bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological and Mechanism Study of a New RIPK1 Inhibitor Via Necroptosis to Treat Hemophagocytic Lymphohistiocytosis
Authors: Zhu Jinbing , Wang Jinjin , Zhao Ailin , Niu Ting 
Published: December 2024

Background: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine-release syndrome with high mortality, primarily treated with corticosteroids, though 30% of patients exhibit resistance. Necroptosis, a caspase-independent programmed cell death, is overly activated in autoimmune diseases, severe COVID-19, and SIRS, leading to sterile inflammation and cytokine storm. Receptor-interacting serine/threonine protein kinase 1 (RIPK1) regulates necroptosis, and inhibitors of RIPK1 show potential as treatments for inflammatory diseases, sepsis, cancer, and neurodegenerative diseases. In this study, we hypothesize that RIPK1 inhibitors can treat HLH by inhibiting necroptosis and sensitizing cells to corticosteroid-induced apoptosis.
Material and method: This study utilizes AI-assisted drug design and deep learning models based on conditionally recurrent neural networks for decentralized learning to develop a novel, highly selective, and potent RIPK1 inhibitor-SKLB-Z30. SKLB-Z30, with a new scaffold, demonstrates superior pharmacodynamics and safety compared to the reported RIPK1 inhibitor GSK2982772. We induced necroptosis in murine macrophage and T cell lines in vitro to explore the inhibitory effects of SKLB-Z30, both as monotherapy and in combination therapy. In secondary and primary murine models of HLH, we used SKLB-Z30 alone or with dexamethasone and preliminarily analyzed the mechanisms of action.
Result: This study successfully induced necroptosis in murine macrophages and T cells in vitro. PI/Hoechst results showed that SKLB-Z30 monotherapy inhibited necroptosis at low concentrations (10 nM), significantly outperforming GSK2982772. SKLB-Z30 dose-dependently inhibited the phosphorylation of key proteins (RIPK1, RIPK3, MLKL) in necroptotic macrophages and T cells. SKLB-Z30 also reduced TNFα and IL-6 levels in the supernatant of necroptotic cells in a concentration-dependent manner. In vivo, macrophage activation syndrome (MAS) and primary HLH animal models were successfully established. MAS and HLH mice exhibited significant anemia, thrombocytopenia, liver dysfunction, elevated body temperature, hepatosplenomegaly, increased ferritin, and bone marrow hemophagocytosis. Transcriptome sequencing revealed that the TNFα-RIPK1-RIPK3 signaling pathway was upregulated in model mice compared to normal mice. Immunohistochemistry showed significantly elevated p-RIPK1 and p-MLKL protein expression both in MAS and HLH mice. SKLB-Z30 monotherapy and combination therapy with dexamethasone significantly reduced liver and spleen size, improved anemia, increased platelet counts, reduced serum ferritin, and decreased levels of TNFα, IL-6, and other cytokines.
Conclusion: The novel RIPK1 inhibitor SKLB-Z30 demonstrated effective therapeutic action against HLH in both in vivo and in vitro experiments. RIPK1 inhibitors represent a promising new approach for the clinical treatment of HLH patients.
Sequential Pembrolizumab Followed By AVD in Advanced Hodgkin Lymphoma: A Retrospective Study from North India
Authors: Chand Rashmi ahmed , Naim Faran , Chand Rashmi , Quasimi Huma , Sharma Rahul , Kapoor Rajan , Kumar Rajiv , Gandhi Lorie , Surange Devyani , Shaikh Mohd Rizwan Mohamad Anwar 
Published: December 2024

Background: Hodgkin lymphoma (HL) is one of the most curable forms of cancer, with high treatment success rates. Advances in treatment options, including chemotherapy, radiation therapy, and immunotherapy, have significantly improved the prognosis for patients with HL.
Methods: We performed a retrospective study of 15 HL patients, including adolescents and elderly, treated at two tertiary centers in north India between 2023 and 2024. The treatment regimen consisted of the sequential administration of Pembrolizumab with Adriamycin, Vinblastine, and Dacarbazine (AVD). Pembrolizumab (IV, 200 mg) was administered every 21 days starting on cycle 1, day 1, followed by interim assessment with PET-CT. Patients who achieved partial or complete metabolic response were subsequently given six cycles of AVD (doxorubicin [IV, 25 mg/m2], vinblastine [IV, 6 mg/m2], and dacarbazine [IV, 375 mg/m2]).
