Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy?

Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)). Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens.

Effectiveness of nurse-home visiting in improving child and maternal outcomes prenatally to age two years: a randomised controlled trial (British Columbia Healthy Connections Project).

BACKGROUND: We investigated the effectiveness of Nurse-Family Partnership (NFP), a prenatal-to-age-two-years home-visiting programme, in British Columbia (BC), Canada. METHODS: For this randomised controlled trial, we recruited participants from 26 public health settings who were: <25 years, nulliparous, <28 weeks gestation and experiencing socioeconomic disadvantage. We randomly allocated participants (one-to-one; computer-generated) to intervention (NFP plus existing services) or comparison (existing services) groups. Prespecified outcomes were prenatal substance exposure (reported previously); child injuries (primary), language, cognition and mental health (problem behaviour) by age two years; and subsequent pregnancies by 24 months postpartum. Research interviewers were masked. We used intention-to-treat analyses. (ClinicalTrials.gov, NCT01672060.) RESULTS: From 2013 to 2016 we enrolled 739 participants (368 NFP, 371 comparison) who had 737 children. Counts for child injury healthcare encounters [rate per 1,000 person-years or RPY] were similar for NFP (223 [RPY 316.17]) and comparison (223 [RPY 305.43]; rate difference 10.74, 95% CI -46.96, 68.44; rate ratio 1.03, 95% CI 0.78, 1.38). Maternal-reported language scores (mean, M [SD]) were statistically significantly higher for NFP (313.46 [195.96]) than comparison (282.77 [188.15]; mean difference [MD] 31.33, 95% CI 0.96, 61.71). Maternal-reported problem-behaviour scores (M [SD]) were statistically significantly lower for NFP (52.18 [9.19]) than comparison (54.42 [9.02]; MD -2.19, 95% CI -3.62, -0.75). Subsequent pregnancy counts were similar (NFP 115 [RPY 230.69] and comparison 117 [RPY 227.29]; rate difference 3.40, 95% CI -55.54, 62.34; hazard ratio 1.01, 95% CI 0.79, 1.29). We observed no unanticipated adverse events. CONCLUSIONS: NFP did not reduce child injuries or subsequent maternal pregnancies but did improve maternal-reported child language and mental health (problem behaviour) at age two years. Follow-up of long-term outcomes is warranted given that further benefits may emerge across childhood and adolescence.

Ten-year risk of cerebrovascular accidents in incident rheumatoid arthritis: a population-based study of trends over time.

OBJECTIVE: To evaluate secular trends in 10-year risk of incident cerebrovascular accidents (CVA), in incident RA relative to the general population. METHODS: We conducted a retrospective study of a population-based incident cohort with RA onset from 1997 to 2004 in British Columbia, Canada, with matched general population controls (2:1), using administrative health data. RA and general population cohorts were divided according to year of RA onset, defined according to the first RA visit of the case definition. Incident CVA was defined as the first CVA occurring within 10 years from the first RA visit. Secular trend was assessed using delayed-entry Cox models with a two-way interaction term between the year of RA onset and indicator of RA vs general population. Linear, quadratic and spline functions of year of RA onset were compared with assess non-linear effects. The model with the lowest Akaike Information Criterion was selected. RESULTS: Overall, 23 545 RA and 47 090 general population experienced 658 and 1220 incident CVAs, respectively. A spline Cox model with a knot at year of onset 1999 was selected. A significant decline in risk of CVA was observed in individuals with RA onset after 1999 [0.90 (0.86, 0.95); P = 0.0001]. The change in CVA risk over time differed significantly in RA with onset from 1999 onwards compared with the general population (P-value of interaction term = 0.03), but not before 1999 (P = 0.06). CONCLUSION: Our findings suggest that people with RA onset from 1999 onwards, had a significantly greater decline in 10-year risk of CVA compared with the general population.

The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study.

