the cytotoxicity of type I and II JAK inhibitors in CRLF2-r Ph-like ALL, and to determine whether nutrient restriction via FMD enhances JAK inhibitor efficacy.
Methods: We conducted both in vitro and in vivo experiments. For in vitro experiments, we used the human B-precursor ALL cell lines MUTZ5 and MHH-CALL-4 as well as patient derived Ph-like ALL cells that carry CRLF2 translocation. We used flow cytometry techniques to measure cell viability. Western blotting analysis was used to quantify pro-survival and pro-apoptotic proteins in the treated cell lines. For in vivo experiments, we used mouse patient-derived xenograft (PDX) model in which NSG mice were injected with patient derived Ph-like ALL cells.
Results: In vitro experiments confirmed that the type II JAK inhibitor CHZ-868 had more potent cytotoxic effects than ruxolitinib in CRLF2-r cell lines and cells derived from PDX models. Short-term starvation with low glucose and low serum strongly sensitized CRLF2-r cell lines to CHZ-868 cytotoxicity. Mechanistically, the combination of CHZ-868 and starvation was associated with decreased expression of the pro-survival protein MCL-1 and increased expression of the pro-apoptotic protein BIM. In vivo experiments using a CRLF2-r PDX model showed that FMD reduced leukemic burden and enhanced the efficacy of CHZ-868.
Conclusion: Efficacy of the type II JAK inhibitor CHZ-868 in CRLF2-r cells is enhanced by nutrient restriction. These results provide proof-of-concept for testing FMD as a diet-based approach to enhance TKI efficacy in Ph-like B-ALL patients.
Anti-CD3/B-Cell Maturation Antigen Bispecific Antibody CM336 in Relapsed/Refractory Multiple Myeloma: An Open-Label, Phase I/II Study
Authors: An Gang , Huang Zhongxia , Liang Aibin , Fang Baijun , Jing Hongmei , Qiu Lu-Gui 
Published: December 2024

Introduction: Multiple myeloma is an incurable malignancy characterized with high relapse rates. Therapeutic options to improve clinical outcomes remain limited for patients with relapsed/refractory multiple myeloma (RRMM). CM336 is a novel bispecific antibody targeting both CD3 and B-cell maturation antigen (BCMA), redirecting T cells to BCMA-expressing myeloma cells. Here, we report the dose-escalation results of CM336 from a first-in-human, open-label, phase I/II study (NCT05299424).
Methods: This study included a dose-escalation and a dose-expansion part. For dose escalation, eligible subjects (18 years or older) were diagnosed with RRMM (per International Myeloma Working Group criteria), had a measurable disease, and had exposed to at least one proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Subjects received CM336 at doses ranging from 0.04 to 160 mg using an accelerated titration design for the first 3 cohorts, followed by a “3+3” design. CM336 was administrated subcutaneously weekly, with a step-up dosing scheme for 40 mg and higher doses.
Results: As of June 30, 2024, 25 subjects received CM336 (median age, 63 years [range 41-76]; 72% female) in the dose-escalation part. Subjects had received a median of 4 (range 2-15) prior lines of therapy, with all being triple-class exposed and 20% with extramedullary plasmacytoma. The median CM336 exposure duration was 4.8 months (range 0.03-12). Maximum tolerated dose was not reached. The most common treatment-emergent adverse events (TEAEs) included cytokine release syndrome (CRS) (any grade: 68%; grade ≥3: only one subject), anaemia (68%; 32%), lymphocyte count decreased (64%; 56%), neutrophil count decreased (56%; 44%), pneumonia (44%; 32%), and pyrexia (44%; 0). All CRS events were resolved completely, and no immune effector cell associated neurotoxicity syndrome (ICANS) events were reported. At a median follow-up of 8.0 months, the confirmed overall response rate (ORR) was 60.9% (14/23; 95% CI, 38.5%-80.3%). Notably, for subjects in the 80 mg and 160mg cohorts who received at least one target dose (n=8), the ORR was 100%. Of the 10 subjects (43.5%) with a confirmed stringent complete response (sCR), 9 were evaluable for minimal residual disease (MRD), and the MRD negativity rate (at a threshold of 10−5 cells) was 88.9% (8/9). The median time to response was 1.4 months (range 0.7-3.8). The median duration of response and median progression-free survival were not reached. All subjects in remission have not experienced disease progression yet.
Conclusions: Treatment with CM336 was well tolerated with preliminary promising anti-myeloma efficacy. CM336 is expected to improve the prognosis of subjects with RRMM. With longer follow-up, additional efficacy/safety data will be presented.