A new strategy for immunotherapy of microsatellite-stable (MSS)-type advanced colorectal cancer: Multi-pathway combination therapy with PD-1/PD-L1 inhibitors.

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)-microsatellite instability-low (MSI-L)/microsatellite stable (MSS) CRC known as 'cold' tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi-pathway regimens combined with PD-1/PD-L1 inhibitors can enhance the efficacy of anti-PD-1/PD-L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD-L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD-1/PD-L1 inhibitors in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR-MSI-L/MSS CRC.

Associations of a proinflammatory diet, habitual salt intake, and the onset of type 2 diabetes: A prospective cohort study from the UK Biobank.

AIM: To explore the relationship between proinflammatory diet, habitual salt intake and the onset of type 2 diabetes. METHODS: This prospective study was conducted among 171 094 UK Biobank participants who completed at least one 24-h dietary questionnaire and were free of diabetes at baseline. Participants were followed up until 1 March 2023 for type 2 diabetes incidence, with diagnosis information obtained from linked medical records. An Energy-adjusted Diet Inflammatory Index (E-DII) was calculated based on 28 food parameters. Habitual salt intake was determined through the self-reported frequency of adding salt to foods. The associations between E-DII, habitual salt intake and type 2 diabetes incidence were tested by the Cox proportional hazard regression model. RESULTS: Over a median follow-up period of 13.5 years, 6216 cases of type 2 diabetes were documented. Compared with participants with a low E-DII (indicative of an anti-inflammatory diet), participants with a high E-DII (indicative of a proinflammatory diet) had an 18% heightened risk of developing type 2 diabetes. The association between E-DII and type 2 diabetes tends to be linear after adjustment for major confounders. Participants with a proinflammatory diet and always adding salt to foods had the highest risk of type 2 diabetes incidence (hazard ratio 1.60, 95% confidence interval 1.32-1.94). CONCLUSIONS: Our findings indicate that a proinflammatory diet and higher habitual salt intake were associated with an increased risk of type 2 diabetes. These results support the public health promotion of an anti-inflammatory diet and reducing salt intake to prevent the onset of type 2 diabetes.

An applicability study of rapid artificial intelligence-assisted compressed sensing (ACS) in anal fistula magnetic resonance imaging.

Objective: To evaluate the applicability of artificial intelligence-assisted compressed sensing (ACS) to anal fistula magnetic resonance imaging (MRI). Methods: 51 patients were included in this study and underwent T2-weighted sequence of MRI examinations both with ACS and without ACS technology in a 3.0 T MR scanner. Subjective image quality scores, and objective image quality-related metrics including scanning time, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR), were evaluated and statistically compared between the images collected with and without ACS. Results: No significant difference in the subjective image quality of lesion conspicuity was observed between the two groups. However, ACS MRI decreased the acquisition time with regard to control group (74.00 s vs. 156.00 s). Besides, SNR of perianal and muscle in the ACS group was significantly higher than that of the control group (164.07 ± 33.35 vs 130.81 ± 29.10, p < 0.001; 109.87 ± 22.01 vs 87.61 ± 17.95, p < 0.001; respectively). The CNR was significantly higher in the ACS group than in the control group (54.02 ± 23.98 vs 43.20 ± 21.00; p < 0.001). Moreover, the accuracy rate of the ACS groups in evaluating the direction and internal opening of the fistula was 88.89 %, exactly the same as that of the control group. Conclusion: We demonstrated the applicability of using ACS to accelerate MR of anal fistulas with improved SNR and CNR. Meanwhile, the accuracy rates of the ACS group and the control were equivalent in evaluating the direction and internal opening of the fistula, based on the results of surgical exploration.

Development and validation of a nomogram for predicting in-hospital mortality of patients with cervical spine fractures without spinal cord injury.

