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Abstract Cardiac myxoma is a commonly encountered tumor within the heart that has the potential to be life-threatening. However, the cellular composition of this condition is still not well understood. To fill this gap, we analyzed 75,641 cells from cardiac myxoma tissues based on single-cell sequencing. We defined a population of myxoma cells, which exhibited a resemblance to fibroblasts, yet they were distinguished by an increased expression of phosphodiesterases and genes associated with cell proliferation, differentiation, and adhesion. The clinical relevance of the cell populations indicated a higher proportion of myxoma cells and M2-like macrophage infiltration, along with their enhanced spatial interaction, were found to significantly contribute to the occurrence of embolism. The immune cells surrounding the myxoma exhibit inhibitory characteristics, with impaired function of T cells characterized by the expression of GZMK and TOX, along with a substantial infiltration of tumor-promoting macrophages expressed growth factors such as PDGFC. Furthermore, in vitro co-culture experiments showed that macrophages promoted the growth of myxoma cells significantly. In summary, this study presents a comprehensive single-cell atlas of cardiac myxoma, highlighting the heterogeneity of myxoma cells and their collaborative impact on immune cells. These findings shed light on the complex pathobiology of cardiac myxoma and present potential targets for intervention.

Objective: To study the spectrum-effect relationship between the extracts of Tetrastigma hemsleyanum and its antioxidant activity, and to clarify the quality markers of its antioxidant activity. Methods: The extract was prepared and separated by macroporous resin elution, six different elution sites were obtained using ethanol at concentrations of 10%, 30%, 50%, 70%, 90% and 100%. The fingerprints of the Tetrastigma hemsleyanum extract and each elution site were established by UPLC-Q-TOF-MS and the characteristic peaks were screened. The free radical scavenging rate of 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) was used as an antioxidant index to investigate the antioxidant activity of the extract and each elution site of Tetrastigma hemsleyanum. The Pearson correlation coefficient method and orthogonal partial least squares (OPLS) method were combined to analyze and study the spectrum-effect relationship between the characteristic peaks and the antioxidant activity, to screen the quality markers, and to analyze and identify the chemical compositions. Results: Under the positive and negative ion modes, 57 and 92 characteristic peaks were identified in the extract and each elution site of Tetrastigma hemsleyanum, respectively. The combined results of Pearson correlation coefficient and OPLS analysis showed that 14 ion peaks contributed more to the antioxidant activity, which was vanillin (P2), catechin (P13, N19), rutin (P27, N54), and isoquercitrin (P28), kaempferol-3-O-rutinoside (P33, N61), proanthocyanidin B (N18), proanthocyanidin C (N22), and ion peaks N23, N25, N26, and N29, respectively. Conclusion: UPLC-Q-TOF-MS fingerprints of Tetrastigma hemsleyanum extract and each elution site were established, and the quality markers of Tetrastigma hemsleyanum antioxidant activity were revealed to provide technical support for the formulation of quality standards and resource development and utilization of Tetrastigma hemsleyanum.

Abstract Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

AbstractContext Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated.Objective This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP).Materials and methods After tabersonine (10 μM) and/or CDDP (10 μM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial–mesenchymal transition (EMT) phenotypes.Results Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 μM for BT549 and 27.0 μM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine.Discussion and conclusions Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.

Non-coding RNAs (ncRNAs), which are usually considered not to encode proteins, are widely involved in important activities including signal transduction and cell proliferation. However, recent studies have shown that small peptides encoded by ncRNAs (SPENs) have important roles in the development of malignant tumors. Some SPENs participate in the regulation of skeleton reorganization, intercellular adhesion, signaling and other processes of tumor cells, with effects on the invasive and migratory abilities of the cells. Therefore, SPENs have potential applications as therapeutic targets and biomarkers of malignant tumors. Invasion and migration of malignant tumor cells are the main reasons for poor prognosis of cancer patients and represent the most challenging aspects of treatment of malignant tumors. Currently, the main treatments for tumors include surgery, radiotherapy, targeted drug therapy. Surgery, however, is reserved for early stages of cancer and carries risks and costs. Radiotherapy and targeted therapy have serious side effects. This review describes the mechanisms of SPENs and their roles in tumor invasion and migration, with the aim of providing new targets for tumor diagnosis and treatment.

Abstract Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.

Abstract The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.

This study investigates the role of Stanniocalcin-1 (STC1) in melanoma progression, with a focus on its impact on metastasis, angiogenesis, and immune evasion. Systematic bioinformatics analysis revealed the potential influence of STC1 dysregulation on prognosis, immune cell infiltration, response to immune therapy, and cellular functions. In vitro assays were conducted to assess the proliferation, invasion, migration, and angiogenesis capabilities of A375 cells. In vivo experiments utilizing C57BL/6 J mice established a lung metastasis model using B16-F10 cells to evaluate macrophage infiltration and M2 polarization. A Transwell co-culture system was employed to explore the crosstalk between melanoma and macrophages. Molecular interactions among STC1, YAP, βPIX, and CCL2 are investigated using mass spectrometry, Co-Immunoprecipitation, Dual-Luciferase Reporter Assay, and Chromatin Immunoprecipitation experiments. STC1 was found to enhance lung metastasis by promoting the recruitment and polarization of M2 macrophages, thereby fostering an immunosuppressive microenvironment. Mechanistically, STC1 competes with YAP for binding to βPIX within the KER domain in melanoma cells, leading to YAP activation and subsequent CCL2 upregulation. CCL2-induced M2 macrophages secrete VEGFA, which enhances tumor vascularization and increases STC1 expression via the AKT signaling pathway in melanoma cells, establishing a pro-metastatic feedback loop. Notably, STC1-induced YAP activation increases PD-L1 expression, promoting immune evasion. Silencing STC1 enhances the efficacy of PD-1 immune checkpoint therapy in mice. This research elucidates STC1's role in melanoma metastasis and its complex interactions with tumor-associated macrophages, proposing STC1 as a potential therapeutic target for countering melanoma metastasis and augmenting the efficacy of PD-1 immunotherapy.

Lateral flow assay (LFA) has firmly established itself as a prominent technique for qualitative assessments. However, its potential in quantitative analysis remains limited. In this study, we adapted the laser-assisted absorption measurement of LFA for quantitative detection. LFA assay relies on immobilization of colloidal gold nanoparticles conjugated to the target analyte on the test strip. The abundance of these gold nanoparticles can be quantified by absorption measurement, allowing to determine the concentration of analytes. Rigorous experimental validation of the laser-assisted technology was performed by testing a cohort of 20 patients for hepatitis B surface antigen (HBsAg). Notably, our results show that the laser-assisted LFA and the gold standard technique like enzyme-linked immunosorbent assay are similar statistically.

Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.

Cisplatin resistance plays a significant role in the dismal prognosis and progression of muscle-invasive bladder cancer (MIBC). However, the strategies to predict prognosis and cisplatin resistance are inefficient, and it remains unclear whether cisplatin resistance is associated with tumor immunity. In this study, we integrated the transcriptional data from cisplatin-resistant cell lines and a TCGA-MIBC cohort to establish cisplatin-resistance-related cluster classification and a cisplatin-resistance-related gene risk score (CRRGRS). Kaplan–Meier survival curves showed that compared with those in low CRRGRS group, MIBC patients belonging to high CRRGRS group had worse prognosis in TCGA-MIBC cohort and external GEO cohorts. Meanwhile, CRRGRS was able to help forecast chemotherapy and immunotherapy response of MIBC patients in the TGCA cohort and IMvigor210 cohort. Moreover, compared with the low CRRGRS group, the high CRRGS group possessed a relatively immunosuppressive “cold tumor” phenotype with a higher tumor immune dysfunction and exclusion (TIDE) score, ESTIMATE score, stromal score and immune score and a lower immunophenoscore (IPS) score. The upregulated expression levels of immune checkpoint genes, including PD-1, PD-L1 and CTLA4, in the high CRRGRS group also further indicated that a relative immunosuppressive tumor microenvironment may exist in MIBC patients belonging to high CRRGRS group. In addition, we integrated CRRGRS and clinical characteristics with prognostic value to develop a nomogram, which could help forecast overall survival of MIBC patients. Furthermore, DIAPH3 was identified as a regulator of proliferation and cisplatin resistance in MIBC. The expression of DIAPH3 was increased in cisplatin-resistant cell lines and chemotherapy-unsensitive people. Further mechanism exploration revealed that DIAPH3 facilitated tumor proliferation and cisplatin resistance by regulating the NF-kB and epithelial-mesenchymal transition (EMT) pathways. In conclusion, the comprehensive investigations of CRRGRS increased the understanding of cisplatin resistance and provided promising insights to restrain tumor growth and overcome chemoresistance by targeting DIAPH3.

Abstract Background Practice-based research networks (PBRNs) have been recognized as essential laboratories and mechanisms for developing primary care research. This scoping review aims to examine and map the features and development trends of productivity, research categories, and methods in original primary care research conducted by global PBRNs between 1991 and 2023. Methods We have assembled an interdisciplinary team that will undertake this scoping review, following the framework developed by Arksey and O’Malley. Targeted literature includes original primary care research conducted by PBRNs, published from January 1, 1991, to December 31, 2023. An integrated search strategy will gather publications from 3 electronic databases (PubMed, Web of Science, and Embase), 16 major primary health care journals, and 364 relevant organizations. Two experienced researchers will independently screen the titles, keywords, and abstracts of all references and extract data regarding eight key elements. Disagreements between the reviewers will be resolved through group discussions, moderated by a third reviewer. Articles to be included will (1) be conducted in the primary care context, (2) be led by PBRNs, (3) provide a full report of original research, and (4) be published in a peer-reviewed journal between the aforementioned dates in any language. Exclusions encompass reviews, letters, commentaries, case reports, and conference papers. Final data will be displayed using tables and charts according to different conceptual categories. Discussion This scoping review is one of the initial attempts to delineate the development trends and features of primary care research conducted by PBRNs. This study will provide reference information for researchers in countries/regions that are building their research infrastructure and capacity in general practice, family medicine, and primary care. Systematic review registration Registered in OSF on July 25, 2022 ( https://osf.io/zgv9c ).

Pyroptosis is a regulated cell death pathway involved in numerous human diseases, especially malignant tumors. Recent studies have identified multiple pyroptosis-associated signaling molecules, like caspases, gasdermin family and inflammasomes. In addition, increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers. Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells, such as CD4+ and CD8+ T cells, thus strengthening the sensitivity to therapeutic strategies. In this review, we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation. We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors. Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy.

Abstract Background Building interprofessional working relationships between general practitioners (GPs) and pharmacists is essential to ensure high-quality patient care. However, there is limited Chinese literature on GP–pharmacist collaboration, and few studies have explored GPs’ experiences with pharmacist integration into general practices. This study aimed to investigate GPs’ attitudes towards and frequency of collaboration with pharmacists in China. Methods This cross-sectional study used an online self-administered questionnaire integrating two scales, ATCI-GP and FICI-GP, which had been translated and validated to investigate 3,248 GPs from February 15 to March 15, 2023 across Zhejiang Province, China. Descriptive analyses were used, and the factors associated with GPs’ frequency of collaboration with pharmacists were explored using logistic regression analysis. Results A total of 2,487 GPs (76.6%) responded and consented to participate in the survey; 52.3% were male and the mean age was 35.4 years. Most GPs agreed that they shared common goals and objectives with pharmacists when caring for patients (90.0%), and pharmacists were open to working with them on patients’ medication management (80.8%). However, half of the GPs did not change or seldom changed the patient’s medication on the pharmacist’s advice (51.4%). Logistic regression analysis showed that GPs who were older and had more years of practice were more likely to agree that pharmacists were willing to collaborate, had common goals for treatment and that they would change the patient’s medication on the advice of the pharmacist. GPs who had regular communication protocols (adjusted odds ratio1 [aOR1] = 1.88, 95% CI 1.45–2.45; aOR2 = 3.33, 95% CI 2.76–4.02), participated in joint continuing education (aOR1 = 1.87, 95% CI 1.44–2.43; aOR2 = 2.27, 95% CI 1.91–2.70), provided recommendations for medication review (aOR1 = 3.01, 95% CI 2.07–4.38; aOR2 = 3.50, 95% CI 2.51–4.86), and communicated with pharmacists during resident training (aOR1 = 2.15, 95% CI 1.78–2.60; aOR2 = 1.38, 95% CI 1.18–1.62) were associated with a more positive attitude towards and higher frequency of cooperation. Conclusions GPs in China displayed a positive attitude towards cooperating with pharmacists, but they did not demonstrate a similar level of practice. As environmental determinants impact interdisciplinary collaboration, healthcare managers and policy-makers need to implement measures that foster a supportive environment conducive to interdisciplinary collaboration.

