Association analyses between urinary concentrations of multiple trace elements and gastric precancerous lesions and gastric cancer in Anhui province, eastern China.

Background: Limited epidemiological evidence suggests that exposure to trace elements adversely impacts the development of gastric precancerous lesions (GPL) and gastric cancer (GC). This study aimed to estimate the association of individual urinary exposure to multiple elements with GPL and GC. Methods: A case-control investigation was conducted in Anhui Province from March 2021 to December 2022. A total of 528 subjects (randomly sampled from 1,020 patients with GPL, 200 patients with GC, and 762 normal controls) were included in our study. Urinary levels of iron (Fe), copper (Cu), zinc (Zn), nickel (Ni), strontium (Sr), and Cesium (Cs) were measured using inductively coupled plasma mass spectrometry (ICP-MS). Four different statistical approaches were employed to explore the risk of GPL and GC with mixed exposure, including multivariate logistic regression, weighted quantile regression (WQS), quantile g-computation (Qgcomp), and the Bayesian kernel machine regression (BKMR) model. Results: The WQS model indicated that urinary exposure to a mixture of elements is positively correlated with both GPL and GC, with ORs for the mixture exposure of 1.34 (95% CI: 1.34-1.61) for GPL and 1.38 (95% CI: 1.27-1.50) for GC. The Qgcomp and BKMR models also demonstrated a statistically significant positive correlation between the mixture and both GPL and GC. Conclusion: Considering the limitations of case-control studies, future prospective studies are warranted to elucidate the combined effects and mechanisms of trace elements exposure on human health.

Esketamine alleviates hypoxia/reoxygenation injury of cardiomyocytes by regulating TRPV1 expression and inhibiting intracellular Ca2+ concentration.

OBJECTIVE: This study aimed to investigate the effect of Esketamine (ESK) on the Hypoxia/Reoxygenation (H/R) injury of cardiomyocytes by regulating TRPV1 and inhibiting the concentration of intracellular Ca2+. METHODS: The H/R injury model of H9c2 cardiomyocytes was established after 4h hypoxia and 6h reoxygenation. H9c2 cells were treated with different concentrations of ESK or TRPV1 agonist capsaicin (10 µM) or TRPV1 inhibitor capsazepine (1 µM). Cell viability was detected by CCK-8 method, and apoptosis by flow cytometry. Intracellular Ca2+ concentration was evaluated by Fluo-4 AM. LDH, MDA, SOD, and GSH-Px were detected with corresponding commercial kits. TRPV1 and p-TRPV1 proteins were detected by Western blot. RESULTS: After H/R, H9c2 cell viability decreased, apoptosis increased, intracellular Ca2+ concentration increased, LDH and MDA levels increased, SOD and GSH-Px levels decreased, and p-TRPV1 expression increased. ESK treatment rescued these changes induced by H/R. After up-regulating TRPV1, the protective effect of ESK on H/R injury of H9c2 cells was weakened, while down-regulating TRPV1 could further protect against H/R injury. CONCLUSION: ESK alleviates H/R injury of cardiomyocytes by regulating TRPV1 expression and inhibiting intracellular Ca2+ concentration.

Functional metal-phenolic cortical cytoskeleton for artificial cells.

Cortex-like cytoskeleton, a thin layer of cross-linked cytoplasmic proteins underlying the cell membrane, plays an essential role in modulating membrane behavior and cell surface properties. However, bottom-up construction of functional cortex-like cytoskeleton in artificial cells remains a challenge. Here, we present metal-phenolic networks as artificial cortical cytoskeletons in liposome-based artificial cells. The metal-phenolic cytoskeleton-reinforced artificial cells exhibit long-term stability, enhanced resistance to a variety of harsh environments, tunable permeability, and well-controlled morphologies. We anticipate that our stable artificial cell models will stride forward to practical applications of liposome-based microsystem.

