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Background Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood. Methods PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations. Results Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers. Conclusions This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.

Background Postoperative delirium is a frequent event after cardiac surgery. This meta-analysis aimed to identify relevant risk factors. Method In this meta-analysis, all original researches regarding patients undergoing mixed types of cardiac surgery (excluding transcatheter procedures) and postoperative delirium were evaluated for inclusion. On July 28th 2020, we searched PubMed, Embase, Web of Science and Scopus. Data about name of first author, year of publication, inclusion and exclusion criteria, research design, setting, method of delirium assessment, incidence of delirium, odds ratio (OR) and corresponding 95% confidence interval (CI) of risk factors, and other information relevant was collected. OR and 95% CI were used as metrics for summarized results. Random effects model was applied. Results Fourteen reports were included with a total sample size of 13,286. The incidence of delirium ranged from 4.1 to 54.9%. Eight risk factors were identified including aging, diabetes, preoperative depression, mild cognitive impairment, carotid artery stenosis, NYHA functional class III or IV, time of mechanical ventilation and length of intensive care unit stay. Conclusion In this study several risk factors associated with postoperative delirium after cardiac surgery were identified. Utilizing the information may allow us to identifying patients at high risk of developing postoperative delirium prior to delirium onset.

The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics, but the underlying mechanism remains poorly understood. Here, we revealed that the transcriptional activation of interferon regulatory factor 1 (IRF1) in response to ionizing radiation, cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells. Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1, enabling it to regulate the transcription of inflammation- and cell death-related genes. Novel posttranslational modification (PTM) sites in the nuclear localization sequence (NLS) of IRF1 were identified. Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation. Mechanistically, reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1, which restrains radiation-induced and STING/p300-mediated PTMs of IRF1, was revealed. In addition, genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death, and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1. Thus, we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.

Accurate indel calling plays an important role in precision medicine. A benchmarking indel set is essential for thoroughly evaluating the indel calling performance of bioinformatics pipelines. A reference sample with a set of known-positive variants was developed in the FDA-led Sequencing Quality Control Phase 2 (SEQC2) project, but the known indels in the known-positive set were limited. This project sought to provide an enriched set of known indels that would be more translationally relevant by focusing on additional cancer related regions. A thorough manual review process completed by 42 reviewers, two advisors, and a judging panel of three researchers significantly enriched the known indel set by an additional 516 indels. The extended benchmarking indel set has a large range of variant allele frequencies (VAFs), with 87% of them having a VAF below 20% in reference Sample A. The reference Sample A and the indel set can be used for comprehensive benchmarking of indel calling across a wider range of VAF values in the lower range. Indel length was also variable, but the majority were under 10 base pairs (bps). Most of the indels were within coding regions, with the remainder in the gene regulatory regions. Although high confidence can be derived from the robust study design and meticulous human review, this extensive indel set has not undergone orthogonal validation. The extended benchmarking indel set, along with the indels in the previously published known-positive set, was the truth set used to benchmark indel calling pipelines in a community challenge hosted on the precisionFDA platform. This benchmarking indel set and reference samples can be utilized for a comprehensive evaluation of indel calling pipelines. Additionally, the insights and solutions obtained during the manual review process can aid in improving the performance of these pipelines.

Although increasing lines of evidence showed associations between serum uric acid (UA) levels and schizophrenia, the causality and the direction of the associations remain uncertain. Thus, we aimed to assess whether the relationships between serum UA levels and schizophrenia are causal and to determine the direction of the association. Two-sample bidirectional Mendelian randomization (MR) analyses and various sensitivity analyses were performed utilizing the summary data from genome-wide association studies within the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium. Secondary MR analyses in both directions were conducted within summary data using genetic risk scores (GRSs) as instrumental variables. Three MR methods provided no causal relationship between serum UA and schizophrenia. Furthermore, GRS approach showed similar results in the three MR methods after adjustment for heterogeneity. By contrast, inverse variance weighted method, weighted median and GRS approach suggested a causal effect of schizophrenia risk on serum UA after adjustment for heterogeneity (per 10-symmetric percentage increase in schizophrenia risk, beta: -0.039, standard error (SE): 0.013, = 0.003; beta: -0.036, SE: 0.018, = 0.043; beta: -0.039, SE: 0.013, = 0.002; respectively). Moreover, in both directions' analyses, the heterogeneity and sensitivity tests suggested no strong evidence of bias due to pleiotropy. Schizophrenia may causally affect serum UA levels, whereas the causal role of serum UA concentrations in schizophrenia was not supported by our MR analyses. These findings suggest that UA may be a useful potential biomarker for monitoring treatment or diagnosis of schizophrenia rather than a therapeutic target for schizophrenia.

The X-ray repair cross-complementing group 3 (XRCC3) in homologous recombination repair (HRR) pathway plays a very important role in DNA double-strand break repair (DSBR). Variations in the XRCC3 gene might lead to altered protein structure or function which may change DSBR efficiency and result in cancer. The XRCC3 C18067T polymorphism has been reported to be associated with skin cancer susceptibility, yet the results of these previous results have been inconsistent or controversial. To derive a more precise estimation of the association, we conducted a meta-analysis. The quality of the studies was assessed according to a predefined scale. The association between the XRCC3 C18067T polymorphism and skin cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Overall, no significant association was observed between XRCC3 C18067T polymorphism and skin cancer risk in any genetic model. Stratified analyses according to tumor type, significant association was found in the relationship between XRCC3 C18067T polymorphism and nonmelanoma skin cancer risk (homozygote comparison TT versus CC: OR = 0.74, 95%CI = 0.61-0.90, P = 0.003; recessive model TT versus OR = 0.81, 95%CI = 0.68-0.95, P = 0.01). Furthermore, significant association was also observed in XRCC3 C18067T polymorphism with both basal cell carcinoma risk (homozygote comparison TT versus CC: OR = 0.70, 95%CI = 0.53-0.92, P = 0.011; recessive model TT versus. OR = 0.74, 95%CI = 0.60-0.92, P = 0.007) and squamous cell carcinoma risk (heterozygote comparison TT versus .CC: OR = 0.81, 95%CI = 0.67-0.99, P = 0.04; dominant model TT/TC versus .CC: OR = 0.81, 95%CI = 0.68-0.98, P = 0.029). The present meta-analysis demonstrates that XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanoma but contributed a decreased risk to both basal cell carcinoma and squamous cell carcinoma.

