Shared genetic factors and causal association between chronic hepatitis C infection and diffuse large B cell lymphoma.

BACKGROUND: Epidemiological research and systematic meta-analyses indicate a higher risk of B-cell lymphomas in patients with chronic hepatitis C virus (HCV) compared to non-infected individuals. However, the genetic links between HCV and these lymphomas remain under-researched. METHODS: Mendelian randomization analysis was employed to explore the association between chronic hepatitis C (CHC) and B-cell lymphomas as well as chronic lymphocytic leukemia (CLL). Approximate Bayes Factor (ABF) localization analysis was conducted to find shared genetic variants that might connect CHC with B-cell lymphomas and chronic lymphocytic leukemia (CLL). Furthermore, The Variant Effect Predictor (VEP) was utilized to annotate the functional effects of the identified genetic variants. RESULTS: Mendelian randomization revealed a significant association between CHC and increased diffuse large B cell lymphoma (DLBCL) risk (OR: 1.34; 95% CI: 1.01-1.78; P = 0.0397). Subsequent colocalization analysis pinpointed two noteworthy variants, rs17208853 (chr6:32408583) and rs482759 (chr6:32227240) between these two traits. The annotation of these variants through the VEP revealed their respective associations with the butyrophilin-like protein 2 (BTNL2) and notch receptor 4 (NOTCH4) genes, along with the long non-coding RNA (lncRNA) TSBP1-AS1. CONCLUSION: This research provides a refined genetic understanding of the CHC-DLBCL connection, opening avenues for targeted therapeutic research and intervention.

Review of Animal Models of Colorectal Cancer in Different Carcinogenesis Pathways.

Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract with increasing morbidity and mortality. Exploring the factors affecting colorectal carcinogenesis and controlling its occurrence at its root is as important as studying post-cancer treatment and management. Establishing ideal animal models of CRC is crucial, which can occur through various pathways, such as adenoma-carcinoma sequence, inflammation-induced carcinogenesis, serrated polyp pathway and de-novo pathway. This article aims to categorize the existing well-established CRC animal models based on different carcinogenesis pathways, and to describe their mechanisms, methods, advantages and limitations using domestic and international literature sources. This will provide suggestions for the selection of animal models in early-stage CRC research.

Outcomes of COVID-19 in multiple myeloma patients treated with daratumumab.

Despite concerns about an increased risk of adverse outcomes following coronavirus disease (COVID-19) in multiple myeloma patients treated with anti-CD38 Abs, the impact of COVID-19 on this group of patients is unclear. We tried to evaluate the clinical outcomes of these patients. We collected data from 1036 patients with multiple myeloma and enrolled 509 cases with COVID-19. We divided enrolled patients into daratumumab or nondaratumumab cohorts based on whether they had received daratumumab-based treatment within 6 months of COVID-19 infection. We applied a propensity score matching method to reduce the bias of baseline characteristics, and then compared the incidence of adverse outcomes between these two cohorts. A total of 117 patients were enrolled in the daratumumab cohort, and 392 patients in the nondaratumumab cohort. After propensity score matching, 204 patients were matched. The proportions of patients who developed COVID-19 pneumonia (59.8% vs. 34.3%, p < 0.001), were hospitalized (33.3% vs. 11.8%, p < 0.001) and developed severe disease (23.5% vs. 6.9%, p = 0.001) were higher in the matched daratumumab cohort. By multivariate analysis, daratumumab exposure was an independent risk factor for severe disease. An ECOG performance status >2 and history of chronic kidney disease were independent risk factors for COVID-19-related mortality among patients who received daratumumab-based therapy. This study suggested that multiple myeloma patients exposed to daratumumab were at a higher risk of adverse outcomes from COVID-19.

Molecular mechanisms of ferroptosis and its roles in leukemia.

Cell death is a complex process required to maintain homeostasis and occurs when cells are damage or reach end of life. As research progresses, it is apparent that necrosis and apoptosis do not fully explain the whole phenomenon of cell death. Therefore, new death modalities such as autophagic cell death, and ferroptosis have been proposed. In recent years, ferroptosis, a new type of non-apoptotic cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation, has been receiving increasing attention. Ferroptosis can be involved in the pathological processes of many disorders, such as ischemia-reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of leukemia still need to be more fully and deeply studied. In this review, we present the research progress on the mechanism of ferroptosis and its role in leukemia, to provide new theoretical basis and strategies for the diagnosis and treatment of clinical hematological diseases.

Metamaterial absorber optimization method based on an artificial neural network surrogate.

