Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity.

The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.

Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.

Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.

Contribution of individual and cumulative social determinants of health underlying gender disparities in periodontitis in a representative US population: A cross-sectional NHANES study.

AIM: To examine the impact of both individual and cumulative social determinants of health (SDoH) on the likelihood of developing periodontitis, while also exploring any gender disparities in this relationship. MATERIALS AND METHODS: Data of self-reported SDoH domains and sub-items based on Healthy People 2030 were obtained from the U.S. National Health and Nutrition Examination Surveys between 1999 and 2014. Logistic regression models, weighted by survey responses, were used to examine the relationship between SDoH (including eight sub-items and the cumulative number of unfavourable SDoH) and periodontitis. The results were further analysed by gender. RESULTS: A total of 18,075 participants (8867 males and 9208 females) were included in the main analysis, of which 5814 (32.2%) had periodontitis. The study found that certain unfavourable SDoH were individually associated with higher odds of periodontitis, and the cumulative number of unfavourable SDoH was positively linked to the odds of developing periodontitis. Furthermore, males exposed to more unfavourable SDoH appeared to be more susceptible to developing periodontitis than females. CONCLUSIONS: The findings suggest that unfavourable SDoH, especially when they accumulate, are associated with an increased odds of periodontitis and contribute to gender disparities within the U.S.

Outdoor gardening activity with different frequency and duration may be associated with reduction of total and cause-specific mortality risk for general U.S. adults: Findings from the NHANES.

BACKGROUND AND AIMS: Engaging in recommended levels of physical activity (PA) is associated with reduced overall and cause-specific mortality rates. Our study aims to examine the relationship between gardening-specific PA and all-cause and cause-specific mortality based on representative U.S. adults. METHODS AND RESULTS: A total of 13,812 adults representing 663.5 million non-institutionalized U.S. adults were included in the National Health and Nutrition Examination Survey. Self-reported gardening activity (GA) was assessed by a validated questionnaire, and outcomes of interest were all-cause mortality and mortality specific to certain causes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using survey-multivariable Cox proportional hazards models. During a median follow-up period of 16.8 years (Interquartile range = 14.8-18.7), there were 3,476 deaths. After adjusting for potential covariates, we found that participants exposed to GA were more likely to have a lower risk of total mortality [HR (95% CI): 0.76 (0.68, 0.85), P-value < 0.001], cancer-specific mortality [HR (95% CI): 0.81 (0.67, 0.99), P-value < 0.05], cardiovascular disease mortality [HR (95% CI): 0.65 (0.53, 0.80), P-value < 0.001], and respiratory disease mortality [HR (95% CI): 0.66 (0.45, 0.98), P-value < 0.05], compared to those without GA exposure. Furthermore, engaging in GA more frequently and for longer durations was significantly associated with a lower total mortality risk. CONCLUSION: Our study provides evidence that engaging in GA is associated with a decreased risk of overall and cause-specific mortality. However, further longitudinal or interventional studies are needed to investigate the potential benefits of GA.

Findings of indoor air pollution and childhood obesity in a cross-sectional study of Chinese schoolchildren.

BACKGROUND: Air pollution exposures are increasingly suspected to influence the development of childhood adiposity, especially focusing on outdoor exposure, but few studies investigated indoor exposure and childhood obesity. OBJECTIVES: We aimed to examine the association between exposure to multiple indoor air pollutants and childhood obesity in Chinese schoolchildren. METHODS: In 2019, we recruited 6499 children aged 6-12 years from five Chinese elementary schools in Guangzhou, China. We measured age-sex-specific body mass index z score (z-BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) on standard procedures. Four different indoor air pollution (IAP) exposures, including cooking oil fumes (COFs), home decoration, secondhand smoke (SHS), and incense burning, were collected by questionnaire and then converted into an IAP exposure index with four categories. Association between indoor air pollutants and childhood overweight/obesity as well as four obese anthropometric indices were assessed by logistic regression models and multivariable linear regression models, respectively. RESULTS: Children exposed to ≥3 types of indoor air pollutants had higher z-BMI (coefficient [ß]:0.142, 95% confidence interval [CI]:0.011-0.274) and higher risk of overweight/obesity (odd ratio [OR]:1.27, 95%CI:1.01-1.60). And a dose-response relationship was discovered between the IAP exposure index and z-BMI as well as overweight/obesity (pfor trend<0.05). We also found that exposure to SHS and COFs was positively associated with z-BMI and overweight/obesity (p < 0.05). Moreover, there was a significant interaction between SHS exposure and COFs on the higher risk of overweight/obesity among schoolchildren. Boys appear more susceptible to multiple indoor air pollutants than girls. CONCLUSIONS: Indoor air pollution exposures were positively associated with higher obese anthropometric indices and increased odds of overweight/obesity in Chinese schoolchildren. More well-designed cohort studies are needed to verify our results.

