bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-Enzymatic Role of Platelet 12-LOX in Platelet Activation
Authors: Sharma Durga Shankar Shankar , Botta Eliana , Tsai Wan-Chen , Holman Theodore , Holinstat Michael
Published: December 2023

Background 12-lipoxygenase (12-LOX) plays an essential role in regulation of vascular disease and human platelet function through oxylipin generation such as 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE) and 12-hydroxyeicosatetraenoic acid (12-HETE). Previous literature has demonstrated that 12-LOX enzymatic function such as oxylipin generation is important for collagen- or thrombin-mediated signaling events. However, the addition of 12(S)-HETE does not completely restore the inhibitory effect of pharmacologically or genetically inhibiting 12-LOX on platelet activation, indicating that 12-LOX may have a non-enzymatic function in platelets. Therefore, we tested the non-enzymatic role of 12-LOX in platelet activation.

Method 12 LOX was co-immunoprecipitated (co-IP) from washed human platelets following FcγRIIa or thrombin stimulation. The bound proteins were eluted by laemmli buffer and the elutes were analyzed on SDS-PAGE. Proteins co-IP with 12-LOX at various times were identified by mass spectrometry and confirmed by western blot analysis.

Result Silver-stained gel of 12-LOX co-IP indicated the presence of several protein bands in complex association with 12-LOX at different time points. These bands were analyzed by mass spectroscopy and several proteins observed in complex with 12-LOX were identified including integrin β3, Talin-1, Myh9, Nexilin, Gelsolin, Actin, cytoplasmic 2, and Actin related protein 2/3 (ARP 2/3) . To confirm the mass spectroscopy identified protein, these proteins were immunoblotted following co-IP of 12-LOX. to confirm their association with 12-LOX prior to and following platelet activation. These interactions were further confirmed with a reverse co-IP. Finally, to determine if the association pattern of these proteins with 12-LOX is disrupted in the presence of a 12-LOX inhibitor already shown to limit platelet activation and which is currently in clinical trials for treatment of HIT (ML355/VLX-1005), we were able to demonstrate that the inhibitor appears to lock the protein complex into place.

Conclusion Our study identified several proteins that are present in 12-LOX complex such as integrin β3, talin-1, Myh9 and ARP 2/3. 12-LOX interacts with Integrin β3, Talin-1 and cytoskeletal proteins. Furthermore, the dynamic movement of the proteins in this complex into and out of association with 12-LOX is essential for normal platelet activation suggesting 12-LOX plays an important non-enzymatic role in regulation of agonist-mediated platelet activation.
Analysis of Allergic Transfusion Reactions at a Children's Tertiary Care Center
Authors: Katato Ghadir Khalil , Ozgonenel Bulent
Published: December 2023

Background: Transfusion reaction adverse events are a relatively rare occurrence in the United States. This is due to specific blood safety measures such as appropriate collection, preparation, testing, storage, and distribution of blood components as well as appropriate monitoring of patients receiving these transfusions. Several years of data have been collected by our institution's blood bank. Through our analysis, we have been able to describe the rate of transfusion- associated adverse events in pediatric patients at Children's Hospital of Michigan from 2018-2022.

Objectives: The aim of this retrospective chart review was to assess the rate of allergic blood transfusion complications and reactions among pediatric patients at Children's Hospital of Michigan in Detroit, Michigan.

Materials and Methods: An institution-based retrospective chart review was conducted for a total of 43,210 transfusions over a span of five years from 2018-2022.

Results: There were a total of 43,210 transfusions. A total of 26,669 of these products were red blood cell (RBC) transfusions, 10,447 were platelets, 4,392 were plasma, and 1,702 were cryoprecipitate (combined plasma and cryoprecipitate was 6,094). A reported reaction was encountered in 176 of the 43,210 transfusions. These reported reactions were part of the patients' underlying diseases. A true acute transfusion reaction (ATR) was encountered in 116 of the 43,210 transfusions. Of the 116 transfusions, 66 (56.9%) were classified as allergic reactions. About 61% of those reactions were skin manifestations (urticaria, itching), 9% were respiratory symptoms (dyspnea, tachypnea), and the remaining 30% were both skin and respiratory symptoms.

