Association of circulating long-chain free fatty acids and incident diabetes risk among normoglycemic Chinese adults: a prospective nested case-control study.

BACKGROUND: Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking. OBJECTIVES: Our study aimed to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults. METHODS: This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using a targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes. RESULTS: The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1, and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95% CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18-26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95% CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR: 0.85; 95% CI: 0.76, 0.94), PUFAs 20:4 (OR: 0.84; 95% CI: 0.75, 0.94), and 24:2 (OR: 0.87; 95% CI: 0.78, 0.97) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 (95% CI: 0.61, 0.99; P = 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset. CONCLUSIONS: These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.

Observation of the Therapeutic Effect of Dual Antiplatelet Therapy with Aspirin and Clopidogrel on the Incidence, Characteristics, and Outcome in Acute Ischemic Stroke Patients with Cerebral Microbleeds at a Teaching Hospital, China.

Background: Cerebral microbleeds (CMBs) are an important risk factor for stroke recurrence and prognosis. However, there is no consensus on the safety of antiplatelet therapy in patients with ischemic stroke and CMBs. Objective: This study aimed to observe the effects of dual antiplatelet therapy with aspirin and clopidogrel on bleeding conversion in patients with different degrees of CMBs. Materials and Methods: An observational retrospective study was conducted on 160 patients with acute mild ischemic stroke admitted to the Stroke Center, Affiliated Hospital of Beihua University between March 2021 and December 2022. Patients were divided into the CMBs and non-CMB groups. The CMB group was then divided into the low, medium and high-risk groups. In two groups, all patients were administered dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg orally once a day for 21 days according to the Chinese Stroke Guidelines of 2018), and no other anticoagulant or antiplatelet drugs were administered during the treatment period. Head CT, National Institutes of Health Stroke Scale(NIHSS) and modified Rankin Scale (mRS) score were re-checked, and the number of bleeding conversions was calculated at 21 days. Results: Five patients in the CMB group had intracranial hemorrhage (5/116, 4.3%), while no intracranial hemorrhage was observed in the non-CMB group. There were no differences in the conversion rate of cerebral hemorrhage, NIHSS score, or mRS score between two groups after dual antiplatelet therapy (p>0.05). The conversion rate of cerebral hemorrhage in the high-risk group was higher than that in the non-CMB group (p<0.05), but the NIHSS and mRS score showed no difference between the high-risk and non-CMB groups (p>0.05). Conclusion: Dual antiplatelet therapy with aspirin and clopidogrel does not significantly increase the risk of bleeding transformation; however, it improves neurological recovery or long-term prognosis in patients with acute ischemic cerebral stroke complicated by low-risk and middle-risk CMBs.

Brain tissue- and cell type-specific eQTL Mendelian randomization reveals efficacy of FADS1 and FADS2 on cognitive function.

Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (FADS) gene, which play a key role in regulating omega-3 fatty acids biosynthesis, on cognitive function is unclear. Hence, we used two-sample Mendelian randomization (MR) to estimate the gene-specific causal effect of omega-3 fatty acids (N = 114,999) on cognitive function (N = 300,486). Tissue- and cell type-specific effects of FADS1/FADS2 expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx, N ≤ 209; MetaBrain, N ≤ 8,613) and single cell cis-eQTL data (N = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data (N ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a FADS gene-specific effect of omega-3 fatty acids on cognitive function [ß = -1.3 × 10-2, 95% confidence interval (CI) (-2.2 × 10-2, -5 × 10-3), P = 2 × 10-3]. Tissue-specific MR showed an effect of increased FADS1 expression in cerebellar hemisphere and FADS2 expression in nucleus accumbens basal ganglia on maintaining cognitive function, while decreased FADS1 expression in nine brain tissues on maintaining cognitive function [colocalization probability (PP.H4) ranged from 71.7% to 100.0%]. Cell type-specific MR showed decreased FADS1/FADS2 expression in oligodendrocyte was associated with maintaining cognitive function (PP.H4 = 82.3%, respectively). Increased FADS1/FADS2 expression in whole blood showed an effect on cognitive function maintenance (PP.H4 = 86.6% and 88.4%, respectively). This study revealed putative causal effect of FADS1/FADS2 expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize FADS gene as potential target gene for maintenance of cognitive function.

