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Abstract PCOS is a widespread disease that primarily caused in-pregnancy in pregnant-age women. Normoandrogen (NA) and Hyperandrogen (HA) PCOS are distinct subtypes of PCOS, while bio-markers and expression patterns for NA PCOS and HA PCOS have not been disclosed. We performed microarray analysis on granusola cells from NA PCOS, HA PCOS and normal tissue from 12 individuals. Afterwards, microarray data were processed and specific genes for NA PCOS and HA PCOS were identified. Further functional analysis selected IL6R and CD274 as new NA PCOS functional markers, and meanwhile selected CASR as new HA PCOS functional marker. IL6R, CD274 and CASR were afterwards experimentally validated on mRNA and protein level. Subsequent causal relationship analysis based on Apriori Rules Algorithm and co-occurrence methods identified classification markers for NA PCOS and HA PCOS. According to classification markers, downloaded transcriptome datasets were merged with our microarray data. Based on merged data, causal knowledge graph was constructed for NA PCOS or HA PCOS and female infertility on NA PCOS and HA PCOS. Gene-drug interaction analysis was then performed and drugs for HA PCOS and NA PCOS were predicted. Our work was among the first to indicate the NA PCOS and HA PCOS functional and classification markers and using markers to construct knowledge graphs and afterwards predict drugs for NA PCOS and HA PCOS based on transcriptome data. Thus, our study possessed biological and clinical value on further understanding the inner mechanism on the difference between NA PCOS and HA PCOS.

Abstract mRNA vaccines have emerged as highly effective strategies in the prophylaxis and treatment of diseases, thanks largely although not totally to their extraordinary performance in recent years against the worldwide plague COVID-19. The huge superiority of mRNA vaccines regarding their efficacy, safety, and large-scale manufacture encourages pharmaceutical industries and biotechnology companies to expand their application to a diverse array of diseases, despite the nonnegligible problems in design, fabrication, and mode of administration. This review delves into the technical underpinnings of mRNA vaccines, covering mRNA design, synthesis, delivery, and adjuvant technologies. Moreover, this review presents a systematic retrospective analysis in a logical and well-organized manner, shedding light on representative mRNA vaccines employed in various diseases. The scope extends across infectious diseases, cancers, immunological diseases, tissue damages, and rare diseases, showcasing the versatility and potential of mRNA vaccines in diverse therapeutic areas. Furthermore, this review engages in a prospective discussion regarding the current challenge and potential direction for the advancement and utilization of mRNA vaccines. Overall, this comprehensive review serves as a valuable resource for researchers, clinicians, and industry professionals, providing a comprehensive understanding of the technical aspects, historical context, and future prospects of mRNA vaccines in the fight against various diseases.

Abstract Cancer cell metabolism contributes to the establishment of an immunosuppressive tumor microenvironment. Aberrant expression of CD73, a critical enzyme in ATP metabolism, on the cell surface results in the extracellular accumulation of adenosine, which exhibits direct inhibitory effects on tumor-infiltrating lymphocytes. However, little is known about the influence of CD73 on negative immune regulation-associated signaling molecules and transduction pathways inside tumor cells. This study aims to demonstrate the moonlighting functions of CD73 in immunosuppression in pancreatic cancer, an ideal model characterized by complex crosstalk among cancer metabolism, immune microenvironment, and immunotherapeutic resistance. The synergistic effect of CD73-specific drugs in combination with immune checkpoint blockade is observed in multiple pancreatic cancer models. Cytometry by time-of-flight analysis shows that CD73 inhibition reduces tumor-infiltrating Tregs in pancreatic cancer. Tumor cell-autonomous CD73 is found to facilitate Treg recruitment, in which CCL5 is identified as a significant downstream effector of CD73 using integrated proteomic and transcriptomic analyses. CD73 transcriptionally upregulates CCL5 through tumor cell-autocrine adenosine–Adora2a signaling-mediated activation of the p38–STAT1 axis, recruiting Tregs to pancreatic tumors and causing an immunosuppressive microenvironment. Together, this study highlights that CD73–adenosine metabolism transcriptionally controls pancreatic cancer immunosuppression in a tumor-autonomous and -autocrine manner.

The deciduous tree hickory (Carya cathayensis) holds economic significance in China due to its high oil content, particularly in unsaturated fatty acids. Oil bodies are crucial for storing triacylglycerol (TAG), with caleosin serving as a predominant oil body protein that aids in oil body formation and stability maintenance. Our study utilized bioinformatics techniques to identify caleosin genes within Carya cathayensis, Carya illinoinensis, and Juglans regia. Three caleosin genes were discovered in the genomes of Carya cathayensis, Carya illi-noinensis, and Juglans regia. These genes encode hydrophilic proteins. Additionally, all caleosin proteins feature a single Ca2+-binding EF-hand, a conserved “proline knot” motif, and a C-terminal hydrophilic region with four potential phosphorylation sites. The caleosin proteins in Carya cathayensis consist of α-helix, β-corner, extended chain, and random curl structures. Cis-acting elements related to stress response and hormone signaling were identified in Carya cathayensis, Carya illinoinensis, and Juglans regia, with distinct cis-acting elements implicated in seed-specific regulation in Carya cathayensis. Additionally, subcellular localization analysis confirmed that CcaCLO1 and CcaCLO2 were localized within oil bodies. Transcriptome analysis and quantitative real-time polymerase chain reaction (qRT-PCR) data demonstrated a significant up-regulation of CcaCLO1 expression during the developmental stages of the Carya cathayensis embryo. Furthermore, qPCR findings indicated that caleosins from Carya cathayensis were responsive to salt stress, with a significant up-regulation of CcaCLO1 following exposure to salt stress treatment. Consequently, caleosin genes in Carya cathayensis, Carya illinoinensis, and Juglans regia share similar physicochemical characteristics and conserved motifs. Specifically, CcaCLO1 in Carya cathayensis primarily responds to embryo development and salt stress. These findings offer foundational insights for future investigations into the regulatory mechanisms of oil accumulation and response to salt stress in hickory.