Of the total amount of RBC transfusions, 35 (0.131%) resulted in an allergic reaction. Similarly, 19 (0.182%) platelet and 12 (0.197%) plasma transfusions resulted in ATRs. ATRs were most associated with plasma, followed by platelets and RBC transfusions. Combining all transfusions received, these represented a total of 66 (0.153%) allergic transfusion reactions. These results are demonstrated in Figure 1.

Conclusion: ATRs were observed in 0.268% of total transfusions (allergic reactions (0.153%) and other reactions (0.115%)) that occurred over the course of five years at our institution. This is about 1 in 655 blood components transfused that was associated with an allergic reaction (more commonly with plasma > platelets > packed RBCs). The rate of allergic reactions is less than what was reported by National Blood Collection and Utilization Survey 2017 (0.282%). This rate is also less than what is reported for children (0.53%) and adults (0.26%) in a meta-analysis (Wang Y, Sun W, Wang X, et al. Comparison of transfusion reactions in children and adults: A systematic review and meta-analysis. Pediatr Blood Cancer. 2022;69(9):e29842.). These lower rates could be secondary to changes in blood processing and under-reporting.
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.
Five-Year Real World Data on AML Retrospective Study from Public Health Center in Brazil
Authors: Salvino Marco Aurelio , Feistauer Felipe , Batista Vieira Lima Marianna , Noblat Lucia
Published: December 2023

Introduction: Acute myeloid leukemia (AML) is a heterogeneous aggressive leukemia with poor prognosis. The standard remission induction regimen for medically eligible patients with AML consists of a backbone of cytarabine & an anthracycline (“7+3” therapy). Brazil is a large country with striking differences in in climate, ethnic heterogeneity and socioeconomic factors. Objectives: To assess effectiveness (Eligible to the Next Treatment-ENT CR and suficient performance status to the next treatment, PFS and OS) and security (Early Mortality) of cytarabine and anthracycline in a public health center in Salvador, Brazil. Subgroups analyzed were about FTL3 and NPM1 mutations, leukocytes (>10,000 or <10,000), platelets (>20,000 or <20,000), and transplanted or non-transplanted. Methods: It was a retrospective analysis of all the cases of non-promyelocytic AML diagnosed between 2018 and 2022 in the University Hospital Professor Edgar Santos of Federal University of Bahia, after being approved by the Ethics Committee of the hospital. Kaplan-Meier methods were used to determine the median of the time to OS and PFS. Results: A total of 45 patients were analyzed. Median age at diagnosis was 43 years (range, 16-69 years) with 62% females. There were 21% and 11% patients with FLT3-ITD and NPM1 mutations, respectively. Only 14 patients had karyotype test (85% with normal karyotype). Regarding effectiveness, 52% of patients were eligible for the next therapy after complete remission (consolidation or stem cell transplantation). Refractory patients were 20%. Early (4 weeks) mortality was 28% (19% in <40a, 27% in 40-55a and 40% in >55a). The median of PFS and OS were 3.6 and 8.2 months respectively. Patients with FLT3 mutation, platelet < 20.000 and leukocytes < 10.000 had poor outcomes. In AML patients after stem cell transplantation, PFS and OS were, respectively 20 and 43 months. Average waiting time for start induction therapy was 12 days. Conclusion: The outcomes were consistent with the literature, adjusted for the population in question. Even with access to diagnostic tests (not common in Brazilian's health public centers), patients did not have access to targeted therapies, with the 7+3 regimen being the only treatment for fit patients. To achieve complete remission followed consolidation/transplantation is still the BEST scenarios in AML eligible patients, but the improvement of access to diagnostic and treatment is still an unmet need.
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<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<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 >11×10 9/L, D-dimer level >0.5mg/L, central venous catheterization, and treatments with doxorubicin ( P<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.
Gilteritinib-Based Combination Therapy in Adult Relapsed/Refractory FLT3 Mutated Acute Myeloid Leukemia
Authors: Chen Nianci , Pan Jiajia , Zhou Yile , Mao Liping , Lou Yinjun , Qian Jiejing , Xu Gaixiang , Wei Juying , Zhou De , Shou Lihong , Li Huang , Yan Minchao , Zeng Hui , Fan Cuihua , Wu Gongqiang , Feng Weiying , Tong Hongyan , Jin Jie , Wang Huafeng
Published: December 2023

