bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of NLRP3 Inflammasome in Monocytes By HT-6184 in a Single-Cell Proteomic Study
Authors: Bursey Devan , Bearss Benjamin , Avei Taylor , Mollard Alexis , Bearss Jared , Janat-Amsbury Margit Maria , Bearss David J. 
Published: December 2023

Background
The NLRP3 inflammasome is associated with the activation of monocytes and plays a crucial role in the innate immune response. The NLRP3 inflammasome is a multi-protein complex expressed primarily in monocytes and other immune cells. When monocytes encounter danger signals, such as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the NLRP3 inflammasome is assembled, leading to the maturation and secretion of potent pro-inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). These cytokines, in turn, induce a robust inflammatory response to clear infections, promote tissue repair, and coordinate adaptive immunity. However, dysregulated NLRP3 inflammasome activation has been associated with various inflammatory disorders, such as autoimmune diseases, metabolic diseases, and neurodegenerative conditions.
Purpose
This study investigated the effects of a potent, allosteric NLRP3 inflammasome modulator, HT-6184, on cytokine release response from the activation of NLRP3 in human monocytes.
Methods
Human peripheral blood mononuclear cells (PBMCs) were utilized, and monocytes were isolated using a Miltenyi pan monocyte isolation kit. Subsequently, these isolated monocytes were exposed to different concentrations of HT-6184 (300 nM and 100 nM) before being stimulated with lipopolysaccharide (LPS) at a concentration of 10 ng/mL, a potent activator of the NLRP3 inflammasome. After 24 hours, the secreted cytokines were analyzed at the single-cell level using the Isospark, with data analysis performed using the Isospeak software.
Results
The results demonstrated that monocytes treated with LPS alone exhibited high levels of pro-inflammatory cytokines, including effector and stimulatory cytokines, and chemoattractive chemokines such as IL-8, MIF, MIP-1b, and TNF-alpha. In contrast, monocytes treated with HT-6184 and LPS showed reduced cytokine secretion, approaching levels observed in the control group. Notably, the HT- 6184-treated group displayed a lower incidence of polyfunctionality (2%) than the LPS-only group (11%), indicating fewer cells capable of simultaneously secreting multiple cytokines. The 3D-TSNE graph analysis revealed that the HT-6184 and LPS-treated groups clustered with the control group, signifying similar cytokine secretion profiles. In contrast, the LPS-only group exhibited a distinct pattern of cytokine secretion.
Conclusions
These findings indicate that HT-6184 effectively inhibits the release of pro-inflammatory cytokines upon NLRP3 activation in monocytes. Further research should explore the characteristics of HT-6184 and its ability to modulate the inflammasome in diverse in vitro and in vivo models. The modulation of the NLRP3 inflammasome by HT-6184 holds potential therapeutic implications for managing inflammatory disorders associated with dysregulated NLRP3 activation.
Serum Ferritin Reflects Bone Marrow Iron Stores in Children with End Stage Kidney Disease
Authors: Sharma Shilpa , Pereira Renata , Nemeth Elizabeta , Hanudel Mark , Ix Joachim , Salusky Isidro , Ganz Tomas 
Published: December 2023

Background: Iron deficiency is common in children with end-stage kidney disease (ESKD) but diagnosing iron deficiency in ESKD is challenging as serum indicators of iron stores may be influenced by inflammation and other factors. We examined which of the clinically used serum iron indices were predictive of bone marrow iron stores (the gold standard) in dialysis-dependent children and young adults with ESKD, in the setting of increased nutritional requirements and co-existing inflammation.
Methods: This cross-sectional study enrolled 71 clinically-stable children and young adults (age range 2 to 28 years) receiving dialysis, who underwent bone biopsy for CKD-mineral bone disorders between 2007 through 2011. Congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary diseases (63.3%) were the main causes of renal failure, followed by primary glomerulonephritis (36.7%). Bone samples were stained with Perls' Prussian blue and independently interpreted by a pathologist unaware of the patients' iron parameters and clinical status. Staining was scored absent vs present for receiver operator curve (ROC) analysis. In ROC analysis, the ability of serum ferritin to predict bone sample iron stores was compared with serum hepcidin, transferrin saturation (TSAT), and clinical guideline-based iron deficiency cut-offs for serum iron, TSAT, and their combination. We generated optimal cut off points using the Youden's J statistic.
Results: Mean age was 17.2 ± 4.4 years, and 30% of subjects were female. Median dialysis vintage was 1.2 (IQR 0.7, 2.0) years, and 56% were supported by peritoneal dialysis. Mean hemoglobin was 12.4 ± 1.7 g/dl, and 35% were receiving iron supplementation at the time of biopsy. Based on gold standard of depleted bone iron stores, 46.5% patients were iron-deficient. As a predictor of bone marrow iron staining, serum ferritin provided the highest area under the ROC curve compared to other tests (Table), but at the usual clinical ferritin cutoff (100 ng/ml) only 22% of true iron-deficient subjects were diagnosed compared to 52% of true iron-deficient subjects using a higher optimal cutoff point for ferritin (188 ng/ml).
Conclusions: In children with ESKD, iron deficiency as determined by the gold standard bone iron staining was highly prevalent (close to 50%), and serum ferritin provided the best prediction of bone sample iron stores. Optimal ferritin cutoff for decision-making about iron administration should reflect the current relative risks and benefits of iron therapy. Future trials testing higher ferritin cut-offs and patient centered outcomes in children with ESKD are timely.
Analysis of Influencing Factors of Positive Antiplatelet Antibody in Patients with Diffuse Large B-Cell Lymphoma
Authors: Zhang Wei , Ran Longrong , Zhao Mingyu , Peng Yu , Luo Xin , Chen Shuang , Yang Zailin , Liu Yao 
Published: December 2023

