Association Between Age at Diabetes Diagnosis and Subsequent Incidence of Cancer: A Longitudinal Population-Based Cohort.

OBJECTIVE: Diabetes presenting at a younger age has a more aggressive nature. We aimed to explore the association of age at type 2 diabetes mellitus (T2DM) diagnosis with subsequent cancer incidence in a large Chinese population. RESEARCH DESIGN AND METHODS: The prospective population-based longitudinal cohort included 428,568 newly diagnosed T2DM patients from 2011 to 2018. Participants were divided into six groups according to their age at diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years. The incidence of overall and 14 site-specific cancers was compared with the Shanghai general population including 100,649,346 person-years. RESULTS: A total of 18,853 and 582,643 overall cancer cases were recorded in the T2DM cohort and the general population. The age-standardized rate of overall cancer in T2DM patients was 501 (95% CI: 491, 511) per 100,000 person-years, and the standardized incidence ratio (SIR) was 1.10 (1.09, 1.12). Younger age at T2DM diagnosis was associated with higher incidence of overall and site-specific cancers. SIRs for overall cancer with T2DM diagnosis at ages 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years were 1.48 (1.41, 1.54), 1.30 (1.25, 1.35), 1.19 (1.15, 1.23), 1.16 (1.12, 1.20), 1.06 (1.02, 1.10), and 0.86 (0.84, 0.89), respectively. Similar trends were observed for site-specific cancers, including respiratory, colorectum, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancer and lymphoma among both males and females. CONCLUSIONS: Our findings highlight the necessity of stratifying management for T2DM according to age of diagnosis. As with a range of vascular outcomes, age-standardized cancer risks are greater in earlier compared with later onset T2DM.

The diagnostic yield of exome sequencing in liver diseases from a curated gene panel.

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10-4 for dominant disorders and MAF ≤ 10-3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06-8.18, p value = 4.5e-12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.

Anticancer therapeutic effect of ginsenosides through mediating reactive oxygen species.

Dysregulation of reactive oxygen species (ROS) production and ROS-regulated pathways in cancer cells leads to abnormal accumulation of reactive oxygen species, displaying a double-edged role in cancer progression, either supporting transformation/proliferation and stimulating tumorigenesis or inducing cell death. Cancer cells can accommodate reactive oxygen species by regulating them at levels that allow the activation of pro-cancer signaling pathways without inducing cell death via modulation of the antioxidant defense system. Therefore, targeting reactive oxygen species is a promising approach for cancer treatment. Ginsenosides, their derivatives, and related drug carriers are well-positioned to modulate multiple signaling pathways by regulating oxidative stress-mediated cellular and molecular targets to induce apoptosis; regulate cell cycle arrest and autophagy, invasion, and metastasis; and enhance the sensitivity of drug-resistant cells to chemotherapeutic agents of different cancers depending on the type, level, and source of reactive oxygen species, and the type and stage of the cancer. Our review focuses on the pro- and anticancer effects of reactive oxygen species, and summarizes the mechanisms and recent advances in different ginsenosides that bring about anticancer effects by targeting reactive oxygen species, providing new ideas for designing further anticancer studies or conducting more preclinical and clinical studies.

Syk Inhibition Reprograms Tumor-Associated Macrophages and Overcomes Gemcitabine-Induced Immunosuppression in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low 5-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAM), which promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In orthotopic PDAC mouse models, genetic deletion of myeloid Syk reprogrammed macrophages into immunostimulatory phenotype, increased the infiltration, proliferation, and cytotoxicity of CD8+ T cells, and repressed PDAC growth and metastasis. Furthermore, gemcitabine (Gem) treatment induced an immunosuppressive microenvironment in PDAC by promoting protumorigenic polarization of macrophages. In contrast, treatment with the FDA-approved Syk inhibitor R788 (fostamatinib) remodeled the tumor immune microenvironment, "re-educated" protumorigenic macrophages towards an immunostimulatory phenotype and boosted CD8+ T-cell responses in Gem-treated PDAC in orthotopic mouse models and an ex vivo human pancreatic slice culture model. These findings illustrate the potential of Syk inhibition for enhancing the antitumor immune responses in PDAC and support the clinical evaluation of R788 either alone or together with Gem as a potential treatment strategy for PDAC. SIGNIFICANCE: Syk blockade induces macrophage polarization to an immunostimulatory phenotype, which enhances CD8+ T-cell responses and improves gemcitabine efficacy in pancreatic ductal adenocarcinoma, a clinically challenging malignancy.