An open, multicenter, exploratory study of apatinib mesylate maintenance therapy for recurrent/metastatic head and neck squamous cell carcinoma (ChiCTR1800019375).

BACKGROUND: This study evaluated the efficacy of apatinib in maintenance therapy in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). METHODS: Twenty-six patients from three centers were enrolled from November 2018 to September 2021. These patients received 2 weeks apatinib, administered at 250 mg qd. Then apatinib dose may be administered to 500 mg qd continuous in 4 weeks cycle if no patients experienced adverse reaction. Enrolled patients can receive a combination of radiotherapy or chemotherapy. The primary endpoints were progression-free survival (PFS), and secondary endpoints included overall survival (OS), disease control rate (DCR), objective response rate (ORR), quality of life (QOL) score, and adverse drug reactions. RESULTS: Median PFS of all patients was 3.2 months (95% CI: 2.06-4.33). Median OS of all patients was 7.3 months (95% CI: 2.14-12.46). The DCR was 92.3%. The ORR was 30.8%. In univariate analysis, the results showed that ECOG score 0-1 (HR = 0.31, p = 0.006) and treated with apatinib for more than 60 days (HR = 0.31, p = 0.003) were independent prognostic indicators affecting PFS, and ECOG score 0-1 (HR = 0.40, p = 0.027) and moderately differentiated or highly differentiated (HR = 0.38, p = 0.048) were independent prognostic indicators of OS. The most common adverse events among treated subjects included hypertension (46.1%), fatigue (42.3%), and hand-foot syndrome (23.1%). There were only two cases (7.7%) of Grade III or above adverse reactions. CONCLUSIONS: Maintenance therapy with apatinib is an effective and well-tolerated regimen in patients with R/M HNSCC.

Early-life famine exposure, adulthood obesity patterns, and risk of low-energy fracture.

Malnutrition in early life increases the risk of osteoporosis, but the association of early-life undernutrition combined with adulthood obesity patterns with low-energy fracture remains unknown. This study included 5323 community-dwelling subjects aged ⩾40 years from China. Early-life famine exposure was identified based on the participants' birth dates. General obesity was assessed using the body mass index (BMI), and abdominal obesity was evaluated with the waist-to-hip ratio (WHR). Low-energy fracture was defined as fracture occurring after the age of ⩾40 typically caused by falls from standing height or lower. Compared to the nonexposed group, the group with fetal, childhood, and adolescence famine exposure was associated with an increased risk of fracture in women with odds ratios (ORs) and 95% confidence intervals (CIs) of 3.55 (1.57-8.05), 3.90 (1.57-9.71), and 3.53 (1.05-11.88), respectively, but not in men. Significant interactions were observed between fetal famine exposure and general obesity with fracture among women (P for interaction = 0.0008). Furthermore, compared with the groups with normal BMI and WHR, the group of women who underwent fetal famine exposure and had both general and abdominal obesity had the highest risk of fracture (OR, 95% CI: 3.32, 1.17-9.40). These results indicate that early-life famine exposure interacts with adulthood general obesity and significantly increases the risk of low-energy fracture later in life in women.

Evaluating the Effects of Omega-3 Polyunsaturated Fatty Acids on Inflammatory Bowel Disease via Circulating Metabolites: A Mediation Mendelian Randomization Study.

