Pan-cancer analysis of heterogeneity of tumor mutational burden and genomic mutation under treatment pressure.

BACKGROUND: High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure. PATIENTS AND METHODS: We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts. RESULTS: This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors. CONCLUSION: Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.

[Development of a grading diagnostic model for schistosomiasis-induced liver fibrosis based on radiomics and clinical laboratory indicators].

OBJECTIVE: To investigate the feasibility of developing a grading diagnostic model for schistosomiasis-induced liver fibrosis based on B-mode ultrasonographic images and clinical laboratory indicators. METHODS: Ultrasound images and clinical laboratory testing data were captured from schistosomiasis patients admitted to the Second People's Hospital of Duchang County, Jiangxi Province from 2018 to 2022. Patients with grade I schistosomiasis-induced liver fibrosis were enrolled in Group 1, and patients with grade II and III schistosomiasis-induced liver fibrosis were enrolled in Group 2. The machine learning binary classification tasks were created based on patients'radiomics and clinical laboratory data from 2018 to 2021 as the training set, and patients'radiomics and clinical laboratory data in 2022 as the validation set. The features of ultrasonographic images were labeled with the ITK-SNAP software, and the features of ultrasonographic images were extracted using the Python 3.7 package and PyRadiomics toolkit. The difference in the features of ultrasonographic images was compared between groups with t test or Mann-Whitney U test, and the key imaging features were selected with the least absolute shrinkage and selection operator (LASSO) regression algorithm. Four machine learning models were created using the Scikit-learn repository, including the support vector machine (SVM), random forest (RF), linear regression (LR) and extreme gradient boosting (XGBoost). The optimal machine learning model was screened with the receiver operating characteristic curve (ROC), and features with the greatest contributions to the differentiation features of ultrasound images in machine learning models with the SHapley Additive exPlanations (SHAP) method. RESULTS: The ultrasonographic imaging data and clinical laboratory testing data from 491 schistosomiasis patients from 2019 to 2022 were included in the study, and a total of 851 radiomics features and 54 clinical laboratory indicators were captured. Following statistical tests (t = -5.98 to 4.80, U = 6 550 to 20 994, all P values < 0.05) and screening of key features with LASSO regression, 44 features or indicators were included for the subsequent modeling. The areas under ROC curve (AUCs) were 0.763 and 0.611 for the training and validation sets of the SVM model based on clinical laboratory indicators, 0.951 and 0.892 for the training and validation sets of the SVM model based on radiomics, and 0.960 and 0.913 for the training and validation sets of the multimodal SVM model. The 10 greatest contributing features or indicators in machine learning models included 2 clinical laboratory indicators and 8 radiomics features. CONCLUSIONS: The multimodal machine learning models created based on ultrasound-based radiomics and clinical laboratory indicators are feasible for intelligent identification of schistosomiasis-induced liver fibrosis, and are effective to improve the classification effect of one-class data models.

[Aqueous extract of Chuan Xiong Rhizoma enhances inhibitory effect of temozolomide against brain metastasis of melanoma in mice].