BACKGROUND: The incidence of cervical spine fractures is increasing every day, causing a huge burden on society. This study aimed to develop and verify a nomogram to predict the in-hospital mortality of patients with cervical spine fractures without spinal cord injury. This could help clinicians understand the clinical outcome of such patients at an early stage and make appropriate decisions to improve their prognosis. METHODS: This study included 394 patients with cervical spine fractures from the Medical Information Mart for Intensive Care III database, and 40 clinical indicators of each patient on the first day of admission to the intensive care unit were collected. The independent risk factors were screened using the Least Absolute Shrinkage and Selection Operator regression analysis method, a multi-factor logistic regression model was established, nomograms were developed, and internal validation was performed. A receiver operating characteristic (ROC) curve was drawn, and the area under the ROC curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the discrimination of the model. Moreover, the consistency between the actual probability and predicted probability was reflected using the calibration curve and Hosmer-Lemeshow (HL) test. A decision curve analysis (DCA) was performed, and the nomogram was compared with the scoring system commonly used in clinical practice to evaluate the clinical net benefit. RESULTS: The nomogram indicators included the systolic blood pressure, oxygen saturation, respiratory rate, bicarbonate, and simplified acute physiology score (SAPS) II. The results showed that our model had satisfactory predictive ability, with an AUC of 0.907 (95% confidence interval [CI] = 0.853-0.961) and 0.856 (95% CI = 0.746-0.967) in the training set and validation set, respectively. Compared with the SAPS-II system, the NRI values of the training and validation sets of our model were 0.543 (95% CI = 0.147-0.940) and 0.784 (95% CI = 0.282-1.286), respectively. The IDI values of the training and validation sets were 0.064 (95% CI = 0.004-0.123; P = 0.037) and 0.103 (95% CI = 0.002-0.203; P = 0.046), respectively. The calibration plot and HL test results confirmed that our model prediction results showed good agreement with the actual results, where the HL test values of the training and validation sets were P = 0.8 and P = 0.95, respectively. The DCA curve revealed that our model had better clinical net benefit than the SAPS-II system. CONCLUSION: We explored the in-hospital mortality of patients with cervical spine fractures without spinal cord injury and constructed a nomogram to predict their prognosis. This could help doctors assess the patient's status and implement interventions to improve prognosis accordingly.

Association between glycemia risk index and arterial stiffness in type 2 diabetes.

AIM: This study aims to investigate the association of glycemia risk index (GRI), a novel composite metric derived from continuous glucose monitoring (CGM), with arterial stiffness in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 342 adults with type 2 diabetes were enrolled between April and June 2023 from 11 communities in Shanghai, China. Medical examinations, including measurements of anthropometric parameters, blood pressure, and venous blood samples were conducted. Brachial-ankle pulse wave velocity (baPWV) was examined to evaluate arterial stiffness. All the participants underwent a 14 day CGM recording and GRI was calculated from the CGM data. RESULTS: The mean age was 70.3 ± 6.8 years, and 162 (47.4%) were male. Participants with a higher baPWV had significantly higher levels of GRI and hyperglycemia component (both P for trend < 0.05). Linear regression revealed the significant positive linear associations of the GRI with baPWV in unadjusted or adjusted models (All P < 0.05). In the multivariable logistic analysis, each increase in the GRI quartile was associated with a 1.30-fold (95% CI 1.01-1.68, P for trend < 0.05) higher prevalence of increased arterial stiffness after adjustment for age, sex, BMI, diabetes duration, current smoking status, blood pressure, and lipid profile. Subgroup analyses showed that the association between the GRI quartiles and increased arterial stiffness was stronger among participants with a diabetes duration ≥15 years (P for interaction = 0.014). CONCLUSION: Glycemia risk index assessed by continuous glucose monitoring is associated with increased arterial stiffness in type 2 diabetes.

Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice.

BACKGROUND: Low-carbohydrate diet (LCD) is effective for weight loss and glycaemic control in humans. Here, the study aimed to explore the effects of LCD/high-fat diet (HFD) in both humans and mice. METHODS: Twenty-two overweight or obese participants received LCD for 3 weeks. Based on carbohydrate intake > 10% or ≤ 10% of calories, the participants were divided into moderate LCD (MLCD) and very LCD (VLCD) groups. The participants completed a 10-question food preference survey. Meanwhile, C57BL/6J mice were assigned to five groups: chow diet (CD, 10% fat), HFD with 60%, 70%, and 75% fat from cocoa butter (HFD-C), and HFD with 60% fat from lard (HFD-L) and fed for 24 weeks. Eight mice were acclimatised for the food-choice test. RESULTS: LCD decreased the total energy intake in humans. The VLCD group showed greater weight loss and better glycaemic control than the MLCD group. A food preference survey showed that 65% of participants tended to choose high-carbohydrate foods. In mice, HFD resulted in energy overconsumption, obesity, and metabolic disorders. When CD and HFD-L were administered simultaneously, mice rarely consumed CD. In the HFD-C groups, the energy intake and body weight increased with increasing dietary fat content. Compared with the HFD-C group, the HFD-L group consumed more energy and had poorer metabolism. CONCLUSIONS: Lower carbohydrate intake contributed to lower energy intake and improved metabolism in humans. In mice, diets with a higher proportion of fat become more attractive and obesogenic by fixing the fat sources. Since the mice preferred lard to cocoa butter, lard induced excess energy intake and poorer metabolism. Different food preferences may be the underlying mechanism behind the opposite effects of the LCD/HFD in humans and mice. TRIAL REGISTRATION: The clinical trial was registered with the Chinese Clinical Trial Registry ( www.chictr.org.cn ). The registration number is ChiCTR1800016786. All participants provided written informed consent prior to enrolment.