CRISPR/Cas9-mediated SERS/colorimetric dual-mode lateral flow platform combined with smartphone for rapid and sensitive detection of Staphylococcus aureus.

Pathogenic bacteria infections pose a significant threat to global public health, making the development of rapid and reliable detection methods urgent. Here, we developed a surface-enhanced Raman scattering (SERS) and colorimetric dual-mode platform, termed smartphone-integrated CRISPR/Cas9-mediated lateral flow strip (SCC-LFS), and applied it to the ultrasensitive detection of Staphylococcus aureus (S. aureus). Strategically, functionalized silver-coated gold nanostar (AuNS@Ag) was prepared and used as the labeling material for LFS assay. In the presence of S. aureus, target gene-induced amplicons can be accurately recognized and unwound by the user-defined CRISPR/Cas9 system, forming intermediate bridges that bind many AuNS@Ag to the test line (T-line) of the strip. As a result, the T-line was colored and a recognizable SERS signal was obtained using a smartphone-integrated portable Raman spectrometer. This design not only maintains the simplicity of visual readout, but also integrates the quantitative capability of SERS, enabling the user to flexibly select the assay mode as needed. With this method, S. aureus down to 1 CFU/mL can be detected by both colorimetric and SERS modes, which is better than most existing methods. By incorporating a rapid extraction procedure, the entire assay can be completed in 45 min. The robustness and practicality of the method were further demonstrated by various real samples, indicating its considerable potential toward reliable screening of S. aureus.

Healthy plant-based diet might be inversely associated with gastric precancerous lesions: new evidence from a case-control study based on dietary pattern and fecal metabolic profiling.

Preventing the progression of gastric precancerous lesions (GPLs) can reduce the morbidity and mortality of gastric cancer (GC). The preventive effect of a plant-based diet on cancers has been widely recognised. In this case-control study, 1,130 subjects were included using 1:1 propensity score matching for age and sex. Dietary habits, anthropometry and sample collection were conducted using standard and effective methods. Plant-based diet indices (PDIs) were calculated using a previously reported method. Faecal samples were analysed by untargeted metabolomics. Our study found that adherence to a healthy plant-based diet was inversely associated with the occurrence of GPLs. Metabolomic analysis identified six different metabolites correlated with GPLs, among which luteolin-related metabolites may be used as biomarkers of the association between PDIs and GPLs. In addition, the difference in N-acyl amides found in PDIs needs further verification. Our findings suggest that a healthy plant-based diet may have a protective effect against GPLs.

Esketamine alleviates hypoxia/reoxygenation injury of cardiomyocytes by regulating TRPV1 expression and inhibiting intracellular Ca2+ concentration

Abstract Objective This study aimed to investigate the effect of Esketamine (ESK) on the Hypoxia/Reoxygenation (H/R) injury of cardiomyocytes by regulating TRPV1 and inhibiting the concentration of intracellular Ca2+. Methods The H/R injury model of H9c2 cardiomyocytes was established after 4h hypoxia and 6h reoxygenation. H9c2 cells were treated with different concentrations of ESK or TRPV1 agonist capsaicin (10 μM) or TRPV1 inhibitor capsazepine (1 μM). Cell viability was detected by CCK-8 method, and apoptosis by flow cytometry. Intracellular Ca2+ concentration was evaluated by Fluo-4 AM. LDH, MDA, SOD, and GSH-Px were detected with corresponding commercial kits. TRPV1 and p-TRPV1 proteins were detected by Western blot. Results After H/R, H9c2 cell viability decreased, apoptosis increased, intracellular Ca2+ concentration increased, LDH and MDA levels increased, SOD and GSH-Px levels decreased, and p-TRPV1 expression increased. ESK treatment rescued these changes induced by H/R. After up-regulating TRPV1, the protective effect of ESK on H/R injury of H9c2 cells was weakened, while down-regulating TRPV1 could further protect against H/R injury. Conclusion ESK alleviates H/R injury of cardiomyocytes by regulating TRPV1 expression and inhibiting intracellular Ca2+ concentration.