MBD3 promotes hepatocellular carcinoma progression and metastasis through negative regulation of tumour suppressor TFPI2.

BACKGROUND: The mechanism of recurrence and metastasis of hepatocellular carcinoma (HCC) is complex and challenging. Methyl-CpG binding domain protein 3 (MBD3) is a key epigenetic regulator involved in the progression and metastasis of several cancers, but its role in HCC remains unknown. METHODS: MBD3 expression in HCC was detected by immunohistochemistry and its association with clinicopathological features and patient's survival was analysed. The effects of MBD3 on hepatoma cells growth and metastasis were investigated, and the mechanism was explored. RESULTS: MBD3 is significantly highly expressed in HCC, associated with the advanced tumour stage and poor prognosis in HCC patients. MBD3 promotes the growth, angiogenesis and metastasis of HCC cells by inhibiting the tumour suppressor tissue factor pathway inhibitor 2 (TFPI2). Mechanistically, MBD3 can inhibit the TFPI2 transcription via the Nucleosome Remodeling and Deacetylase (NuRD) complex-mediated deacetylation, thus reactivating the activity of matrix metalloproteinases (MMPs) and PI3K/AKT signaling pathway, leading to the progression and metastasis of HCC CONCLUSIONS: Our results unravel the novel regulatory function of MBD3 in the progression and metastasis of HCC and identify MBD3 as an independent unfavourable prognostic factor for HCC patients, suggesting its potential as a promising therapeutic target as well.

Optimal whole blood dilution protocol for preprocessing samples prior to circulating tumor cell capture by size-based isolation.

BACKGROUND: This study compared whole blood dilution versus density gradient centrifugation for pre-processing blood samples prior to circulating tumor cell (CTC) capture on the efficiency of CTC separation by size-based isolation. MATERIALS AND METHODS: Whole blood from a healthy volunteer spiked with SKBR3 cells was used to optimize the whole blood dilution protocol for sample volume, dilution ratio, and paraformaldehyde (PFA) concentration. Whole blood from healthy volunteers spiked with SKBR3, A549, or PC3 cells, and whole blood from patients with advanced gastric, esophageal, or liver cancer, was used to compare pre-processing by the optimal whole blood dilution protocol with density-gradient centrifugation. All statistical evaluations were performed using Student t test of the Statistical Package for Social Sciences (SPSS version 17.0). RESULTS: In blood samples from healthy volunteers, spiked SKBR3 cell recovery rates were highest in 5 ml of whole blood, diluted with 2.5 ml buffer, and fixed with 0.2% PFA, and spiked SKBR3, A549, and PC3 cell recovery rates from 5 ml whole blood were significantly greater when using the optimized whole blood dilution protocol (87.67% ± 1.76%, 79.50% ± 0.50% and 71.83% ± 1.04%, respectively) compared to density-gradient centrifugation (46.83 ± 1.76%, 37.00 ± 1.50% and 41.00 ± 1.50%, respectively).

Dual inhibition of αvß6 and αvß1 reduces fibrogenesis in lung tissue explants from patients with IPF.

RATIONALE: αv integrins, key regulators of transforming growth factor-ß activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvß6) and fibroblasts (αvß1) in fibrotic lungs. OBJECTIVES: We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. METHODS: Selective αvß6 and αvß1, dual αvß6/αvß1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-ß cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-ß signaling. Bleomycin-challenged mice treated with dual αvß6/αvß1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. MEASUREMENTS AND MAIN RESULTS: Inhibition of integrins αvß6 and αvß1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvß6/αvß1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. CONCLUSIONS: In the fibrotic lung, dual inhibition of integrins αvß6 and αvß1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-ß.

Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer.