With the development of digital economy, especially the Mobile payment, the lifestyles such as the private donation, is undergoing accelerated changes in the last decades. Based on the China Family Panel Studies 2018 data, this paper systematically investigated the donation models, empowered by digital technology, have realized economy system refinement and intelligent development. Compared with residents who do not use the Internet, residents who use the Internet are about 10% more likely to donate, and the amount of donations will increase by about 56%. After considering the potential endogeneity problem, results still hold with Propensity Score Matching (PSM) and Instrumental Variable. The mechanism analysis shows that the searching cost and information asymmetry play an important role. The research of this paper has enlightening that the widespread use of digital technologies can effectively change the private donation behavior and penetrate energy consumption via dramatically decreasing searching cost.

Doping can improve the structural stability and photoelectric properties of perovskite materials. In this study, indium element was added into Tl-Co double based perovskite material to stabilize its structure and improve its photoelectric performance. The results show that the doped material Cs2In0.5Tl0.5CoX6(X = I, Br, Cl) has better ductility and stability than the original Cs2TlCoI6 by elastic constants and phonon spectra. Moreover, indium doping can improve the band structure of Tl-Co double-base perovskite materials, such as changing the band value to the optimal band gap value of solar energy absorber and transforming from indirect band structure to quasi-direct band structure. In terms of optical properties, indium doping can expand the wavelength range of the material's light absorption, making its absorption spectrum more matching with the simulated AM1.5 spectrum. Cs2In0.5Tl0.5CoCl6 is proposed to be a promising candidate for optoelectronic applications based on its structural stability, bandgap value and optical absorption spectrum.

Ferroptosis is a new form of regulatory cell death that is closely related to the balance of redox reactions and the occurrence and development of cancer. There is increasing evidence that inducing ferroptosis in cells has great potential in the treatment of cancer. Especially when combined with traditional therapy, it can improve the sensitivity of cancer cells to traditional therapy and overcome the drug resistance of cancer cells. This paper reviews the signaling pathways regulating ferroptosis and the great potential of ferroptosis and radiotherapy (RT) in cancer treatment and emphasizes the unique therapeutic effects of ferroptosis combined with RT on cancer cells, such as synergy, sensitization and reversal of drug resistance, providing a new direction for cancer treatment. Finally, the challenges and research directions for this joint strategy are discussed.

Abstract Background Determining the prognosis of lung adenocarcinoma (LUAD) is challenging. The present study aimed to identify prognostic ferroptosis-related long noncoding RNAs (FRLs) and construct a prognostic model. Moreover, differential analysis of immune and N6-methyladenosine (m6A)-related genes was systematically conducted. Methods A total of 504 patients selected from a dataset from The Cancer Genome Atlas were included. The patients with LUAD were randomly divided into a training group and a test group at a ratio of 1:1. Pearson correlation analysis and univariate Cox regression analysis were used to identify the prognostic FRLs. Then, a prognostic model was constructed from the optimized subset of prognostic FRLs based on the least absolute shrinkage and selection operator (LASSO) algorithm. Subsequently, the receiver operating characteristic (ROC) curve and survival analysis were used to evaluate the performance of the model. The risk score based on the prognostic model was analyzed using Cox regression analysis. Moreover, gene set enrichment analysis and differential analysis of immune- and m6A-related genes were conducted. Results After univariate Cox regression analysis and LASSO algorithm analysis, a total of 19 prognostic FRLs were selected to construct the final model to obtain the risk score. The area under the ROC curve of the prognostic model for 1-year, 3-year, and 5-year overall survival (OS) was 0.763, 0.745, and 0.778 in the training set and 0.716, 0.724, and 0.736 in the validation set, respectively. Moreover, the OS of the high-risk group was significantly worse than that of the low-risk group in the training group (P

Background & Aims: Non-invasive stratification of the liver decompensation risk remains unmet in people with compensated cirrhosis. This study aimed to develop a non-invasive tool (NIT) to predict hepatic decompensation. Methods: This retrospective study recruited 689 people with compensated cirrhosis (median age, 54 years; 441 men) from 5 centres from January 2016 to June 2020. Baseline abdominal computed tomography (CT), clinical features, and liver stiffness were collected, and then the first decompensation was registered during the follow-up. The spleen-based model was designed for predicting decompensation based on a deep learning segmentation network to generate the spleen volume and least absolute shrinkage and selection operator (LASSO)-Cox. The spleen-based model was trained on the training cohort of 282 individuals (Institutions I–III) and was validated in 2 external validation cohorts (97 and 310 individuals from Institutions IV and V, respectively) and compared with the conventional serum-based models and the Baveno VII criteria. Results: The decompensation rate at 3 years was 23%, with a 37.6-month median (IQR 21.1–52.1 months) follow-up. The proposed model showed good performance in predicting decompensation (C-index ≥0.84) and outperformed the serum-based models (C-index comparison test p

NEK2 is a serine-threonine kinase overexpressed in a variety of human cancers. Here the authors show that NEK2 controls the stability of PD-L1 by preventing its proteasome-mediated degradation and that NEK2 targeting restores anti-tumor immune responses in preclinical models of pancreatic cancer.