Epidemiological evidence regarding the effect of omega-3 polyunsaturated fatty acid (PUFA) supplementation on inflammatory bowel disease (IBD) is conflicting. Additionally, little evidence exists regarding the effects of specific omega-3 components on IBD risk. We applied two-sample Mendelian randomization (MR) to disentangle the effects of omega-3 PUFAs (including total omega-3, α-linolenic acid, eicosapentaenoic acid (EPA), or docosahexaenoic acid (DHA)) on the risk of IBD, Crohn's disease (CD) and ulcerative colitis (UC). Our findings indicated that genetically predicted increased EPA concentrations were associated with decreased risk of IBD (odds ratio 0.78 (95% CI 0.63-0.98)). This effect was found to be mediated through lower levels of linoleic acid and histidine metabolites. However, we found limited evidence to support the effects of total omega-3, α-linolenic acid, and DHA on the risks of IBD. In the fatty acid desaturase 2 (FADS2) region, robust colocalization evidence was observed, suggesting the primary role of the FADS2 gene in mediating the effects of omega-3 PUFAs on IBD. Therefore, the present MR study highlights EPA as the predominant active component of omega-3 fatty acids in relation to decreased risk of IBD, potentially via its interaction with linoleic acid and histidine metabolites. Additionally, the FADS2 gene likely mediates the effects of omega-3 PUFAs on IBD risk.

Efficacy and safety of nintedanib in patients with non-small cell lung cancer, and novel insights in radiation-induced lung toxicity.

Nintedanib is a tyrosine kinase inhibitor of fibroblast growth factor-, vascular endothelial growth factor-, and platelet-derived growth factor receptors. These three receptors promote new blood vessel formation and maintenance, which is essential for tumor growth and spread. Several trials have shown that nintedanib plays a substantial role in treating patients with non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis. Recently, several clinical trials of nintedanib to treat NSCLC have been reported. In this review, we focus on our current understanding of nintedanib treatment for advanced NSCLC patients and summarize the literature on using nintedanib in radiation-induced lung toxicity and the efficacy and tolerability of nintedanib.

Plasma protein biomarkers trailblaze as early predictors of type 1 diabetes.

Nakayasu et al.'s investigation1 on children from TEDDY study revealed robust predictive value of plasma protein biomarkers in identifying the emergence of persistent autoantibodies and type 1 diabetes. Remarkably, this predictive accuracy was observed six months prior to autoimmunity initiation.

Platelet-rich plasma alleviates knee arthritis in rats by inhibiting p65.

Knee osteoarthritis (KOA) is a chronic joint disease characterized by the degeneration of articular cartilage. In this study, we explored the potential therapeutic effects of platelet-rich plasma (PRP) and identified molecular targets for treating KOA. A rat model of KOA was established via the Hulth method and primary knee joint chondrocytes were isolated to evaluate the effects of PRP and shRNA targeting p65 (sh-p65). ELISA was used to detect inflammatory factors, including IL-6, IL-1ß, and TNF-α. HE staining, Safranin O/Fast Green staining and Masson staining were performed to evaluate the morphology of articular cartilage, followed by detection of p65, COL2A1, ACAN, MMP13, and ADAMTS5 expression. The proliferation and apoptosis of primary knee chondrocytes were detected by the CCK-8 assay and TUNEL staining, respectively. Treatment with either PRP or sh-p65 decreased IL-6, IL-1ß, and TNF-α levels in the peripheral blood of KOA rats and chondrocyte culture supernatants, increased COL2A1 and ACAN levels, and decreased MMP13 and ADAMTS5 expression. Furthermore, administration of PRP or sh-p65 exerted protective effects on articular cartilage, enhanced the vitality of knee joint chondrocytes, and inhibited apoptosis. Collectively, PRP inhibited inflammation, promoted chondrocyte proliferation and cartilage matrix secretion, and induced cartilage regeneration by suppressing p65 expression; these effects allow PRP to alleviate KOA progression. P65-based targeted therapy administered in combination with PRP might be a promising strategy for treating KOA.

Evaluating the distinct pleiotropic effects of omega-3 fatty acids on type 2 diabetes mellitus: a mendelian randomization study.