OBJECTIVE: To investigate the effect of the aqueous extract of Chuan Xiong Rhizoma (CR) on brain metastasis of melanoma B16F10 cells in mice. METHODS: C57BL/6J mouse models of brain metastasis of melanoma were established by ultrasound-guided intraventricular injection of Luc-labeled B16F10 cells, and brain tumor growth was monitored by in vivo imaging. The mouse models were then randomized for daily gavage of saline or aqueous extract of CR (equivalent crude drug concentration of 1 mg/g). Behavioral tests were used to evaluate the neuroprotective effects of CR in the tumor-bearing mice, and the changes in proteins associated with blood-brain barrier integrity, neuronal cell proliferation and apoptosis, and microglial cell apoptosis and activation were observed using immunofluorescence assay. The efficacy of CR combined with temozolomide (25 mg/kg) against brain metastases of B16F10 cells was observed by in vivo imaging. RESULTS: CR-treated mouse models did not show obvious progression of brain metastases and had a reduced rate of body weight loss and lowered protein expressions of ZO-1, claudin-5, occludin, P-gp, TNF-α, AQP4 and PDGFRß. In the behavioral tests, the CR-treated mice showed prolonged stay on the wooden stick with a shortened time of sticky stick removal. Immunofluorescence assay showed increased proliferation and decreased apoptosis of neuronal cells and microglia in CR-treated mice. CR treatment significantly increased the levels of CD86, CD206, IL-4 and IL-10 and decreased the levels of CD163 and IL-1ß in the microenvironment of brain metastases. The mice receiving combined treatments with CR and temozolomide showed significantly lower intensity of fluorescent signals in the brain than those treated with temozolomide alone. CONCLUSION: CR does not promote brain metastasis of melanoma while inducing opening of the blood-brain barrier, and its combined use with TMZ results in enhanced inhibition against brain metastasis of melanoma B16F10 cells in mice.

"Keep trying": a qualitative investigation into what patients with chronic pain gain from Project ECHO.

Objective: The study aims to investigate the patient perspective on the pathway from healthcare practitioners' presentations of their cases at a Project ECHO (Extension for Community Healthcare Outcomes) tele-clinic to the management of those patients' chronic pain. Introduction: Managing patients with chronic and complex pain constitutes a prevalent, stressful challenge in the primary care setting. Primary care physicians typically have received little training in treating such patients and, until recently, have relied heavily on opioid and other pharmaceutical therapies as part of their regimen. Project ECHO Ontario Chronic Pain and Opioid Stewardship is an interprofessional telementoring program connecting pain specialists to primary care practitioners with the aim of supporting them in managing their patients with chronic pain, although the patients concerned do not generally participate in the telementoring sessions. While a number of papers have described the benefits accruing to healthcare professionals through participating in Project ECHO, there has been little exploration concerning patients' perceptions of their care subsequent to case presentation. Methods: Using data from in-depth interviews with 20 patients along with their associated case presentation forms and the recommendations following the presentation, we look at the alignment of patient and practitioner views and inquire about the patient's perceptions of how Project ECHO affects them. Results: Results suggest that the impact on patients is indirect but positive: most respondents express pleasure in contributing to research around chronic pain management, though only two of them identified a direct impact on their own treatment. They also appreciated their practitioner's efforts to bring expert attention to the patient's situation. Conclusions: Patients whose cases are presented to Project ECHO sessions experience positive emotions at being part of the process of research and quality improvement, regardless of changes in their own conditions. This study highlights the importance to patients of their practitioners' commitment to managing their chronic pain.

Fabrication and evaluation of porous coatings doped with bioactive elements on titanium surfaces.

OBJECTIVE: Although pure titanium (PT) and its alloys exhibit excellent mechanical properties, they lack biological activity as implants. The purpose of this study was to improve the biological activity of titanium implants through surface modification. MATERIALS AND METHODS: Titanium was processed into titanium discs, where the titanium discs served as anodes and stainless steel served as cathodes, and a copper- and cobalt-doped porous coating [pure titanium model (PTM)] was prepared on the surface of titanium via plasma electrolytic oxidation. The surface characteristics of the coating were evaluated using field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and profilometry. The corrosion resistance of PTM was evaluated with an electrochemical workstation. The biocompatibility and bioactivity of coated bone marrow mesenchymal stem cells (BMSCs) were evaluated through in vitro cell experiments. RESULTS: A copper- and cobalt-doped porous coating was successfully prepared on the surface of titanium, and the doping of copper and cobalt did not change the surface topography of the coating. The porous coating increased the surface roughness of titanium and improved its resistance to corrosion. In addition, the porous coating doped with copper and cobalt promoted the adhesion and spreading of BMSCs. CONCLUSIONS: A porous coating doped with copper and cobalt was prepared on the surface of titanium through plasma electrolytic oxidation. The coating not only improved the roughness and corrosion resistance of titanium but also exhibited good biological activity.