OBJECTIVES: To estimate the overall risk of venous thromboembolism (VTE), pulmonary embolism (PE) and deep vein thrombosis (DVT) among patients newly diagnosed with RA compared with the general population without RA; and to estimate the risk trends of VTE, PE and DVT after RA diagnosis up to 5 years compared with the general population. METHODS: Using previously validated RA case definition, we conducted a matched cohort study using the population-based administrative health database from the province of British Columbia, Canada. We calculated incidence rates (IRs) and fully adjusted hazard ratios (HRs) for the risk of VTE, DVT and PE after RA index date. RESULTS: Among 39 142 incident RA patients (66% female, mean age 60), 1432, 543 and 1068 developed VTE, PE and DVT, respectively. IRs for the RA cohort were 3.79, 1.43 and 2.82 per 1000 person-years vs 2.70, 1.03 and 1.94 per 1000 person-years for the non-RA cohort. After adjusting for VTE risk factors, the HRs (95% CI) were 1.28 (1.20, 1.36), 1.25 (1.13, 1.39) and 1.30 (1.21, 1.40) for VTE, PE and DVT, respectively. The fully adjusted HRs for VTE during the first five years after RA diagnosis were 1.60, 1.47, 1.40, 1.30 and 1.28, respectively. A similar trend was shown in PE. CONCLUSION: This population-based study demonstrates that RA patients have an increased risk of VTE, PE and DVT after diagnosis compared with the general population. This risk is independent of traditional VTE risk factors and is highest during the first year after RA diagnosis, then progressively declined.

Chinese Propolis Suppressed Pancreatic Cancer Panc-1 Cells Proliferation and Migration via Hippo-YAP Pathway.

Pancreatic cancer is one of the most malignant cancers with high mortality. Therefore, it is of great urgency to develop new agents that could improve the prognosis of Pancreatic cancer patients. Chinese propolis (CP), a flavonoid-rich beehive product, has been reported to have an anticancer effect. In this study, we applied CP to the human Pancreatic cancer cell line Panc-1 to verify its impact on tumor development. CP induced apoptosis in Panc-1 cells from 12.5 µg/mL in a time- and dose-dependent manner with an IC50 value of approximately 50 µg/mL. Apoptosis rate induced by CP was examined by Annexing FITC/PI assay. We found that 48 h treatment with 50 µg/mL CP resulted in 34.25 ± 3.81% apoptotic cells, as compared to 9.13 ± 1.76% in the control group. We further discovered that the Panc-1 cells tended to be arrested at G2/M phase after CP treatment, which is considered to contribute to the anti-proliferation effect of CP. Furthermore, our results demonstrated that CP suppressed Panc-1 cell migration by regulating epithelial-mesenchymal transition (EMT). Interestingly, the Hippo pathway was activated in Panc-1 cells after CP treatment, serving as a mechanism for the anti-pancreatic cancer effect of CP. These findings provide a possibility of beehive products as an alternative treatment for pancreatic cancer.

Heart disease and the risk of allopurinol-associated severe cutaneous adverse reactions: a general population-based cohort study.

BACKGROUND: Allopurinol is commonly prescribed for gout, and its clinical use may expand with ongoing trials assessing its potential cardiorenal benefits. Because heart disease has been suggested to be a risk factor for allopurinol-associated severe cutaneous adverse reactions, we sought to confirm this association in a Canadian general population cohort. METHODS: We used population data from British Columbia, Canada, to identify all incident allopurinol users between 1997 and 2015. We examined the association between heart disease (ischemic heart disease and heart failure) and the risk of hospital admission for severe cutaneous adverse reactions, adjusting for known and purported risk factors. We also evaluated the joint effects of combined clinical and demographic risk factors. RESULTS: Among 130 325 allopurinol initiators, 109 hospital admissions occurred for allopurinol-associated severe cutaneous adverse reactions. The multivariable relative risk among those with heart disease was 1.55 (95% confidence interval 1.01-2.37). Patients with heart disease and chronic kidney disease who were started on an allopurinol dosage of greater than 100 mg/d had an 11-fold higher risk. Allopurinol initiation at a lower dosage among patients with heart disease and chronic kidney disease resulted in a fivefold reduction in risk. Older women with heart disease from regions with large Asian populations had a 23-fold higher risk of allopurinol-associated severe cutaneous adverse reactions than younger men without heart disease from other regions. INTERPRETATION: Heart disease is independently associated with risk of allopurinol-associated severe cutaneous adverse reactions, similar to chronic kidney disease, and low-dosage allopurinol initiation may substantially mitigate this risk. Risk factors for these rare but serious reactions should be considered when initiating allopurinol.

The British Columbia Healthy Connections Project: findings on socioeconomic disadvantage in early pregnancy.