BACKGROUND: Observational studies and conventional Mendelian randomization (MR) studies showed inconclusive evidence to support the association between omega-3 fatty acids and type 2 diabetes. We aim to evaluate the causal effect of omega-3 fatty acids on type 2 diabetes mellitus (T2DM), and the distinct intermediate phenotypes linking the two. METHODS: Two-sample MR was performed using genetic instruments derived from a recent genome-wide association study (GWAS) of omega-3 fatty acids (N = 114,999) from UK Biobank and outcome data obtained from a large-scale T2DM GWAS (62,892 cases and 596,424 controls) in European ancestry. MR-Clust was applied to determine clustered genetic instruments of omega-3 fatty acids that influences T2DM. Two-step MR analysis was used to identify potential intermediate phenotypes (e.g. glycemic traits) that linking omega-3 fatty acids with T2DM. RESULTS: Univariate MR showed heterogenous effect of omega-3 fatty acids on T2DM. At least two pleiotropic effects between omega-3 fatty acids and T2DM were identified using MR-Clust. For cluster 1 with seven instruments, increasing omega-3 fatty acids reduced T2DM risk (OR: 0.52, 95%CI 0.45-0.59), and decreased HOMA-IR (ß = - 0.13, SE = 0.05, P = 0.02). On the contrary, MR analysis using 10 instruments in cluster 2 showed that increasing omega-3 fatty acids increased T2DM risk (OR:1.10; 95%CI 1.06-1.15), and decreased HOMA-B (ß = - 0.04, SE = 0.01, P = 4.52 × 10-5). Two-step MR indicated that increasing omega-3 fatty acid levels decreased T2DM risk via decreasing HOMA-IR in cluster 1, while increased T2DM risk via decreasing HOMA-B in cluster 2. CONCLUSIONS: This study provides evidence to support two distinct pleiotropic effects of omega-3 fatty acids on T2DM risk influenced by different gene clusters, which could be partially explained by distinct effects of omega-3 fatty acids on insulin resistance and beta cell dysfunction. The pleiotropic feature of omega-3 fatty acids variants and its complex relationships with T2DM need to be carefully considered in future genetic and clinical studies.

Data-driven subgroups of prediabetes and the associations with outcomes in Chinese adults.

Prediabetes and its pathophysiology remain important issues. We aimed to examine the cluster characteristics of prediabetes and explore their associations with developing diabetes and its complications based on 12 variables representing body fat, glycemic measures, pancreatic ß cell function, insulin resistance, blood lipids, and liver enzymes. A total of 55,777 individuals with prediabetes from the China Cardiometabolic Disease and Cancer Cohort (4C) were classified at baseline into six clusters. During a median of 3.1 years of follow-up, significant differences in the risks of diabetes and its complications between clusters were observed. The odds ratios of diabetes stepwisely increase from cluster 1 to cluster 6. Clusters 1, 4, and 6 have increased chronic kidney diseases risks, while the prediabetes in cluster 4, characterized by obesity and insulin resistance, confers higher risks of cardiovascular diseases compared with others. This subcategorization has potential value in developing more precise strategies for targeted prediabetes prevention and treatment.

Reproductive Toxicity and Teratogenicity of Fluorene-9-bisphenol on Chinese Medaka (Oryzias sinensis): A Study from Laboratory to Field.

Fluorene-9-bisphenol (BHPF), a bisphenol A (BPA) substitute, has been increasingly used as a material in syntheses of polymers that are widely used in road markings, artificial tracks, coating floors, building paints, etc., increasing the likelihood of BHPF contamination in the aquatic environment due to its release from the products. However, to date, it is unknown whether it may have actual impacts on fish in real environments. In this study, a 105-day exposure experiment of BHPF at various concentrations (0.01, 0.1, 1, and 10 µg/L) on Chinese medaka (Oryzias sinensis) was performed under laboratory conditions and found decreased fecundity, such as lower egg qualities and quantities, retarded oogenesis, and atretic follicles in the fish and deformed eyes and bodies in its F1 generation. Toxico-transcriptome analyses showed that estrogen-responsive genes were significantly suppressed by BHPF, indicating that antagonist properties of BHPF on estrogen receptors might be causes for the decreased fecundity. Field investigations (Beijing) demonstrated that BHPF was detectable in 60% surface waters, with a mean concentration of 10.49 ± 6.33 ng/L, by gas chromatography-mass spectrometry, and similar effects in wild Chinese medaka were also observed, some of which the parameters were found to be obviously correlated with the BHPF levels in corresponding waters.

Secukinumab attenuates neuroinflammation and neurobehavior defect via PKCß/ERK/NF-κB pathway in a rat model of GMH.