Background Diffuse large B-cell lymphoma (DLBCL) is a common malignant tumor of the hematological system. Chemotherapy is the main treatment. As a cytotoxic drug, chemotherapeutic drugs can lead to thrombocytopenia, increase the risk of bleeding and require platelet transfusion if necessary. Since platelet antibody is the main cause of ineffective platelet transfusion, the detection of platelet antibody is of great significance to prevent the inefficacy of platelet transfusion in patients with diffuse large B-cell lymphoma.
Objective To analyze the screening results of antiplatelet antibodies in patients with diffuse large B-cell lymphoma and to explore the main factors affecting the production of antiplatelet antibodies so as to provide basis for safe blood transfusion.
Methods Patients with diffuse large B-cell lymphoma treated in our department from August 2022 to May 2023 were selected as subjects. Antiplatelet antibodies (GP IX, GP Ⅰ b, GPIIb, GPIIa, GMP140) were detected by flow cytometry. The factors affecting the positive antiplatelet antibodies were analyzed from the aspects of clinical characteristics and laboratory indexes.
Results In 155 patients with diffuse large B-cell lymphoma, the positive rate of antiplatelet antibody was 63.23% (98/155). Among them, the positive rate of antiplatelet antibody in male patients was 63.75% (51/80), higher than that in female patients was 62.67%(47/75), and the difference was statistically significant (P&lt;0.05). The positive rate of antiplatelet antibody in patients over 60 years old was 65.18% (43/67), higher than that in patients aged ≤ 60 years old was 62.5%(55/88). The difference was statistically significant (P&lt;0.05). In addition, the positive detection of antiplatelet antibody was related to the abnormal results of large platelet ratio, mean platelet volume, D-dimer and aspartate aminotransferase. In the positive distribution of antiplatelet antibodies, the positive rates of GP IX, GP Ⅰ b, GPIIb, GPIIa and GMP140 autoantibodies were 1.29% (2/155), 29.03% (45/155), 37.42% (58/155), 1.29% (2/155), 49.68% (77/155), respectively. The positive number of antiplatelet antibodies was related to the abnormal results of partial prothrombin time, prothrombin time, prothrombin activity, international standardized ratio, thrombin time, fibrin (prothrombin) degradation products, globulin, alanine aminotransferase and aspartate aminotransferase.
Conclusion Patients with diffuse large B-cell lymphoma with abnormal results of large platelet ratio, mean platelet volume, D-dimer and aspartate aminotransferase should pay attention to the detection of antiplatelet antibodies before platelet transfusion to prevent transfusion failure.
Risk Factors of Venous Thromboembolism in Lymphoma Patients: A Meta-Analysis
Authors: Jiang Cuiting , Lv Jing , Liu Tingting , Liu Yao 
Published: December 2023