Adequate Intake of Dietary Fiber May Relieve the Detrimental Impact of Blood Lead on Dyslipidemia among US Adults: A Study of Data from the National Health and Nutrition Examination Survey Database.

Lead (Pb) exposure is a well-established risk factor for dyslipidemia, and people are exposed to it in multiple ways daily. Dietary fiber is presumed to improve lipid metabolism disorders, but it is still unknown whether it can relieve the detrimental impact of Pb on dyslipidemia. We used publicly accessible data from the 2011-2016 cycles of the National Health and Nutrition Examination Survey (NHANES). A total of 2128 US adults were enrolled for the subsequent analysis. Heavy metal concentrations in blood were measured using inductively coupled plasma mass spectrometry (ICP-MS). A weighted logistic regression was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The dose-response relationship between blood heavy metals and dyslipidemia was explored using a weighted restricted cubic spline (RCS) analysis. After fully adjusting for potential confounding factors (age, gender, race, education level, ratio of family income to poverty, marital status, body mass index, physical activity, waist circumference, smoke, alcohol drinking and history of metabolic syndrome, hypertension, and diabetes), a positive association between blood Pb levels and dyslipidemia risk was revealed (OR = 1.20, 95% CI: 1.03-1.40). Dietary fiber intake may significantly modify the association between blood Pb levels and dyslipidemia (p-interaction = 0.049), with a stronger association (OR = 1.26, 95% CI: 1.05-1.52) being revealed in individuals with an inadequate intake of dietary fiber (<14 g/1000 kcal/day), but a null association (OR = 1.01, 95% CI: 0.72-1.42) being observed in those with an adequate intake of dietary fiber (≥14 g/1000 kcal/day). Moreover, the weighted RCS analysis showed that compared with the average blood Pb exposure level (4.24 µg/dL), a lower blood Pb exposure level (3.08 µg/dL) may contribute to the risk of dyslipidemia in the group with an inadequate dietary fiber intake. Our findings suggest that Pb exposure in blood may be a risk factor for dyslipidemia. However, an adequate dietary fiber intake may offset the risk of dyslipidemia caused by blood Pb exposure. Since avoiding Pb exposure in daily life is difficult, increasing dietary fiber intake in the future might be a promising approach to alleviate dyslipidemia caused by Pb exposure.

Controlled oxidation and digestion of Pickering emulsions stabilized by quinoa protein and (-)-epigallocatechin-3-gallate (EGCG) hybrid particles.

In this study, we prepared Pickering emulsions stabilized by quinoa protein isolate (QPI) and (-)-epigallocatechin-3-gallate (EGCG) non-covalent hybrid particles using ultrasonic emulsification technique and demonstrated lipid oxidation and in vitro digestion process of Pickering emulsions. The interaction forces between QPI and EGCG were characterized using fluorescence spectroscopy, isothermal titration calorimetry, and Fourier transform infrared spectroscopy. Results indicated that the non-covalent QPI/EGCG hybrid particles were formed mainly via hydrophobic interactions, hydrogen bonds, and electrostatic interactions at pH 5. Then, the QPI/EGCG non-covalent hybrid particles were applied to modify the Pickering emulsion with ultrasonic homogenization. The rheological experimental results showed that the energy storage modulus (G') was higher than the loss modulus (G″), indicating that the emulsion had solid-like properties. As a physical barrier, interfacial layer fabricated by antioxidant QPI/EGCG hybrid particles limited lipid oxidation at 60 °C for 15 days. At 37 °C, the QPI/EGCG hybrid particles stabilized Pickering emulsions with robust antioxidant interfacial structure limited the lipid digestion under simulated gastrointestinal tract (gastric, small intestine phases). Thus, EGCG and quinoa proteins were more resistant to free radical oxidation and gastrointestinal digestion with the assistance of ultrasound. It provides a basis for better development of food and drug delivery systems by fully utilizing the antioxidant properties of plant polyphenols.