[Association between long-term exposure to ambient ozone and sperm quality in Shandong Province].

Objective: To evaluate the association between long-term exposure to ambient ozone (O3) and sperm quality. Methods: From January 1, 2014, to December 31, 2019, healthy sperm donors were recruited through the Human Sperm Bank of Shandong University Affiliated Reproductive Hospital. A total of 37 977 sperm donation data from 2 971 healthy volunteers were analyzed. The average annual O3 concentration (0.01°× 0.01°) was matched according to household address. A multivariate mixed-effect model was used to analyze the exposure-response relationship between the average O3 exposure concentration and sperm quality in the previous year, with each donor as a random intercept. All results were presented as % changes with 95% confidence intervals (CIs) for all sperm parameters associated with 10 µg/m3 increases in O3. The effects of individual characteristics on the association between O3 and sperm quality were evaluated by stratified analysis. Results: The average O3 concentration in the year before semen collection was (107.09±7.50) µg/m3. Each 10 µg/m3 increase in O3 was associated with declined sperm concentration (-3.12%, 95%CI:-4.55%, -1.67%), total sperm count (-5.21%, 95%CI:-7.28%, -3.09%), total sperm motility (-1.49%, 95%CI:-2.37%, -0.61%), progressive motility (-2.53%, 95%CI:-3.78%, -1.26%), total motile sperm count (-5.82%, 95%CI:-8.17%, -3.41%), and progressively motile sperm count (-6.22%, 95%CI:-8.73%, -3.64%). Men aged 30 and above, obese, and with lower education levels might be more susceptible to the influence of O3 on sperm quality, but the difference was not statistically significant (P>0.05). Conclusion: Long-term exposure to O3 in Shandong Province is associated with a decrease in sperm quality.

The association between histopathologic effects and liver weight changes induced in mice and rats by chemical exposures: An analysis of the data from Toxicity Reference Database (ToxRefDB).

Absolute (ALW) and relative (RLW) liver weight changes are sensitive endpoints in repeat-dose rodent toxicity studies, and their changes are often used for quantitative assessment of health effects induced by hepatotoxic chemicals using the benchmark dose-response modeling (BMD) approach. To find biologically relevant liver weight changes to chemical exposures, we evaluated all data available for liver weight changes and associated liver histopathologic findings from the Toxicity Reference Database (ToxRefDB). Our analysis of 389 subchronic mouse and rat studies for 273 chemicals found significant differences in treatment-related ALW and RLW changes between dose groups with and without liver histopathologic changes. In addition, we demonstrate that chemical treatment-induced ALW and RLW changes can predict the presence of histopathologic findings and inform the selection of biologically relevant liver weight changes for BMD modeling and derivation of toxicity values.

[Liver cancer treatment with mitochondrial homeostasis].

Systemic treatment, including molecular targeted therapy, immunotherapy, and chemotherapy, is an important means of achieving long-term survival in patients with intermediate-and advanced-stage liver cancer. However, some patients are insensitive to treatment and even develop drug resistance. Mitochondria are the center of cellular energy metabolism and, at the same time, are the priority targets for systemic therapy. Mitochondrial homeostasis plays an important role in the treatment of liver cancer. The relationship between the two advances is elucidated so as to provide better ideas for the clinical treatment of liver cancer.

Circular RNA ath-circ032768, a competing endogenous RNA, response the drought stress by targeting miR472-RPS5 module.

