Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.

Background The angiotensin‐receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin‐converting enzyme inhibitor enalapril in terms of reducing cardiovascular mortality in the PARADIGM‐HF (Prospective Comparison of ARNI with angiotensin‐converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study. However, the impact of ARNI on cardiac reverse remodeling (CRR) has not been established. Methods and Results We conducted a meta‐analysis to compare the effects of ARNI versus angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers on CRR indices. We searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Effect size was expressed as mean difference (MD) with 95% CIs. Twenty studies enrolling 10 175 patients were included. ARNI improved functional capacity in patients with heart failure (HF) and a reduced ejection fraction (EF), including increasing New York Heart Association functional class (MD −0.79, 95% CI −0.86, −0.71) and 6‐minute walking distance (MD 27.62 m, 95% CI 15.76, 39.48). ARNI outperformed angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. However, there were no significant improvements in indices except left ventricular mass index (MD −3.25 g/m 2 , 95% CI −3.78, −2.72) and left atrial volume (MD −7.20 mL, 95% CI −14.11, −0.29) in HF patients with preserved EF treated with ARNI. Improvements in CRR indices were observed at 3 months and became more significant with longer follow‐up to 12 months. The regression equation for the relationship between left ventricular EF and end‐diastolic dimension was y=0.041+0.071x+0.045x 2 +0.006x 3 . Conclusions ARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers in HF with reduced EF patients, even after short‐term follow‐up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as possible and for at least 3 months. Further large sample trials are required to determine the effects of ARNI on CRR in HF with preserved EF patients.

Background: To evaluate and compare the prognostic performance of four nutritional indicators body mass index (BMI), serum albumin (ALB), prognostic nutritional index (PNI) and nutritional risk index (NRI) in oral cancer patients, and to predict the response to chemotherapy in patients with different nutritional status. Methods: This prospective study which involved 1395 oral cancer patients was conducted in Fujian, China from September 2007 to November 2018. The BMI, PNI and NRI were calculated according to the following formulas: BMI = weight / height 2 (kg/m 2), PNI = albumin (g/l) + 0.005 × lymphocyte (count/μl) and NRI = (1.519 × albumin, g/ l) + (41.7× present/ideal body weight), respectively. The univariate and multivariate Cox proportional hazards models were used to compare the prognostic value of BMI, ALB, PNI and NRI in overall survival (OS) in oral cancer. Results: Patients with BMI < 18.5 kg/m 2 (VS 18.5 kg/m 2 ≤ BMI < 24 kg/m 2) had a poor survival outcome (HR = 1.585; 95% CI: 1.207-2.082). ALB, PNI, NRI were inversely correlated with OS of oral cancer (HR = 0.716; 95% CI: 0.575-0.891; HR = 0.793; 95% CI: 0.633-0.992; HR = 0.588; 95% CI: 0.469-0.738, respectively). In addition, the prognostic predictive performance of NRI was superior to BMI or ALB or PNI. Interestingly, compared with patients with better nutritional status, chemotherapy was significantly associated with poorer OS in malnourished oral cancer patients. Conclusions: BMI, ALB, PNI and NRI are of prognostic value in patients with oral cancer and the prognostic performance of NRI was superior to BMI or ALB or PNI. Malnutrition (BMI < 18.5 kg/m 2 or ALB< 40 g/l or PNI < 49.3 or NRI < 97.5) could predict an unfavorable response to chemotherapy in oral cancer patients.

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Whether circulating tumor cells (CTCs) can be used as an indicator of treatment response in breast cancer (BC) needs to be clarified. We addressed this issue by a meta-analysis. PubMed, EMBase and Cochrane library databases were searched in June 2016. Effect measures were estimated as pooled risk ratio (RR), odds ratio (OR) or mean difference by fixed- or random-effect models, according to heterogeneity of included studies. In total, 50 studies with 6712 patients were recruited. Overall analysis showed that there was a significant reduction of CTC-positive rate (RR = 0.68, 95% CI: 0.61–0.76, P < 0.00001) after treatment. Subgroup analyses revealed that neoadjuvant treatment, adjuvant treatment, metastatic treatment or combination therapy could reduce the CTC-positive rate, but surgery could not; moreover, the reduction was only found in HER2+ or HER2- patients but not in the triple-negative ones. Reduction of CTC-positive rate was associated with lower probability of disease progression (OR = 0.54, 95% CI: 0.33–0.89, P = 0.01) and longer overall survival period (mean difference = 11.61 months, 95% CI: 8.63–14.59, P < 0.00001) as well as longer progression-free survival period (mean difference = 5.07 months, 95% CI: 2.70–7.44, P < 0.0001). These results demonstrate that CTC status can serve as an indicator to monitor the effectiveness of treatments and guide subsequent therapies in BC.