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3 mutated acute myeloid leukemia (AML) patients but still showed limited efficacy. Here, the efficacy and safety of different gilteritinib-based combination therapy (gilteritinib plus hypomethylating agent [HMA] and venetoclax, G+HMA+VEN; gilteritinib plus HMA, G+HMA; gilteritinib plus venetoclax, G+VEN) in 33 R/R FLT3 mutated AML patients were retrospectively analyzed. Composite complete response (CRc) rate (complete response [CR]+CR with partial hematologic recovery [CRh]+CR with incomplete blood count recovery [CRi]), modified CRc rate (mCRc, CRc+morphologic leukemia-free state [MLFS]), overall survival (OS), duration of remission (DOR), and adverse events were analyzed and compared.The CRc and mCRc rate were 66.7% (12/18) and 88.9% (16/18) in patients who received G+HMA+VEN, which was higher compared with that in G+HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G+VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median OS for G+HMA+VEN, G+HMA, G+VEN treatment was not reached, 145.5 days, and 231.0 days, respectively (G+HMA+VEN vs G+HMA, p=0.011). The median DOR for G+HMA+VEN, G+HMA, G+VEN treatment was not reached, 82.0 days, and 77.0 days, respectively (G+HMA+VEN vs G+VEN, p=0.040). Four patients in G+HMA+VEN group received allogenic hematopoietic stem cell transplantation (alloHSCT) after remission exhibited prolonged OS and DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection, there were no difference among three groups.In conclusion, our data demonstrated promising response of G+HMA+VEN combination therapy in R/R FLT3 mutated AML patients, and it may consider as an effective bridge to transplantation.
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<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 <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=<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.
The Impact of Peer Education on the Quality of Life and Self-Management Efficacy in Patients with Lymphoma
Authors: He Yang , Zhu Weiyi , Zhao Weili
Published: December 2023

Object：

Effect of peer education model on quality of life and self-management efficacy in patients with lymphoma:

Methods:

500 patients with lymphoma were divided into control group (n=250) and observation group (n=250) according to the order of admission. The control group received routine nursing care, while the observation group received peer education on the basis of the control group's nursing interventions, with a nursing duration of 3 months for both groups. A comparison was made between the quality of life before and after intervention and the self-efficacy and self-management levels after intervention in both groups.

Results:

After intervention, the observation group showed significantly higher scores in overall health, physical role limitations, physical functioning, bodily pain, vitality, social functioning, emotional role limitations, and mental health compared to before intervention and the control group after intervention (P<0.05). The observation group also exhibited significantly higher scores in self-efficacy, self-management, treatment compliance, communication with healthcare professionals, and cognitive management compared to the control group (P<0.05).

Conclusion:

The peer education model significantly improves the quality of life in patients receiving chemotherapy for malignant tumors, and significantly enhances self-efficacy and self-management levels.
Gain or Amplification of Chromosome 1q Mediate Multiple Myeloma Resistant to Xpo-1 Inhibitor Selinexor Via Transcription Factor ETV3
Authors: Gu Huiyao , Zhong Yi , Zhang Enfan , Cao Liqin , Cai Zhen , He Jingsong
Published: December 2023

Background: Gain or amplification of chromosome 1q, which characterized as a poor prognosis indicater, is one of the most frequent cytogenetic abnormalities in multiple myeloma (MM), occurring in nearly 40% of newly diagnosed patients. Though several genes, such as IL6R and CKS1B, have been reported to related to its severity, there still remains a mist for us to explore. So, we further explore the potential mechanism that may illustrate the malignant phenotype of gain or amplification of chromosome 1q in multiple myeloma, and the ETS transcription factors ETV3 may make sense.

Objective：Explore the functions ETV3 played in the malignant phenotype of gain or amplification of chromosome 1q in multiple myeloma.

Methods：Dataset GSE2658 from GEO database was used to analyze the correlation of ETV3 expression and survival of newly diagnosed multiple myeloma (NDMM). Dataset GSE4581 from GEO database was used to investigate the relationship between the number of 1q copies and expression of ETV3. Next, ETV3 expression on different myeloma cell lines was detected by RT-PCR,WB and high ETV3 expression cell lines were selected for further study. Knocking down of ETV3 on these cell lines were performed and CCK-8 was used to detected the proliferation ability. XPO-1 inhibitor selinexor was used with different concentrations (0-300nM) to treat these cells for 24h and 48h, and apoptosis was detected by flow cytometry. Further, RNAseq was performed to explore the related changed genes that might be regulated by ETV3.