Results: This study includes patients with a median age of 43 years, spanning from 16 to 74 years. The cohort comprises 66.7% males and 33.3% females. All patients were advanced stage (stage III or IV). The distribution of the International Prognostic Score (IPS) is as follows: 46.7% with scores of 0-1, 20% with a score of 2, 13.3% with a score of 3, and 20% with a score of ≥4. B symptoms are present in 46.7% of the patients. After three cycles pembrolizumab immunotherapy, the observed responses are: 46.6% with a complete response, 40.0% with a partial response, 6% with progressive disease, and 6% resulting in death. Following the administration of six AVD cycles of Pembrolizumab 14 patients are evaluable as 1 is still on treatment, the complete metabolic response is 78.5%, with 14.2 % showing refractory disease.
Conclusion: Sequential pembrolizumab followed by AVD is a promising first-line treatment for advanced-stage Hodgkin's lymphoma, but it doesn't always result in a fairytale outcome for every patient. Here, for the first time, we demonstrate that sequential Pembrolizumab-AVD therapy has shown a refractory response in 14.2 % patients, whereas it has achieved 100% complete response rates in studies conducted worldwide. This suggests potential regional differences in treatment efficacy or patient response. Further studies are needed to explore the underlying reasons and to optimize therapeutic strategies for Hodgkin Lymphoma in diverse populations.
Safety and Efficacy of Iruplinalkib for Patients with Relapsed or Refractory (r/r) ALK+ Lymphoma: A Phase II Trial
Authors: Wang Yue , Wei Fang , Wang Wanli , Zhao Linjun , Chen Jie , Song Yuqin , Zhu Jun , Liu Weiping 
Published: December 2024

Background：
Anaplastic lymphoma kinase-positive (ALK+) lymphoma includes ALK+ anaplastic large cell lymphoma (ALCL) and ALK+ large B cell lymphoma (LBCL). ALK is a receptor tyrosine kinase in the insulin receptor superfamily. ALK inhibitor such as crizotinib exhibited significant effectiveness in relapsed or refractory (r/r) ALK+ lymphoma. Iruplinalkib, a highly selective oral ALK and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI), has shown promising anti-tumor activity with a manageable safety profile in r/r ALK+ non-small cell lung cancer. Herein, we reported the efficacy and safety of iruplinalkib for r/r ALK+ lymphoma.
Aims:
To evaluate the efficacy and safety of iruplinalkib in patients with r/r ALK+ lymphoma.
Methods:
This prospective stage II study enrolled patients aged 18-65 years with histologically confirmed r/r ALK+ lymphoma, including the r/r ALK+ ALCL and ALK+ LBCL. The primary endpoint were overall response rate (ORR), and the secondary endpoints included complete response rate (CRR) , progression-free survival(PFS) and safety.
Results:
As of the database cutoff on July 30, 2024, 6 patients were enrolled. The median age was 39 years (range, 23-70). Three patients (50.0%) were male. Five (83.3%) patients were diagnosed with ALK+ ALCL, 1 patient (16.7%) had ALK+ LBCL. The median line of prior chemotherapy was 1 (range, 1-2).
Among 5 patients with evaluable response, the ORR was 80% with a CRR of 20.0%.One patient with ALK+ ALCL achieved complete remission, 2 with ALK+ ALCL and 1 with ALK+LBCL achieved partial remission，and 1 with ALK+ ALCL achieved stable disease. The median PFS was 2.5 months (range, 0.9-6.0 months). Serious adverse events (SAEs) were not observed in all patients. No treatment discontinuation or death due to treatment-related adverse events (TRAEs) was reported.
Summary/Conclusion:
Iruplinalkib demonstrated a tolerable safety and a good efficacy in r/r ALK+ lymphoma patients.
Keywords:Anaplastic lymphoma kinase; Iruplinalkib; Lymphoma; Therapeutics; Prognosis
DNA Methylation in Juvenile Myelomonocytic Leukemia and Its Clinical Significance
Authors: Liu Chenmeng , Wang Xingchen , Chen Yunlong , Wan Yang , An Wenbin , Ren Yuanyuan , Liu Fang , Guo Ye , Yang Wenyu , Zhu Xiaofan 
Published: December 2024

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm that develops during infancy and early childhood. Aberrant DNA methylation constitutes an independent risk factor in JMML .
A total of 41 newly diagnosed JMML were enrolled in this study, including 31 males and 11 females from Dec 2013 to Dec 2023 at our single center. Quantification of DNA methylation was performed using an Illumina Infinium MethylationEPIC Beadchip platform (Illumina). Unsupervised hierarchical clustering of the most variable CpG sites across all JMML samples classified three clusters, low methylation (LM), intermediate methylation (IM), and high methylation (HM).