Colorectal cancer is one of the major causes of death from cancer. Metastasis is the leading cause of treatment failure, in which cancer stem cells and circulating tumor cells play crucial roles. Identifying the involved metastatic biomarkers and clarifying the regulation mechanisms are of great importance for targeting tumor metastasis. In the current research, we discovered that KIAA1199, a cell-migration inducing protein, showed higher expression in CD44+ cancer cells from metastatic compared with the paired primary tissues, and was upregulated in colorectal cancer and positively correlated with numbers and mesenchymal phenotype of circulating tumor cells, and predicted shorter progress-free survival. Moreover, we indicated that down-regulation of KIAA1199 suppressed migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Furthermore, we demonstrated that KIAA1199 was one of the direct and functional targets of miR-216a, and miR-216a overexpression led to decreased migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Collectively, KIAA1199 plays a critical role in maintaining an aggressive phenotype of tumor cells, and suppression of KIAA1199-related motilities of tumor cells contributes to reduced tumor metastasis in colorectal cancer.

Circulating tumor microemboli (CTM) and vimentin+ circulating tumor cells (CTCs) detected by a size-based platform predict worse prognosis in advanced colorectal cancer patients during chemotherapy.

BACKGROUND: Circulating tumor cells (CTCs) detected in peripheral blood (PB) of cancer patients can be identified as isolated CTCs and circulating tumor microemboli (CTM). This study aimed to evaluate the prognostic value of CTM detection and CTC phenotype in advanced colorectal cancer (CRC) patients during chemotherapy. METHODS: A size-based platform for CTC isolation was applied. PB samples (5 ml) from 98 advanced CRC patients during 2-6 cycles chemotherapy were collected for CTC detection, and CTC count was correlated to patient's clinicopathological characteristics and clinical outcome. And CTC phenotype was measured by immunofluorescent staining and evaluate the predictive significance on survival in 32 CTCs-positive patients with advanced CRC. RESULTS: Forty-eight of 98 patients were CTCs-positive, including 18 CTM-positive patients, and CTC detection was positively correlated with lymphatic invasion (P = 0.049), TNM stage (P = 0.023), and serum CEA level (P = 0.014). Moreover, Kaplan-Meier survival and Cox regression analyses revealed that the presence of CTCs was an independent factor for poor PFS and OS (P < 0.05) in advanced CRC patients during chemotherapy, and CTM-positive patients had shooter survival than isolated CTCs-positive patients (P < 0.05). Furthermore, patients with vimentin+ isolated CTCs/CTM had shorter PFS and OS compared with CK+ CTCs (P < 0.05). CONCLUSIONS: This study provided evidence that the presence of CTCs was positively correlated with poor prognosis, and furthermore, CTM and vimentin+ CTCs predicted poorer survival, which indicated that CTM and vimentin+ CTCs detected by a sensitive platform could be used to improve prognostic value of CTCs in advanced CRC patients under treatment.

Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis.

Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-Apc(Min)/J (Apc(Min)) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.

Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain.

Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo(-/-) mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo(-/-) mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo(-/-) mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD(+), did not differ between Kmo(-/-) and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo(-/-) mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo(-/-) mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease.

NFKB1 -94 insertion/deletion polymorphism and cancer risk: a meta-analysis.

Previous studies on the associations of the NFKB1 -94 insertion/deletion polymorphism with cancer risk have produced conflicting results. The purpose of this meta-analysis is to define the effect of the NFKB1 -94 insertion/deletion polymorphism on cancer risk. A search of the literature by PubMed was performed to identify studies based on the predetermined inclusion criteria. Twenty-three studies consisting of 6,494 cases and 9,884 controls were identified and analyzed. Overall, significant association was observed between the polymorphism and cancer risk under all genetic models. Subgroup analysis according to ethnicity and cancer type also detected significant association. The NFKB1 -94 insertion/deletion polymorphism was associated with cancer risk in Asian population (dominant model: OR=1.52, 95 % CI=1.17-1.98; recessive model: OR=1.50, 95 % CI=1.26-1.79; II vs. DD: OR=1.90, 95 % CI=1.37-2.65; ID vs. DD: OR=1.32, 95 % CI=1.05-1.66; I vs. D: OR=1.37, 95 % CI=1.17-1.60), but not in Caucasian population. In addition, significant associations in OC, HCC, and OSCC were observed, but significant associations were not found in BC and LC. The current meta-analysis suggested that NFKB1 -94 insertion/deletion polymorphism may influence cancer risk in Asian population.