CircRNAs (circular RNAs) reduce the abundance of miRNAs through ceRNA (competing endogenous RNA), to regulate many physiological processes and stress responses in plants. However, the role of circRNA in drought stress is poorly understood. Through ring identification and sequencing verification of ath-circ032768, bioinformatics analysis predicted the interaction of ath-circ032768-miR472-RPS5, and further obtained transgenic plants overexpressing ath-circ032768 and silencing STTM-miR472. The change in drought stress was analysed using biochemical and molecular biological methods. Sequencing and biological analysis confirmed that ath-circ032768, miR472 and RPS5 were responsive to drought stress, and changes in gene expression were consistent with the prediction of ceRNA. The silencing vectors ath-circ032768 and STTM-miR472 were constructed using molecular biology techniques, and stable transgenic plants with drought tolerance obtained. Further physiological and biochemical studies showed that ath-circ032768 could bind to miR472, and that miR472 could bind to the RPS5 gene, resulting in decreased expression of RPS5. Hence, ath-circ032768 can competitively inhibit degradation of RPS5 by miR472 through ceRNA. This process is accompanied by increased expression of DREB2A, RD29A and RD29B genes. Through the ath-circ032768-miR472-RPS5 pathway, the RPS5 stress resistance protein interacts with DREB2A protein to enhance expression of downstream drought resistance genes, RD29A and RD29B, and participate in the regulation mechanism of plant drought resistance, thereby improving drought tolerance of plants.

[Progress in application of aspirin desensitization and maintenance therapy in aspirin-exacerbated respiratory disease].

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyps, asthma and the development of significant airway symptoms following the ingestion of aspirin and other nonsteroid anti-inflammatory drugs (NSAIDs). At present, aspirin challenge is the gold standard for diagnosis. Aspirin desensitization and aspirin therapy after desensitization (ATAD) is one of the classical therapies. This paper described the application of aspirin desensitization and ATAD in AERD and provided the reference for the comprehensive treatment of AERD.

[Multi-omics combined test performance effectiveness on opportunistic screening of high-risk liver cancer population].

Objective: To validate the performance of a multi-omics combined test for early screening of high-risk liver cancer populations. Methods: 173 high-risk patients with liver cancer were prospectively screened in a real-world setting, and 164 cases were finally enrolled. B-ultrasound, alpha-fetoprotein (AFP), and HCC screens were conducted in all patients. A multi-omics early screening test was performed for liver cancer in combination with multi-gene methylation, TP53/TERT/CTNNB1 mutations, AFP, and abnormal prothrombin (PIVKA-II). Differences in rates were compared using the chi-square test, adjusted chi-square test, or Fisher's exact probability method for count data. A non-parametric rank test (Mann-Whitney) was used to compare the differences between the two groups of data. Results: The HCCscreen detection had a sensitivity of 100% for liver cancer screening, 93.8% for liver cancer and precancerous diseases, 34.1% for positive predictive value, 99.2% for negative predictive value, and 0.89 for an area under the curve (AUC). Parallel detection of AFP, AFP+B-ultrasound, and methylation+mutation had a sensitivity/specificity and AUC of 31.3%/88.5% (AUC=0.78), 56.3%/88.2% (AUC=0.86), and 81.3%/82.4 % (AUC=0.84). At the same time, the disease severity range was significantly correlated with the methylation+mutation score, HCCscreen score, or positive detection rate (PDR). There was no significant correlation between AFP serum levels and methylation+mutation or HCCscreen scores, while there was a significant linear correlation between methylation+mutation scores and HCCscreen scores (r = 0.73, P < 0.001). Conclusion: In real-world settings, HCCscreen shows high sensitivity for screening opportunistic, high-risk liver cancer populations. Furthermore, it may efficaciously detect liver cancer and precancerous diseases, with superior performance to AFP and AFP+ultrasound. Hence, HCCscreen has the potential to become an effective screening tool that is superior to existing screening methods for high-risk liver cancer populations.

[Disease burden of colorectal cancer attributable to dietary risk factors from 1990 to 2019 in China].