Finding the optimal design parameters for the target EM response of a metamaterial absorber is still a challenging task even if the layout of the absorber has been determined. To effectively address this issue, we introduce the idea of surrogate-based optimization into the area of metamaterial absorber design. This paper proposes a surrogate based optimization method combining artificial neural network (ANN) and trust region algorithm for metamaterial absorbers. Each optimization iteration utilizes the optimal solution from the previous iteration and the sample points surrounding it as the training dataset to build an effective ANN surrogate model. To improve the convergence of the optimization method for metamaterial absorbers based on ANN surrogate model, we incorporate a trust region algorithm. The proposed method employs a simple forward neural network architecture and requires less training data, leading to a quick convergence towards the target solution after only a few iterations. Compared to the three commonly used alternative methods, the proposed method can optimize geometric and material parameters more efficiently in the same time. The validity of the proposed method is demonstrated by two examples of electromagnetic optimizations of metamaterial absorbers.

Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05-1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02-1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01-1.2; P = 0.03], tumor necrosis factor beta (TNF-ß) [OR: 1.16; 95% CI: 1.02-1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01-1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-ß, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.

Integration analysis of tumor metagenome and peripheral immunity data of diffuse large-B cell lymphoma.

Background/purpose: It has been demonstrated that gut microbes are closely associated with the pathogenesis of lymphoma, but the gut microbe landscape and its association with immune cells in diffuse large B-cell lymphoma (DLBCL) remain largely unknown. In this study, we explored the associations between gut microbiota, clinical features and peripheral blood immune cell subtypes in DLBCL. Method: A total of 87 newly diagnosed DLBCL adults were enrolled in this study. The peripheral blood samples were collected from all patients and then submitted to immune cell subtyping using full-spectral flow cytometry. Metagenomic sequencing was applied to assess the microbiota landscape of 69 of 87 newly diagnosed DLBCL patients. The microbiotas and peripheral blood immune cell subsets with significant differences between different National Comprehensive Center Network-International Prognostic Indexes (NCCN-IPIs) (low-risk, low-intermediate-risk, intermediate-high-risk, high-risk) groups were screened. Results: A total of 10 bacterial phyla, 31 orders and 455 bacteria species were identified in 69 patients with newly diagnosed DLBCL. The abundances of 6 bacteria, including Blautia sp.CAG 257, Actinomyces sp.S6 Spd3, Streptococcus parasanguinis, Bacteroides salyersiae, Enterococcus faecalls and Streptococcus salivarius were significantly different between the low-risk, low-intermediate-risk, intermediate-high-risk and high-risk groups, among which Streptococcus parasanguinis and Streptococcus salivarius were markedly accumulated in the high-risk group. The different bacteria species were mostly enriched in the Pyridoxal 5'-phosphate biosynthesis I pathway. In addition, we found that 2 of the 6 bacteria showed close associations with the different immune cell subtypes which were also identified from different NCCN-IPIs. In detail, the abundance of Bacteroides salyersiae was negatively correlated with Treg cells, CD38+ nonrescue exhausted T cells, nature killer 3 cells and CD38+CD8+ effector memory T cells, while the abundance of Streptococcus parasanguinis was negatively correlated with HLA-DR+ NK cells, CD4+ Treg cells, HLA-DR+ NKT cells and HLA-DR+CD94+CD159c+ NKT cells. Conclusion: This study first reveals the gut microbiota landscape of patients with newly diagnosed DLBCL and highlights the association between the gut microbiota and immunity, which may provide a new idea for the prognosis assessment and treatment of DLBCL.

Analysis of genetic test results in 378 patients suspected of thalassaemia.

OBJECTIVE: To analyze the genetic test results of 378 patients suspected of thalassemia. METHODS: 378 suspected thalassemia patients in Shaoxing People's Hospital from 2014 to 2020 were selected and venous blood was tested using Gap-PCR and PCR-reversed dot blottin. The distribution of genotypes and other information of gene-positive patients was observed. RESULTS: Thalassemia genes were detected in 222 cases, with an overall detection rate of 58.7%, of which 41.4% were α deletion type, 1.35% were α dot, 52.7% were α thalassemia, and 4.5% were αß complex type. Among the 86 people with provincial household registration, the α-thalassemia gene accounted for 65.1% and the ß-thalassemia gene accounted for 25.6%. Follow-up found that Shaoxing nationality accounted for 53.1% of positive patients, of which ß-thalassemia gene accounted for 72.9% and α-thalassemia gene accounted for 25.4%; other cities in the province accounted for 8.1% of the total. Other provinces and cities accounted for 38.7%, most of which were from Guangxi and Guizhou. Among all positive patients, the most common α-thalassemia genotypes were --sea / αα, --α / αα,--α 3.7 4.2 / αα , --α3.7 / --sea. The most common mutations in ß-thalassemia were IVS-II-654, CD41-42, CD17 and CD14-15. CONCLUSION: The thalassemia gene carrier status was sporadically distributed outside the traditional thalassemia high prevalence areas. The local population in Shaoxing has a high detection rate of thalassemia genes, and the genetic composition is different from the traditional high prevalence area of thalassemia in the south.

