Little is known about the link between gastric microbiota and the epidemiology of gastric cancer. In order to determine the epidemiologic and clinical relevance of gastric microbiota, we used 16 S ribosomal RNA gene sequencing analysis to characterize the composition and structure of the gastric microbial community of 80 paired samples (non‐malignant and matched tumor tissues) from gastric cardia adenocarcinoma (GCA) patients in Shanxi, China. We also used PICRUSt to predict microbial functional profiles. Compared to patients without family history of upper gastrointestinal (UGI) cancer in the non‐malignant gastric tissue microbiota, patients with family history of UGI cancer had higher Helicobacter pylori ( Hp) relative abundance (median: 0.83 vs . 0.38, p = 0.01) and lower alpha diversity (median observed species: 51 vs . 85, p = 0.01). Patients with higher ( vs . lower) tumor grade had higher Hp relative abundance (0.73 vs . 0.18, p = 0.03), lower alpha diversity (observed species, 66 vs . 89, p = 0.01), altered beta diversity (weighted UniFrac, p = 0.002) and significant alterations in relative abundance of five KEGG functional modules in non‐malignant gastric tissue microbiota. Patients without metastases had higher relative abundance of Lactobacillales than patients with metastases (0.05 vs . 0.01, p = 0.04) in non‐malignant gastric tissue microbiota. These associations were observed in non‐malignant tissues but not in tumor tissues. In conclusion, this study showed a link of gastric microbiota to a major gastric cancer risk factor and clinical features in GCA patients from Shanxi, China. Studies with both healthy controls and gastric cardia and noncardia cancer cases across different populations are needed to further examine the association between gastric cancer and the microbiota.
Large language models (LLMs) have demonstrated impressive capabilities in various reasoning tasks but face significant challenges with complex, knowledge-intensive multi-hop queries, particularly those involving new or long-tail knowledge. Existing benchmarks often fail to fully address these challenges. To bridge this gap, we introduce MINTQA (Multi-hop Question Answering on New and Tail Knowledge), a comprehensive benchmark to evaluate LLMs' capabilities in multi-hop reasoning across four critical dimensions: question handling strategy, sub-question generation, retrieval-augmented generation, and iterative or dynamic decomposition and retrieval. MINTQA comprises 10,479 question-answer pairs for evaluating new knowledge and 17,887 pairs for assessing long-tail knowledge, with each question equipped with corresponding sub-questions and answers. Our systematic evaluation of 22 state-of-the-art LLMs on MINTQA reveals significant limitations in their ability to handle complex knowledge base queries, particularly in handling new or unpopular knowledge. Our findings highlight critical challenges and offer insights for advancing multi-hop reasoning capabilities. The MINTQA benchmark is available at https://github.com/probe2/multi-hop/.
Herein, we aimed to determine the clinical efficacy of recombinant human thrombopoietin (rhTPO) combined with glucocorticoids for treating immune thrombocytopenia (ITP).Clinical data of 87 patients with ITP admitted to our hospital were retrospectively analyzed, and patients were divided into two groups according to the treatment employed: 42 patients in the control group (CG) were prescribed glucocorticoids, and 45 patients in the study group (SG) received rhTPO combined with glucocorticoids.The total effective treatment rate in the SG (95.56%) was higher than that in the CG (76.19%) (P < 0.05). The SG achieved a platelet (PLT) count > 50 × 109/L faster and required fewer PLT transfusions than the CG (P < 0.05). At 1, 7, and 14 days after treatment, the PLT count increased in both groups and was higher in the SG than in the CG (P < 0.05). After treatment, CD3+, CD4+, and CD4+/CD8+ T cells increased, whereas CD8 + decreased in both groups, with the SG exhibiting a superior improvement to the CG (P < 0.05). Considering prothrombin time, activated partial thromboplastin time, and fibrinogen, differences between the two groups were not statistically significant, both before and after treatment (P > 0.05).rhTPO combined with glucocorticoids for treating ITP can effectively enhance the therapeutic effect, regulate the T lymphocyte subpopulation, rapidly increase the PLT level, and induce no significant effect on the coagulation function of patients, with good safety and high clinical promotion value.