AIMS: Germinal matrix hemorrhage (GMH) is a disastrous clinical event for newborns. Neuroinflammation plays an important role in the development of neurological deficits after GMH. The purpose of this study is to investigate the anti-inflammatory role of secukinumab after GMH and its underlying mechanisms involving PKCß/ERK/NF-κB signaling pathway. METHODS: A total of 154 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. Secukinumab was administered intranasally post-GMH. PKCß activator PMA and p-ERK activator Ceramide C6 were administered intracerebroventricularly at 24 h prior to GMH induction, respectively. Neurobehavioral tests, western blot and immunohistochemistry were used to evaluate the efficacy of Secukinumab in both short-term and long-term studies. RESULTS: Endogenous IL-17A, IL-17RA, PKCß and p-ERK were increased after GMH. Secukinumab treatment improved short- and long-term neurological outcomes, reduced the synthesis of MPO and Iba-1 in the perihematoma area, and inhibited the synthesis of proinflammatory factors, such as NF-κB, IL-1ß, TNF-α and IL-6. Additionally, PMA and ceramide C6 abolished the beneficial effects of Secukinumab. CONCLUSION: Secukinumab treatment suppressed neuroinflammation and attenuated neurological deficits after GMH, which was mediated through the downregulation of the PKCß/ERK/NF-κB pathway. Secukinumab treatment may provide a promising therapeutic strategy for GMH patients.

Genome and transcriptome of Chinese medaka (Oryzias sinensis) and its uses as a model fish for evaluating estrogenicity of surface water.

Ecological toxicity assessments of contaminants in aquatic environments are of great concern. However, a dilemma in ecological toxicity assessments often arises when linking the effects found in model animals in the laboratory and the phenomena observed in wild fishes in the field due to species differences. Chinese medaka (Oryzias sinensis), widely distributed in East Asia, is a satisfactory model animal to assess aquatic environment in China. Here, we domesticated this species and assembled its genome (814 Mb) using next-generation sequencing (NGS). A total of 21,922 high-confidence genes with 41,306 transcripts were obtained and annotated, and their expression patterns in tissues were determined by RNA-sequencing. Six mostly sensitive biomarker genes, including vtg1, vtg3, vtg6, zp3a.2, zp2l1, and zp2.3 to estrogen exposure were screened and validated in the fish exposed to concentrations of estrone (E1), 17ß-estradiol (E2), and estriol (E3) under laboratory condition. Field investigations were then performed to evaluating the gene expression of biomarkers in wild Chinese medaka and levels of E1, E2, and E3 in the fish habitats. It was found that in 40 sampling sites, the biomarker genes were obviously highly expressed in the wild fish from about half sites, and the detection frequencies of E1, E2, and E3, were 97.5%, 42.5%, and 45% with mean concentrations of 82.48, 43.17, 52.69 ng/L, respectively. Correlation analyses of the biomarker gene expressions in the fish with the estrogens levels which were converted to EEQs showed good correlation, indicating that the environmental estrogens and estrogenicity of the surface water might adversely affect wild fishes. Finally, histologic examination of gonads in male wild Chinese medaka was performed and found the presence of intersex in the fish. This study facilitated the uses of Chinese medaka as a model animal for ecotoxicological studies.

Association of serum secreted protein acidic and rich in cysteine-like protein 1 with metabolic measures and dyslipidemia among Chinese adults.