Background: The prevalence and risk factors of venous thromboembolism (VTE) in lymphoma patients have been extensively studied, but with varying degrees of research quality and inconsistent findings. The primary objective of our study was to investigate the prevalence and identify risk factors associated with VTE in lymphoma patients.
Methods: We conducted a systematic search of PubMed, EMBASE, Web of Science, and Cochrane Library databases up to February 2023 to identify relevant studies investigating VTE in lymphoma patients. We calculated the pooled odds ratio using a fixed- or random-effect model and evaluated the quality of each study using the Newcastle-Ottawa Scale. To evaluate the robustness of our findings, we conducted sensitivity analysis. We also identified any potential publication bias using funnel plots and Egger's test. Two researchers independently assessed eligibility and extracted data to ensure accuracy.
Results: Our analysis included a total of 17 studies with a combined sample size of 4,983 lymphoma patients (Figure 1). The pooled prevalence of VTE among these patients was 12% (with a confidence interval of 0.09-0.15). Sensitivity analyses were performed, and the results were consistent with the overall pooled estimate. Our meta-analysis revealed that several factors were significant risk factors for VTE in lymphoma patients, including female sex, older age, history of VTE, DLBCL lymphoma type, Ann Arbor stage III~IV, higher ECOG-PS, bulky disease, central nervous system involvement, WBC count &gt;11×10 9/L, D-dimer level &gt;0.5mg/L, central venous catheterization, and treatments with doxorubicin ( P&lt;0.05) (Table 1). However, the funnel plot suggested that there may be some potential publication bias, which was further confirmed by statistical tests. Nevertheless, the results of the trim-and-fill method demonstrated that the pooled estimate remained stable after the addition of nine “missing” studies.
Conclusions: Our study revealed that the pooled prevalence of VTE in OC was approximately 12% across lymphoma patients. Risk factors for VTE were identified which may aid in preventative measures for VTE in lymphoma patients.
Transcriptional Heterogeneity and Clonal Evolution between Diagnosis and Relapse in Pediatric Acute Myeloid Leukemia
Authors: Grasso Cristoforo , Brazda Peter , te Pas Brigit M. , Dharmadhikari Gitanjali , Koedijk Joost B. , Goemans Bianca F. , Heidenreich Olaf , Belderbos Mirjam E. , Zwaan C. Michel , Stunnenberg Hendrik G. , Megchelenbrink Wout 
Published: December 2023

Clonal evolution of leukemia is driven by different selection pressures operating on a heterogeneous population of cells. These pressures may include therapy-induced and immune-mediated effects which eradicate the majority of cells, but which simultaneously provide a selective advantage to a minor population of cells that is genetically or transcriptionally distinct and which grow out towards relapse.
We integrated single-cell RNA-seq, DNA-seq, ATAC-seq and long-read Oxford Nanopore sequencing of matched diagnosis and relapse samples of 20 pediatric AML patients with various genetic driver mutations representative of the mutational spectrum to map the genetic and transcriptional evolution of these cancers (Figure 1). We investigated whether and how differences in AML-initiating mutations impact on transcriptional programs in AML blasts and their surrounding microenvironmental cells and how the mutational and transcriptional features of these cells are impacted by cancer therapy. Specifically, we traced the progression of these traits from the point of diagnosis to the occurrence of relapse.
Our single cell RNA and ATAC data showed high patient-to-patient heterogeneity, with gene expression patterns that were largely conserved between diagnosis and relapse. Analyses of the differentially expressed genes and factorization into “metaprograms” revealed gene sets that were shared between relapse samples but could not be tied to interpretable common “biological signatures”. Exome-seq revealed highly significant changes in somatic variants, most notably in members of the RAS-signaling pathway (i.e., KRAS, NRAS, PTPN11, NF1 and CBL). Interestingly, pathogenic RAS mutations were often gained, but also lost, or switched between different RAS-pathway members, indicating that RAS-mutations are associated with extensive clonal evolution/rewiring. To unveil the effect of accumulation or loss of (sub)clones with RAS mutations on the transcriptional phenotype and epigenetic landscape of leukemic blasts, we performed targeted screening of somatic variants at single-cell resolution. To this aim, we combined long-read nanopore sequencing with 10x Genomics single-cell technologies, enabling us to directly link genetic, transcriptomics and epigenetic changes in distinct (sub)clones.
Taken together, we successfully reconstructed patient-specific genetic and transcriptional evolutionary trajectories in pediatric AML. This knowledge will be essential for our understanding of AML relapse and therapy resistance.
Overexpression of Integrin β7 in Newly Diagnosed Multiple Myeloma with High Risk Cytogenetic Abnormality and Poorer Prognosis
Authors: Zheng Dong , Wan Wenli , Zhu Mingxia , Jing Hongmei 
Published: December 2023