Oncolytic peptides are highly effective on remodeling the tumor microenvironment and potentiating the anticancer immunity through multiple mechanisms, particularly by inducing immunogenic cell death. Intriguingly, a recent study demonstrates that LTX-315, one of the most promising and extensively studied oncolytic peptides, inhibits PD-L1 expression via ATP11B, thus enhancing the effectiveness of cancer immunotherapy by targeting the PD-1/PD-L1 axis. Therefore, this commentary discusses the broad effects and perspectives of oncolytic peptides on anticancer immunity, further highlighting the potential issues and directions of oncolytic peptides in cancer immunotherapy.

Abstract Background The mRNA-based cancer vaccine has been considered a promising strategy and the next hotspot in cancer immunotherapy. However, its application on cholangiocarcinoma remains largely uncharacterized. This study aimed to identify potential antigens of cholangiocarcinoma for development of anti-cholangiocarcinoma mRNA vaccine, and determine immune subtypes of cholangiocarcinoma for selection of suitable patients from an extremely heterogeneous population. Methods Gene expression profiles and corresponding clinical information were collected from GEO and TCGA, respectively. cBioPortal was used to visualize and compare genetic alterations. GEPIA2 was used to calculate the prognostic index of the selected antigens. TIMER was used to visualize the correlation between the infiltration of antigen-presenting cells and the expression of the identified antigens. Consensus clustering analysis was performed to identify the immune subtypes. Graph learning-based dimensionality reduction analysis was conducted to visualize the immune landscape of cholangiocarcinoma. Results Three tumor antigens, such as CD247, FCGR1A, and TRRAP, correlated with superior prognoses and infiltration of antigen-presenting cells were identified in cholangiocarcinoma. Cholangiocarcinoma patients were stratified into two immune subtypes characterized by differential molecular, cellular and clinical features. Patients with the IS1 tumor had immune “hot” and immunosuppressive phenotype, whereas those with the IS2 tumor had immune “cold” phenotype. Interestingly, patients with the IS2 tumor had a superior survival than those with the IS1 tumor. Furthermore, distinct expression of immune checkpoints and immunogenic cell death modulators was observed between different immune subtype tumors. Finally, the immune landscape of cholangiocarcinoma revealed immune cell components in individual patient. Conclusions CD247, FCGR1A, and TRRAP are potential antigens for mRNA vaccine development against cholangiocarcinoma, specifically for patients with IS2 tumors. Therefore, this study provides a theoretical basis for the anti-cholangiocarcinoma mRNA vaccine and defines suitable patients for vaccination.

Abstract Background Although mRNA vaccines have been effective against multiple cancers, their efficacy against pancreatic adenocarcinoma (PAAD) remains undefined. Accumulating evidence suggests that immunotyping can indicate the comprehensive immune status in tumors and their immune microenvironment, which is closely associated with therapeutic response and vaccination potential. The aim of this study was to identify potent antigens in PAAD for mRNA vaccine development, and further distinguish immune subtypes of PAAD to construct an immune landscape for selecting suitable patients for vaccination. Methods Gene expression profiles and clinical information of 239 PAAD datasets were extracted from ICGC, and RNA-Seq data of 103 samples were retrieved from TCGA. GEPIA was used to calculate differential expression levels and prognostic indices, cBioPortal program was used to compare genetic alterations, and TIMER was used to explore correlation between genes and immune infiltrating cells. Consensus cluster was used for consistency matrix construction and data clustering, DAVID was used for functional annotation, and graph learning-based dimensional reduction was used to depict immune landscape. Results Six overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in PAAD, including ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A. Furthermore, five immune subtypes (IS1-IS5) and nine immune gene modules of PAAD were identified that were consistent in both patient cohorts. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to the other subtypes. IS4 and IS5 tumors were immunologically cold and associated with higher tumor mutation burden. Immunogenic cell death modulators, immune checkpoints, and CA125 and CA199, were also differentially expressed among the five immune subtypes. Finally, the immune landscape of PAAD showed a high degree of heterogeneity between individual patients. Conclusions ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A are potent antigens for developing anti-PAAD mRNA vaccine, and patients with IS4 and IS5 tumors are suitable for vaccination.

Abstract Background Accurate diagnosis of high-grade branching type intraductal papillary mucinous neoplasms (BD-IPMNs) is challenging in clinical setting. We aimed to construct and validate a nomogram combining clinical characteristics and radiomic features for the preoperative prediction of low and high-grade in BD-IPMNs. Methods Two hundred and two patients from three medical centers were enrolled. The high-grade BD-IPMN group comprised patients with high-grade dysplasia and invasive carcinoma in BD-IPMN (n = 50). The training cohort comprised patients from the first medical center (n = 103), and the external independent validation cohorts comprised patients from the second and third medical centers (n = 48 and 51). Within 3 months prior to surgery, all patients were subjected to magnetic resonance examination. The volume of interest was delineated on T1-weighted (T1-w) imaging, T2-weighted (T2-w) imaging, and contrast-enhanced T1-weighted (CET1-w) imaging, respectively, on each tumor slice. Quantitative image features were extracted using MITK software (G.E.). The Mann-Whitney U test or independent-sample t-test, and LASSO regression, were applied for data dimension reduction, after which a radiomic signature was constructed for grade assessment. Based on the training cohort, we developed a combined nomogram model incorporating clinical variables and the radiomic signature. Decision curve analysis (DCA), a receiver operating characteristic curve (ROC), a calibration curve, and the area under the ROC curve (AUC) were used to evaluate the utility of the constructed model based on the external independent validation cohorts. Results To predict tumor grade, we developed a nine-feature-combined radiomic signature. For the radiomic signature, the AUC values of high-grade disease were 0.836 in the training cohort, 0.811 in external validation cohort 1, and 0.822 in external validation cohort 2. The CA19–9 level and main pancreatic duct size were identified as independent parameters of high-grade of BD-IPMNs using multivariate logistic regression analysis. The CA19–9 level and main pancreatic duct size were then used to construct the radiomic nomogram. Using the radiomic nomogram, the high-grade disease-associated AUC values were 0.903 (training cohort), 0.884 (external validation cohort 1), and 0.876 (external validation cohort 2). The clinical utility of the developed nomogram was verified using the calibration curve and DCA. Conclusions The developed radiomic nomogram model could effectively distinguish high-grade patients with BD-IPMNs preoperatively. This preoperative identification might improve treatment methods and promote personalized therapy in patients with BD-IPMNs.