Objectives: Recent studies found that secreted protein acidic and rich in cysteine-like protein 1 (Sparcl1) could inhibit lipid droplets accumulation by peroxisome proliferator-activated receptor-gamma (PPARγ) signal pathway. However, the associations of serum Sparcl1 level with lipids profiles and other metabolic phenotypes remain unknown in human population study. Methods: We determined serum Sparcl1 using sandwich enzyme-linked immunosorbent assays among 1750 adults aged 40 years and older from a community in Shanghai, China. Generalized linear regression models were used to evaluate the association between Sparcl1 and metabolic measures. Multivariable-adjusted logistic regression analyses were performed to evaluate the relationship of serum Sparcl1 with prevalent dyslipidemia. Results: With the increment of serum Sparcl1, participants tended to have lower level of triglycerides, and higher level of high-density lipoprotein cholesterol (all P for trend < 0.01). No significant associations between serum Sparcl1 and glucose, blood pressure, or body size were observed. The generalized linear regression models suggested that per standard deviation (SD) increment of serum Sparcl1 was significantly inversely associated with triglycerides (ß= -0.06, P=0.02). The prevalence of dyslipidemia decreased across the sparcl1 quartiles (P for trend <0.01). After controlling the potential confounders, participants in the highest quartile of sparcl1 concentration had the lowest prevalence of dyslipidemia (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.52-0.91), compared with the lowest quartile. Per SD increment of Sparcl1 was associated with 20% (OR, 0.80; 95%CI, 0.69-0.94) lower prevalence of hypertriglyceridemia and 12% (OR, 0.88; 95%CI, 0.79-0.97) lower prevalence of dyslipidemia. The association between serum Sparcl1 and dyslipidemia were generally consistent across subgroups (all P for interaction > 0.05). Conclusion: Serum Sparcl1 was significantly associated with decreased risk of prevalent dyslipidemia in Chinese population. Further studies are warranted to confirm this association.

Efficacy and safety of apatinib in patients with recurrent or metastatic head and neck squamous cell carcinoma: a retrospective multi-center study.

Apatinib is a novel antiangiogenic agent that targets vascular endothelial growth factor 2. The aim of our study was to explore the efficacy and safety of apatinib in the treatment of patients with recurrence or metastasis (R/M) inoperable head and neck squamous cell carcinoma (HNSCC). This multi-center retrospective study analyzed 53 cases of recurrent or metastatic inoperable HNSCC who had progressed or recurred after undergoing standard radiotherapy, chemotherapy, and immunotherapy treated with apatinib from March 2017 to August 2021. Patients continued apatinib until the time of disease progression or onset of intolerable adverse events. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and disease control rate (DCR) and incidence of adverse events. Univariable and multivariable analyses were performed to determine prognostic factors. The main adverse events were counted, and the severity of the adverse reactions was evaluated. Fifty-three patients with recurrent or metastatic inoperable R/M HNSCC who had progressed or recurred after standard radiotherapy, chemotherapy, and immunotherapy were included. The ORR was 15.1%, and the DCR was 86.8%. The median PFS was 4.4 months (95% confidence interval [CI] 3.7-5.0 months) and the median OS was 6.6 months (95% CI 5.3-7.9 months). The number of apatinib lines was an influencing factor for both PFS and OS, and the Eastern Cooperative Oncology Group (ECOG) score, tumor differentiation, and apatinib duration were only the influencing factors for OS. Of these, only the ECOG score was an independent predictor of OS. The most common adverse reactions were hypertension (39.6%), hand-foot syndrome (32.1%), fatigue (32.1%), oral ulcers (28.3%), and nausea and vomiting (20.8%). Most adverse reactions were grade 1 or 2. Apatinib mesylate has good efficacy for recurrent/metastatic inoperable HNSCC as second-line and above-line treatment. ECOG score was an independent prognostic factors of OS in patients who were treated with apatinib. In addition, the adverse effects of apatinib mesylate were relatively mild.

4,4'-(9-Fluorenylidene)dianiline (BAFL) is antiestrogenic and has adverse effects on female development in CD-1 mice.