BACKGROUND: Maternal exposure to socioeconomic disadvantage increases the risk of child injuries and subsequent child developmental and mental health problems - particularly for young mothers. To inform early intervention planning, this research therefore aimed to describe the health and social adversities experienced by a cohort of girls and young women in early pregnancy in British Columbia (BC), Canada. METHODS: Participants were recruited for the BC Healthy Connections Project (BCHCP), a randomized controlled trial examining the effectiveness of Nurse-Family Partnership, a home visitation program, in improving child and maternal outcomes. Baseline data were collected from 739 participants on trial entry. Participants were selected on the basis of preparing to parent for the first time and experiencing socioeconomic disadvantage. Analyses involved descriptive statistics and age-group comparisons. RESULTS: Most participants reported having low income (84%), having limited education (52%) and being single (91%) at trial entry. Beyond these eligibility criteria, other health and social adversities included: housing instability (52%); severe anxiety or depression (47%); other diagnosed mental disorders (22%); prenatal nicotine and cannabis use (27 and 21%); physical health problems (20%); child maltreatment when younger (56%); and intimate partner violence recently (50%). As well, few (29%) had received income assistance entitlements. More than two thirds (70%) were experiencing four or more forms of adversity. Age-group differences were observed for cognitive functioning, being single, low income, limited education, psychological distress and service use (p-value ≤0.05). CONCLUSIONS: This cohort was selected on the basis of socioeconomic disadvantage. Yet all participants were experiencing substantial added adversities - at higher rates than other Canadians. Furthermore, despite Canada's public programs, these pregnant girls and young women were not being adequately reached by social services. Our study adds new data to inform early intervention planning, suggesting that unacceptably high levels of socioeconomic disadvantage exist for some young British Columbians. Therefore greater health and social supports and services are warranted for these young mothers and their children. TRIAL REGISTRATION: Registered August 24, 2012 with ClinicalTrials.gov Identifier: NCT01672060 . Active not recruiting.

A New Propolis Type from Changbai Mountains in North-east China: Chemical Composition, Botanical Origin and Biological Activity.

Propolis is a bee product with a wide range of biological activities and its chemical compounds depend highly on the type of plant accessible to the bees. The Changbai Mountains are a major mountain range in Northeast China and are one of the major bee product-producing areas in China. In this study, we evaluated the total phenolic acids and flavonoid contents as well as the antioxidant activity of propolis sampled from the Changbai Mountains area (CBM). We identified the major compounds and qualified their contents by HPLC-ESI/MS and HPLC-UV, and found that the content of p-coumaric acid and an unknown peak (CBE) in CBM propolis was higher than in propolis from other parts of China. The unknown compound CBE was isolated, purified, and identified as benzyl p-coumarate by MS and NMR. Possible plant sources of CBM propolis are Populus davidiana dode and Populus simonii Carr, which widely distributed in the Changbai Mountains area. CBM propolis is a new propolis type, that could be an excellent raw material for health foods and pharmaceuticals.

In Vitro Anti-Inflammatory Effects of Three Fatty Acids from Royal Jelly.

Trans-10-hydroxy-2-decenoic acid (10-H2DA), 10-hydroxydecanoic acid (10-HDAA), and sebacic acid (SEA) are the three major fatty acids in royal jelly (RJ). Previous studies have revealed several pharmacological activities of 10-H2DA and 10-HDAA, although the anti-inflammatory effects and underlying mechanisms by which SEA acts are poorly understood. In the present study, we evaluated and compared the in vitro anti-inflammatory effects of these RJ fatty acids in lipopolysaccharide-stimulated RAW 264.7 macrophages. The results showed that 10-H2DA, 10-HDAA, and SEA had potent, dose-dependent inhibitory effects on the release of the major inflammatory-mediators, nitric oxide, and interleukin-10, and only SEA decreased TNF-α production. Several key inflammatory genes have also been modulated by these RJ fatty acids, with 10-H2DA showing distinct modulating effects as compared to the other two FAs. Furthermore, we found that these three FAs regulated several proteins involved in MAPK and NF-κB signaling pathways. Taken together, these findings provide additional references for using RJ against inflammatory diseases.

Trends and Regional Variation in Hospital Mortality, Length of Stay and Cost in Hospital of Ischemic Stroke Patients in Alberta Accompanying the Provincial Reorganization of Stroke Care.