The association between the polymorphisms of TNF-α and non-Hodgkin lymphoma: a meta-analysis.

Many genetic variations in the promoter region of tumor necrosis factor alpha (TNF-α) may confer host susceptibility to cancer by influencing TNF-α expression. Nevertheless, the results remain inconclusive. The current meta-analysis was performed to investigate the association between three common TNF-α promoter polymorphisms and the risk of non-Hodgkin lymphoma (NHL). A literature search was conducted mainly from PubMed for all eligible studies. The pooled odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were used to assess the association of TNF-α polymorphisms with the risk of NHL. TNF-α -308 A allele showed a statistically significant increased risk for NHL under the homozygous (AA vs. GG, OR = 1.51, 95 % CI = 1.26-1.80) and recessive (OR = 1.47, 95 % CI = 1.23-1.75) models, respectively. The stratified analyses showed an increased risk of NHL with the presence of TNF-α -308 A allele among Africans and Caucasians, but a decreased risk among Asians. No association was observed between -238 G/A polymorphism and NHL risk either in the overall analysis or in the stratified analysis. Similarly, pooled analysis did not reveal an altered risk of NHL with -857 C/T polymorphism. Nonetheless, a statistically significant association was observed among Asians when stratified by ethnicity. Among the three genetic variations of interest, TNF-α -308 G/A polymorphism was significantly associated with the risk of NHL; neither -238 G/A nor -857 C/T polymorphism was shown to alter the overall NHL risk; however, stratified analysis by ethnicity observed a statistically significant association between -857 C/T polymorphism and the risk of NHL among Asians.

Human biodistribution and radiation dosimetry for the tau tracer [18F]Florzolotau in healthy subjects.

BACKGROUND: Tau pathology plays a crucial role in neurodegeneration diseases including Alzheimer's disease (AD) and non-AD diseases such as progressive supranuclear palsy. Tau positron emission tomography (PET) is an in-vivo and non-invasive medical imaging technique for detecting and visualizing tau deposition within a human brain. In this work, we aim to investigate the biodistribution of the dosimetry in the whole body and various organs for the [18F]Florzolotau tau-PET tracer. A total of 12 healthy controls (HCs) were enrolled at Chang Gung Memorial Hospital. All subjects were injected with approximately 379.03 ± 7.03 MBq of [18F]Florzolotau intravenously, and a whole-body PET/CT scan was performed for each subject. For image processing, the VOI for each organ was delineated manually by using the PMOD 3.7 software. Then, the time-activity curve of each organ was acquired by optimally fitting an exponential uptake and clearance model using the least squares method implemented in OLINDA/EXM 2.1 software. The absorbed dose for each target organ and the effective dose were finally calculated. RESULTS: From the biodistribution results, the elimination of [18F]Florzolotau is observed mainly from the liver to the intestine and partially through the kidneys. The highest organ-absorbed dose occurred in the right colon wall (255.83 µSv/MBq), and then in the small intestine (218.67 µSv/MBq), gallbladder wall (151.42 µSv/MBq), left colon wall (93.31 µSv/MBq), and liver (84.15 µSv/MBq). Based on the ICRP103, the final computed effective dose was 34.9 µSv/MBq with CV of 10.07%. CONCLUSIONS: The biodistribution study of [18F]Florzolotau demonstrated that the excretion of [18F]Florzolotau are mainly through the hepatobiliary and gastrointestinal pathways. Therefore, a routine injection of 370 MBq or 185 MBq of [18F]Florzolotau leads to an estimated effective dose of 12.92 or 6.46 mSv, and as a result, the radiation exposure to the whole-body and each organ remains within acceptable limits and adheres to established constraints. TRIAL REGISTRATION: Retrospectively Registered at Clinicaltrials.gov (NCT03625128) on 12 July, 2018, https://clinicaltrials.gov/study/NCT03625128 .

Single dual-specific anti-PD-L1/TGF-ß antibody synergizes with chemotherapy as neoadjuvant treatment for pancreatic ductal adenocarcinoma: a preclinical experimental study.

AIMS: Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-ß bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-ß) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. METHODS: Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. RESULTS: BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. CONCLUSION: Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.

Sexual orientation disparities in the prevalence of suicidal ideation among U.S adults aged 20 to 59 years: Results from NHANES 2005-2016.