Many phenolic compounds have been found to have endocrine disrupting activities, but their arylamine analogs, the phenolic hydroxyl groups substituted by aniline amino groups, have rarely been reported. 4,4'-(9-Fluorenylidene)dianiline (BAFL) is an arylamine analog of fluorene-9-bisphenol (BHPF) and BHPF has been reported to be a strong antiestrogen which could cause endometrial atrophy, ovarian damage and adverse pregnancy outcomes in animals. BAFL has been widely used as material to synthetize polymers, such as polyimides, polyamide, and polyamine, for various uses since the 1970s. Here, we assessed the antiestrogenicity of BAFL using a variety of methods and looked into its impacts on the development of females in CD-1 mice. With the aid of a yeast estrogen screen assay, we found BAFL possessed obviously antiestrogenic activity (IC50 = 8.15 × 10-6 M), which close to that of tamoxifen and BHPF. Using a 10-d mouse uterotrophic assay, we found that BAFL obviously decreased uterine weight in a dose-dependent way. Histological analyses of mouse uteri revealed that BAFL induced marked endometrial atrophy and inhibited the uterine development. Immunohistochemical analyses showed that Sprr2d, an estrogen-responsive gene encoding protein, was mainly expressed in endometrial epithelial cells and BAFL decreased the areas and levels of Sprr2d staining in mouse uteri. It was clear from uterine transcriptome investigations that BAFL significantly downregulated the expressions of multiple genes responding to estrogen. Molecular docking showed that BAFL could effectively occupy the antagonist-binding pocket of hERα, and one of the amino groups of BAFL formed hydrogen bonds with the side chains of Arg394 and Glu353 in the receptor. These results indicated that BAFL exhibited clearly antiestrogenic characteristics and could interfere with normal female development in mice, which should be avoided using in commodities that come into direct contact with humans. Moreover, this study indicated that the arylamine analogs of phenolic endocrine disrupting chemicals might also have endocrine disrupting activities.

Biosynthesis of value-added bioproducts from hemicellulose of biomass through microbial metabolic engineering.

Hemicellulose is the second most abundant carbohydrate in lignocellulosic biomass and has extensive applications. In conventional biomass refinery, hemicellulose is easily converted to unwanted by-products in pretreatment and therefore can't be fully utilized. The present study aims to summarize the most recent development of lignocellulosic polysaccharide degradation and fully convert it to value-added bioproducts through microbial and enzymatic catalysis. Firstly, bioprocess and microbial metabolic engineering for enhanced utilization of lignocellulosic carbohydrates were discussed. The bioprocess for degradation and conversion of natural lignocellulose to monosaccharides and organic acids using anaerobic thermophilic bacteria and thermostable glycoside hydrolases were summarized. Xylose transmembrane transporting systems in natural microorganisms and the latest strategies for promoting the transporting capacity by metabolic engineering were summarized. The carbon catabolite repression effect restricting xylose utilization in microorganisms, and metabolic engineering strategies developed for co-utilization of glucose and xylose were discussed. Secondly, the metabolic pathways of xylose catabolism in microorganisms were comparatively analyzed. Microbial metabolic engineering for converting xylose to value-added bioproducts based on redox pathways, non-redox pathways, pentose phosphate pathway, and improving inhibitors resistance were summarized. Thirdly, strategies for degrading lignocellulosic polysaccharides and fully converting hemicellulose to value-added bioproducts through microbial metabolic engineering were proposed.

Association between triglyceride glucose index and carotid intima-media thickness in obese and nonobese adults.

BACKGROUND: The triglyceride glucose (TyG) index is closely associated with subclinical atherosclerosis. However, the association remains inconclusive among obese and nonobese individuals. METHODS: This prospective study was conducted in 5751 adults with normal carotid intima-media thickness (CIMT) at baseline. We divided the population into four groups based on the TyG index, which was calculated by the following formula: Ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Information on CIMT was acquired by ultrasonography. Incident elevated CIMT was defined as IMT values greater than 0.9 mm at follow-up. Odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between TyG index and elevated CIMT were estimated using multivariable logistic regression models. RESULTS: After a median follow-up of 4.3 years, 722 (12.6%) individuals had progressed to elevated CIMT. Compared with the second quartile of the TyG index, the first and fourth quartile both conferred higher risks of elevated CIMT after adjusting for potential confounders. In the total population, the ORs for the first and fourth quartile were 1.29 (95% CI, 1.00-1.66) and 1.42 (95% CI, 1.11-1.83), respectively. Restricted cubic splines demonstrated an approximately U-shaped association between TyG index and elevated CIMT among the total and nonobese adults (P for nonlinearity <.05), but not in those with general or abdominal obesity. CONCLUSIONS: A U-shaped association was observed between TyG index and elevated CIMT only among nonobese Chinese adults.