Our previous study found that circulating and urinary levels of high mobility group box-1 (HMGB1) were closely associated with disease activity in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Moreover, HMGB1 participates in ANCA-induced neutrophil activation. Cross-reactivity between moesin and anti-myeloperoxidase (MPO) antibody has been reported in both human and mouse. The current study investigated whether HMGB1 participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV. The effects of HMGB1 on expression of moesin on GEnCs and anti-MPO antibody binding to GEnCs were measured. MPO expression on GEnCs was explored. The effects of HMGB1 in MPO-ANCA induced GEnC injury were measured, during which the role of moesin was explored. Antagonists for various relevant receptors were employed. Sera from AAV patients at the active stage could mediate GEnC injury, while this effect could be attenuated by preblocking HMGB1. HMGB1 could increase the expression of moesin on GEnCs and the binding of anti-MPO antibody to moesin. The colocalization of moesin expression and anti-MPO antibody binding can be detected. Little, if any, MPO was expressed in GEnCs. HMGB1 increased GEnC activation and injury in the presence of patient-derived MPO-ANCA-positive IgGs through moesin. The effects of HMGB1 on expression of moesin on GEnCs, anti-MPO antibody binding to GEnCs, GEnC activation and injury were mainly toll like receptor 4 (TLR4) dependent. HMGB1 can increase the expression of moesin but not MPO on GEnCs, and can further participate in MPO-ANCA-induced GEnC activation and injury by cross-reactivity between moesin and anti-MPO antibody.
Esophageal squamous cell carcinoma is a common fatal cancer, and Shanxi province, a region in north-central China, has some of the highest esophageal cancer rates in the world. Chromosomal regions with frequent allelic loss may point to major susceptibility genes that will assist us in understanding the molecular events involved in esophageal carcinogenesis and may serve as the basis for the development of markers for genetic susceptibility and screening for early detection of this cancer. This study was designed to identify events in the molecular progression of precursor and invasive lesions of squamous esophageal cancer. Twelve marker loci identified during our previous studies as having some of the highest rates of loss of heterozygosity (LOH) in invasive esophageal cancer were evaluated in laser-microdissected DNA obtained from low- and high-grade dysplastic lesions and invasive tumor foci from 10 fully embedded esophageal resection specimens. Each resection specimen contained a spectrum of disease, from epithelium that appeared histologically normal to invasive cancer, including a single dominant tumor surrounded by a region of precursor lesions (low- and high-grade dysplasia) and occasional "remote," nonadjacent precancerous foci. Using the 12 polymorphic markers, LOH was found in all of the three stages of disease. The frequency of LOH for all of the markers together increased with increasing disease severity. Among the informative low-grade dysplasia samples, LOH was detected with markers D3S1766 (3p), D4S2632 (4p), D9S910 (9q), and D13S1493 (13q), suggesting that LOH at these loci may be associated with early stages of tumor initiation and/or progression. LOH was detected among the informative high-grade (but not low-grade) dysplasia samples for the other eight markers tested, suggesting that LOH at these loci may occur later in the neoplastic process. In addition to the association between disease progression and these genetic changes, considerable genetic heterogeneity was found in each fully embedded resection specimen both between and within geographically separate neoplastic lesions.
Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Previous studies on GBM biomarkers focused on the effect of the biomarkers on overall survival (OS). Until now, no study has been published that evaluates the performance of biomarkers for prognosing OS. We examined the performance of microRNAs, gene expressions, gene signatures, and methylation that were previously identified to be prognostic. In addition, we investigated whether using clinical risk factors in combination with biomarkers can improve the prognostic performance. Methods: The Cancer Genome Atlas, which provides both biomarkers and OS information, was used in this study. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the prognostic accuracy. Results: For prognosis of OS by 2 years from diagnosis, the area under the ROC curve (AUC) of microRNAs, Mir21 and Mir222, was 0.550 and 0.625, respectively. When age was included in the risk prediction score of these biomarkers, the AUC increased to 0.719 and 0.701, respectively. The SAMSN1 gene expression attains an AUC of 0.563, and the “8-gene” signature identified by Bao achieves an AUC of 0.613. Conclusions: Although some biomarkers are significantly associated with OS, the ability of these biomarkers for prognosing OS events is limited. Incorporating clinical risk factors, such as age, can greatly improve the prognostic performance.
On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells.We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA-mediated knockdown of BTK expression in primary human nonmalignant lymph node-derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor.Altogether, our data uncover novel unexpected properties of follicular lymphoma-associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.See related commentary by Afaghani and Taylor, p. 2123.
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