Synergistic effects of low-dose arsenic and N-methyl-N'-nitro-N-nitrosoguanidine co-exposure by altering gut microbiota and intestinal metabolic profile in rats.

Biological organisms are exposed to low-dose arsenic or N-nitro compounds (NOCs) alone or in combination worldwide, especially in areas with high cancer prevalence through drinking water or food exposure; however, information on their combined exposure effects is limited. Here, we conducted an in-depth study of the effects on the gut microbiota, metabolomics, and signaling pathways using rat models exposed to arsenic or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), one of the most active carcinogenic NOCs, separately or in combination with metabolomics and high-throughput sequencing. Compared to exposure alone, combined exposure to arsenic and MNNG exacerbated damage to gastric tissue morphology, interfered with intestinal microflora and substance metabolism, and exerted a stronger carcinogenic effect. This may be related to intestinal microbiota disorders, including Dyella, Oscillibacter, Myroides, and metabolic pathways such as glycine, serine, and threonine metabolism, arginine biosynthesis, central carbon metabolism in cancer, and purine and pyrimidine metabolism, thereby enhancing the cancer-causing effects of gonadotrophin-releasing hormone (GnRH), P53, and Wnt signaling pathways.

Co-exposure to iron, copper, zinc, selenium and titanium is associated with the prevention of gastric precancerous lesions.

Gastric cancer is the third leading cause of cancer death, and gastric precancerous lesions (GPLs) are an important stage in the transformation of normal gastric mucosa to gastric cancer. Matched for age and sex, a total of 316 subjects were eventually included from our prospective observation population (including 1007 patients with GPLs and 762 normal controls), and a questionnaire survey was conducted. In total, 10 plasma elements (iron, copper, zinc, selenium, rubidium, strontium, titanium, aluminum, vanadium and arsenic) were measured by applying inductively coupled plasma‒mass spectrometry (ICP‒MS). A multivariate conditional logistic regression model and Bayesian kernel logistic regression model (BKMR) were used to analyze the association between plasma element concentrations and GPLs. In the multimetal model, plasma titanium concentrations were significantly and positively associated with the prevalence of GPLs, with a fourth-quartile OR of 11.56 ([95% CI]: [2.78-48.13]). Plasma selenium and copper were negatively correlated with GPLs, with the highest quartiles of selenium and copper having an OR of 0.03 ([95% CI]: [0.01-0.15]; P < 0.001) and 0.24 ([95% CI]: [0.07-0.82]), respectively. In the BKMR model, there was a significant negative combined correlation of five metals on GPLs: iron, copper, zinc, selenium, and titanium. The results of this study showed that plasma concentrations of selenium and copper were negatively correlated with GPLs, while plasma concentrations of titanium were positively correlated with GPLs, and the combined action of the five elements was negatively correlated with GPLs.

Role of the blood-spinal cord barrier: An adheren junction regulation mechanism that promotes chronic postsurgical pain.

Chronic postsurgical pain (CPSP) is a serious postoperative complication with high incidence, and its pathogenesis involves neuroimmune interactions and the breakdown of the blood-spinal cord barrier (BSCB), the decreased level of adheren junction (AJ)-related proteins is an important cause of BSCB injury. Vascular endothelial-cadherin (VE-cadherin) and p120 catenin (p120) constitute the endothelial barrier adheren junction. The Src/p120/VE-cadherin pathway is involved in the regulation of the endothelial barrier function. However, the role of the BSCB-AJ regulatory mechanism in CPSP has not been reported. In this study, we established a skin/muscle incision and retraction (SMIR) model and evaluated the paw withdrawal threshold (PWT), the effects of an Src inhibitor and p120 knockdown on p-Src, p120 and VE-cadherin expression, as well as BSCB-AJ function in rat spinal cord were observed to explore the regulation of BSCB-AJ function by the p-Src/p120/VE-cadherin pathway in promoting SMIR-induced CPSP. The levels of p-Src, p120 and VE-cadherin in the spinal cord were detected by Western blot. Meanwhile, BSCB permeability test was used to detect the changes in BCSB function. Finally, the spatial and temporal localization of p120 in spinal cord was detected by immunofluorescence. Our findings indicated that p-Src/p120/VE-cadherin could induce BSCB-AJ dysfunction and promote the development of CPSP.