Abstract Background RCC1 functions as a pivotal guanine nucleotide exchange factor and was reported to be involved in mitosis, the assembly of the nuclear envelope, nucleocytoplasmic transport in cell physiological processes. Recent studies reported that RCC1 could regulate immunological pathways and promote the growth of some malignant solid tumors. However, the prognostic value and exact function of RCC1 remain unknown in patients with clear cell renal cell carcinoma (cRCC). Methods The UALCAN and KM plotter portals were used to analyze the expression profile and related tumor prognosis of RCC1 in ccRCC using data from TCGA. The expression profile of RCC1 was also confirmed in clinical samples using qRT‐PCR, western blotting, and immunohistochemistry. The role of RCC1 on ccRCC cells in vitro was confirmed by a series of functional assays. Animal experiments were performed to verify the suppressive effect of RCC1 knockdown on tumor growth in vivo. The correlation of RCC1 expression with that of EZH2 was explored in clinical samples using IHC. The interaction between RCC1 and EZH2 was further verified using a CO‐IP assay and a protein stability assay. Results RCC1 was upregulated in ccRCC tissues compared with normal tissues in TCGA dataset and paired clinical samples. RCC1 promoted ccRCC progression by accelerating the cell cycle and suppressing apoptosis. In addition, RCC1 could bind EZH2 and regulate its expression at the posttranscriptional level. RCC1 and EZH2 expression showed a strong correlation in clinical samples. Further investigation proved that RCC1 regulated EZH2 protein stability through the ubiquitin–proteasome pathway. Conclusions RCC1 could be a potential therapeutic target in ccRCC. The RCC1/EZH2 axis takes part in the development of ccRCC.

This work explores the effect of a Zn1−xSnxOy (ZTO) layer as a potential replacement for CdS in Sb2(S,Se)3 devices. Through the use of Afors-het software v2.5, it was determined that the ZTO/Sb2(S,Se)3 interface exhibits a lower conduction band offset (CBO) value of 0.34 eV compared to the CdS/Sb2(S,Se)3 interface. Lower photo-generated carrier recombination can be obtained at the interface of the ZTO/Sb2(S,Se)3 heterojunction. In addition, the valence band offset (VBO) value at the ZTO/Sb2(S,Se)3 interface increases to 1.55 eV. The ZTO layer increases the efficiency of the device from 7.56% to 11.45%. To further investigate the beneficial effect of the ZTO layer on the efficiency of the device, this goal has been achieved by five methods: changing the S content of the absorber, changing the thickness of the absorber, changing the carrier concentration of ZTO, using various Sn/(Zn+Sn) ratios in ZTO, and altering the thickness of the ZTO layer. When the S content in Sb2(S,Se)3 is around 60% and the carrier concentration is about 1018 cm−3, the efficiency is optimal. The optimal thickness of the Sb2(S,Se)3 absorber layer is 260 nm. A ZTO/Sb2(S,Se)3 interface with a Sn/(Zn+Sn) ratio of 0.18 exhibits a better CBO value. It is also found that a ZTO thickness of 20 nm is needed for the best efficiency.

BackgroundPre-eclampsia and eclampsia are among the major threats to pregnant women and fetuses, but they can be mitigated by prevention and early screening. Existing observational research presents conflicting evidence regarding the causal effects of coronavirus disease 2019 (COVID-19) on pre-eclampsia risk. Through Mendelian randomization (MR), this study aims to investigate the causal effect of three COVID-19 severity phenotypes on the risk of pre-eclampsia and eclampsia to provide more rigorous evidence.MethodsTwo-sample MR was utilized to examine causal effects. Summary-level data from genome-wide association studies (GWAS) of individuals of European ancestry were acquired from the GWAS catalog and FinnGen databases. Single-nucleotide polymorphisms associated with COVID-19 traits at p

BackgroundNotwithstanding the acknowledged interplay between atrial fibrillation (AF) and the emergence of digestive system neoplasms, the intricacies of this relationship remain ambiguous. By capitalizing univariable Mendelian Randomization (MR) complemented by a mediated MR tactic, our pursuit was to elucidate the causative roles of AF in precipitating digestive system malignancies and potential intermediary pathways.MethodThis research endeavor seeks to scrutinize the causal clinical implications of whether genetic predispositions to AF correlate with an increased risk of digestive system malignancies, employing MR analytical techniques. Utilizing a dataset amalgamated from six studies related to AF, encompassing over 1,000,000 subjects, we performed univariable MR assessments, employing the random-effects inverse-variance weighted (IVW) methodology as our principal analytical paradigm. Subsequently, a mediated MR framework was employed to probe the potential mediating influence of AF on the nexus between hypertension (HT), heart failure (HF), ischemic stroke (IS), coronary artery disease (CAD), and digestive system neoplasms.ResultThe univariable MR evaluation unveiled a notable causal nexus between the genetic inclination toward AF and the genetic susceptibility to colon, esophageal, and small intestine malignancies. The mediated MR scrutiny ascertained that the genetic inclination for AF amplifies the risk profile for colon cancer via IS pathways and partially explains the susceptibility to esophageal and small intestine tumors through the HF pathway.ConclusionOur investigative endeavor has highlighted a definitive causative association between genetic inclination to AF and specific digestive system neoplasms, spotlighting IS and HF as instrumental mediators. Such revelations furnish pivotal perspectives on the complex genetic interconnections between cardiovascular anomalies and certain digestive tract tumors, emphasizing prospective therapeutic and diagnostic worthy of pursuit.

ObjectivesTo understand the attitudes and health behaviors of middle-aged and older adults in China after receiving elevated results of tumor markers (TMs) test in the annual health examinations (AHEs) and explore the influencing factors.MethodsA three-section online questionnaire survey was conducted from March 1 to April 30, 2020 in Hangzhou, China, to people who were aged 45 and older and had at least one elevated result of TMs test. Clinical information was collected from the online survey and medical records. Descriptive statistics were carried out followed by regression analyses.ResultsOf 380 participants, 76.1% were unwilling to quit the TMs test in AHEs, whereas 75.3% would take the doctor’s advice and quit unnecessary TMs test; 67.4% felt stressed about their TMs. Among participants with elevated TMs, 76.8% changed lifestyle to keep healthy, 74.2% sought health information, 58.9% requested a TMs retest, and 50.3% did further tests to confirm a diagnosis. Family history of cancer was associated with lifestyle changing; education level, area of residence and health insurance were associated with health information seeking; comorbidity were associated with retests and sequential confirming tests.ConclusionThe application of the TMs test in AHEs among Chinese people may lead to positive and negative behavioral consequences and psychological distress. Doctors have a significant impact on patients’ health behaviors. Accurate indications and adequate communication with patients before and after the TMs test are in great need.