Abstract Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.

BackgroundPatient-directed selection and sharing of health information “granules” is known as granular information sharing. In a previous study, patients with behavioral health conditions categorized their own health information into sensitive categories (eg, mental health) and chose the health professionals (eg, pharmacists) who should have access to those records. Little is known about behavioral health professionals’ perspectives of patient-controlled granular information sharing (PC-GIS). ObjectiveThis study aimed to assess behavioral health professionals’ (1) understanding of and opinions about PC-GIS; (2) accuracy in assessing redacted medical information; (3) reactions to patient rationale for health data categorization, assignment of sensitivity, and sharing choices; and (4) recommendations to improve PC-GIS. MethodsFour 2-hour focus groups and pre- and postsurveys were conducted at 2 facilities. During the focus groups, outcomes from a previous study on patients’ choices for medical record sharing were discussed. Thematic analysis was applied to focus group transcripts to address study objectives. ResultsA total of 28 health professionals were recruited. Over half (14/25, 56%) were unaware or provided incorrect definitions of granular information sharing. After PC-GIS was explained, all professionals demonstrated understanding of the terminology and process. Most (26/32 codes, 81%) recognized that key medical data had been redacted from the study case. A majority (41/62 codes, 66%) found the patient rationale for categorization and data sharing choices to be unclear. Finally, education and other approaches to inform and engage patients in granular information sharing were recommended. ConclusionsThis study provides detailed insights from behavioral health professionals on granular information sharing. Outcomes will inform the development, deployment, and evaluation of an electronic consent tool for granular health data sharing.

BackgroundPatient-controlled granular information sharing (PC-GIS) allows a patient to select specific health information “granules,” such as diagnoses and medications; choose with whom the information is shared; and decide how the information can be used. Previous studies suggest that health professionals have mixed or concerned opinions about the process and impact of PC-GIS for care and research. Further understanding of behavioral health professionals’ views on PC-GIS are needed for successful implementation and use of this technology. ObjectiveThe aim of this study was to evaluate changes in health professionals’ opinions on PC-GIS before and after a demonstrative case study. MethodsFour focus groups were conducted at two integrated health care facilities: one serious mental illness facility and one general behavioral health facility. A total of 28 participants were given access to outcomes of a previous study where patients had control over medical record sharing. Participants were surveyed before and after focus groups on their views about PC-GIS. Thematic analysis of focus group output was paired with descriptive statistics and exploratory factor analysis of surveys. ResultsBehavioral health professionals showed a significant opinion shift toward concern after the focus group intervention, specifically on the topics of patient understanding (P=.001), authorized electronic health record access (P=.03), patient-professional relationship (P=.006), patient control acceptance (P

Background LTX-315 is an oncolytic peptide deriving from bovine lactoferrin, with the ability to induce cancer immunogenic cell death. However, the mechanism used by LTX-315 to trigger the antitumor immune response is still poorly understood. The expression of programmed cell death ligand 1 (PD-L1) largely determines the efficacy and effectiveness of cancer immunotherapies targeting this specific immune checkpoint. This study aimed to demonstrate the potential effect and mechanism of LTX-315 in PD-L1 inhibition-induced anti-pancreatic cancer immunity.Methods Both immunodeficient and immunocompetent mouse models were used to evaluate the therapeutic efficacy of monotherapy and combination therapy. Flow cytometry and immunohistochemistry were used to assess the immune microenvironment. Multiomic analysis was used to identify the potential target and down-streaming signaling pathway. Both in-house tissue microarray and open accessed The Cancer Genome Atlas data sets were used to evaluate the clinical relevance in pancreatic cancer prognosis.Results LTX-315 treatment inhibited PD-L1 expression and enhanced lymphocyte infiltration in pancreatic tumors. ATP11B was identified as a potential target of LTX-315 and a critical regulator in maintaining PD-L1 expression in pancreatic cancer cells. As regards the mechanism, ATP11B interacted with PD-L1 in a CKLF-like MARVEL transmembrane domain containing 6 (CMTM6)-dependent manner. The depletion of ATP11B promoted CMTM6-mediated lysosomal degradation of PD-L1, thus reactivating the immune microenvironment and inducing an antitumor immune response. The significant correlation among ATP11B, CMTM6, and PD-L1 was confirmed in clinical samples of pancreatic cancer.Conclusions LTX-315 was first identified as a peptide drug inducing PD-L1 downregulation via ATP11B. Therefore, LTX-315, or the development of ATP11B-targeting drugs, might improve the efficacy of cancer immunotherapy.

Abstract VISTA (V-domain immunoglobulin suppressor of T cell activation) is a well-established immune regulatory receptor. However, pre-clinical investigations indicated more complicated influences of VISTA on cancer immunity than previously recognized. Here, we review the current knowledge on the therapeutic phenotypes and molecular mechanisms that underlie the contradictory roles of VISTA in checking anti-cancer immune responses. Furthermore, we highlight the potential indeterminacy of VISTA-targeted strategies in cancer immunotherapy, with in silico analyses. In fact, VISTA functions like a homeostatic regulator that actively normalizes immune responses. Thus, the regulatory role of VISTA in anti-cancer immunity remains to be fully elucidated.