Association between age at diabetes onset or diabetes duration and subsequent risk of pancreatic cancer: Results from a longitudinal cohort and mendelian randomization study.

Background: The aim of the study is to estimate the incidence of pancreatic cancer among individuals with new-onset type 2 Diabetes (T2DM) and evaluate the relationship of pancreatic cancer risk with age at diabetes onset and diabetes duration. Methods: This longitudinal cohort study included 428,362 new-onset T2DM patients in Shanghai and Mendelian randomization (MR) in the east-Asian population were used to investigate the association. Incidence rates of pancreatic cancer in all patients and by subgroups were calculated and compared to the general population. Findings: A total of 1056 incident pancreatic cancer cases were identified during eight consecutive years of follow-up. The overall pancreatic cancer annual incidence rate was 55·28/100,000 person years in T2DM patients, higher than that in the general population, with a standardized incidence ratio (SIR) of 1·54 (95% confidence interval [CI], 1·45-1·64). The incidence of pancreatic cancer increased with age and a significantly higher incidence was observed in the older groups with T2DM. However, the relative pancreatic cancer risk was inversely related to age of T2DM onset, and a higher SIR of 5·73 (95%CI, 4·49-7·22) was observed in the 20-54 years old group. The risk of pancreatic cancer was elevated at any diabetes duration. Fasting blood glucose ≥10·0 mmol/L was associated with increased risk of pancreatic cancer. MR analysis indicated a positive association between T2DM and pancreatic cancer risk. Interpretation: Efforts toward early and close follow-up programs, especially in individuals with young-onset T2DM, and the improvement of glucose control might represent effective strategies for improving the detection and results of treatment of pancreatic cancer. Funding: Chinese National Natural Science Foundation.

Integrating Network Pharmacology and Transcriptomic Strategies to Explore the Pharmacological Mechanism of Hydroxysafflor Yellow A in Delaying Liver Aging.

Aging affects the structure and function of the liver. Hydroxysafflor yellow A (HSYA) effectively improves liver aging (LA) in mice, but the potential mechanisms require further exploration. In this study, an integrated approach combining network pharmacology and transcriptomics was used to elucidate the potential mechanisms of HSYA delay of LA. The targets of HSYA were predicted using the PharmMapper, SwissTargetPrediction, and CTD databases, and the targets of LA were collected from the GeneCards database. An ontology (GO) analysis and a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation of genes related to HSYA delay of LA were performed using the DAVID database, and Cytoscape software was used to construct an HSYA target pathway network. The BMKCloud platform was used to sequence mRNA from mouse liver tissue, screen differentially expressed genes (DEGs) that were altered by HSYA, and enrich their biological functions and signaling pathways through the OmicShare database. The results of the network pharmacology and transcriptomic analyses were combined. Then, quantitative real-time PCR (qRT-PCR) and Western blot experiments were used to further verify the prediction results. Finally, the interactions between HSYA and key targets were assessed by molecular docking. The results showed that 199 potentially targeted genes according to network pharmacology and 480 DEGs according to transcriptomics were involved in the effects of HSYA against LA. An integrated analysis revealed that four key targets, including HSP90AA1, ATP2A1, NOS1 and CRAT, as well as their three related pathways (the calcium signaling pathway, estrogen signaling pathway and cGMP-PKG signaling pathway), were closely related to the therapeutic effects of HSYA. A gene and protein expression analysis revealed that HSYA significantly inhibited the expressions of HSP90AA1, ATP2A1 and NOS1 in the liver tissue of aging mice. The molecular docking results showed that HSYA had high affinities with the HSP90AA1, ATP2A1 and NOS1 targets. Our data demonstrate that HSYA may delay LA in mice by inhibiting the expressions of HSP90AA1, ATP2A1 and NOS1 and regulating the calcium signaling pathway, the estrogen signaling pathway, and the cGMP-PKG signaling pathway.

Adaptive Fiber-Ring Lasers Based on Isopropanol Filled Microfiber Coupler for High-Sensitivity Temperature Sensing.