Abstract Gliomas are the most prevalent primary tumor in the central nervous system, with an abysmal 5-year survival rate and alarming mortality. The current standard management of glioma is maximum resection of tumors followed by postoperative chemotherapy with temozolomide (TMZ) or radiotherapy. Low chemosensitivity of TMZ in glioma treatment eventuates limited therapeutic efficacy or treatment failure. Hence, overcoming the resistance of glioma to TMZ is a pressing question. Our research centered on identifying the drug metabolism-related genes potentially involved in TMZ-treated resistance of glioma through several bioinformatics datasets and cell experiments. One efflux transporter, ATP-binding cassette transporter subfamily A1 (ABCA1), was discovered with an upregulated expression level and signaled poor clinical outcomes for glioma patients. The transcript level of ABCA1 significantly elevated across the TMZ-resistant glioma cells in contrast with non-resistant cells. Over-expressed ABCA1 restrained the drug activity of TMZ, and ABCA1 knockdown improved the treatment efficacy. Meanwhile, the results of molecular docking between ABCA1 protein and TMZ showed a high binding affinity. Additionally, co-expression and immunological analysis revealed that ABCA1 facilitates the immune infiltration of M2 macrophages in glioma, thereby stimulating tumor growth and aggravating the poor survival of patients. Altogether, we discovered that the ABCA1 transporter was involved in TMZ chemoresistance and the immune infiltration of M2 macrophages in glioma. Treatment with TMZ after ABCA1 knockdown enhances the chemosensitivity, suggesting that inhibition of ABCA1 may be a potential strategy for improving the therapeutic efficacy of gliomas.

Abstract Staging lymph nodes (LN) is crucial in diagnosing and treating cancer metastasis. Biotechnologies for the specific localization of metastatic lymph nodes (MLNs) have attracted significant attention to efficiently define tumor metastases. Bioimaging modalities, particularly magnetic nanoparticles (MNPs) such as iron oxide nanoparticles, have emerged as promising tools in cancer bioimaging, with great potential for use in the preoperative and intraoperative tracking of MLNs. As radiation-free magnetic resonance imaging (MRI) probes, MNPs can serve as alternative MRI contrast agents, offering improved accuracy and biological safety for nodal staging in cancer patients. Although MNPs’ application is still in its initial stages, exploring their underlying mechanisms can enhance the sensitivity and multifunctionality of lymph node mapping. This review focuses on the feasibility and current application status of MNPs for imaging metastatic nodules in preclinical and clinical development. Furthermore, exploring novel and promising MNP-based strategies with controllable characteristics could lead to a more precise treatment of metastatic cancer patients.

In this paper, a novel laser-induced TIG arc narrow-gap welding technology is proposed for thick plates of TC4 titanium alloy. The feasibility of achieving high-performance welding joints is investigated by adjusting the spatial deviation position of the laser, arc, and filler wire. The results exhibited remarkable capabilities. By augmenting the laser-arc malposition, a stable deflection of the arc can be achieved, resulting in enhanced heat input to the sidewall adjacent to the laser side and improved fusion capability. Moreover, an inclined weld can be obtained through increased malposition between the filler wire and arc, which helps to improve interlayer fusion and suppress porosity defects. This method, involving alternating bilateral offsets between passes, successfully achieved narrow-gap welding of 24 mm-thick TC4 titanium alloy with an average tensile strength of 880.68 MPa (equivalent to 95.05% of base material strength). Therefore, this technology exhibits promising potential as an automated welding technique for achieving high-quality narrow-gap welding in titanium alloys.

Wind turbine (WT) foundations with an embedded steel ring (ESR) are widely used in onshore WTs due to construction convenience. The research group found that WT foundations with damage were often accompanied by blade issues. To investigate the potential correlation between aerodynamic imbalance and fatigue damage of the WT foundation with an ESR, this study focuses on a 2 MW WT with an ESR. It investigates the influence of an error in pitch angle (PAE) on the WT’s foundation load and stress, utilizing one year of SCADA data to analyze the fatigue damage caused by PAE. The main conclusions are as follows: Firstly, the effect of PAE on the amplitude value of load and stress is significantly greater than on the average value of load and stress. Secondly, when the PAE is within the range of −3° to 3°, the foundation fatigue damage incurred over one year is minimal, but once this limit is exceeded, the foundation fatigue damage increases dramatically. Thirdly, the peak value of fatigue damage to the foundation caused by PAE does not necessarily occur in the main wind direction, but in the direction with the highest probability of the occurrence of high wind speeds, and the larger the PAE, the more significant the trend.

Abstract Metal regulatory transcription factor 1 (MTF1) has been reported to be correlated with several human diseases, especially like cancers. Exploring the underlying mechanisms and biological functions of MTF1 could provide novel strategies for clinical diagnosis and therapy of cancers. In this study, we conducted the comprehensive analysis to evaluate the profiles of MTF1 in pan-cancer. For example, TIMER2.0, TNMplot and GEPIA2.0 were employed to analyze the expression values of MTF1 in pan-cancer. The methylation levels of MTF1 were evaluated via UALCAN and DiseaseMeth version 2.0 databases. The mutation profiles of MTF1 in pan-cancers were analyzed using cBioPortal. GEPIA2.0, Kaplan–Meier plotter and cBioPortal were also used to explore the roles of MTF1 in cancer prognosis. We found that high MTF1 expression was related to poor prognosis of liver hepatocellular carcinoma (LIHC) and brain lower grade glioma (LGG). Also, high expression level of MTF1 was associated with good prognosis of kidney renal clear cell carcinoma (KIRC), lung cancer, ovarian cancer and breast cancer. We investigated the genetic alteration and methylation levels of MTF1 between the primary tumor and normal tissues. The relationship between MTF1 expression and several immune cells was analyzed, including T cell CD8 + and dendritic cells (DC). Mechanically, MTF1-interacted molecules might participate in the regulation of metabolism-related pathways, such as peptidyl-serine phosphorylation, negative regulation of cellular amide metabolic process and peptidyl-threonine phosphorylation. Single cell sequencing indicated that MTF1 was associated with angiogenesis, DNA repair and cell invasion. In addition, in vitro experiment indicated knockdown of MTF1 resulted in the suppressed cell proliferation, increased reactive oxygen species (ROS) and promoted cell death in LIHC cells HepG2 and Huh7. Taken together, this pan-cancer analysis of MTF1 has implicated that MTF1 could play an essential role in the progression of various human cancers.

Abstract Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.