Abstract Although immune checkpoint blockade is considered to be the dominant approach in future cancer immunotherapy, whether it will apply to pancreatic cancer remains largely unknown. To address this issue, pancreatic cancer–associated datasets were individually collected by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), cBioPortal, and Tumor and Immune System Interaction Database (TISIDB), and subsequently subjected to prognostic, genomic, and immunologic analyses of all well‐established immune checkpoints. The results indicate that immune checkpoints might not be ideal targets for pancreatic cancer therapy. Intriguingly, the genomic alteration of calreticulin, the key mediator of chemotherapy‐induced cancer immunogenic cell death, was found to couple with immune checkpoints in pancreatic cancer. Moreover, calreticulin was observed to be highly expressed in pancreatic adenocarcinoma, and high calreticulin expression significantly favors both overall survival and disease‐free survival of patients with pancreatic adenocarcinoma. Importantly, calreticulin was further revealed to be closely related to anti‐tumor immunity in pancreatic adenocarcinoma, including multiple immune effector molecules and T‐cell signatures. Taken together, calreticulin‐based therapy may represent a more promising prospect for pancreatic cancer immunotherapy than immune checkpoint blockade therapy.

Abstract Background The effect of cooking frequency on hypertension is understudied. This study aimed to examine the effect of cooking on hypertension with a particular focus on gender differences. Methods The present study utilized cross-sectional data from China Kadoorie Biobank with a 512,891-population of China. Hypertension was identified by established diagnosis or by the 1999 WHO/ISH Guidelines for the Management of Hypertension on examination. Cooking frequency was obtained from a self-reported questionnaire and categorized as daily cooking, weekly or monthly cooking and never cooking. Multivariable logistic regression models were employed to examine the associations between cooking frequency and hypertension in men and women, respectively. Stratified analyses by demographic and socio-economic characteristics were conducted. Results Men who ever cooked had higher odds of hypertension compared with those who never cooked (weekly or monthly cooking adjusted odds ratio (AOR): 1.05, 95% CI: 1.02–1.07; Daily cooking AOR: 1.09, 95% CI: 1.06–1.11), while protective effects of cooking against hypertension were observed in women (weekly or monthly cooking AOR: 0.94, 95% CI: 0.89–0.99; daily cooking AOR: 0.96, 95% CI: 0.92–0.99). Socio-economic status including occupation, household income, education and region could further modify the effect of daily cooking on hypertension among men and women, respectively. Conclusion The present study highlighted the effect of cooking on hypertension. We found the opposite trends in men and women with regards to the association between cooking and hypertension. Factors relating to socio-economic status such as education, household income and occupation could further modify the gender-specific effects. Interventions to reduce hypertension should consider the gender differences in food choice and psycho-social stress related to cooking.

Abstract Background Irregular menstruation is clinically associated with an increased risk for ovarian cancer and disease-related mortality. This relationship remains poorly understood, and a mechanism explaining it has yet to be described. Methods Ovarian tissues from women with polycystic ovary syndrome (PCOS) and regular menstruation (n = 10) or irregular menstruation (n = 10) were subjected to DNA methylation sequencing, real-time PCR array, whole-exome sequencing, and bioinformatics analysis. Results We demonstrated that ovarian tissue from PCOS patients with irregular menstruation displayed global DNA hypomethylation, as well as hypomethylation at several functionally and oncologically significant regions. Furthermore, we showed that several cancer-related genes were aberrantly expressed in ovarian tissue from patients with irregular menstruation, and that their mRNA and microRNA profiles shared appreciable levels of coincidence with those from ovarian cancer tissue. We identified multiple point mutations in both the BRCA1 and MLH1 genes in patients with irregular menstruation, and predicted the potential pathogenicity of these mutations using bioinformatics analyses. Conclusions Due to the nature of ovarian cancer, it is important to broaden our understanding of the pathogenesis and risk factors of the disease. Herein, we provide the first description of a genetic and epigenetic basis for the clinical relationship between irregular menstruation and an increased risk for ovarian cancer.

The efficacy of cancer immunotherapy depends on the fine interplay between tumoral immune checkpoints and host immune system. However, the up-to-date clinical performance of checkpoint blockers in cancer therapy revealed that higher-level regulation should be further investigated for better therapeutic outcomes. It is becoming increasingly evident that the expression of immune checkpoints is largely associated to the immunotherapeutic response and consequent prognosis. Deubiquitinating enzymes (DUBs) with their role of cleaving ubiquitin from proteins and other molecules, thus reversing ubiquitination-mediated protein degradation, modulate multiple cellular processes, including, but not limited to, transcriptional regulation, cell cycle progression, tissue development, and antiviral response. Accumulating evidence indicates that DUBs also have the critical influence on anticancer immunity, simply by stabilizing pivotal checkpoints or key regulators of T-cell functions. Therefore, this review summarizes the current knowledge about DUBs, highlights the secondary checkpoint-like role of DUBs in cancer immunity, in particular their direct effects on the stability control of pivotal checkpoints and key regulators of T-cell functions, and suggests the therapeutic potential of DUBs-based strategy in targeted immunotherapy for cancer.