Objective: To analyze the trend of mortality rate and disability-adjusted life year (DALY) of colorectal cancer attributable to dietary risk factors from 1990 to 2019 in China. Methods: Mortality rate and DALY rate of colorectal cancer attributable to dietary risk factors (diet high in processed meat, diet high in red meat, diet low in calcium, diet in low in fiber, diet low in milk, diet low in whole grains, dietary risks) were collected from the Global Burden of Disease study 2019 (GBD2019). Joinpoint regression model was selected to analyze the trend and an age-period-cohort model was used to estimate the effects of age, period and birth cohort. Results: Joinpoint regression analysis showed that the age-standardized mortality rate and age-standardized DALY rate of colorectal cancer attributable to diet high in processed meat, diet high in red meat, diet low in milk, diet low in whole grains and dietary risks showed an upward trend (P<0.05) from 1990 to 2019, while those attributable to diet low in calcium and diet low in fiber showed a downward trend (P<0.05). The mortality rate and DALY rate of colorectal cancer attributable to diet high in processed meat, diet high in red meat, diet low in milk, diet low in whole grains and dietary risks in age groups from 65 to 79 years showed a quicker upward trend than those in age groups from 25 to 64 years. The mortality rate and DALY rate attributable to diet low in calcium and diet low in fiber in age groups from 65 to 79 years showed a slower downward trend than those in age groups from 25 to 64 years. The mortality rate and DALY rate of colorectal cancer attributable to diet high in processed meat, diet high in red meat, diet low in calcium, diet low in fiber, diet low in milk, diet low in whole grains, and dietary risks increased with age after adjusting for period effect and cohort effect (P<0.05). The mortality rate and DALY rate attributable to diet high in processed meat, diet high in red meat, diet low in calcium, diet low in milk, diet low in whole grains and dietary risks increased with period or cohort, while those attributable to diet low in fiber decreased with period or cohort. Period and cohort effect of dietary risk factors in this study were statistically significant (P<0.001). Conclusions: Disease burden of colorectal cancer attributable to dietary risk factors in China showed an upward trend in general. Elderly population is high at risk and more attention should be paid to science popularization and education on dietary risk factors in prevention and treatment of colorectal cancer.

[Study of the effects of dietary patterns on glycemic control in community type 2 diabetic mellitus patients].

Objective: To understand the impact of diet on glycemic control in community-managed patients with type 2 diabetes mellitus (T2DM) and provide evidence for implementing prevention strategies and measures for diabetes patients. Methods: Eight communities were randomly selected from Changshu and Wuhan in 2015, and T2DM patients managed in the community were selected to conduct questionnaire surveys, physical measurements, and blood glucose testing. Factor analysis was used to obtain dietary patterns. A binary logistic regression model was used to analyze the factors affecting glycemic control. Results: Finally, 1 818 T2DM patients were included, and the control rate of FPG was 57.59% (95%CI: 55.30%-59.86%), and the control rate of 2 h postprandial blood glucose (2 h PBG) was 24.90% (95%CI: 22.93%- 26.91%). Five dietary patterns were obtained by factor analysis: animal food pattern, fruit-aquatic products-potato patterns, vegetable-grain pattern, egg-milk-bean pattern, and oil-salt patterns. No-conditional multivariate logistic regression analysis showed that after adjusting for confounding factors, the reduced probability of FPG control was related to animal food pattern (OR=0.71, 95%CI: 0.52-0.98) and fruit-aquatic products-potato patterns (OR=0.71, 95%CI: 0.51-0.97). The decrease in the 2 h PBG control probability was related to fruit-aquatic products-potato patterns (OR=0.60, 95%CI: 0.40-0.90). The increased probability of FPG and 2 h postprandial glucose control were both related to vegetable-grain pattern (OR=1.41, 95%CI: 1.03-1.94; OR=1.68, 95%CI: 1.13-2.51) and egg-milk-bean pattern (OR=1.75, 95%CI: 1.25-2.46; OR=1.56, 95%CI: 1.00-2.42). Compared with the Q4 group of egg-milk-bean pattern, the FPG control rate of the combination of "fruit-aquatic products-potato pattern (Q4 group), vegetable-grain pattern (Q2 group), egg-milk-bean pattern (Q3 group)" was higher (OR=6.79, 95%CI: 1.15-40.23, P=0.035). Compared with the Q4 group of vegetable-grain pattern, the combination of "fruit-aquatic products-potato pattern (Q4 group), vegetable-grain pattern (Q3 group), egg-milk-bean pattern (Q2 group), oil-salt pattern (Q2 group)" had higher control rate of 2 h PBG (OR=12.78, 95%CI: 1.26-130.05, P=0.031). Conclusions: A proper combination of dietary patterns and dietary patterns are more conducive to the control of FPG and 2 h PBG in T2DM patients managed in the communities of Wuhan and Changshu. Patient nutrition education should be strengthened, and the food-matching ability of patients should be improved.