GPR120 promotes neutrophil control of intestinal bacterial infection.

G-protein coupled receptor 120 (GPR 120) has been implicated in anti-inflammatory functions. However, how GPR120 regulates the neutrophil function remains unknown. This study investigated the role of GPR120 in the regulation of neutrophil function against enteric bacteria. 16S rRNA sequencing was used for measuring the gut microbiota of wild-type (WT) mice and Gpr120-/- mice. Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced colitis models were performed in WT and Gpr120-/- mice. Mouse peritoneal-derived primary neutrophils were used to determine the neutrophil functions. Gpr120-/- mice showed altered microbiota composition. Gpr120-/- mice exhibited less capacity to clear intestinal Citrobacter rodentium and more severe intestinal inflammation upon infection or DSS insults. Depletion of neutrophils decreased the intestinal clearance of Citrobacter rodentium. GPR120 agonist, CpdA, enhanced WT neutrophil production of reactive oxygen species (ROS) and extracellular traps (NETs), and GPR120-deficient neutrophils demonstrated a lower level of ROS and NETs. CpdA-treated neutrophils showed an enhanced capacity to inhibit the growth of Citrobacter rodentium, which was abrogated by the inhibition of either NETs or ROS. CpdA promoted neutrophil inhibition of the growth of commensal bacteria Escherichia coli O9:H4 and pathobiont Escherichia coli O83:H1 isolated from a Crohn's disease patient. Mechanically, mTOR activation and glycolysis mediated GPR120 induction of ROS and NETs in neutrophils. Additionally, CpdA promoted the neutrophil production of IL-17 and IL-22, and treatment with a conditioned medium of GPR120-activated neutrophils increased intestinal epithelial cell barrier functions. Our study demonstrated the critical role of GPR120 in neutrophils in protection against enteric bacterial invasion.

A Healthful Plant-Based Diet Is Associated with Lower Odds of Nonalcoholic Fatty Liver Disease.

There is little evidence for the associations of the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) with the odds of nonalcoholic fatty liver disease (NAFLD). We present a nationwide cross-sectional study among US adults aged 18 years or older. Diet was assessed by 24-h recalls. Overall PDI, hPDI, and uPDI were constructed based on 18 food groups. NAFLD was defined based on controlled attenuation parameter derived via transient elastography (TE) in the absence of other causes of chronic liver disease. Among 3900 participants with eligible TE examination, 1686 were diagnosed with NAFLD. The overall PDI was not associated with NAFLD prevalence (comparing extreme tertiles of PDI score OR = 1.03, 95% CI 0.76, 1.38, ptrend = 0.609). However, hPDI was inversely (OR = 0.50, 95% CI 0.35, 0.72, ptrend < 0.001), while uPDI was positively associated with odds of NAFLD (OR = 1.37, 95% CI 0.93, 2.02, ptrend = 0.009) in the multivariable-adjusted models without body mass index (BMI). After further adjustment for BMI, only the association of hPDI with NAFLD remained statistically significant (OR = 0.64, 95% CI 0.46, 0.87, ptrend = 0.006). Such inverse association appeared stronger in non-Hispanic whites, but not in other racial/ethnic groups (pinteraction = 0.009). Our findings suggest that a plant-based diet rich in healthy plant foods might be associated with lower odds of NAFLD, particularly among US non-Hispanic whites. Clinical trials and cohort studies to validate our findings are needed.