Among hundreds of thousands of signal receptors contributing to oncogenic activation, tumorigenesis, and metastasis, the hepatocyte growth factor (HGF) receptor – also called tyrosine kinase MET – is a promising target in cancer therapy as its axis is involved in several different cancer types. It is also associated with poor outcomes and is involved in the development of therapeutic resistance. Several HGF/MET-neutralizing antibodies and MET kinase-specific small molecule inhibitors have been developed, resulting in some context-dependent progress in multiple cancer treatments. Nevertheless, the concomitant therapeutic resistance largely inhibits the translation of such targeted drug candidates into clinical application. Until now, numerous studies have been performed to understand the molecular, cellular, and upstream mechanisms that regulate HGF/MET-targeted drug resistance, further explore novel strategies to reduce the occurrence of resistance, and improve therapeutic efficacy after resistance. Intriguingly, emerging evidence has revealed that, in addition to its conventional function as an oncogene, the HGF/MET axis stands at the crossroads of tumor autophagy, immunity, and microenvironment. Based on current progress, this review summarizes the current challenges and simultaneously proposes future opportunities for HGF/MET targeting for therapeutic cancer interventions.

Objective To investigate the association between maternal education and breast feeding in the Chinese population, with a consideration of household income and health-seeking behaviours.Design A nationally representative population-based cross-sectional study.Setting 77 counties from 12 geographically distinct regions in China.Participants 10 408 mothers with children from 0 to 12 months of age, aged 15–53 years old (mean: 29.15, SD: 5.11) were classified into primary school or below group (n=781), middle school group (n=3842), high school/vocational school group (n=1990), college or above group (n=3795), according to their highest completed education.Outcomes Five breastfeeding outcomes, including early initiation of breast feeding (EIB), exclusive breast feeding (EBF) under 6 months, predominant breast feeding under 6 months, current breast feeding and children ever breast fed, were calculated based on the standardised questionnaire from the WHO and Wellstart International’s toolkit for monitoring and evaluating breastfeeding activities.Results The absolute risk of EIB and EBF in the lowest maternal education level was 64.85% and 26.53%, respectively, whereas the absolute risk of EIB and EBF in the highest maternal education level was 77.21% and 14.06%, respectively. A higher level of maternal education was positively associated with EIB (risk ratio (RR): 1.22; 95% CI: 1.12 to 1.30) and was inversely associated with EBF (RR: 0.59; 95% CI: 0.38 to 0.88). Stratified by household income, a positive association with EIB was observed only in the group with the highest household income and an inverse association with EBF was found in both low household and high household income groups.Conclusions Mothers with a higher education were more likely to initiate early breast feeding when they were also from a high-income household while also being less likely to exclusively breast feed their babies. Routine and successful nursing is crucial for the health of infants and is influenced by maternal education. Future public health interventions to promote breast feeding should consider the issues related to the educational level of mothers.

Objective: Hearing loss, one main risk factor of tinnitus and hyperacusis, is believed to involve significant central functional abnormalities. The recruitment of the auditory cortex in non-auditory sensory and higher-order cognitive processing has been demonstrated in the hearing-deprived brain. The dorsolateral prefrontal cortex (dlPFC), which has dense anatomical connections with the auditory pathway, is known to play a crucial role in multi-sensory integration, auditory regulation, and cognitive processing. This study aimed to verify the role of the dlPFC in the cross-modal reorganization and cognitive participation of the auditory cortex in long-term sensorineural hearing loss (SNHL) by combining functional and structural measurements.Methods: Thirty five patients with long-term bilateral SNHL and 35 matched healthy controls underwent structural imaging, resting-state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI), and neuropsychological assessments. Ten SNHL patients were with subjective tinnitus.Results: No differences in gray matter volume, spontaneous neural activity, or diffusion characteristics in the dlPFC were found between the SNHL and control groups. The functional connectivity (FC) between the dlPFC and the auditory cortex and visual areas, such as the cuneus, fusiform, lingual cortex, and calcarine sulcus was increased in patients with SNHL. ANOVA and post hoc tests revealed similar FC alterations in the SNHL patients with and without tinnitus when compared with the normal hearing controls, and SNHL patients with and without tinnitus showed no difference in the dlPFC FC. The FC in the auditory cortex was associated with the symbol digit modality test (SDMT) scores in the SNHL patients, which reflect attentional function, processing speed, and visual working memory. Hearing-related FC with the dlPFC was found in the lingual cortex. A tract-based spatial statistics (TBSS) analysis revealed decreased fractional anisotropy (FA) values, mainly in the temporal inferior fronto-occipital fasciculus (IFOF), which showed remarkable negative correlations with the mean hearing thresholds in SNHL.Conclusion: Higher functional coupling between the dlPFC and auditory and visual areas, accompanied by decreased FA along the IFOF connecting the frontal cortex and the occipito-temporal area, might mediate cross-modal plasticity via top-down regulation and facilitate the involvement of the auditory cortex in higher-order cognitive processing following long-term SNHL.

Objects: Sensorineural hearing loss (SNHL) involves wide-ranging functional reorganization, and is associated with accumulating risk of cognitive and emotional dysfunction. The coordination of multiple functional networks supports normal brain functions. Here, we aimed to evaluate the functional connectivity (FC) patterns involving multiple resting-state networks (RSNs), and the correlations between the functional remodeling of RSNs and the potential cognitive or emotional impairments in SNHL.Methods: Thirty long-term bilateral SNHL patients and 39 well-matched healthy controls were recruited for assessment of resting-state functional magnetic resonance imaging and neuropsychological tests.Results: Using independent component analysis, 11 RSNs were identified. Relative to the healthy controls, patients with SNHL presented apparent abnormalities of intra-network FC involving right frontoparietal network, posterior temporal network, and sensory motor network. Disrupted between-network FC was also revealed in the SNHL patients across both higher-order cognitive control networks and multiple sensory networks. Eight of the eleven RSNs showed altered functional synchronization using a seed network to whole brain FC method, particularly in the ventromedial prefrontal cortex. In addition, these functional abnormalities were correlated with cognition- and emotion-related performances.Interpretations: These findings supported our hypotheses that long-term SNHL involves notable dysconnectivity of multiple RSNs. Our study provides important insights into the pathophysiological mechanisms of SNHL, and sheds lights on the neural substrates underlying the possible cognitive and emotional dysfunctions following SNHL.