The median age of patients is 34 months (range: 3-144 months). All patients were followed up until 1 June 2024. The median follow-up time was 23months (range: 2-96 months). The median level of HbF was 14.65% (1.2%-76.1%). The median blast percentage in BM, as measured by flow cytometry, was 2.18% (0-11%). Among the samples analyzed, 8 were classified into the LM subgroup, 16 exhibited IM, and 17 showed HM. In the methylation analysis, a total of 15 patients had both peripheral blood and bone marrow samples sent for testing. Interestingly, both sample types from the same patient exhibited consistent results. The methylation level of one case transitioned from LM to HM during relapse. 34.1% of children carried PTPN11 mutation. Patients with PTPN11 mutations tended to be classified into HM(P=0.02). In univariate analysis, children with PTPN11 mutations had a lower probability of overall survival (OS) (84%±7% vs 42%±13%, P&lt;0.001). Patients in HM subgroup were more likely to have a higher blast percentage in BM (4.39% vs 1.2%, P=0.003) and higher level of HbF (49.9% vs 3.1%, P=0.003) at diagnosis compared to those not. Among children who did not undergo HSCT, those in the HM subgroup exhibited a poorer OS compared to those in the IM and LM subgroups (P=0.06). The 2-year OS for children in the HM subgroup was 65%. HSCT significantly improved the OS of children within the HM (89%±10% vs 25%±15%, P=0.002).
Overall, Patients in the HM subgroup exhibited poor overall survival.HSCT can significantly improve the OS of patients in HM subgroup. Peripheral blood and bone marrow samples from the same patients exhibited consistent patterns of methylation grouping.
The Thrombosis in Patients with Lower Limb Injuries Requiring Immobilisation Study . (TILLIRI study)
Authors: O'Keeffe Denis , O'Halloran Thomas , Ni Ainle Fionnuala , Bassa Bibi , Watts Michael , Egan Siobhan 
Published: December 2024

Background: Patients requiring temporary lower limb immobilisation after injury have an increased venous thromboembolism (VTE) risk. The extent of this risk in published studies varies. The TRiP(cast) model (Thrombosis Risk Prediction following cast immobilization) quantifies VTE risk using clinical risk factors. Delineating low from high VTE risk patients is challenging in the clinical setting.
Aims: To determine the 90-day incidence of symptomatic VTE following temporary lower limb immobilisation after injury in an undifferentiated patient population. To prospectively collect data on VTE risk factors, including those incorporated in the TRiP(cast) model, to retrospectively calculate TRiP(cast) scores.
Methods: TILLIRI is a prospective multicentre cohort study including 10 sites within the Irish Network for VTE Research (INViTE). Patients ≥ 18 years with an immobilised injured lower limb following injury were included. Twenty-one clinical variables were collected at presentation. Thromboprophylaxis was prescribed according to clinical gestalt. Patients were followed up at 90-days to determine if a VTE occurred.
Results: Between November 2018 and February 2023, 1243 patients were recruited. Follow up was complete for 1200 patients. 43 patients (3.5%) were lost to follow up. 44 (3.6%) patients and 126 (10%) patients were prescribed an anticoagulant and aspirin respectively. VTE incidence at 90-day follow-up was 7/1222 (0.57%; CI 0.15%-0.99%). TRiP(cast) scores were calculated for 1177/1222 patients. 846 patients (71.9%) had a TRiP(cast) Score &lt; 7, received no prophylaxis and had no VTE.
Conclusion: TILLIRI indicates a low incidence of VTE in an undifferentiated patient population following lower limb immobilization with low rates of anticoagulation and aspirin use. The proportion of patients with low TRiP(cast) scores and no symptomatic VTE rate suggests that thromboprophylaxis may potentially be avoided in patients with a TRiP(cast) score &lt; 7, with a low risk of VTE at 90 days. Future studies examining targeted strategies to identify low-risk patients can help safely avoid unnecessary anticoagulation.