Endostar Synergizes with Radiotherapy to Inhibit Angiogenesis of Cervical Cancer in a Subcutaneous Xenograft Mouse Model.

BACKGROUND: To investigate the synergic effect and underlying mechanism of Endostar, a recombinant human endostatin used for anti-angiogenesis, in radiotherapy for cervical cancer. METHODS: The Cell Counting Kit-8 (CCK-8) assay and plate cloning experiment were first employed to analyze the proliferation of HeLa and SiHa cervical cancer cells and human umbilical vein vascular endothelial cells (HUVECs). Flow cytometry was used to detect apoptosis and cell cycle progression. A tube formation assay was used to assess angiogenesis in vitro. The expression of gamma H2A histone family member X (γ-H2AX) and activation of the vascular endothelial growth factor receptor (VEGFR) signaling pathway were detected by immunofluorescence and western blotting, respectively. In a HeLa xenograft model, tumor tissue expression of CD31 and alpha smooth muscle actin and serum expression of VEGF-A were detected by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay, respectively. RESULTS: The CCK-8 and plate cloning assays showed that Endostar and radiotherapy synergistically inhibited the growth of HUVECs but not HeLa and SiHa cells. The flow cytometric results showed that Endostar only promoted radiotherapy-induced apoptosis and G2/M phase arrest in HUVECs (p < 0.05). Endostar combined with radiotherapy also significantly inhibited tube formation by HUVECs (p < 0.05). Furthermore, Endostar inhibited the radiotherapy-induced expression of γH2AX (p < 0.05) and phosphorylation of VEGFR2/PI3K/AKT/DNA-PK in HUVECs (p < 0.05). IHC showed that Endostar enhanced the inhibitory effect of radiotherapy on the microvessel density in xenograft tumor tissues (p < 0.05), as well as serum VEGF-A expression (p < 0.05). The tumor volume in the combination therapy groups (1200 mm3) was significantly lower than in the control group (2500 mm3; p < 0.05). CONCLUSIONS: Our findings provide experimental evidence and a theoretical basis for the application of Endostar in combination with irradiation for anti-cervical cancer treatment.

Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis.

(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients.

High Concentration of Fermentable Sugars Prepared from Steam Exploded Lignocellulose in Periodic Peristalsis Integrated Fed-Batch Enzymatic Hydrolysis.

High concentrations of fermentable sugars are a demand for economical bioethanol production. A single process strategy cannot comprehensively solve the limiting factors in high-solid enzymatic hydrolysis. The multiple intensification strategies in this study achieved the goal of preparing high-concentration fermentable sugars of corn stalk with high solid loading and low enzyme loading. First, steam explosion pretreatment enhanced the hydrophilicity of substrates and enzymatic accessibility. Second, periodic peristalsis was used to improve the mass transfer efficiency and short the liquefaction time. Additionally, fed-batch feeding and enzyme reduced the enzyme loading. Ultimately, the intensification strategies above showed that the highest fermentable sugar content was 313.8 g/L with a solids loading as much as 50% (w/w) and enzyme loading as low as 12.5 FPU/g DM. Thus, these multiple intensification strategies were promising in the high-solid enzymatic hydrolysis of steam-exploded lignocellulose.

A prospective study of carbohydrate intake and risk of all-cause and specific-cause mortality.