BackgroundThis study aimed to evaluate the short-term outcomes of enhanced recovery after surgery (ERAS) protocol in perioperative robotic-assisted McKeown esophagectomy (RAME) among esophageal cancer patients.MethodsFor this retrospective study, all patients who had undergone RAME with esophageal cancer using ERAS protocol and conventional management strategy at the surgery center of our hospital from February 2019 to March 2022 were performed for analysis.ResultsA total of 211 patients were included. Compared to the conventional group, the ERAS group has shorter median operative time [207 (147.5-267.5) vs. 244 (183-305), P

Background & Aims: β-1,4-N-Acetyl-galactosaminyltransferase 1 (B4GALNT1) has been reported to contribute to the development of human malignancies. However, its role in hepatocellular carcinoma (HCC) remains uncharacterised. In this study, we aimed to elucidate the role of B4GALNT1 in HCC stemness and progression. Methods: Immunohistochemical staining was used to evaluate B4GALNT1 expression in HCC tissues and adjacent normal liver tissues. Flow cytometry analysis and sphere formation analysis were performed to investigate the role of B4GALNT1 in HCC stemness. Colony formation, Incucyte, wound-healing, Transwell migration, and invasion assays, and an animal model were used to study the role of B4GALNT1 in HCC progression. RNA-sequencing and co-immunoprecipitation were used to investigate the downstream targets of B4GALNT1. Results: B4GALNT1 was upregulated in HCC and associated with poor clinical outcome of patients with the disease. Moreover, B4GALNT1 promoted HCC stemness, migration, invasion, and growth. Mechanistically, B4GALNT1 not only promoted the expression of the integrin α2β1 ligand THBS4, but also directly interacted with the β subunit of integrin α2β1 ITGB1 to inhibit its ubiquitin-independent proteasomal degradation, resulting in activation of FAK and AKT. Ophiopogonin D inhibited HCC stemness and progression by reducing ITGB1 and THBS4 expression and inhibiting FAK and AKT activation. Conclusions: Our study suggests the B4GALNT1/integrin α2β1/FAK/PI3K/AKT axis as a therapeutic target for the inhibition of HCC stemness and tumour progression. Impact and implications: The role and regulatory mechanism of B4GALNT1 in HCC have not been studied previously. Here, we reveal that B4GALNT1 has a crucial role in HCC stemness and progression by activating the integrin α2β1/FAK/PI3K/AKT axis, providing a potential target for HCC therapy. In addition, we find Ophiopogonin D as a potential therapeutic drug for patients with HCC.

Atrial fibrillation (AF) is a common clinical arrhythmia whose pathogenesis has not been fully elucidated, and the inflammatory response plays an important role in the development of AF. The inflammasome is an important component of innate immunity and is involved in a variety of pathophysiologic processes. The NLRP3 inflammasome is by far the best studied and validated inflammasome that recognizes multiple pathogens through pattern recognition receptors of innate immunity and mediates inflammatory responses through activation of Caspase-1. Several studies have shown that NLRP3 inflammasome activation contributes to the onset and development of AF. Ecological dysregulation of the gut microbiota has been associated with the development of AF, and some evidence suggests that gut microbiota components, functional byproducts, or metabolites may induce or exacerbate the development of AF by directly or indirectly modulating the NLRP3 inflammasome. In this review, we report on the interconnection of NLRP3 inflammasomes and gut microbiota and whether this association is related to the onset and persistence of AF. We discuss the potential value of pharmacological and dietary induction in the management of AF in the context of the association between the NLRP3 inflammasome and gut microbiota. It is hoped that this review will lead to new therapeutic targets for the future management of AF.

BackgroundBoth benign prostatic hyperplasia (BPH) and sarcopenic obesity (SO) are common conditions among older adult/adults males. The prevalent lifestyle associated with SO is a significant risk factor for the development of BPH. Therefore, we investigated the causal relationship between SO factors and BPH.MethodThe instrumental variables for SO factors were selected using the inverse variance-weighted method, which served as the primary approach for Mendelian randomization analysis to assess the causal effect based on summary data derived from genome-wide association studies of BPH.ResultThe increase in BMR (OR = 1.248; 95% CI = (1.087, 1.432); P = 0.002) and ALM (OR = 1.126; 95% CI = (1.032, 1.228); P = 0.008) was found to be associated with an elevated risk of BPH. However, no genetic causality between fat-free mass distribution, muscle mass distribution, and BPH was observed.ConclusionOur findings indicate that a genetic causal association between BMR, ALM and BPH. BMR and ALM are risk factors for BPH. The decrease in BMR and ALM signified the onset and progression of SO, thus SO is a protective factor for BPH.

Abstract Background The past few years have witnessed a significant increase in research related to plant-derived extracellular vesicles (PDEVs) in biological and medical applications. Using biochemical technologies, multiple independent groups have demonstrated the important roles of PDEVs as potential mediators involved in cell-cell communication and the exchange of bio-information between species. Recently, several contents have been well identified in PDEVs, including nucleic acids, proteins, lipids, and other active substances. These cargoes carried by PDEVs could be transferred into recipient cells and remarkably influence their biological behaviors associated with human diseases, such as cancers and inflammatory diseases. Main body of the abstract This review summarizes the latest updates regarding PDEVs and focuses on its important role in nanomedicine applications, as well as the potential of PDEVs as drug delivery strategies to develop diagnostic and therapeutic agents for the clinical management of diseases, especially like cancers. Conclusion Considering its unique advantages, especially high stability, intrinsic bioactivity and easy absorption, further elaboration on molecular mechanisms and biological factors driving the function of PDEVs will provide new horizons for the treatment of human disease.

Abstract Smalls scale challenges suggest some missing pieces in our current understanding of dark matter. A cascade theory for dark matter is proposed to provide extra insights, similar to the cascade phenomenon in hydrodynamic turbulence. The kinetic energy is cascaded in dark matter from small to large scales involves a constant rate $$\varepsilon _u$$ ε u ( $$\approx -\,4.6\times 10^{-7}{\text { m}}^2/{\text { s}}^3$$ ≈ - 4.6 × 10 - 7 m 2 / s 3 ). Confirmed by N-body simulations, the energy cascade leads to a two-thirds law for kinetic energy $$v_r^2$$ v r 2 on scale r such that $$v_r^2 \propto (\varepsilon _u r)^{2/3}$$ v r 2 ∝ ( ε u r ) 2 / 3 . Equivalently, a four-thirds law can be established for mean halo density $$\rho _s$$ ρ s enclosed in the scale radius $$r_s$$ r s such that $$\rho _s \propto \varepsilon _u^{2/3}G^{-1}r_s^{-4/3}$$ ρ s ∝ ε u 2 / 3 G - 1 r s - 4 / 3 , which was confirmed by galaxy rotation curves. Critical properties of dark matter might be obtained by identifying key constants on relevant scales. First, the largest halo scale $$r_l$$ r l can be determined by $$-u_0^3/\varepsilon _u$$ - u 0 3 / ε u , where $$u_0$$ u 0 is the velocity dispersion. Second, the smallest scale $$r_{\eta }$$ r η is dependent on the nature of dark matter. For collisionless dark matter, $$r_{\eta } \propto (-{G\hbar /\varepsilon _{u}}) ^{1/3}\approx 10^{-13}\,{\text {m}}$$ r η ∝ ( - G ħ / ε u ) 1 / 3 ≈ 10 - 13 m , where $$\hbar$$ ħ is the Planck constant. An uncertainty principle for momentum and acceleration fluctuations is also postulated. For self-interacting dark matter, $$r_{\eta } \propto \varepsilon _{u}^2 G^{-3}(\sigma /{{m}})^3$$ r η ∝ ε u 2 G - 3 ( σ / m ) 3 , where $$\sigma /m$$ σ / m is the cross-section of interaction. On halo scale, the energy cascade leads to an asymptotic density slope $$\gamma =-\,4/3$$ γ = - 4 / 3 for fully virialized haloes with a vanishing radial flow, which might explain the nearly universal halo density. Based on the continuity equation, halo density is analytically shown to be closely dependent on the radial flow and mass accretion, such that simulated haloes can have different limiting slopes. A modified Einasto density profile is proposed accordingly.