We demonstrated a new method for temperature measurement inside a fiber ring laser (FRL) cavity. Different from traditional FRL temperature sensing system which need additional filter working as a sensor, a micro-fiber coupler (MFC) was designed as a beam splitter, filter, and temperature sensor. In addition, isopropanol, a liquid with very high photothermal coefficient, is selectively filled in the MFC in order to improve the sensitivity of the system on temperature. In the dynamic range of 20-40 °C, we obtained a good temperature sensitivity of -1.29 nm/°C, with linear fitting up to 0.998. Benefiting from the advantages of laser sensing, the acquired laser has a 3 - dB bandwidth of less than 0.2 nm and a signal-to-noise ratio (SNR) of up to 40 dB. The proposed sensor has a low cost and high sensitivity, which is expected to be used in biomedical health detection, real-time monitoring of ocean temperature, and other application scenarios.

An Ex Vivo Organotypic Culture Platform for Functional Interrogation of Human Appendiceal Cancer Reveals a Prominent and Heterogenous Immunological Landscape.

PURPOSE: Epithelial neoplasms of the appendix are difficult to study preclinically given their low incidence, frequent mucinous histology, and absence of a comparable organ in mice for disease modeling. Although surgery is an effective treatment for localized disease, metastatic disease has a poor prognosis as existing therapeutics borrowed from colorectal cancer have limited efficacy. Recent studies reveal that appendiceal cancer has a genomic landscape distinct from colorectal cancer and thus preclinical models to study this disease are a significant unmet need. EXPERIMENTAL DESIGN: We adopted an ex vivo slice model that permits the study of cellular interactions within the tumor microenvironment. Mucinous carcinomatosis peritonei specimens obtained at surgical resection were cutoff using a vibratome to make 150-µm slices cultured in media. RESULTS: Slice cultures were viable and maintained their cellular composition regarding the proportion of epithelial, immune cells, and fibroblasts over 7 days. Within donor specimens, we identified a prominent and diverse immune landscape and calcium imaging confirmed that immune cells were functional for 7 days. Given the diverse immune landscape, we treated slices with TAK981, an inhibitor of SUMOylation with known immunomodulatory functions, in early-phase clinical trials. In 5 of 6 donor samples, TAK981-treated slices cultures had reduced viability, and regulatory T cells (Treg). These data were consistent with TAK981 activity in purified Tregs using an in vitro murine model. CONCLUSIONS: This study demonstrates an approach to study appendiceal cancer therapeutics and pathobiology in a preclinical setting. These methods may be broadly applicable to the study of other malignancies.

Immunogenetics of gastrointestinal cancers: A systematic review and retrospective survey of inborn errors of immunity in humans.

BACKGROUND AND AIM: Humans with inborn errors of immunity (IEI), or primary immunodeficiencies, may be associated with a potential risk factor for early-onset gastrointestinal (GI) cancer. METHODS: We systematically reviewed all cases with clinical diagnoses of both an IEI and a GI cancer in three databases (MEDLINE, SCOPUS, and EMBASE). In total, 76 publications satisfying our inclusion criteria were identified, and data for 149 cases were analyzed. We also searched our institutional cancer registry for such cases. RESULTS: We identified 149 patients with both an IEI and a GI cancer, 95 presented gastric cancer, 13 small bowel cancer, 35 colorectal cancer, and 6 had an unspecified cancer or cancer at another site. Gastric and colon adenocarcinomas were the most common. For both gastric and colorectal cancers, age at onset was significantly earlier in patients with IEIs than in the general population, based on the SEER database. Common variable immunodeficiency (CVID) was the most common IEI associated with gastrointestinal cancer. About 12% of patients had molecular genetic diagnoses, the three most frequently implicated genes being ATM, CARMIL2, and CTLA4. Impaired humoral immunity and Epstein-Barr virus (EBV) infection were frequently reported as factors potentially underlying early-onset GI cancers in patients with IEIs. We identified one patient with CVID and early-onset gastric adenocarcinoma, recurrent diarrhea, and gastrointestinal CMV infection from a retrospective survey. CONCLUSION: Patients with IEIs should be considered at risk of early-onset GI cancers and should therefore undergo cancer screening at an earlier age.

Safflower oil body nanoparticles deliver hFGF10 to hair follicles and reduce microinflammation to accelerate hair regeneration in androgenetic alopecia.