OBJECTIVES: This study aimed to evaluate the trends and regional variation of stroke hospital care in 30-day in-hospital mortality, hospital length of stay (LOS), and 1-year total hospitalization cost after implementation of the Alberta Provincial Stroke Strategy. METHODS: New ischemic stroke patients (N = 7632) admitted to Alberta acute care hospitals between 2006 and 2011 were followed for 1 year. We analyzed in-hospital mortality with logistic regression, LOS with negative binomial regression, and the hospital costs with generalized gamma model (log link). The risk-adjusted results were compared over years and between zones using observed/expected results. RESULTS: The risk-adjusted mortality rates decreased from 12.6% in 2006/2007 to 9.9% in 2010/2011. The regional variations in mortality decreased from 8.3% units in 2008/2009 to 5.6 in 2010/2011. The LOS of the first episode dropped significantly in 2010/2011 after a 4-year slight increase. The regional variation in LOS was 15.5 days in 2006/2007 and decreased to 10.9 days in 2010/2011. The 1-year hospitalization cost increased initially, and then kept on declining during the last 3 years. The South and Calgary zones had the lowest costs over the study period. However, this gap was diminishing. CONCLUSIONS: After implementation of the Alberta Provincial Stroke Strategy, both mortality and hospital costs demonstrated a decreasing trend during the later years of study. The LOS increased slightly during the first 4 years but had a significant drop at the last year. In general, the regional variations in all 3 indicators had a diminishing trend.

Oral Propolis Nanoemulsions Modulate Gut Microbiota to Balance Bone Remodeling for Enhanced Osteoporosis Therapy.

The discovery of the bone-gut axis linking bone metabolism to gut microbiota (GM) dysbiosis has revolutionized our understanding of managing degenerative skeletal diseases. Targeting GM regulation has emerged as a promising approach to osteoporosis treatment. Herein, we develop propolis nanoemulsions (PNEs) with enhanced gastrointestinal stability and oral bioavailability for GM-based osteoporosis therapy. Orally administered PNEs exhibit superior antiosteoporosis efficacy in an ovariectomized (OVX) mouse model by modulating the GM structure and metabolites and restoring the intestinal barrier function. Multiomics analysis reveals that a reduction in Streptococcus abundance and an increase in the GM metabolite l-arginine are key factors in osteoporosis management. These changes suppress osteoclast activity and enhance osteoblast function, leading to balanced bone remodeling and, thus, significant antiosteoporotic effects via the gut-bone axis. Our results deepen insights into the intricate relationship between GM and bone remodeling, suggesting a promising strategy that maintains the homeostasis of the GM structure and metabolite for osteoporosis treatment.

Global burden of gynaecological cancers in 2022 and projections to 2050.

Background: The incidence and mortality of gynaecological cancers can significantly impact women's quality of life and increase the health care burden for organisations globally. The objective of this study was to evaluate global inequalities in the incidence and mortality of gynaecological cancers in 2022, based on The Global Cancer Observatory (GLOBOCAN) 2022 estimates. The future burden of gynaecological cancers (GCs) in 2050 was also projected. Methods: Data regarding to the total cases and deaths related to gynaecological cancer, as well as cases and deaths pertaining to different subtypes of GCs, gathered from the GLOBOCAN database for the year 2022. Predictions for the number of cases and deaths in the year 2050 were derived from global demographic projections, categorised by world region and Human Development Index (HDI). Results: In 2022, there were 1 473 427 new cases of GCs and 680 372 deaths. The incidence of gynecological cancer reached 30.3 per 100 000, and the mortality rate hit 13.2 per 100 000. The age-standardised incidence of GCs in Eastern Africa is higher than 50 per 100 000, whereas the age-standardised incidence in Northern Africa is 17.1 per 100 000. The highest mortality rates were found in East Africa (ASMR (age-standardised mortality rates) of 35.3 per 100 000) and the lowest in Australia and New Zealand (ASMR of 8.1 per 100 000). These are related to the endemic areas of HIV and HPV. Very High HDI countries had the highest incidence of GCs, with ASIR (age-standardised incidence rates) of 34.8 per 100 000, and low HDI countries had the second highest incidence rate, with an ASIR of 33.0 per 100 000. Eswatini had the highest incidence and mortality (105.4 per 100 000; 71.1 per 100 000) and Yemen the lowest (5.8 per 100 000; 4.4 per 100 000). If the current trends in morbidity and mortality are maintained, number of new cases and deaths from female reproductive tract tumours is projected to increase over the next two decades. Conclusions: In 2022, gynaecological cancers accounted for 1 473 427 new cases and 680 372 deaths globally, with significant regional disparities in incidence and mortality rates. The highest rates were observed in Eastern Africa and countries with very high and low HDI, with Eswatini recording the most severe statistics. If current trends continue, the number of new cases and deaths from gynaecological cancers is expected to rise over the next two decades, highlighting the urgent need for effective interventions.