Efficacy of preventive interventions against ventilator-associated pneumonia in critically ill patients: an umbrella review of meta-analyses.

Many meta-analyses have assessed the efficacy of preventive interventions against ventilator-associated pneumonia (VAP) in critically ill patients. However, there has been no comprehensive analysis of the strength and quality of evidence to date. Systematic reviews of randomized and quasi-randomized controlled trials, which evaluated the effect of preventive strategies on the incidence of VAP in critically ill patients receiving mechanical ventilation for at least 48 h, were included in this article. We identified a total of 34 interventions derived from 31 studies. Among these interventions, 19 resulted in a significantly reduced incidence of VAP. Among numerous strategies, only selective decontamination of the digestive tract (SDD) was supported by highly suggestive (Class II) evidence (risk ratio (RR)=0.439, 95% CI: 0.362-0.532). Based on data from the sensitivity analysis, the evidence for the efficacy of non-invasive ventilation in weaning from mechanical ventilation (NIV) was upgraded from weak (Class IV) to highly suggestive (Class II) (RR=0.32, 95% CI: 0.22-0.46). All preventive interventions were not supported by robust evidence for reducing mortality. Early mobilization exhibited suggestive (Class III) evidence in shortening both intensive length of stay (LOS) in the intensive care unit (ICU) (mean difference (MD)=-0.85, 95% CI: -1.21 to -0.49) and duration of mechanical ventilation (MD=-1.02, 95% CI: -1.41 to -0.63). In conclusion, SDD and NIV are supported by robust evidence for prevention against VAP, while early mobilization has been shown to significantly shorten the LOS in the ICU and the duration of mechanical ventilation. These three strategies are recommendable for inclusion in the ventilator bundle to lower the risk of VAP and improve the prognosis of critically ill patients.

Neutron-gamma discrimination with broaden the lower limit of energy threshold using BP neural network.

Neutron-gamma discrimination is a tough and significative in experimental neutrons measurements procedure, especially for low-energy neutrons signal discrimination. In this work, based on the Pulse Shape Discrimination (PSD) and Back-Propagation (BP) artificial neural networks, a neutron-gamma discrimination method is developed to broaden the lower limit of energy threshold with the hidden layer of 20 neurons. Compared with neutron-gamma discrimination method based on PSD only, the developed neutron-gamma discrimination method based on the PSD and BP-ANN can discriminate neutron and gamma-ray signals with low energy threshold, which can discriminate signals up to 99.93%. Moreover, this work can reduce the energy threshold from 350 keV to 70 keV, as well as the acquired data utilization increased from 60% to more than 99.9%, which overcome the hardware limitations and distinguish neutron and gamma-ray signals, effectively. The developed neutron-gamma discrimination method and the trained neural network can be directly used to other experimental neutrons measurements.

Association of serum lipids and abnormal lipid score with cancer risk: a population-based prospective study.