Several types of modifications have been proven to participate in the metabolism and processing of different RNA types, including non-coding RNAs (ncRNAs). N-6-methyladenosine (m6A) is a dynamic and reversible RNA modification that is closely involved in the ncRNA homeostasis, and serves as a crucial regulator for multiple cancer-associated signaling pathways. The ncRNAs usually regulate the epigenetic modification, mRNA transcription and other biological processes, displaying enormous roles in human cancers. In this review, we summarized the significant implications of m6A-ncRNA interaction in various types of cancers. In particular, the interplay between m6A and ncRNAs in cancer pathogenesis and therapeutic resistance are being widely recognized. We also discussed the relevance of m6A-ncRNA interaction in immune regulation, followed by the interference on cancer immunotherapeutic procedures. In addition, we briefly highlighted the computation tools that could identify the accurate features of m6A methylome among ncRNAs. In summary, this review would pave the way for a better understanding of the biological functions of m6A-ncRNA crosstalk in cancer research and treatment.

Cancer stem cells (CSCs) are responsible for tumor progression and recurrence. However, the mechanisms regulating hepatocellular carcinoma (HCC) stemness remain unclear. Applying a genome-scale CRISPR knockout screen, we identified that the H3K4 methyltransferase SETD1A and other members of Trithorax group proteins drive cancer stemness in HCC. SET domain containing 1A (SETD1A) was positively correlated with poor clinical outcome in patients with HCC. Combination of SETD1A and serum alpha fetoprotein substantially improved the accuracy of predicting HCC relapse. Mechanistically, SETD1A mediates transcriptional activation of various histone-modifying enzymes, facilitates deposition of trimethylated H3K4 (H3K4me3) and H3K27me3, and activates oncogenic enhancers and super-enhancers, leading to activation of oncogenes and inactivation of tumor suppressor genes simultaneously in liver CSCs. In addition, SETD1A cooperates with polyadenylate-binding protein cytoplasmic 1 to regulate H3K4me3 modification on oncogenes. Our data pinpoint SETD1A as a key epigenetic regulator driving HCC stemness and progression, highlighting the potential of SETD1A as a candidate target for HCC intervention and therapy.

Objectives The implementation of outpatient training in primary care settings is an essential part of residency training for general practitioner (GP) residents. However, limited research exists on their experiences and perceptions of this training. This study aimed to explore the experiences and perceptions of GP residents regarding outpatient training in primary care settings in China and provide insights and recommendations to enhance training quality.Design A qualitative descriptive study employing in-depth interviews.Setting Two community healthcare centres (CHCs) that implement outpatient training programmes for GP residents in Zhejiang Province, China.Participants In total, 20 GP residents affiliated with 14 CHCs and two hospitals across Zhejiang Province and Guizhou Province who had completed outpatient training in either CHC for over 1 month.Results Of the 20 participants in this study, 11 (55%) were women, and the mean age was 28 years. GP residents completed the process of consultation, physical examination and therapy independently; subsequently, the community preceptors provided feedback based on their clinical performance and modelled their clinical skills. The benefits perceived by GP residents included improved clinical skills and confidence in practice, and they learned approaches to maintaining good relationships with patients. They preferred dealing with complex cases, discussions with peers and the indirect supervision of community preceptors in the training session. Residents recommended that measures be taken to improve the training quality regarding patient selection and recruitment, clinical skills in the training session, and assessment of clinical performance.Conclusions The outpatient training in primary care settings provides constructive opportunities for GP residents to improve their professional competencies. Although the current training sessions and the abilities of community preceptors largely satisfy the needs of GP residents, further research is needed to evaluate the effectiveness of training and explore approaches to improve its quality.

A series of bi- or mononuclear hexacoordinate iron(III) complexes, [Fe(L)][Fe(bpb)(CN)2]·CH3OH·0.5H2O (1), [Fe(L)][Co(bpb)(CN)2]·CH3OH (2) [(Fe (L))2(4,4’-bipy)](BPh4)2 (3), [Fe(L)(py)](BPh4) (4) and [Fe(L)(dmap)](BPh4) (5) (bpb = 1,2-bis(pyridine-2-carboxamido)benzenate, L = N,N’-bis(2-hydroxybenzyliden)-1,7-diamino-4-azaheptane, dmap = 4-dimethylaminopyridine), have been prepared with the pentadentate Schiff base iron(III) compound as assemble precursor and characterized by element analysis, IR and X-ray diffraction. Single crystal structural determination revealed the neutral cyanide-bridged binuclear entity for complexes 1 and 2 and the cationic di- or mononuclear structure for complexes 3–5 with the positive charge(s) balanced by BPh4– ion(s). The experimental study and theoretical simulation of the magnetic property discovered the ferromagnetic coupling between the Fe(III) ions bridged by cyanide group in complex 1 and the always high spin state of the Fe(III) ion coordinated to the Schiff base ligand in both complexes 1 and 2. The temperature dependent magnetic susceptibility investigation over complexes 3–5 showed the occurrence of the thermo-induced gradual complete spin crossover (SCO) property at about 115, 170 and 200 K, respectively.

Abstract Ferroptosis is a cell death process caused by metabolic dysfunction with the feature of aberrant iron accumulation. Emerging studies have identified that ferroptosis is an important biological function involving in the tumorigenesis, and targeting ferroptosis could provide promising therapeutic targets for lung cancer. However, such therapeutic strategies show limited therapeutic effect owing to drug resistance and other unknown underlying mechanisms. In this study, lysine-specific demethylase 1 (LSD1/KDM1A) was found to be significantly upregulated in lung cancer cells and tissues. The patients with KDM1A downregulation displayed the good prognosis. Using gene set enrichment analysis (GSEA), we demonstrated that KDM1A-associated genes might participate in the regulation of cell ferroptosis and Myc signaling in lung cancer. Knockdown of KDM1A inhibited the level of c-Myc and increased the concentration of malondialdehyde (MDA) and irons in human lung cancer cells H1299 and A549. Downregulation of c-Myc could facilitate KDM1A knockdown-mediated ferroptosis. Our study has elucidated the effect of KDM1A/c-Myc regulatory axis in the ferroptosis resistance of lung cancer cells.