Objective: To analyze the efficacy of Pyrotinib combined with Trastuzumab in the treatment of human epidermal growth factor-2 (HER-2) positive breast cancer (BC). Methods: This was a retrospective study that enrolled 150 patients with HER-2 positive BC admitted to Hengyang Medical School, University of South China from January 2021 to October 2023. Among them, 73 patients were treated with Trastuzumab alone (Trastuzumab group), and 77 cases were treated with combined Pyrotinib and Trastuzumab (combined group). Tumor response, tumor marker levels, immune function, and incidence of toxic side effects were compared between the two groups. Results: Tumor response of the combined group (94.81%) was significantly higher than that of the Trastuzumab group (84.93%) (P<0.05). After treatment, the levels of carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), carbohydrate antigen 125 (CA125), carbohydrate Antigen 19-9 (CA19-9), COX-2, DcR3 and Caspase-3 in both groups were significantly reduced compared to pretreatment levels, and were significantly lower in the combined group compared to the Trastuzumab group (all P<0.05). After treatment, the levels of CD3+, CD4+, and CD8+ in both groups were significantly reduced compared to before treatment, but the combined group was higher than the Trastuzumab group (all P<0.05). There was no significant difference in the incidence of toxic side effects between the groups (P>0.05). Conclusions: Compared with Trastuzumab alone, a combined regimen of Pyrrolitinib and Trastuzumab is equally safe, and improving immune function, reducing the level of tumor markers, and improving tumor response in patients with HER-2 positive BC. doi: https://doi.org/10.12669/pjms.41.6.11682 How to cite this: Tang B, Yi X, Mo Q, Tang Y, Zhang L, Xie L. Efficacy of Pyrotinib combined with Trastuzumab in the treatment of patients with human epidermal growth factor receptor-2 positive breast cancer. Pak J Med Sci. 2025;41(6):1749-1754.  doi: https://doi.org/10.12669/pjms.41.6.11682 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) has a poor prognosis, and there is no consensus on optimal treatment strategies for pulmonary LCNEC. Certain patients with pulmonary LCNEC may benefit from targeted and traditional programmed cell death protein-1 (PD-1) monoclonal antibody therapies, however, for most patients, only a few drugs are effective after chemotherapy. The present report describes the case of a 68-year-old man with advanced pulmonary LCNEC treated with cadonilimab and anlotinib after becoming resistant to PD-1 monoclonal antibody therapy and multiple chemotherapies. Computed tomography was used to evaluate treatment response. The treatment was efficacious and met the partial response criteria after three treatment cycles, and the coughing and dyspnea resolved. The primary mass and lymph node metastases continued to shrink after five treatment cycles. Therefore, the present case report suggests that a combination of cadonilimab and anlotinib is a potential treatment strategy for patients with pulmonary LCNEC.

We aimed to develop an artificial intelligence (AI) diagnosis system for uterine smooth muscle tumors (UMTs) by using deep learning. We analyzed the morphological features of UMTs on whole-slide images (233, 108, and 30 digital slides of leiomyosarcomas, leiomyomas, and smooth muscle tumors of uncertain malignant potential stained with hematoxylin and eosin, respectively). Aperio ImageScope software randomly selected ≥10 areas of the total field of view. Pathologists randomly selected a marked region in each section that was no smaller than the total area of 10 high-power fields in which necrotic, vascular, collagenous, and mitotic areas were labeled. We constructed an automatic identification algorithm for cytological atypia and necrosis by using ResNet and constructed an automatic detection algorithm for mitosis by using YOLOv5. A logical evaluation algorithm was then designed to obtain an automatic UMT diagnostic aid that can “study and synthesize” a pathologist’s experience. The precision, recall, and F1 index reached more than 0.920. The detection network could accurately detect the mitoses (0.913 precision, 0.893 recall). For the prediction ability, the AI system had a precision of 0.90. An AI-assisted system for diagnosing UMTs in routine practice scenarios is feasible and can improve the accuracy and efficiency of diagnosis.

ObjectiveAlthough previous epidemiological studies have demonstrated that serum uric acid (SUA) is associated with major depressive disorder (MDD), these analyses are prone to biases. Here, we applied the Mendelian Randomization approach to determine whether SUA is causally associated with MDD.MethodsWe conducted a meta-analysis to evaluate the relationship between SUA and MDD, then applied summary data from the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium to estimate their causal effect using a two-sample bidirectional Mendelian Randomization (MR) analysis. Thereafter, the causal effect was further researched using genetic risk scores (GRS) as instrumental variables (IVs).ResultsResults of a meta-analysis of articles comprising 6975 and 13,589 MDD patients and controls, respectively, revealed that SUA was associated with MDD (SMD = −0.690, 95% CI: −0.930 to −0.440, I2 = 97.4%, P < 0.001). In addition, the five MR methods revealed no causal relationship existed between SUA and MDD, which corroborated the results obtained via the GRS approach.ConclusionThis paper found little evidence that this association between SUA and MDD is casual. Genetically, there was no significant causal association between SUA and MDD.