Androgenetic alopecia (AGA) affects physical and mental health with limited therapeutic options. Novel materials and delivery methods have considerable potential to improve the current paradigm of treatment. In this study, we used a novel plant nanoparticle of safflower oil body (SOB) loaded with human fibroblast growth factor 10 (hFGF10) to target hair follicles and accelerate hair regeneration in AGA mice with few adverse effects. Our data revealed that the average particle size of SOB-hFGF10 was 226.73 ± 9.98 nm, with a spherical and uniform structure, and that SOB-hFGF10 was quicker to preferentially penetrate into hair follicles than hFGF2 alone. Using a mouse model of AGA, SOB-hFGF10 was found to significantly improve hair regeneration without any significant toxicity. Furthermore, SOB-hFGF10 inhibited dihydrotestosterone (DHT)-induced TNF-α, IL-1ß, and IL-6 overproduction in macrophages in relation to hair follicle microinflammation, thereby enhancing the proliferation of dermal papilla cells. Overall, this study provides an applicable therapeutic method through targeting hair follicles and reducing microinflammation to accelerate hair regeneration in AGA.

Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice.

Obesity and its associated complications are highly related to a current public health crisis around the world. A growing body of evidence has indicated that G-protein coupled bile acid (BA) receptor TGR5 (also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders. We have identified notoginsenoside Ft1 (Ft1) from Panax notoginseng as an agonist of TGR5 in vitro. However, the pharmacological effects of Ft1 on diet-induced obese (DIO) mice and the underlying mechanisms are still elusive. Here we show that Ft1 (100 mg/100 diet) increased adipose lipolysis, promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1 (GLP-1) secretion in the ileum of wild type but not Tgr5 -/- obese mice. In addition, Ft1 elevated serum free and taurine-conjugated bile acids (BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues. The metabolic benefits of Ft1 were abolished in Cyp27a1 -/- mice which have much lower BA levels. These results identify Ft1 as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.

Bile acid signaling and bariatric surgery.

The rapid worldwide rise in obesity rates over the past few decades imposes an urgent need to develop effective strategies for treating obesity and associated metabolic complications. Bariatric surgical procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), currently provide the most effective treatment for obesity and type 2 diabetes (T2D), as well as for non-alcoholic steatohepatitis (NASH). However, the underlying mechanisms of the beneficial effects of bariatric surgery remain elusive. Recent studies have identified bile acids as potential signaling molecules involved in the beneficial effects of bariatric surgery. This review focuses on the most recent studies on the roles of bile acids and bile acid receptors Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 5 (TGR5) in bariatric surgery. We also discuss the possibility of modulating bile acid signaling as a pharmacological therapeutic approach to treating obesity and its associated metabolic complications.

Gender-related affecting factors of prediabetes on its 10-year outcome.

OBJECTIVE: To investigate the gender-related affecting factors of prediabetes on its 10-year outcome, in a longitudinal study. METHODS AND RESULTS: This longitudinal population-based study was performed in the Ping Liang community, Yangpu district, Shanghai, between November 2002 and October 2014. There were 334 participants with prediabetes enrolled in the final analysis. While a certain proportion of the prediabetic population progress to diabetes, the majority remain at the same level or even revert to normal glucose regulation. No gender difference was observed in the change of glucose regulation. However, results from an adjusted logistic regression analysis in males showed that physical activity was significantly associated with both elevated odds of reverting to normal glucose regulation (active vs inactive, OR 3.00, 95% CI 1.09 to 8.30) and developing diabetes (OR 0.34, 95% CI 0.13 to 0.92). Age, baseline 2 h glucose, triglycerides and smoking status were also risk factors significantly associated with diabetes development; while for females, waist circumference played a key role in the outcome. Every unit elevation of waist circumference was associated with lower odds of reverting to normal glucose regulation (OR, 0.94; 95% CI 0.89 to 0.98) and higher odds of progressing to diabetes (OR, 1.05; 95% CI 1.01 to 1.10). Baseline hypertension and family history of diabetes carried higher risk for developing diabetes as well. CONCLUSIONS: Physical activity in males and waist circumference in females are important factors predicting both progression to diabetes and regression to normal glucose regulation, indicating that more exercise for males and lower waist circumference for females are beneficial for prediabetes to achieve reversion.