Abstract Background Unnecessary drug use can cause avoidable harm to older adults and is particularly common in primary care, but how primary care physicians (PCPs) respond to older adult requests for unnecessary drugs has not been well studied. This study is to explore PCPs’ responses to requests for unnecessary drugs from older adults, and their influencing factors and potential solutions. Methods This qualitative study was conducted through semi-structured, in-depth interviews from January 4 to September 30, 2020 using a grounded theory methodology. A purposive sample of PCPs affiliated with community healthcare centers in Zhejiang Province and Guangdong Province, China were recruited. The face-to-face interviews were audio-recorded, transcribed verbatim, and independently coded by two investigators. Themes surrounding PCPs’ responses to requests for unnecessary drugs, their influencing factors and potential solutions were analysed using a constant comparative approach. Results Of the 23 participants involved in this study, 12 (52%) were women and the mean age was 35 years. PCPs frequently declined older adults’ requests for unnecessary drugs through dissuasion, and occasionally rebuffed patients or referred them to another practitioner. PCPs may fulfill requests due to physician acquiescence, patient pressure, or inadequate supervision and support. Participants recommended four potential solutions to improve the quality of prescribing, including developing professional communication skills, enhancing pharmacist-physician collaboration, improving electronic prescription systems, and strengthening prescription management. Conclusions PCPs typically deny requests by older adults for unnecessary drugs according to three main patterns, and guidance is necessary to reduce the potential for adverse consequences. Factors contributing to request fulfillment by PCPs require attention, and the potential solutions recommended by participants deserve consideration to improve the service quality of prescribing for older adults in primary care practices.

Abstract RET (rearranged during transfection), encoding a tyrosine kinase receptor, is a novel therapeutic target for cancers. The aberrations of RET are commonly found in cancers. Here, we profiled a comprehensive genomic landscape of RET mutations, copy number variants (CNVs), co-occurrence of RET and its mRNA expression and methylation levels in pan cancer, paving the way to the development of new RET-targeted therapies in clinic. Analysis of RET somatic mutations, CNVs, co-occurrence, mRNA expression and methylation were performed among 32 cancer types from The Cancer Genome Atlas (TCGA) dataset covering a total of 10,953 patients with 10,967 samples. RET aberrations were found in 3.0% of diverse cancers. The top two RET-altered tumors were skin cutaneous melanoma (SKCM) and uterine corpus endometrial carcinoma (UCEC) with dominant mutations in the other and PKinase_Tyr domains. RET-G823E and RET-S891L were most commonly found in SKCM and UCEC. Thyroid carcinoma (THCA) demonstrated the highest rate of coiled-coil domain containing 6 (CCDC6)-RET fusions, which constitutively activate RET kinase. Two FDA-approved RET inhibitors—pralsetinib and selpercatinib have been implied for the treatment of patients with RET S891L mutant UCEC and the treatment of patients with metastatic RET-fusion positive THCA and non-small cell lung cancer (NSCLC) at therapeutic level 1. We also identified four RET M918T-altered cases in patients with pheochromocytoma and paraganglioma (PCPG), which may induce drug resistance against multikinase inhibitors. Next, 273 co-occurring aberrations, most frequently in Notch signaling, TGF-β pathway, cell cycle, and Ras-Raf-MEK-Erk/JNK signaling, were uncovered among 311 RET altered cases. TP53 mutations (162 patients) leads to the most significant co-occurrence associated with RET aberrations. Furthermore, the RET expression was found most significantly increased in breast invasive carcinoma (BRCA) and neck squamous cell carcinoma (HNSC), as compared to their corresponding normal tissues. At last, patients with higher expression and sequence variant frequency have a worse prognosis, such as sarcoma patients. This work provided a profound and comprehensive analysis of RET and co-occurred alterations, RET mRNA expression and the clinical significance in pan cancer, offering new insights into targeted therapy for patients with RET anomalies.

BackgroundThe dissemination of online health information (OHI) on medication use via WeChat Official Accounts (WOAs) is an effective way to help primary care practitioners (PCPs) address drug-related problems (DRPs) in the community. Although an increasing number of primary care institutions in China have published WOA posts on medication use, their content and quality have not yet been assessed.ObjectiveThis study aimed to explore the general features and content of WOA posts on medication use published by community healthcare centers (CHCs) in Shanghai, China and to assess their quality of content. It also aimed to explore the factors associated with the number of post views.MethodsFrom June 1 to October 31, 2022, two coauthors independently screened WOA posts on medication use published throughout 2021 by the CHCs in Shanghai. Content analysis was performed to analyze their general features (format, length, and source, etc.) and content (types of medicines and diseases). The QUEST tool was used to assess the quality of the posts. We compared the differences among posts published by CHCs in central urban areas and suburban areas, and used multiple linear regression to explore the factors associated with the number of post views.ResultsA total of 236 WOAs of interest published 37,147 posts in 2021, and 275 (0.74%) of them were included in the study. The median number of post views was 152. Thirty percent of the posts were reviewed by the CHCs’ staff before publication and only 6% provided information on PCPs’ consultations. The most commonly mentioned medicines and diseases in the posts were Chinese patent medicines (37.1%) and respiratory diseases (29.5%). The posts frequently provided information on indications (77%) and usage (56%) but rarely on follow-up (13%) and storage (11%). Of the posts, 94.9% had a total QUEST score

Immunogenic cell death (ICD) is a novel cell death mechanism that activates and regulates the immune system against cancer. However, its prognostic value in liver cancer remains unclear. Here, several algorithms such as correlation analysis, Cox regression analysis, and Lasso regression analysis were carried out to evaluate the prognostic value of ICD-related genes in patients with liver cancer. Three ICD-related prognostic genes, the prion protein gene (PRNP), dynamin 1-like gene (DNM1L), and caspase-8 (CASP8), were identified and used to construct a risk signature. Patients with liver cancer were categorized into high- and low-risk groups using the ICD-related signature. Subsequently, a multivariate regression analysis revealed that the signature was an independent risk factor in liver cancer [hazard ratio (HR) = 6.839; 95% confidence interval (CI) = 1.625–78.785]. Patient survival was also predicted using the risk model, with area under the curve values of 0.75, 0.70, and 0.69 for 1-, 3-, and 5-year survival, respectively. Finally, a prognostic nomogram containing the clinical characteristics and risk scores of patients was constructed. The constructed ICD-related signature could serve as a prognostic and immunotherapeutic biomarker in liver cancer.