The rules governing cerebellar output are not fully understood, but must involve Purkinje cell (PC) activity, as PCs are the major input to deep cerebellar nuclear (DCN) cells (which form the majority of cerebellar output). Here, the influence of PC complex spikes (CSs) was investigated by simultaneously recording DCN activity with CSs from PC arrays in anesthetized rats. Crosscorrelograms were used to identify PCs that were presynaptic to recorded DCN cells (presynaptic PCs). Such PCs were located within rostrocaudal cortical strips and displayed synchronous CS activity. CS-associated modulation of DCN activity included a short-latency post-CS inhibition and long-latency excitations before and after the CS. The amplitudes of the post-CS responses correlated with the level of synchronization among presynaptic PCs. A temporal precision of ≤10 ms was generally required for CSs to be maximally effective. The results suggest that CS synchrony is a key control parameter of cerebellar output.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Cold atmospheric pressure plasma (CAP) and plasma-activated medium (PAM) induce cell death in diverse cancer cells and may function as powerful anti-cancer agents. The main components responsible for the selective anti-cancer effects of CAP and PAM remain elusive. CAP or PAM induces selective cell death in hepatocellular carcinoma cell lines Hep3B and Huh7 containing populations with cancer stem cell markers. Here, we investigated the major component(s) of CAP and PAM for mediating the selective anti-proliferative effect on Hep3B and Huh7 cells. The anti-proliferative effect of CAP was mediated through the medium; however, the reactive oxygen species scavenger N-acetyl cysteine did not suppress PAM-induced cell death. Neither high concentrations of nitrite or nitrite/nitrate nor a low concentration of H2O2 present in the PAM containing sodium pyruvate affected the viability of Hep3B and Huh7 cells. Inhibitors of singlet oxygen, superoxide anions, and nitric oxide retained the capacity of PAM to induce anti-cancer effects. The anti-cancer effect was largely blocked in the PAM prepared by placing an aluminum metal mesh, but not a dielectric PVC mesh, between the plasma source and the medium. Hence, singlet oxygen, hydrogen peroxide, nitric oxide, and nitrite/nitrate are not the main factors responsible for PAM-mediated selective death in Hep3B and Huh7 cells. Other factors, such as charged particles including various ions in CAP and PAM, may induce selective anti-cancer effects in certain cancer cells.

Hepatocellular carcinoma (HCC) is a major histological subtype of primary liver cancer. Ample evidence suggests that the pathological properties of HCC originate from hepatic cancer stem cells (CSCs), which are responsible for carcinogenesis, recurrence, and drug resistance. Cold atmospheric-pressure plasma (CAP) and plasma-activated medium (PAM) induce apoptosis in cancer cells and represent novel and powerful anti-cancer agents. This study aimed to determine the anti-cancer effect of CAP and PAM in HCC cell lines with CSC characteristics. We showed that the air-based CAP and PAM selectively induced cell death in Hep3B and Huh7 cells with CSC characteristics, but not in the normal liver cell line, MIHA. We observed both caspase-dependent and -independent cell death in the PAM-treated HCC cell lines. Moreover, we determined whether combinatorial PAM therapy with various anti-cancer agents have an additive effect on cell death in Huh7. We found that PAM highly increased the efficacy of the chemotherapeutic agent, cisplatin, while enhanced the anti-cancer effect of doxorubicin and the targeted-therapy drugs, trametinib and sorafenib to a lesser extent. These findings support the application of CAP and PAM as anti-cancer agents to induce selective cell death in cancers containing CSCs, suggesting that the combinatorial use of PAM and some specific anti-cancer agents is complemented mechanistically.

Cervical cancer outcomes remain poor among disadvantaged populations, including ethnic minorities, low-income, and underinsured women. The aim of this study was to evaluate the mechanisms that underlie the observed association between race/ethnicity and cervical cancer survival. We identified 13,698 women, ages 21 to 64 years, diagnosed with stages I-III primary cervical cancer between 2007-2013 in Surveillance, Epidemiology, and End Results (SEER). Multivariable Cox proportional hazards regression models evaluated associations between race/ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Other) and cervical cancer-specific mortality. We conducted mediation analysis to calculate the mediation proportion and its 95% confidence interval. Non-Hispanic black women had an increased risk of cervical cancer-specific mortality (HR: 1.23, 95% CI: 1.08-1.39), and Hispanic women a decreased risk of dying from their disease (HR: 0.82, 95% CI: 0.72-0.93), compared with non-Hispanic white. The estimated proportion of excess cervical cancer mortality for non-Hispanic black women relative to non-Hispanic white women that was mediated by insurance was 18.6% and by treatment was 47.2%. Furthermore, non-Hispanic black women were more likely to receive radiation and less likely to receive surgery for early-stage disease. In this population-based study we found that some of the excess cervical cancer-specific mortality for non-Hispanic black women is mediated by factors such as insurance status and treatment. These findings suggest that enhancing existing insurance coverage and ensuring equal and adequate treatment in all women may be a key strategy for improving cervical cancer outcomes.