PURPOSE: To investigate the associations between carbohydrate intake and the risk of overall and specific-cause mortality in a prospective cohort study. METHODS: Diet was measured using 24 h dietary recalls. Underlying cause of death was identified through linkage to the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. RESULTS: During a median follow-up of 7.1 years among 35,692 participants who aged 20-85 years, a total of 3854 deaths [783 cardiovascular disease (CVD)-specific and 884 cancer-specific death] were identified. Carbohydrate intake was not associated with risk of overall mortality (multivariable-adjusted HR comparing extreme quartiles 1.03, 95% CI 0.94, 1.13, ptrend = 0.799), while higher fiber intake was associated with lower mortality risk (HR 0.86, 95% CI 0.77, 0.95, ptrend = 0.004). Replacing 5% of energy from carbohydrate with both plant fat and plant protein was associated with 13% (95% CI 8%, 17%) and 13% (95% CI 3%, 22%) lower risk of total and CVD mortality, respectively. Whereas a positive or null association was found when replacing carbohydrate with both animal fat and animal protein. Higher carbohydrate-to-fiber ratio was associated with increased risk of overall (HR 1.20, 95% CI 1.09, 1.33, ptrend < 0.001) and cancer-specific (HR 1.17, 95% CI 0.95, 1.44, ptrend = 0.031) mortality. CONCLUSIONS: Our findings suggested that high fiber diet or diet with low carbohydrate-to-fiber ratio was associated with lower long-term death risk, and provided evidence for the health benefit from dietary substitution of both plant fat and plant protein for carbohydrate.

CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma.

The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti-PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor-associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.

PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment.

BACKGROUND: Oncogenes act in a cell-intrinsic way to promote tumorigenesis. Whether oncogenes also have a cell-extrinsic effect on suppressing the immune response to cancer is less well understood. METHODS: We use an in vivo expression screen of known cancer-associated somatic mutations in mouse syngeneic tumor models treated with checkpoint blockade to identify oncogenes that promote immune evasion. We then validated candidates from this screen in vivo and analyzed the tumor immune microenvironment of tumors expressing mutant protein to identify mechanisms of immune evasion. RESULTS: We found that expression of a catalytically active mutation in phospho-inositol 3 kinase (PI3K), PIK3CA c.3140A>G (H1047R) confers a selective growth advantage to tumors treated with immunotherapy that is reversed by pharmacological PI3K inhibition. PIK3CA H1047R-expression in tumors decreased the number of CD8+ T cells but increased the number of inhibitory myeloid cells following immunotherapy. Inhibition of myeloid infiltration by pharmacological or genetic modulation of Ccl2 in PIK3CA H1047R tumors restored sensitivity to programmed cell death protein 1 (PD-1) checkpoint blockade. CONCLUSIONS: PI3K activation enables tumor immune evasion by promoting an inhibitory myeloid microenvironment. Activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy. Our data suggest that some oncogenes promote tumorigenesis by enabling tumor cells to avoid clearance by the immune system. Identification of those mechanisms can advance rational combination strategies to increase the efficacy of immunotherapy.

All-Trans Retinoic Acid Prevents the Progression of Gastric Precancerous Lesions by Regulating Disordered Retinoic Acid Metabolism.

Retinoic acid (RA) is the most biologically active metabolite of vitamin A and is important for stomach physiological function. However, little is known about the metabolic status of RA in human gastric lesions. From 2015 to 2018, 1,392 local residents in Lujiang County were recruited into a cross-sectional survey program, which included a questionnaire interview and blood collection. We detected the mRNA and protein expression of RA metabolism-relevant factors in gastric tissues from 68 local patients with gastric lesions. The effects of all-trans retinoic acid (ATRA) supplementation were investigated in a gastric precancerous lesions (GPLs) rat model. In the cross-sectional survey, no significant differences in the level of RA precursor (P > 0.05) between the H. pylori seronegative and seropositive residents were observed. However, the mRNA and protein expression of RA synthesizing enzymes (RDH10 and ALDH1A1) were significantly decreased and catabolic enzyme (CYP26B1) was significantly increased in the patients (P < 0.05). Consistently, in the GPL rat model, we observed a similar disorder; however, ATRA supplementation significantly not only corrected the disorder by increasing Rdh10, Aldh1a1 and decreasing Cyp26b1, but also reduced claudin-18 (P < 0.05). Our study suggested that RA metabolism is disrupted in individuals with gastric lesions, while ATRA supplementation can prevent GPL from progressing to gastric cancer.