Challenges in Interpreting Avws Screening in Polycythemia Vera: Correlations with Clinical and Laboratory Features
Authors: Weihermann Viktoria , Melo Raphael B. , Kayano Alexandre , Silva Camila Alves , Rocha Tania Rubia , Silva Wellington F. , Rocha Vanderson , Seguro Fernanda Salles 
Published: December 2024

Background: The risk of thrombotic and hemorrhagic complications frequently coexists in myeloproliferative neoplasms (MPN), partly due to the occurrence of acquired von Willebrand syndrome (AVWS), particularly in essential thrombocythemia. However, the value of screening for AVWS in other MPNs is not so clear. Additionally, it is unknown whether laboratory-diagnosed AVWS correlates with clinical manifestations. Therefore, we aimed to investigate the connection between specific clinical and laboratory features and AVWS, and to determine if AVWS was associated with bleeding in our polycythemia vera (PV) cohort.
Methods: This is a cross-sectional study involving adult PV patients followed at Hospital das Clínicas of the Faculty of Medicine, University of São Paulo, Brazil. Screening for AVWS was conducted using von Willebrand factor antigen (VWF Ag) and activity levels measured by the ristocetin cofactor assay (RCO). AVWS was defined as a VWF:RCo/Ag ratio &lt; 0.6. Additionally, we collected data on thrombotic and bleeding complications.
Results: We evaluated 46 of 597 patients (54% male, median age 62.5 years) diagnosed with polycythemia vera who were screened for AVWS from 2012 until 2023. In only three patients, the tests were ordered immediately after a bleeding event. At the moment of the screening, the median blood counts were: hematocrit 43% (IQR 38-51), leukocytes 11.7 x 109/L (8.0-16.8), platelets 572 x 109/L (IQR 307-952). Median VWF antigen was 146% (range 64-464), median VWF:RCo was 58% (range 1-159) and median function/antigen ratio (VWF:RCo/Ag) was 0.42 (range 0.01-0.78). Thirty-six patients (78%) had a screening test (VWF:RCO / Ag &lt; 0.6) positive for AVWS, and this parameter was correlated to thrombosis (p=0.03), but not to bleeding (p=0.58).
There were 12 bleeding events (26% of the cohort) and neither VWF antigen, VWF:RCo, hematocrit, leukocyte count, platelet count or risk group could be associated with these events. It was observed that VWF antigen was higher with higher platelet counts (p=0.02). A reduced function/antigen ratio (VWF:RCo/Ag) showed a significant association with leukocytosis and thrombocytosis, but not with hematocrit above normal range.
In nine patients, the AVWS screening tests were done on at least two occasions. We observed that the level of VWF:RCo increases when the patients achieve the target hematocrit level below 45%.However, the VWF:RCo/VWF ratio improved only when the platelets levels lowered after cytoreduction.
Conclusions: Most of the patients in our cohort (78%) had a positive screening for AVWS by the VWF:RCO / Ag ratio criteria. However, we did not show a correlation with bleeding events or blood count parameters. Despite the significant number of bleeding events, establishing the diagnosis of AVWS or a correlation with bleeding events is a challenge for patients with PV.
Prospective Study of Avapritinib in Patients with Relapsed/Refractory or MRD-Positive Core-Binding Factor Acute Myeloid Leukemia with KIT Mutations
Authors: Dou Xueqing , Chen Suning , Wu Depei 
Published: December 2024

Core-binding factor acute myeloid leukemia (CBF-AML), which includes the recurrent genetic abnormalities RUNX1::RUNX1T1 and CBFβ::MYH11 fusions, is generally associated with a favorable prognosis. However, KIT gene mutations are a common co-occurring event in CBF-AML, and the presence of KIT mutations is associated with a poorer prognosis in these patients. Avapritinib is a tyrosine kinase inhibitor that was developed to specifically target mutations in the KIT and PDGFRA genes. While avapritinib has been approved for the treatment of gastrointestinal stromal tumors (GIST) with PDGFRA mutations and advanced systemic mastocytosis, its efficacy and safety in CBF-AML with KIT mutations have not been extensively investigated.
In this study, we evaluated the efficacy and safety of avapritinib in patients with relapsed/refractory or measurable residual disease (MRD)-positive CBF-AML harboring RUNX1::RUNX1T1 or CBFβ::MYH11 fusions. A total of 40 patients, including 24 males and 16 females, with a median age of 41 years (range, 13-77), were enrolled from two big medical centers in China. The majority of patients (33/40, 82.5%) had RUNX1::RUNX1T1 fusions, while the remaining 17.5% (7/40) had CBFβ::MYH11 fusions. In these patients, 23 (57.5%) had KIT N822 mutations, 5 (12.5%) had KIT N822 mutations, 8 (20%) had complex KIT mutations, and 4 (10%) patients had other KIT mutations. Thirteen patients had relapsed/refractory AML, and the other 27 had a positive molecular MRD of fusion genes after two consolidation treatment at least. All of the patients received avapritinib monotherapy at a dose of 100mg daily (in combination with azole antibiotics) or 200mg daily orally, with or without in combination with chemotherapy.