Natural compounds are widely used to prevent and treat various diseases due to their antioxidant and anti-inflammatory effects. As a kind of promising natural compound, plant-derived exosome-like nanoparticles (PELNs) are extracted from multivesicular bodies of various edible plants, including vegetables, foods, and fruits, and mainly regulate the cellular immune response to pathogen attacks. Moreover, PELNs could remarkably interfere with the dynamic imbalance between pro-inflammatory and anti-inflammatory effects, facilitating to maintain the homeostasis of cellular immune microenvironment. PELNs may serve as a better alternative to animal-derived exosomes (ADEs) owing to their widespread sources, cost-effectiveness, and easy accessibility. PELNs can mediate interspecies communication by transferring various cargoes such as proteins, lipids, and nucleic acids from plant cells to mammalian cells. This review summarizes the biogenesis, composition, and classification of exosomes; the common separation, purification, and characterization methods of PELNs, the potential advantages of PELNs over ADEs; and the anti-inflammatory and immunomodulatory functions of PELNs in various diseases including colitis, cancer, and inflammation-associated metabolic diseases. Additionally, the future perspectives of PELNs and the challenges associated with their clinical application are discussed.

With the development of intelligent manufacturing, the production and assembly accuracy of components in factories is increasing in line with growing demand. However, the traditional manual quality inspection is inefficient, inaccurate, and costly. To this end, digital and optical imaging techniques are used to achieve intelligent quality inspection. However, during the reconstruction process, the high reflectivity of object materials affects the speed and accuracy of reconstruction results. To overcome these problems, this study investigated the three-dimensional (3D) digital imaging techniques based on line laser scanning. It advances a novel methodology for image segmentation, underpinned by deep learning algorithms, to augment the precision of the reconstruction results while simultaneously enhancing processing velocity. After the reconstruction phase, the research assesses flatness tolerance using point cloud registration technology. Finally, we constructed a measurement platform with a cost of less than CNY 100,000 (about USD 14,000) and obtained a measurement accuracy of 30 microns.

Abstract Hot rolling and annealing are critical intermediate steps for controlling microstructures and thickness variations when fabricating uranium alloyed with 10% molybdenum (U-10Mo), which is highly relevant to worldwide nuclear non-proliferation efforts. This work proposes a machine-learning surrogate model combined with sensitivity analysis to identify and predict U-10Mo microstructure development during thermomechanical processing. Over 200 simulations were collected using physics-based microstructure models covering a wide range of thermomechanical processing routes and initial alloy grain features. Based on the sensitivity analysis, we determined that an increase in rolling reduction percentage at each processing pass has the strongest effect in reducing the grain size. Multi-pass rolling and annealing can significantly improve recrystallization regardless of the reduction percentage. With a volume fraction below 2%, uranium carbide particles were found to have marginal effects on the average grain size and distribution. The proposed stratified stacking ensemble surrogate predicts the U-10Mo grain size with a mean square error four times smaller than a standard single deep neural network. At the same time, with a significant speedup (1000×) compared to the physics-based model, the machine learning surrogate shows good potential for U-10Mo fabrication process optimization.

Abstract Pyroptosis is an inflammatory form of cell death triggered by certain inflammasomes. However, research concerning pyroptosis-related lncRNAs in hepatocellular carcinoma (HCC) remains scarce. This study aims to explore the prognostic pyroptosis-related long non-coding RNAs (lncRNAs) of HCC patients. Data of 373 HCC patients were obtained from the TCGA database. The entire cohort was randomly divided into a training cohort and a validation cohort in a 2:1 ratio. Pyroptosis-related lncRNAs were identified by the Pearson correlation analysis with reported pyroptosis-related genes. LASSO Cox regression was used to construct the signature. A prognostic signature consisting of nine pyroptosis-related lncRNAs was identified, and patients with lower risk scores had a better prognosis than those with higher risk scores. Multivariate Cox regression analysis showed that the signature was an independent risk factor for prognosis in both the training and validation cohorts. In the training cohort, the area under the signature curve reached 0.8043 at 1-year, 0.7878 at 2-year, and 0.8118 at 3-year; in the validation cohort, it reached 0.7315 at 1-year, 0.7372 at 2-year, and 0.7222 at 3-year. Gene set enrichment analysis (GSEA) suggested associations between the signature and several immune-related pathways. The expression of multiple immune checkpoints was also increased in the high-risk group, including PD-1, PD-L1, CTLA4, B7-H3, VSIR, LAG3, and TIGIT. A novel pyroptosis-related lncRNA signature, which may be associated with tumor immunity and potentially serve as an indicator for immunotherapy, has been identified to precisely predict the prognosis of HCC patients.

Autophagy is a self-recycling and conserved process, in which the senescent cytoplasmic components are degraded in cells and then recycled to maintain homeostatic balance. Emerging evidence has suggested the involvement of autophagy in oncogenesis and progression of various cancers, such as ovarian cancer (OC). Meanwhile, the non-coding RNAs (ncRNAs) frequently regulate the mRNA transcription and other functional signaling pathways in cell autophagy, displaying promising roles in human cancer pathogenesis and therapeutic response. This article mainly reviews the cutting-edge research advances about the interactions between ncRNAs and autophagy in OC. This review not only summarizes the underlying mechanisms of dynamic ncRNA-autophagy association in OC, but also discusses their prognostic implications and therapeutic biomarkers. The aim of this review was to provide a more in-depth knowledge framework exploring the ncRNA-autophagy crosstalk and highlight the promising treatment strategies for OC patients.

Exosomes are nanoscale extracellular vesicles secreted by a variety of cells, affecting the physiological and pathological homeostasis. They carry various cargoes including proteins, lipids, DNA, and RNA and have emerged as critical mediators of intercellular communication. During cell–cell communication, they can internalize either by autologous or heterologous recipient cells, which activate different signaling pathways, facilitating malignant progression of cancer. Among different types of cargoes in exosomes, the endogenous non-coding RNAs, such as circular RNAs (or circRNAs), have gained tremendous attention for their high stability and concentration, playing promising functional roles in cancer chemotherapeutic response by regulating the targeted gene expression. In this review, we primarily described the emerging evidence demonstrating the important roles of circular RNAs derived from exosomes in the regulation of cancer-associated signaling pathways that were involved in cancer research and therapeutic interventions. Additionally, the relevant profiles of exosomal circRNAs and their biological implications have been discussed, which is under investigation for their potential effect on the control of cancer therapeutic resistance.