Updated Intrinsic Role of Phytochemicals against Glyphosate-induced Neurotoxicity: Systematic Review.

BACKGROUND: Glyphosate-based herbicide (GBH) formulations are organophosphorus pesticides implicated for agricultural use. Several epidemiological reports have reported that the occupational exposure of farmers to glyphosate can cause age-related neurodegeneration. OBJECTIVE: the objective of this study is to examine the neurotoxic effects of glyphosate and its intricate role in triggering several neurodegenerative diseases like dementia, nootropic defects, Parkinson's disease, and neurological teratogenic effects due to its negative effects on the nervous system. Furthermore, the efficacy of phytochemicals against glyphosate-induced neurotoxicity was discussed. METHODS: We have searched public databases such as NLM, Pubmed, google scholar and collected a total of 103 articles including reviews, original articles, and obtained information related to glyphosate-induced neurotoxicity and novel phytochemicals implicated to ameliorate the glyphosate-induced neurotoxicity. We performed a systematic review without comprehensive meta-analysis. RESULTS: the efficacy of several phytochemicals as a nutritional intervention against glyphosate-induced neurotoxicity including Parkinsonism was elucidated by vivid review analysis of neurobehavioral alterations from in vitro and in vivo study models. CONCLUSION: These kinds of research projects will bring awareness about the neurotoxic effects of glyphosate and the protective nutritional intervention strategies against glyphosate-induced neurotoxicity including Parkinsonism for farmers.

Artificially reprogrammed stem cells deliver transcytosable nanocomplexes for improved spinal cord repair.

Stem cell transplantation holds great promise for restoring function after spinal cord injury (SCI), but its therapeutic efficacy heavily depends on the innate capabilities of the cells and the microenvironment at the lesion site. Herein, a potent cell therapeutic (NCs@SCs) is engineered by artificially reprogramming bone marrow mesenchymal stem cells (BMSCs) with oxidation-responsive transcytosable gene-delivery nanocomplexes (NCs), which endows cells with robust oxidative stress resistance and improved cytokine secretion. NCs@SCs can accumulate in the injured spinal cord after intravenous administration via chemotaxis and boost successive transcytosis to deliver NCs to neurons, augmenting ciliary neurotrophic factor (CNTF) production in both BMSCs and neurons in response to elevated ROS levels. Furthermore, NCs@SCs can actively sense and eliminate ROS and re-educate recruited M1-like macrophages into the anti-inflammatory M2 phenotype via a paracrine pathway, ultimately reshaping the inflammatory microenvironment. Synergistically, NCs@SCs exhibit durable survival and provide neuroprotection against secondary damage, enabling significant locomotor function recovery in SCI rats. Transcriptome analysis reveals that regulation of the ROS/MAPK signaling pathway is involved in SCI therapy by NCs@SCs. This study presents a nanomaterial-mediated cell-reprogramming approach for developing live cell therapeutics, showing significant potential in the treatment of SCI and other neuro-injury disorders.

Molecular classification of human papilloma virus-negative head and neck squamous cell carcinomas: Cell cycle-based classifier and prognostic signature.

The molecular classification of human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) remains questionable. Differentially expressed genes were detected between tumor and normal tissues and GSEA showed they are associated with cell cycle pathways. This study aimed to classify HPV-negative HNSCCs based on cell cycle-related genes. The established gene pattern was correlated with tumor progression, clinical prognosis, and drug treatment efficacy. Biological analysis was performed using HNSCC patient sample data obtained from the Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Gene Expression Omnibus (GEO) databases. All samples included in this study contained survival information. RNA sequencing data from 740 samples were used for the analysis. Previously characterized cell cycle-related genes were included for unsupervised consensus clustering. Two subtypes of HPV-negative HNSCCs (C1, C2) were identified. Subtype C1 displayed low cell cycle activity, 'hot' tumor microenvironment (TME), earlier N stage, lower pathological grade, better prognosis, and higher response rate to the immunotherapy and targeted therapy. Subtype C2 was associated with higher cell cycle activity, 'cold' TME, later N stage, higher pathological grade, worse prognosis, and lower response rate to the treatment. According to the nearest template prediction method, classification rules were established and verified. Our work explored the molecular mechanism of HPV-negative HNSCCs in the view of cell cycle and might provide new sights for personalized anti-cancer treatment.

MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies.

Small non-coding RNAs (microRNA, miR), powerful epigenetic regulators, were found involved in the regulation of most biological functions via post-translational inhibition of protein expression. Increased expression of pro-oncogenic miRs (known as miR cancer biomarkers) and inhibition of pro-apoptotic miR expression have been demonstrated in different tumors. The recently identified miR-183 was found implicated in gastrointestinal tumor metabolism regulation. Elevated miR-183 expression and cancer-promoting effects were reported in esophageal and colorectal cancers, which was partially contradicted by controversial data observed in gastric cancers. Anti-cancer effect of miR-183 in gastric cancer cells was associated with the Bim-1 and Ezrin genes regulation. Many studies indicated that miR-183 can inhibit tumor suppressor genes in most cell lines, promoting tumor cell proliferation and migration. Increased miR-183 level results in the downregulation of FOXO1, PDCD4, and other tumor suppressor genes in gastrointestinal tumor cells. MiR-183 also influences the signaling of PI3K/AKT/mTOR, Wnt/ß-catenin, and Bcl-2/p53 signaling pathways. Mir-183 inhibits apoptosis and autophagy, and promotes epithelial-to-mesenchymal transition, cancer cell proliferation, and migration. Accordingly, gastrointestinal cancer occurrence, development of chemoradiotherapy resistance, recurrence/metastasis, and prognosis were associated with miR-183 expression. The current study assessed reported miR-183 functions and signaling, providing new insights for the diagnosis and treatment of gastrointestinal malignancies.

Evaluating the effectiveness and cost-effectiveness of a digital, app-based intervention for depression (VMood) in community-based settings in Vietnam: Protocol for a stepped-wedge randomized controlled trial.

The COVID-19 pandemic has amplified mental health problems and highlighted inequitable gaps in care worldwide. In response there has been an explosion of digital interventions such as smartphone applications ("apps") to extend care. The objective of this trial is to evaluate the effectiveness and cost-effectiveness of a digital depression intervention (VMood), delivered via a smartphone app. VMood is adapted from an in-person intervention that was delivered by non-specialist providers and shown to be effective in the Vietnamese context in our previous trial (2016-2019). A stepped-wedge, randomized controlled trial will be conducted across eight provinces in Vietnam. Adults aged 18 years and over will be recruited through community-based primary care centres and screened for depression using the embedded Patient Health Questionnaire-9 (primary outcome measure). Participants scoring 10-19, indicating depression caseness, will be randomly allocated to the intervention or control group until the target of 336 is reached. Secondary outcome measures will examine the effect of the intervention on commonly co-occuring anxiety, quality of life and work productivity, along with use of alcohol and tobacco products. Assessments will be administered through an online survey platform (REDCap) at baseline, and at every 3 months until 3 months post-intervention. Intervention-group participants will receive VMood for a 3-month period, with online support provided by social workers. Control-group participants will receive a limited version of the app until they cross into the intervention group. Generalized Linear Mixed-effect Models for clustered measures will be used for all outcomes data. We will conduct a cost-effectiveness analysis alongside the trial to capture VMood's costs and benefits. This trial will provide evidence on the effectiveness and cost-effectiveness of a digital mental health intervention adapted from an in-person intervention. This trial will also contribute important information to the growing and promising field of digital mental health. Trail regulation. Registered at ClinicalTrials.gov, identifier [NCT05783531].

AIFM2 promotes hepatocellular carcinoma metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling.

AIFM2 is a crucial NADH oxidase involved in the regulation of cytosolic NAD+. However, the role of AIFM2 in the progression of human cancers remains largely unexplored. Here, we elucidated the clinical implications, biological functions, and molecular mechanisms of AIFM2 in hepatocellular carcinoma (HCC). We found that AIFM2 is significantly upregulated in HCC, which is most probably caused by DNA hypomethylation and downregulation of miR-150-5p. High expression of AIFM2 is markedly associated with poor survival in patients with HCC. Knockdown of AIFM2 significantly impaired, while forced expression of AIFM2 enhanced the metastasis of HCC both in vitro and in vivo. Mechanistically, increased mitochondrial biogenesis and oxidative phosphorylation by activation of SIRT1/PGC-1α signaling contributed to the promotion of metastasis by AIFM2 in HCC. In conclusion, AIFM2 upregulation plays a crucial role in the promotion of HCC metastasis by activating SIRT1/PGC-1α signaling, which strongly suggests that AIFM2 could be targeted for the treatment of HCC.