Result s : Survival analysis showed MM patients with higher ETV3 expression exhibit worse prognosis according to Dataset GSE2658 (P mini=0.046). As for Dataset GSE4581, 414 patients were included, among which 186 patients carried more than 2 copies of 1q21. We found that along with the increasing of 1q21+ copies, expression of ETV3 increased (p<0.01).

The results of RT-PCR and West-blots showed that all the MM cell lines expressed different level of ETV3, among which H929 and AMO1 were extremely high. Hence, we knocked down ETV3 on these two cell lines (H929 Sh-ETV3 and AMO1 Sh-ETV3) in subsequent experiments. Results showed that after knocking down of ETV3, the proliferation rate of myeloma cells was reduced (p<0.05). Besides, myeloma cells knocked down of ETV3 were more sensitive to selinexor (p<0.01). Based on the above results, we analyzed the genes changed after knocking down of ETV3 by RNAseq, results indicated several genes such as PKN1 might play a part in this process.

Conclusion s : MM patients carrying with higher 1q21+ copies expressed higher level of ETV3 genes, which indicated a worse prognosis. Knocking down ETV3 on myeloma cells reduced their proliferation ability and enhanced their sensitivity to selinexor. PKN1 might involved in this process.

Key words: ETV3, multiple myeloma, Gain or amplification of chromosome 1q, selinexor
The Role of Radiotherapy in Patients with Refractory Hodgkin Lymphoma after Brentuximab Vedotin and -/or Immune Checkpoint Inhibitors
Authors: Liu Ting-Bo , Li Xiaofan , Zhao Rui-Zhi , Shao Han , Shi Gui-Qing , Qiu Yan-Yan , Tang Tian-Lan , Lin Yu-Ping , Chen Si-Lin , Huang Cheng , Liao Si-Qin , Chen Jin-Hua , Fu Hai-Ying , Liu Jian-Zhi , Shen Jian-Zhen , Xu Ben-Hua , Zhang Yu-jing , Yang Yong
Published: December 2023

Background: Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) had important roles in the treatment of relapse or refractory (R/R) Hodgkin lymphoma (HL). Treatment of refractory disease after BV and -/or ICIs remains a challenge. This study was conducted to evaluate the efficacy and safety of radiotherapy for R/R HL after failure to BV or ICIs.

Patients and methods: We retrospectively analyzed patients in two institutions with R/R HL who had failed after first-line therapy, and were refractory to BV or ICIs, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were analyzed.

Results: A total of 19 patients were enrolled. First-line systemic therapy consisted of ABVD (84.2%), AVD + ICIs (10.5%) and BEACOPP (5.3%), respectively. After first-line therapy, 15 patients (78.9%) were refractory, and 4 patients (21.1%) relapsed. After diagnosis of R/R HL, 8 patients (42.1%) received BV, and 17 patients (89.5%) received ICIs. RT was delivered in all 19 patients who failed after BV or ICIs. In 16 efficacy-evaluable patients, the ORR and CR rate were 100% and 100%. The median DOR was 17.2 months (range, 7.9 to 46.7 months). 3 patients progressed at outside of the radiation field. The in-field-response rate was 100%. The 12-month PFS and OS were 84.4% and 100%, respectively. No patients were reported with sever adverse events.

Conclusion: This study concluded that radiotherapy was effective and safe for refractory HL after BV or ICIs. Further prospective studies were warranted.

KEY WORDS: Radiotherapy; Hodgkin lymphoma; Brentuximab vedotin; Immune checkpoint inhibitors; Refractory; Relapse
The Ratio of Urea Nitrogen to Albumin Is a Better Predictor of OS in MM Patients Than That of Urea Nitrogen Alone
Authors: Dong Mengmeng , Shao Jiaqi , Zhang Enfan , Chen Haoguang , Cai Zhen , Cheng Tao
Published: December 2023

Background

Multiple myeloma (MM) is a malignant proliferative disease of plasma cells. Abnormally cloned plasma cells secrete large amounts of monoclonal immunoglobulins in the bone marrow of MM patients. Serum urea nitrogen (sUN) is a byproduct of protein metabolism, and its effect on MM patients' prognoses remains unknown. Therefore, we analysed MM patients' clinical data to explore the role of sUN and serum urea nitrogen/serum albumin (sUAR) in the baseline tumor load and MM prognosis of MM patients.