Introduction
The second most prevalent malignant blood malignancy is multiple myeloma (MM), but the condition is still incurable. In the interaction between MM cells and the bone marrow microenvironment, adhesion molecules are known to mediate adhesion and promote the survival and proliferation of MM cells. Integrin β7 (ITGB7) is a member of the adhesion molecule family. However, there are few clinical studies on ITGB7 in MM and there is no prognostic analysis. By analyzing the relationship between ITGB7 expression and clinical signs and prognosis, this study thus provides a basis for evaluating the clinical and prognostic importance of ITGB7 expression in MM patients.
Methods
In 39 patients with newly diagnosed multiple myeloma from 2021.1 to 2022.9, we assessed the expression of ITGB7 in relation to clinical characteristics and prognosis. Flow cytometry was used to detect the median fluorescence of ITGB7, detecting that ITGB7 median fluorescence intensity (MFI) in abnormal plasma cell was significantly higher than that in mature B cells (18.76 vs 5.62, P&lt;0.001). ROC curve defines that ITGB7 best indicator for predicting MM disease is the abnormal plasma cell to mature B cells median fluorescence intensity ratio (MFI P/B), with a cut-off value of 4.025.
Results
Compared to patients with low expression of ITGB7, patients with high expression of ITGB7 showed a significant increase in mSMART stratification risk (82.60% vs 50.00%, P=0.041), while those with IgH/FGFR3 showed a significant increase (38.9% vs 6.30%, P=0.043). Patients with high expression of ITGB7 had poorer prognostic trends in PFS and OS, (PFS: P=0.071; OS: P=0.070).
Conclusion
Overexpression of ITGB7 is prone to merging with high risk cytogenetic abnormality and poorer prognosis in newly diagnosed MM patients.
Outcomes Among Hospitalized Patients with Amyloidosis and Atrial Fibrillation: A Nationwide Analysis
Authors: Arya Yajur , Syal Arshi , Casipit Bruce Adrian , Dourado Claudia , Mayo Ryan J , Casipit Carlo 
Published: December 2023

Background
Amyloidosis can affect virtually any organ system; deposition in the heart usually occurs in primary (AL) and mutated transthyretin (ATTR) subtypes. Clinical presentation ranges from heart failure and infiltrative cardiomyopathy to life threatening ventricular arrythmias. Atrial fibrillation has often been described in literature to manifest in patients with amyloidosis, although its clinical significance needs further exploration.
Methods
We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified hospitalized patients with amyloidosis and atrial fibrillation using appropriate ICD-10 CM codes. We stratified patients based on whether they had atrial fibrillation during the hospitalization or not. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of &lt;0.05 was considered statistically significant. The aim of this study is to investigate the outcomes among hospitalized patients with amyloidosis and atrial fibrillation looking primarily at the in-hospital mortality, risk for cardiogenic shock, and hospital length of stay (LOS).
Results
We identified a total of 84604 hospitalized patients with amyloidosis, of which 31.73% (26845/84604) had comorbid atrial fibrillation. The overall in-hospital mortality among those with amyloidosis was 6.42% (5432/84604). Among those who had atrial fibrillation, the overall in-hospital mortality rate was significantly higher at 7.17% (389/5432) (p=0.011). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, atrial fibrillation among hospitalized patients with amyloidosis did not significantly increase the risk for in-hospital mortality (adjusted OR 1.12, 95% confidence interval [CI], 0.96-1.31; p=0.150) or prolong hospital LOS (p=0.199). However, concomitant atrial fibrillation among hospitalized patients with amyloidosis increased the risk for cardiogenic shock (aOR 1.65, 95% confidence interval [CI], 1.31-2.06; p=&lt;0.001)
Conclusion
Atrial fibrillation continues to be a significant comorbidity in patients with amyloidosis. Our study found a statistically significant increase in the risk for cardiogenic shock, but not for in-patient mortality and hospital LOS. Early identification and prompt management with medical therapy or cardioversion is necessary to prevent disastrous complications. Further prospective cohort studies will help to better assess both short- and long-term outcomes in this patient population.
Chemotherapy-Induced Cellular Senescence Promotes Stemness of B-Cell Non-Hodgkin's Lymphoma Via CCL21/CCR7/NF-Κb Signaling Activation
Authors: Wang Jiyu , Tao Qianshan , Wang Yangyang , Huang Keke , Liu Chaohong , Zhai Zhimin 
Published: December 2023