Gene Mutations and Targeted Therapies of Myeloid Sarcoma.

OPINION STATEMENT: Myeloid sarcoma, a rare malignant tumor characterized by the invasion of extramedullary tissue by immature myeloid cells, commonly occurs concomitantly with acute myeloid leukemia, myelodysplastic syndromes, or myeloproliferative neoplasms. The rarity of myeloid sarcoma poses challenges for diagnosis and treatment. Currently, treatments for myeloid sarcoma remain controversial and primarily follow protocols for acute myeloid leukemia, such as chemotherapy utilizing multi-agent regimens, in addition to radiation therapy and/or surgery. The advancements in next-generation sequencing technology have led to significant progress in the field of molecular genetics, resulting in the identification of both diagnostic and therapeutic targets. The application of targeted therapeutics, such as FMS-like tyrosine kinase 3(FLT3) inhibitors, isocitrate dehydrogenases(IDH) inhibitors, and the B cell lymphoma 2(BCL2) inhibitors, has facilitated the gradual transformation of traditional chemotherapy into targeted precision therapy for acute myeloid leukemia. However, the field of targeted therapy for myeloid sarcoma is relatively under-investigated and not well-described. In this review, we comprehensively summarize the molecular genetic characteristics of myeloid sarcoma and the current application of targeted therapeutics.

Testing and Evaluation of Flexural Tensile Strength of Prestressed CFRP Cables.

To expand the application scope of prestressed carbon fiber-reinforced polymer (CFRP) cables in civil engineering, the ultimate tensile strength of these cables was tested and evaluated under bending conditions. First, the study analyzed the tensile failure mechanism of CFRP cables under bending conditions based on elastic bending analysis theory. Thereafter, the ultimate stress state of individual tendons and cables was derived and a calculation model for the tensile strength of bent CFRP cables was established. Second, 14 sets of test conditions were created for CFRP cables under bending angles of 20-40° and bending radii of 1.5-3 m. Then, bending tensile tests were conducted to evaluate the effects of the above factors on the ultimate tensile strength, and the correctness of the computational model was verified using experiments. Finally, the ultimate performance of CFRP cables was theoretically predicted using the established model. The results showed that the cable bending tensile strength was associated with the radius r, tensile strength f, and elastic modulus E of the reinforced material and the bending radius R, but was not correlated with the interface buffer material or the bending angle of the steering system. Moreover, the flexural tensile residual strength was only affected by R/r and E/f. When E/f involved conventional material parameters, the residual strength increased nonlinearly with increased R/r. When R/r ≥ 600, the residual strength reached more than 80%. Therefore, R/r at 600 could be used as the design basis for a safe critical radius.

A Novel Prognostic Scoring Model for Myelodysplastic Syndrome Patients With SF3B1 Mutation.

The outcomes of myelodysplastic syndrome (MDS) patients with SF3B1 mutation, despite identified as a favorable prognostic biomarker, are variable. To comprehend the heterogeneity in clinical characteristics and outcomes, we reviewed 140 MDS patients with SF3B1 mutation in Zhejiang province of China. Seventy-three (52.1%) patients diagnosed as MDS with ring sideroblasts (MDS-RS) following the 2016 World Health Organization (WHO) classification and 118 (84.3%) patients belonged to lower risk following the revised International Prognostic Scoring System (IPSS-R). Although clonal hematopoiesis-associated mutations containing TET2, ASXL1 and DNMT3A were the most frequent co-mutant genes in these patients, RUNX1, EZH2, NF1 and KRAS/NRAS mutations had significant effects on overall survival (OS). Based on that we developed a risk scoring model as IPSS-R×0.4+RUNX1×1.1+EZH2×0.6+RAS×0.9+NF1×1.6. Patients were categorized into two subgroups: low-risk (L-R, score <= 1.4) group and high risk (H-R, score > 1.4) group. The 3-year OS for the L-R and H-R groups was 91.88% (95% CI, 83.27%-100%) and 38.14% (95% CI, 24.08%-60.40%), respectively (P<0.001). This proposed model distinctly outperformed the widely used IPSS-R. In summary, we constructed and validated a personalized prediction model of MDS patients with SF3B1 mutation that can better predict the survival of these patients.