Associations of Relative Fat Mass, a Novel Adiposity Indicator, with Non-Alcoholic Fatty Liver Disease and Cardiovascular Disease: Data from SPECT-China.

Purpose: This study aimed to determine the associations of relative fat mass (RFM), a novel adiposity indicator, with the prevalence of non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) and compared the disease discriminative ability of RFM with other common adiposity indicators in the general Chinese population. Patients and Methods: This cross-sectional study consisted of 11,532 adult participants from the SPECT-China study (2014-2016). We included RFM and six other adiposity indicators, including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), visceral adiposity index (VAI), and lipid accumulation product (LAP). Binary logistic regression analysis was used to assess the relationship between adiposity indicators and the prevalence of NAFLD and CVD. The receiver operating characteristic (ROC) curve was used to evaluate the ability to screen NAFLD and CVD. Results: After adjusting for confounding variables, RFM showed a strong association with the prevalence of NAFLD and CVD. In men, each 1-SD (standard deviation) increase in RFM was associated with more than 3-fold increased risk of NAFLD (OR: 4.33, 95% CI: 3.79-4.93) and 66% increased risk of CVD (OR: 1.66, 95% CI: 1.36-2.02); in women, per 1-SD increase in RFM was associated with about 4-fold increased risk of NAFLD (OR: 5.16, 95% CI: 4.62-5.77) and 26% increased risk of CVD (OR: 1.26, 95% CI: 1.08-1.47). ROC analysis showed that RFM and WHtR were the strongest predictors for CVD. Conclusion: RFM was significantly associated with prevalent NAFLD and CVD in Chinese adults and might be considered a simple tool for disease prediction. Further large longitudinal studies are needed to verify our findings.

On the road to colorectal cancer development: crosstalk between the gut microbiota, metabolic reprogramming, and epigenetic modifications.

An increasing number of studies have reported the role of gut microbes in colorectal cancer (CRC) development, as they can be influenced by dietary metabolism and mediate alterations in host epigenetics, ultimately affecting CRC. Intake of specific dietary components can affect gut microbial composition and function, and their metabolism regulates important epigenetic functions that may influence CRC risk. Gut microbes can regulate epigenetic modifications through nutrient metabolism, including histone modification, DNA methylation, and noncoding RNAs. Epigenetics, in turn, determines the gut microbial composition and thus influences the risk of developing CRC. This review discusses the complex crosstalk between metabolic reprogramming, gut microbiota, and epigenetics in CRC and highlights the potential applications of the gut microbiota as a biomarker for the prevention, diagnosis, and therapy of CRC.

Deep learning enabled miniature mass spectrometer for rapid qualitative and quantitative analysis of pesticides on vegetable surfaces.

Excessive pesticide use poses a significant threat to food safety. Rapid on-site detection of multi-target pesticide residues in vegetables is crucial due to their widespread distribution and limited shelf life. In this study, a rapid on-site screening method for pesticide residues on vegetable surfaces was developed by employing a miniature mass spectrometer. A direct pretreatment method involves placing vegetables and elution solution into a customized flexible ziplock bag, allowing thorough mixing, washing, and filtration. This process effectively removes pesticide residues from vegetable surfaces with minimal organic solvent usage and can be completed within 2 min. Moreover, this study introduced a deep learning algorithm based on a one-dimensional convolutional neural network, coupled with a feature database, to autonomously discriminate detection outcomes. By combining full scan MS and tandem MS analysis methods, the proposed method achieved a qualitative recognition accuracy of 99.62%. Following the qualitative discrimination stage, the target pesticide residue and internal standard can be simultaneously isolated and fragmented in the ion trap, thus enabling on-site quantitative analysis and warning. This method achieved a quantitative detection limit of 10 µg/kg for carbendazim in cowpea. These results demonstrate the feasibility of the proposed analytical system and strategy in food safety applications.