In the 13 relapsed/refractory AML patients, 6 had a good response to avapritinib, achieving an overall response rate（ORR) of 46.2%. Five of the 6 responding patients then underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and achieved molecular MRD-negative remission, although one patient subsequently died of pulmonary infection. Among the 27 patients with positive molecular MRD, 19 (70.4%) demonstrated a good response to avapritinib, with a reduction in molecular MRD level of at least 1 log, and 11 (40.7%) achieved molecular MRD negativity.The most common adverse event (AE) was hematological toxicity, and other AEs included facial edema, gastrointestinal reactions, rash, QT interval prolongation, and hair depigmentation.
In general, the study results suggest that avapritinib demonstrated good efficacy and safety in patients with CBF-AML harboring KIT gene mutations. These findings may support expanding the indications for this therapy in the treatment of AML.
Clinical Characteristics and Risk Factors of Chronic Kidney Disease Among Patients with Myeloproliferative Neoplasms
Authors: Gao Zicheng , Zhou Xuan , Wang Qiang , Xu Dan , Liu Xiaoli , Xu Na , Liu Qifa 
Published: December 2024

Abstract:
Background: Classical BCR::ABL-negative myeloproliferative neoplasms (MPN), which mainly include essential thrombocytopenia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), characterized by the overproduction of mature myeloid blood cell lineages and commonly complicate with thrombosis. Recently, reports of MPN related kidney dysfunction especially chronic kidney disease gradually gained attention. However, the clinical characteristics of CKD in MPN patients is still unclear.
Aim: The aim of this study was to investigate the clinical characteristics and risk factors of complicated with CKD in patients with MPN.
Methods: We retrospectively analyzed the clinical characteristics and genetic characteristics of MPN patients who visited Nanfang hospital regularly from June 2008 to December 2023. The predictors of complicated with CKD and over survival (OS) were analyzed by logistic regression or Cox proportional hazards model.
Result: A total of 1373 patients were included, 15.4% of whom had CKD. 1216 clonal hematopoiesis of indeterminate potential (CHIP) related mutations were detected.78.6% of patients had at least one CHIP-related mutation. Patients with CHIP-related mutations were more likely to be older, with 24% being ≥ 65 years of age compared with 7.2% in non-CHIP-related mutation (P &lt; 0.001), and also had fewer CALR mutations (8.1% vs. 27.6%, p &lt; 0.001), and a higher incidence of cardiovascular events, hypertension, diabetes and CKD (25.3% vs. 11.3%, P&lt;0.001; 10.6% vs. 5.8%, P = 0.014; 13% vs. 8.5%, P = 0.040; 17.3% vs. 8.5%, P &lt; 0.001).The multivariate logistic analysis indicated that age ≥65 years old (HR:0.95, 95% CI, 0.94-0.97, p &lt; 0.001), mutation in TET2 (HR:6.54, 95% CI, 2.88-14.88, p &lt; 0.001)、ASXL1 (HR: 2.29, 95% CI, 1.00-5.24,p = 0.049), complicated with cardiovascular events (HR:90.82, 95% CI, 48.62-169.65, p &lt; 0.001), hypertension (HR: 3.42, 95% CI, 1.94-6.03, p &lt; 0.001) and diabetes (HR: 2.16, 95% CI, 1.31-3.54, p = 0.002) are risk factors for CKD in MPN. The multivariable COX analysis revealed that age ≥ 65 years old (HR: 1.88, 95% CI, 1.20 - 2.96, P = 0.006), diagnosed PMF (HR: 11.23, 95% CI, 6.36 - 19.82, P &lt; 0.001), complicated with CKD (HR: 3.48, 95% CI, 2.15 - 5.64, P &lt; 0.001) were the unfavorable predictors of OS, while female (HR: 0.50, 95% CI, 0.34 - 0.75, P &lt; 0.001) was the favorable factors.
Conclusion: Our single-center data indicates that MPN patients have a 15.4% incidence rate of complicated with CKD. Age ≥65 years old, mutation in TET2, ASXL1, complicated with cardiovascular events, hypertension and diabetes are independent risk factors for CKD in MPN patients. Diagnosed PMF, male, complicated with CKD were the unfavorable factors for OS.
Keywords: Myeloproliferative neoplasms; Chronic kidney disease; Clonal hematopoiesis; Clonal hematopoiesis of indeterminate potential