Rules of incidental operation risk propagation in metro networks under fully automatic operations mode.

The frequent interruptions of network operation due to any incident suggest the necessity to study the rules of operational risk propagation in metro networks, especially under fully automatic operations mode. In this study, risk indicator computation models were developed by analyzing risk propagation processes within transfer stations and metro networks. Moreover, indicator variance rules for a transfer station and different structural networks were discussed and verified through simulation. After reviewing the simulation results, it was concluded that under the impacts of both sudden incident and peak passenger flow, the more the passengers coming from platform inlets, the longer the non-incidental line platform total train operation delay and the higher the crowding degree. However, train headway has little influence on non-incidental line platform risk development. With respect to incident risk propagation in a metro network, the propagation speed varies with network structure, wherein an annular-radial network is the fastest, a radial is moderately fast, and a grid-type network is the slowest. The conclusions are supposed to be supports for metro operation safety planning and network design.

Bortezomib-Based Regimens for Newly Diagnosed Multiple Myeloma in China: A Report of 12-Year Real-World Data.

Background: Improve the treatment quality might affect patients' efficacy and survival. Methods: Five hundred thirty multiple myeloma patients treated in four hematological centers in China from February 2006 to August 2018 were enrolled. General characteristics, treatment regimens and cycles, efficacy, survival and adverse events of the patients treated before and after August 2013 (later refer to as the before-2013 and after-2013 group) were analyzed and compared. Results: The results suggested that patients who received optimized treatment regimen and route of administration completed more cycles of treatment in the after-2013 group. Although the overall response rate was similar between the two groups (88.6 vs. 90.5%), patients in the after-2013 group had higher complete remission rate (39.1 vs. 28.6%) and better progression-free survival. Subgroup analysis suggested that patients aged 65 years and older, with non-high-risk D-S, ISS, and R-ISS stages, had a significant benefit in progression-free survival. Conclusion: Therefore, in clinical practice in China, by reducing the economic burden brought by the treatment on patients and optimizing the treatment regimen, more patients can be treated with better regimens in a prolonged duration to achieve better efficacy and survival, especially in elderly and non-high-risk patients.

Associations between genetic polymorphisms in interleukin-10 and hematological oncology: evidence from a meta-analysis.

Background: Associations between polymorphisms in interleukin-10 (IL-10) and hematological oncology were already explored by many genetic association studies, with controversial findings. The aim of this meta-analysis was to more comprehensively analyze associations between polymorphisms in IL-10 and hematological oncology by combing the results of all relevant studies.Methods: Eligible articles were searched from Pubmed, Embase, WOS and CNKI. The latest literature searching update was performed on 8 October 2019. We used Review Manager to combine the results of eligible studies.Results: Forty-one articles were included in this meta-analysis. IL-10 rs1800890 polymorphism was found to be significantly associated with hematological oncology under AA vs. TT+TA (recessive comparison, OR = 1.12, 95% CI 1.02-1.24), and rs1800896 polymorphism was also found to be significantly associated with hematological oncology under AA vs. AG+GG (dominant comparison, OR = 0.89, 95% CI 0.83-0.95) in overall combined analyses. In subgroup analyses, we observed positive results for rs1800871 (recessive comparison), rs1800872 (dominant, recessive and allele comparisons), and rs1800896 (dominant and allele comparisons) polymorphisms in the non-Hodgkin's lymphoma (NHL) subgroup. Besides, we also detected positive associations between rs1800872 polymorphism and acute leukemia (AL) (dominant and recessive comparisons) and found significant associations between rs1800896 polymorphism and chronic leukemia (CL) (recessive comparison).Conclusion: In summary, this meta-analysis demonstrated that IL-10 rs1800890, rs1800896, rs1800871 and rs1800872 polymorphisms may confer susceptibility to hematology oncology, especially for NHL.

Identification and characterization of abundant repetitive sequences in Allium cepa.

Species of the genus Allium are well known for their large genomes. Allium cepa is of great economic significance. Among vegetables, it ranks second after tomato in terms of the global production value. However, there is limited genomics information available on A. cepa. In this study, we sequenced the A. cepa genome at low-coverage and annotated repetitive sequences by using a combination of next-generation sequencing (NGS) and bioinformatics tools. Nearly 92% of 16 Gb haploid onion genome were defined as repetitive sequences, organized in 162 clusters of at least 0.01 percent of the genome. Of these, a proportion representing 40.5% of the genome were further analyzed in detail to obtain an overview of representative repetitive elements present in the A. cepa genome. Few representative satellite repeats were studied by fluorescence in situ hybridization (FISH) and southern blotting. These results provided a basis for evolutionary cytogenomics within the Allium genus.