Vehicle detection with orientation estimation in aerial images has received widespread interest as it is important for intelligent traffic management. This is a challenging task, not only because of the complex background and relatively small size of the target, but also the various orientations of vehicles in aerial images captured from the top view. The existing methods for oriented vehicle detection need several post-processing steps to generate final detection results with orientation, which are not efficient enough. Moreover, they can only get discrete orientation information for each target. In this paper, we present an end-to-end single convolutional neural network to generate arbitrarily-oriented detection results directly. Our approach, named Oriented_SSD (Single Shot MultiBox Detector, SSD), uses a set of default boxes with various scales on each feature map location to produce detection bounding boxes. Meanwhile, offsets are predicted for each default box to better match the object shape, which contain the angle parameter for oriented bounding boxes’ generation. Evaluation results on the public DLR Vehicle Aerial dataset and Vehicle Detection in Aerial Imagery (VEDAI) dataset demonstrate that our method can detect both the location and orientation of the vehicle with high accuracy and fast speed. For test images in the DLR Vehicle Aerial dataset with a size of 5616 × 3744 , our method achieves 76.1% average precision (AP) and 78.7% correct direction classification at 5.17 s on an NVIDIA GTX-1060.

Detecting vehicles in aerial imagery plays an important role in a wide range of applications. The current vehicle detection methods are mostly based on sliding-window search and handcrafted or shallow-learning-based features, having limited description capability and heavy computational costs. Recently, due to the powerful feature representations, region convolutional neural networks (CNN) based detection methods have achieved state-of-the-art performance in computer vision, especially Faster R-CNN. However, directly using it for vehicle detection in aerial images has many limitations: (1) region proposal network (RPN) in Faster R-CNN has poor performance for accurately locating small-sized vehicles, due to the relatively coarse feature maps; and (2) the classifier after RPN cannot distinguish vehicles and complex backgrounds well. In this study, an improved detection method based on Faster R-CNN is proposed in order to accomplish the two challenges mentioned above. Firstly, to improve the recall, we employ a hyper region proposal network (HRPN) to extract vehicle-like targets with a combination of hierarchical feature maps. Then, we replace the classifier after RPN by a cascade of boosted classifiers to verify the candidate regions, aiming at reducing false detection by negative example mining. We evaluate our method on the Munich vehicle dataset and the collected vehicle dataset, with improvements in accuracy and robustness compared to existing methods.

In the search for high-stiffness and damage-tolerant materials, Fe-based A3BX carbide and nitride antiperovskites were studied using first-principles calculations. These perovskites were found to be stable in cubic structures, as substantiated by the formation energy, elastic Born stability criterion, and phonon dispersion spectrum analysis. The GGA functional was applied for geometry optimization, and the lattice constants are found to be 3.730 Å, 3.715 Å, 3.832 Å, and 3.828 Å for Fe3AlC, Fe3AlN, Fe3SnC, and Fe3SnN, respectively. Elastic property analysis reveals that all the materials have large elastic moduli, high sound velocities, and high Debye temperatures. Among them, carbides have superior stiffness and quasi-ductile properties, and they can be further improved by applying additional pressure. Preliminary analysis of electronic properties indicates that they are ferromagnetic and metallic compounds. Their high melting temperatures (42600 K) confirm their potential in high-temperature applications. The lowest thermal conductivity of Fe3SnN suggests its potential in efficient solid-state refrigeration application. Moreover, Fe3SnC is proposed to be a viable damage-tolerant material with good prospects. Under 10 GPa external pressure, it possesses a ductile structure with a Young's modulus of 402.15 GPa and bulk modulus of 280.25 GPa. [ABSTRACT FROM AUTHOR]

Background: Undetectable occult liver metastases block the long-term survival of pancreatic ductal adenocarcinoma (PDAC). This study aimed to develop a radiomics-based model to predict occult liver metastases and assess its prognostic capacity for survival. Materials and methods: Patients who underwent surgical resection and were pathologically proven with PDAC were recruited retrospectively from five tertiary hospitals between January 2015 and December 2020. Radiomics features were extracted from tumors, and the radiomics-based model was developed in the training cohort using LASSO-logistic regression. The model's performance was assessed in the internal and external validation cohorts using the area under the receiver operating curve (AUC). Subsequently, the association of the model's risk stratification with progression-free survival (PFS) and overall survival (OS) was then statistically examined using Cox regression analysis and the log-rank test. Results: A total of 438 patients [mean (SD) age, 62.0 (10.0) years; 255 (58.2%) male] were divided into the training cohort (n=235), internal validation cohort (n =100), and external validation cohort (n =103). The radiomics-based model yielded an AUC of 0.73 (95% CI: 0.66-0.80), 0.72 (95% CI: 0.62-0.80), and 0.71 (95% CI: 0.61-0.80) in the training, internal validation, and external validation cohorts, respectively, which were higher than the preoperative clinical model. The model's risk stratification was an independent predictor of PFS (all P <0.05) and OS (all P <0.05). Furthermore, patients in the high-risk group stratified by the model consistently had a significantly shorter PFS and OS at each TNM stage (all P <0.05). Conclusion: The proposed radiomics-based model provided a promising tool to predict occult liver metastases and had a great significance in prognosis. [ABSTRACT FROM AUTHOR]

This study investigated the influence of different surface treatments on unfiring or firing zirconia-reinforced lithium silicate (ZLS) glass-ceramics. Celtra Duo and IPS e.max CAD blocks were cut and process following manufacturer protocols. The specimen surface was treated with seven different protocols. Two ceramic blocks with the same surface treatment were bonded with luting agent and prepared for mini-interfacial fracture toughness tests (mini-iFT). The specimens were tested after 1-week storage. The data was statistically analyzed using two-way ANOVA and Dunnett's T3 comparison (a=0.05). The highest mini-iFT of both Celtra Duo unfired and fired was shown in the HF+S group, which was not significantly different from HF+S+UA. For IPS e.max CAD, the mini-iFT was higher in the groups treated with hydrofluoric acid. Additional adhesive after silane application did not significantly improve bonding effectiveness. Therefore, surface treatment with hydrofluoric acid and silane is recommended for both unfiring and firing ZLS glass ceramics. [ABSTRACT FROM AUTHOR]