Existing studies have been limited in providing nationally representative data on the relationship between sexual orientation and suicidal ideation (SI) among adults in the U.S. particularly in terms of gender and racial differences. To fill this research gap, we conducted a study using data from the NHANES conducted between 2005 and 2016. Survey-weighted logistic regression models were used to investigate the relationship between sexual orientation and SI risk. Additionally, we performed further analysis by stratifying the data based on demographic variables and performed sensitivity analysis to ensure the reliability of our findings. This study included a weighted sample of 16,564 adults, representing a noninstitutionalized U.S population of 840.1 million. The overall age-adjusted prevalence of SI was found to be 3.5 %. After adjusting for relevant covariates, the study revealed that individuals who identified as something else, homosexual, and bisexual had a higher prevalence risk of suicidal ideation (SI) compared to heterosexual participants. Additionally, the study found that heterosexual participants were 74.4 % less likely to experience SI compared to bisexual individuals. These findings highlight the urgent requirement for inclusive and supportive prevention strategies to effectively address SI among adult sexual minorities in the U.S.

Urban greenspace and visual acuity in schoolchildren: a large prospective cohort study in China.

BACKGROUND: Greenspace is known to have a positive impact on human health and well-being, but its potential effects on visual acuity have not been extensively studied. OBJECTIVES: Our aim was to examine the relationship between long-term greenspace exposure and visual acuity in children, while also exploring the potential mechanisms in this association. METHODS: We conducted this prospective cohort study based on the Children's growth environment, lifestyle, physical, and mental health development project (COHERENCE), which screened 286,801 schoolchildren in Guangzhou, China, starting in the 2016/17 academic year and followed them up for three academic years (2017/18-2019/20). Visual acuity was measured using a standardized logarithmic chart, and visual impairment was defined as visual acuity worse than 0.0 logarithm of the minimum angle of resolution (LogMAR) units in the better eye. We used the Normalized Difference Vegetation Index (NDVI), the Soil-Adjusted Vegetation Index (SAVI), and the Enhanced Vegetation Index (EVI) to assess the greenspace surrounding child's geocoded home and school at each visit. RESULTS: Our analysis indicated that higher greenspace exposure was associated with greater visual acuity z-score at baseline and with slower decline in visual acuity z-score during the 3-year follow-up. An interquartile range increase in home-school-based NDVI 300m was associated with a 7% decrease [hazard ratios (HRs): 0.93, 95% confidence interval (CI): 0.92, 0.94] in the risk of visual impairment. We also found that air pollution, physical activity, outdoor time, and recreational screen time partially mediated the greenspace-visual acuity association. CONCLUSION: Our findings suggest that increasing greenspace exposure could benefit children's visual acuity development and reduce the risk of visual impairment by reducing air pollution and recreational screen time while increasing physical activity and outdoor time. All results could have potential policy implications, given the individual and societal burdens associated with visual impairment.

Deficiency of Trex1 leads to spontaneous development of type 1 diabetes.

BACKGROUND: Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the important role of type I interferon in the development of type 1 diabetes. METHODS: Trex1-deficient rats were generated by using CRISPR-Cas9. The fasting blood glucose level of rat was measured by a Roche Accuchek blood glucose monitor. The levels of insulin, islet autoantibodies, and interferon-ß were measured using enzyme-linked immunosorbent assay. The inflammatory genes were detected by quantitative PCR and RNA-seq. Hematein-eosin staining was used to detect the pathological changes in pancreas, eye and kidney. The pathological features of kidney were also detected by Masson trichrome and periodic acid-Schiff staining. The distribution of islet cells, immune cells or ssDNA in pancreas was analyzed by immunofluorescent staining. RESULTS: In this study, we established a Trex1-deletion Sprague Dawley rat model, and unexpectedly, we found that the Trex1-/- rats spontaneously develop type 1 diabetes. Similar to human diabetes, the hyperglycemia in rats is accompanied by diabetic complications such as diabetic nephropathy and cataract. Mechanistical investigation revealed the accumulation of ssDNA and the excessive production of proinflammatory cytokines, including IFN-ß, in Trex1 null pancreas. These are likely contributing to the inflammation in pancreas and eventually leading to the decline of pancreatic ß cells. CONCLUSIONS: Our study links the DNA-induced chronic inflammation to the pathogenesis of type 1 diabetes, and also provides an animal model for type 1 diabetes studies.