[Clinical Significance of the Balanceshift of Th1 and Th2 Type Cytokines in Patients with Primary Immune Thrombocytopenic Purpura Detected by Cytometric Bead Array].

OBJECTIVE: To investigate the levels of Th1/Th2 cytokines in peripheral blood of patients with primary immune thrombocytopenic purpura(ITP) before and after treatment and their clinical significance. METHODS: Ninety-eight cases of ITP were treated with glucocorticoid(GC), then were divided into 2 groups: effectively treated group and uneffectively treated group according to efficacy of treatment, 40 healthy persons confirmed by health examination were selected and enrolled in control group. The levels of Th1 cytokines(IFN-γ,TNFα,IL-2) and Th2 cytokines(IL-4,IL-5,IL-10) were detected by cytometric bead array before and at 4 weeks, 3 and 6 months after treatment and the relationship among detected indexes was analyzed. RESULTS: Before treatment with glucocorticoid, the levels of Th1 type cytokines were in 98 patients with ITP were higher and the levels of Th2 type cytokines were lower, compared with the healthy controls(P<0.05). The IL-2/IL-4 ratio was significantly higher than that of healthy controls(P<0.05). After treatment, the levels of Th1 type cytokines in effectively treated group were significantly decreased and the levels of Th2 type cytokines were significantly increased, compared with level before treatment(P<0.05). The IL-2/IL-4 ratio was significantly decreased after treatment for 6 months, compared with that before treatment(1.05±0.43 vs 2.53±0.72)(P<0.05), but the level of Th1 or Th2 type cytokines did not obviously changed. CONCLUSION: Peripheral blood Th1 and Th2 cells express abnormally in ITP patients, ITP is a Th1 dominated disease; the change of IL-2/IL-4 ratio before and after treatment correlated with the prognosis of ITP patients, displaying clinical significance for ITP individual therapy.

Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia.

Targeted therapy has been the forefront of cancer treatment. Cancer immunotherapy is the most recent focus. In addition, novel immunotherapeutics targeting B cell receptor signaling (e.g., ibrutinib), T cell receptor ( e.g., CART19), and NK cells (e.g., AFM13) are being developed. This review summarized the new development in blinatumomab (MT103/MEDI-538), a first-in-class bispecific T engager (BiTE) antibody against CD19/CD3 in patients with relapsed/refractory precursor B cell acute lymphoid leukemia.

AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy.

Monoclonal antibodies against CD20 molecule have been leading the revolution of lymphoma treatment. In addition to monoclonal antibodies against CD20 and CD30, novel agents of immunotherapeutics in clinical development are being developed and are rapidly migrating to clinical application. One area of active development is NK cell activators, such as AFM13. This review will highlight the latest development of AFM13 as the first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy.

The choice of regimens based on bortezomib for patients with newly diagnosed multiple myeloma.

INTRODUCTION: Bortezomib has significantly improved multiple myeloma (MM) response rates, but strategies for choosing bortezomib-based regimens for initial MM therapy are not standardized. Here, we describe four bortezomib-based therapies in Chinese MM patients to determine the optimal chemotherapeutic approach. METHODS: Newly diagnosed symptomatic MM patients at three hematological centers between February 1, 2006 and May 31, 2013 were treated with therapies including bortezomib plus dexamethasone (PD) or combinations of PD with either adriamycin (PAD), cyclophosphamide (PCD) or thalidomide (PTD) for every 28 days. RESULTS: The overall response rate of all the 215 eligible patients was 90.2%. The ORR for PCD, PAD, PTD and PD were 97.4%, 93.2%, 85.3% and 77.8% while the effects with VGPR or better were 63.7%, 62.7%, 44.2% and 37.8%, respectively. The effect of ORR, VGPR and CR/nCR for the PCD regimen was better than the PD protocol. Median PFS for all patients was 29.0 months with significant differences observed among treatment groups. Median OS of all the patients was not reached, but three-drug combinations were superior to PD alone. Frequently observed toxicities were neutropenia, thrombocytopenia, fatigue, infection, herpes zoster, and peripheral neuropathy. The incidence of peripheral neuropathy (PN) in PTD group was significantly higher than other three groups, especially grade 2-3 PN. Treatment with anti-viral agent acyclovir significantly reduced the incidence of herpes zoster. CONCLUSIONS: Our experience indicated that bortezomib-based regimens were effective and well-tolerated in the Chinese population studied; three-drug combinations PCD, PAD were superior to PD, especially with respect to PCD.