BACKGROUND: Serum lipid levels are associated with cancer risk. However, there still have uncertainties about the single and combined effects of low lipid levels on cancer risk. METHODS: A prospective cohort study of 33,773 adults in Shanghai between 2016 and 2017 was conducted. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured. Cox proportional hazard models were used to assess the association of single and combined lipids with overall, lung, colon, rectal, thyroid gland, stomach, and female breast cancers. The effect of the combination of abnormal lipid score and lifestyle on cancer was also estimated. RESULTS: A total of 926 incident cancer cases were identified. In the RCS analysis, hazard ratios (HRs) of overall cancer for individuals with TC < 5.18 mmol/L or with LDL-C < 3.40 mmol/L were higher. Low TC was associated with higher colorectal cancer risk (HR [95% CI] = 1.76 [1.09-2.84]) and low HDL-C increased thyroid cancer risk by 90%. Abnormal lipid score was linearly and positively associated with cancer risk, and smokers with high abnormal lipid scores had a higher cancer risk, compared to non-smokers with low abnormal lipid scores (P < 0.05). CONCLUSIONS: Low TC levels were associated with an increased risk of overall and colorectal cancer. More attention should be paid to participants with high abnormal lipid scores and unhealthy lifestyles who may have a higher risk of developing cancer. Determining the specific and comprehensive lipid combinations that affect tumorigenesis remains a valuable challenge.

Efficacy and Safety of First-line Therapies for Advanced Unresectable Oesophageal Squamous Cell Cancer: a Systematic Review and Network Meta-analysis.

AIM: To compare the clinical efficacy and safety of first-line treatments for advanced unresectable oesophageal squamous cell cancer. MATERIALS AND METHODS: A systematic review and network meta-analysis was carried out by retrieving and retaining relevant literature from databases. The studies were randomised controlled trials comparing first-line treatments for advanced unresectable oesophageal squamous cell cancer. A Bayesian network meta-analysis was used to assess clinical outcomes. RESULTS: Nine studies including 4499 patients receiving first-line treatments were analysed. For all populations, toripalimab plus chemotherapy tended to provide the best overall survival (hazard ratio 0.58, 95% confidence intervals 0.43-0.78) and sintilimab plus chemotherapy provided the best progression-free survival (0.56, 0.46-0.68). Nivolumab plus chemotherapy presented the best objective response rate (odds ratio 2.45, 1.78-3.42) and camrelizumab plus chemotherapy (0.47, 0.29-0.74) appeared to be the safest. Sintilimab plus chemotherapy (0.55, 0.40-0.75) and nivolumab (0.54, 0.37-0.80) plus chemotherapy had the best overall survival in programmed death ligand 1 (PD-L1) tumour proportion score <1% and ≥1% subgroups. Toripalimab plus chemotherapy (0.61, 0.40-0.93) and pembrolizumab (0.57, 0.43-0.75) were the best in overall survival in combined positive score <10 and ≥10 subgroups, respectively. Toripalimab plus chemotherapy showed the best overall survival in the Asian group; pembrolizumab presented better overall survival in the Asian population than the non-Asian group. CONCLUSION: Most immunotherapy combined with chemotherapy showed superior clinical benefits and sintilimab plus chemotherapy, toripalimab plus chemotherapy and tislelizumab plus chemotherapy had better comprehensive clinical efficacy. PD-L1 expression detection and ethnicity differences are still of great significance and most suitable regimens varied from each subgroup.

Chronically high stress hormone levels dysregulate sperm long noncoding RNAs and their embryonic microinjection alters development and affective behaviours.

Previous studies on paternal epigenetic inheritance have shown that sperm RNAs play a role in this type of inheritance. The microinjection of sperm small noncoding RNAs into fertilised mouse oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. While sperm long noncoding RNAs (lncRNAs) have also been investigated in a previous study, their microinjection into fertilised oocytes did not yield conclusive results regarding their role in modulating brain development and adult behavioural phenotypes. Therefore, in the current study we sought to investigate this further. We used our previously established paternal corticosterone (stress hormone) model to assess sperm lncRNA expression using CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable element transcripts. Although they have limited functional annotation, bioinformatic approaches indicated the potential of these lncRNAs in regulating brain development and function. We then separated and isolated the sperm lncRNAs and performed microinjections into fertilised oocytes, to generate embryos with modulated lncRNA populations. We observed that the resulting adult offspring had lower body weight and altered anxiety and affective behavioural responses, demonstrating roles for lncRNAs in modulating development and brain function. This study provides novel insights into the roles of lncRNAs in epigenetic inheritance, including impacts on brain development and behaviours of relevance to affective disorders.