Chinese Clinical Trial Registry 13-year data collection and analysis: geographic distribution, financial support, research phase, duration, and disease categories.

Objective: To evaluate the current status of trial registration on the Chinese Clinical Trial Registry (ChiCTR). Design: In this descriptive study, a multi-dimensional grouping analysis was conducted to estimate trends in the annual trial registration, geographical distribution, sources of funding, targeted diseases, and trial subtypes. Setting: We have analyzed all clinical trial records (over 30,000) registered on the Chinese Clinical Trial Registry (ChiCTR) from 2007 to 2020 executed in China. Main outcomes and measures: The main outcome was the baseline characteristics of registered trials. These trials were categorized and analyzed based on geographical distribution, year of implementation, disease type, resource and funding type, trial duration, trial phase, and the type of experimental approach. Results: From 2008 to 2017, a consistent upward trend in clinical trial registrations was observed, showing an average annual growth rate of 29.2%. The most significant year-on-year (yoy%) growth in registrations occurred in 2014 (62%) and 2018 (68.5%). Public funding represented the predominant source of funding in the Chinese healthcare system. The top five ChiCTR registration sites for all disease types were highly populated urban regions of China, including Shanghai (5,658 trials, 18%), Beijing (5,127 trials, 16%), Guangdong (3,612 trials, 11%), Sichuan (2,448 trials, 8%), and Jiangsu (2,196 trials, 7%). Trials targeting neoplastic diseases accounted for the largest portion of registrations, followed by cardio/cerebrovascular disease (CCVD) and orthopedic diseases-related trials. The largest proportions of registration trial duration were 1-2 years, less than 1 year, and 2-3 years (at 27.36, 26.71, and 22.46%). In the case of the research phase, the top three types of all the registered trials are exploratory research, post-marketing drugs, and clinical trials of new therapeutic technology. Conclusion and relevance: Oncological and cardiovascular diseases receive the highest share of national public funding for medical clinical trial-based research in China. Publicly funded trials represent a major segment of the ChiCTR registry, indicating the dominating role of public governance in this health research sector. Furthermore, the growing number of analyzed records reflect the escalation of clinical research activities in China. The tendency to distribute funding resources toward exceedingly populated areas with the highest incidence of oncological and cardiovascular diseases reveals an aim to reduce the dominating disease burden in the urban conglomerates in China.

Inflammation and Stem Cell Stochasticity of HPV-induced Cervical Cancer: Epigenetics Based Biomarkers through Microbiome and Metabolome for Personalized Medicine: A Systematic Review.

BACKGROUND: Chemoresistance by stemness in HPV-induced cervical carcinogenesis has significant implications for the overall disease-specific survival of the patients. To date, there are no reports related to the implications of significant aspects of inflammation and microbiome-- mediated epigenetics in cervical cancers. OBJECTIVE: The current systematic review delineates the significant aspects of the inflammation-related pathophysiology, cervical cancer diagnosis based on the HPV-indued stemness, and microbiome- mediated epigenetic markers to develop personalized therapies to target the stemness-acquired indefinitely dividing cancer stem cells. METHODS: We performed a systematic review without a meta- analysis. We searched several public databases, such as Pubmed, ReleMed, National Library of Medicine, and Scopus, related to inflammation, metabolomics, microbiome-mediated epigenetic markers, and HPV-induced stemness. RESULTS AND CONCLUSION: The review significantly described the correlation between microbial inflammation and stem cell stochasticity of HPV-Induced cervical cancer and the expression of epigenetics- based biomarkers through microbiome and metabolome to foster the cervical cancer progression. These are major risk factors that can cause cervical dysplasia with substantial therapy resistance in cervical cancer patients. The qualitative and quantitative examination of the spatial transcriptomic expression of these stemness markers in the dividing cervical cancer stem cells has significant implications in the clinical sector to develop early personalized medicine to prevent cervical precancerous lesions depending on the prognosis of the cervical cancer patients. Mainly, the combinatorial regimen of current therapeutic modalities, along with microbiome-related therapies with future landscape of epigenetics-modulated therapies, may enhance overall disease-specific survival by modulating the stochastic dynamics of basal epithelial cells across the cervical region.