A bs tract: Resistance to existing therapies is currently the main reason for treatment failure in refractory/relapsed B-NHL patients, and treatment-induced cellular senescence (TIS) is one of the important mechanisms of tumor drug resistance. In our previous studies, we found that the anti-apoptotic and tumorigenic ability of chemotherapy-induced senescent B-NHL cells was significantly enhanced, and the survival period of tumor-bearing mice was significantly shortened, but the mechanism is still unclear. In this study, we identified the C-C chemokine receptor 7 (CCR7) by single-cell RNA-sequencing, which showed significant differential expression in senescent B-NHL cell population and non-senescent cell population. CCL21/CCR7 dependent B-NHL-TIS initiates downstream transcription of NF-κB, thereby enhancing phenotypic and functional stemness features, including the up-regulation of stemness markers, CD34, CD44, LGR5, CD150, and stronger colony forming ability and cell sphere forming ability. The analysis results of clinical patients showed that the expression of CCR7 in the peripheral blood of B-NHL patients was significantly higher than that of healthy normal people and leukemia patients. The expression of CCR7 in peripheral blood of B-NHL patients before treatment was significantly lower than that of relapsed patients, and The expression in abnormal B lymphocyte population is significantly higher than that in normal T and B lymphocyte population, high expression of CCR7 is associated with recurrence and poor prognosis in B-NHL patients. Targeting CCR7/NF-κB signaling has positive significance in inhibiting the acquisition and maintenance of stemness in aging B-NHL cells and preventing tumor drug resistance and recurrence.
K ey words: Stress-induced senescence; CCR7; CCL21; senescence related stemness; B-cell non-Hodgkin's lymphoma
Upfront Autologous Stem Cell Transplant at First Complete Remission in Patients with Advanced-Stage Extra-Nodal NK/T Cell Lymphoma: A Multicenter Retrospective Study
Authors: Hu Shaoxuan , Zhao Linjun , Liu Weiping , Huang Wenrong , Qi Shunan , Wang Xiaopei , Song Yuqin , Li Yexiong , Zhu Jun 
Published: December 2023

Objective: Treatment outcome of patients with advanced-stage extranodal NK/T cell lymphoma (NKTCL) remains unsatisfactory. The role of consolidation therapy with autologous stem cell transplantation (ASCT) at first complete remission (CR1) in these patients is controversial. This study aimed to investigate the effect of upfront ASCT on the prognosis of patients with advanced-stage NKTCL achieving CR1 to frontline therapy.
Methods:This is a multicenter retrospective study. Data were collected from patients diagnosed with NKTCL between 2006 and 2021 in the China Lymphoma Collaborative Group (CLCG) database. The inclusion criteria were as follows: pathologically confirmed diagnosis of NKTCL, age≤65 years at diagnosis, stage III or IV disease, and achievement of CR1 at the completion of frontline induction therapy. Clinical characteristics, treatment including the use of ASCT, and follow-up information were reviewed. The primary endpoints were progression-free survival (PFS) and overall survival (OS).
Results: A total of 99 patients from 14 medical centers in China were included in this study. The median age was 38 years (range: 6-64 years). Sixteen patients (16%) had an ECOG-PS≥2 at diagnosis, and 26 patients (26%) presented with primary extra-nasal disease. The baseline Prognostic Index for NK-cell lymphoma (PINK) was≥2 in 63 patients (64%). Regarding first-line treatment, 85 patients (86%) received non-anthracycline-based chemotherapy, and the remaining patients received anthracyline-based chemotherapy. At the time of CR1, 32 patients (32%) received upfront ASCT consolidation and 67 patients did not. Baseline clinical characteristics were comparable between the ASCT group and non-ASCT group. With a median follow-up time of 33 months, median PFS was not reached in the ASCT group versus 46 months in the non-ASCT group (3-year PFS: 76.6% versus 54.9%, P=0.012). OS was not significantly different between the ASCT group and the non-ASCT group (3-year OS: 85.2% versus 69.4%, P=0.098). In multivariate analyses, upfront ASCT was independently associated with better PFS (HR=0.40, 95%CI 0.17-0.94, P=0.037) after adjusting for baseline PINK score and types of first-line chemotherapy (anthracyline-based versus non-anthracyline-based). Only non-anthracyline-based first-line chemotherapy (HR=0.32, 95%CI 0.11-0.88, P=0.028) was associated with better OS in multivariate analysis.
Conclusions: In this multicenter real-world study, upfront ASCT improves PFS of patients with advanced stage NKTCL achieving CR1 to front-line chemotherapy, but the effect of upfront ASCT on OS in the era of non-anthracycline-based chemotherapy remains uncertain. The specific subgroups of patients most likely to gain a survival benefit from upfront ASCT need to be further investigated.