Methods

We downloaded the clinical data of 762 MM patients from the MMRF database. After excluding those without baseline sUN, 452 patients were finally included in the study. Smoothed curve fitting, threshold analysis, Tamhane's T2 test, multivariate adjusted Cox regression analysis, Kaplan‒Meier (K-M) curves, and receiver operating characteristic (ROC) analysis were applied in the study.

Results

There were 452 newly diagnosed MM patients included in this study. In most patient groups, sUN and sUAR were positively linked with β2-microglobulin (β2-MG) and lactic dehydrogenase (LDH) according to smoothing curve fitting and threshold analysis. The higher the ISS stage, the greater the values of sUN and sUAR. Furthermore, smoothed curve fitting and threshold analysis showed that sUN was correlated with OS, although sUAR had a stronger correlation with OS and could be applied to a broader group. The results of a multivariate adjusted Cox regression analysis demonstrated that sUN and sUAR were independent prognostic factors for OS. The K-M curve confirmed the correlation between higher sUN and sUAR levels and worse OS. β2-MG and LDH are generally recognized prognostic factors of OS. ROC analysis revealed that sUN might boost β2-MG and LDH's predictive value and sUAR had a higher predictive value.

Conclusion

This retrospective study based on the MMRF database showed that high sUN and sUAR levels were positively associated with β2-MG, LDH, and ISS staging, and sUAR exhibited a stronger correlation with OS than sUN alone.

Key words

Serum urea nitrogen, ratio of serum urea nitrogen to serum albumin, multiple myeloma, overall survival, β2-microglobulin, lactic dehydrogenase
Mutational Changes in Solid Cancer Cells Induce DNA Damage Repair Deficiency in Hematopoietic Cells Leading to a Distinct Spectrum of Clonal Hematopoiesis Independent from Age-Related Clonal Hematopoiesis
Authors: Leitner Theo , Künstner Axel , Kohl Michael , Barmwater Tobias , Ahmed Helal Mohammed , Caliebe Almuth , Dazert-Klebsattel Eva , Fähnrich Anke , Fliedner Stephanie , Gebauer Niklas , Spielmann Malte , Kirfel Jutta , Sailer Verena-Wilbeth , Bastian Lorenz , Von Bubnoff Nikolas , Busch Hauke , Khandanpour Cyrus
Published: December 2023

Clonal hematopoiesis (CH) is characterized by the acquisition of defined somatic mutations in hematopoietic stem cells (HSC). It is well known that CH contributes to the development of hematological malignancies but also increases the risk of developing non-malignant conditions such as cardiovascular, pulmonary, and inflammatory liver disease.

However, less is known about the association between clonal hematopoiesis and solid cancer. Reports suggest that patients with solid cancer have a higher incidence of clonal hematopoiesis at an earlier age and an inferior prognosis. To investigate whether the presence of solid cancer itself can drive the development of clonal hematopoiesis, we analyzed 392 paired tumor and blood samples from patients with advanced cancer. In our cohort, all patients had evidence of clonal hematopoiesis based on a variant allele frequency (VAF) of at least 2%. With respect to a defined set of the 20 most frequently CH-associated genes, we discovered an increased CH rate of 23% of all patients (90 cases, median age of 61 years, defined by a VAF from 2% to 30%). The frequency of mutated genes differed greatly from published data from the general population and cancer patients, with the most common mutations being PABPC1 (39%), KMT2C (28%), RUNX1 (18%), and DNMT3A (10%). In addition, we observed a strong correlation between certain mutations in tumor samples and the frequency of CH. The mutational signature of CH was not mainly associated with a typical chemotherapy-dependent mutational signature, but with an impaired DNA repair capacity. For further investigation, we performed additional experiments in mice, which showed that the presence of malignant cells impairs DNA repair capacity in HSC through inflammatory changes in the stroma.

In summary, we were able to show that patients with advanced or recurrent solid tumors have a significantly increased frequency of CH, which is not only the result of prior chemotherapy exposure but the result of diminished DNA repair capacity. This suggests a possible role of solid cancer in promoting the development of CH independent from chemotherapy exposure, which is supported by our additional murine experiments.