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Sphingomonads DC-6 and DC-2 degrade the chloroacetanilide herbicides alachlor, acetochlor, and butachlor via N-dealkylation. In this study, we report a three-component Rieske non-heme iron oxygenase (RHO) system catalyzing the N-dealkylation of these herbicides. The oxygenase component gene cndA is located in a transposable element that is highly conserved in the two strains. CndA shares 24 to 42% amino acid sequence identities with the oxygenase components of some RHOs that catalyze N-or O-demethylation. Two putative [2Fe-2S] ferredoxin genes and one glutathione reductase (GR)-type reductase gene were retrieved from the genome of each strain. These genes were not located in the immediate vicinity of cndA. The four ferredoxins share 64 to 72% amino acid sequence identities to the ferredoxin component of dicamba O-demethylase (DMO), and the two reductases share 62 to 65% amino acid sequence identities to the reductase component of DMO. cndA, the four ferredoxin genes, and the two reductases genes were expressed in Escherichia coli, and the recombinant proteins were purified using Ni-affinity chromatography. The individual components or the components in pairs displayed no activity; the enzyme mixture showed Ndealkylase activities toward alachlor, acetochlor, and butachlor only when CndA-His 6 was combined with one of the four ferredoxins and one of the two reductases, suggesting that the enzyme consists of three components, a homo-oligomer oxygenase, a [2Fe-2S] ferredoxin, and a GR-type reductase, and CndA has a low specificity for the electron transport component (ETC). The N-dealkylase utilizes NADH, but not NADPH, as the electron donor.

BackgroundOccupational exposure to chromium compounds may result in adverse health effects. This study aims to investigate whether low-level hexavalent chromium (Cr(VI)) exposure can cause DNA damage in electroplating workers.Methods157 electroplating workers and 93 control subjects with no history of occupational exposure to chromium were recruited in Hangzhou, China. Chromium levels in erythrocytes were determined by graphite furnace atomic absorption spectrophotometer. DNA damage in peripheral lymphocytes was evaluated with the alkaline comet assay by three parameters: Olive tail moment, tail length and percent of DNA in the comet tail (tail DNA%). Urinary 8-OHdG levels were measured by ELISA.ResultsChromium concentration in erythrocytes was about two times higher in electroplating workers (median: 4.41 μg/L) than that in control subjects (1.54 μg/L, P < 0.001). The medians (range) of Olive tail moment, tail length and tail DNA% in exposed workers were 1.13 (0.14-6.77), 11.17 (3.46-52.19) and 3.69 (0.65-16.20), and were significantly higher than those in control subjects (0.14 (0.01-0.39), 3.26 (3.00-4.00) and 0.69 (0.04-2.74), P < 0.001). Urinary 8-OHdG concentration was 13.65 (3.08-66.30) μg/g creatinine in exposed workers and 8.31 (2.94-30.83) μg/g creatinine in control subjects (P < 0.001). The differences of urinary 8-OHdG levels, Olive tail moment, tail length and tail DNA% between these two groups remained significant (P < 0.001) even after stratification by potential confounding factors such as age, gender, and smoking status. Chromium exposure was found to be positively associated with chromium levels in erythrocytes, urinary 8-OHdG levels, Olive tail moment, tail length and tail DNA%. Positive dose-response associations were also found between chromium levels in erythrocytes and Olive tail moment, tail length and tail DNA%.ConclusionThe findings in this study indicated that there was detectable chromium exposure in electroplating workers. Low-level occupational chromium exposure induced DNA damage.