Obstacles to home-based dietary management for caregivers of children with citrin deficiency: a qualitative study.

BACKGROUND: Dietary management is the most important and effective treatment for citrin deficiency, as well as a decisive factor in the clinical outcome of patients. However, the dietary management ability of caregivers of children with citrin deficiency is generally poor, especially in East Asia where carbohydrate-based diets are predominant. The aim of this study was to identify the difficulties that caregivers encounter in the process of home-based dietary management, and the reasons responsible for these challenges. RESULTS: A total of 26 caregivers of children with citrin deficiency were recruited, including 24 mothers, one father, and one grandmother. Grounded theory was employed to identify three themes (covering 12 sub-themes) related to the dilemma of dietary management: dietary management that is difficult to implement; conflicts with traditional concepts; and the notion that children are only a part of family life. The first theme describes the objective difficulties that caregivers encounter in the process of dietary management; the second theme describes the underlying reasons responsible for the non-adherent behavior of caregivers; the third theme further reveals the self-compromise by caregivers in the face of multiple difficulties. CONCLUSIONS: This study reflects the adverse effects of multi-dimensional contradictions on the adherence of caregivers to dietary management. These findings reveal that the dietary management of citrin deficiency is not only a rational process, rather it is deeply embedded in family, social, and dietary traditions.

Low-carbohydrate diets lead to greater weight loss and better glucose homeostasis than exercise: a randomized clinical trial.

Lifestyle interventions, including dietary adjustments and exercise, are important for obesity management. This study enrolled adults with overweight or obesity to explore whether either low-carbohydrate diet (LCD) or exercise is more effective in metabolism improvement. Forty-five eligible subjects were randomly divided into an LCD group (n = 22) and an exercise group (EX, n = 23). The subjects either adopted LCD (carbohydrate intake < 50 g/day) or performed moderate-to-vigorous exercise (⩾ 30 min/day) for 3 weeks. After the interventions, LCD led to a larger weight loss than EX ( - 3.56 ± 0.37 kg vs. - 1.24 ± 0.39 kg, P < 0.001), as well as a larger reduction in fat mass ( - 2.10 ± 0.18 kg vs. - 1.25 ± 0.24 kg, P = 0.007) and waist circumference ( - 5.25 ± 0.52 cm vs. - 3.45 ± 0.38 cm, P = 0.008). Both interventions reduced visceral and subcutaneous fat and improved liver steatosis and insulin resistance. Triglycerides decreased in both two groups, whereas low-density lipoprotein cholesterol increased in the LCD group but decreased in the EX group. Various glycemic parameters, including serum glycated albumin, mean sensor glucose, coefficient of variability (CV), and largest amplitude of glycemic excursions, substantially declined in the LCD group. Only CV slightly decreased after exercise. This pilot study suggested that the effects of LCD and exercise are similar in alleviating liver steatosis and insulin resistance. Compared with exercise, LCD might be more efficient for weight loss and glucose homeostasis in people with obesity.

Increased Serum GDF15 Related to Improvement in Metabolism by Lifestyle Intervention Among Young Overweight and Obese Adults.

AIM: Growth differentiation factor 15 (GDF15) is closely related to obesity. This study aimed to explore the influence of weight loss intervention on serum GDF15 levels and the relationship between GDF15 and metabolism. MATERIALS AND METHODS: Forty-four overweight and obese adults either adopted a low-carbohydrate diet or performed moderate-to-vigorous exercise for 3 weeks. Weekly follow-ups were conducted to measure body composition, glucose and lipid metabolism and serum GDF15 levels. RESULTS: After 3 weeks of intervention, body weight, fat mass and waist circumference in both groups decreased (P < 0.05). No significant change in GDF15 levels was observed in the two groups. Among all the subjects, 10 of them (22.7%, group of Down) showed a decrease in GDF15 and 34 (77.3%, group of Up) showed an increase in GDF15 after the intervention. We found that GDF15 increased significantly with the follow-up time in the UP group and waist circumference, fasting serum insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and triglycerides (TG) decreased (P for trend <0.05). However, no significant differences in all parameters were detected in Down group. In addition, GDF15 was elevated between 30 mins and 120 mins in a 75-g oral glucose tolerance test. Its trend was negatively correlated with plasma glucose and serum insulin. CONCLUSION: Increased serum GDF15 was associated with improvement in metabolism by lifestyle intervention among young overweight and obese adults. The increase of GDF15 could be an indicator to evaluate metabolic improvements in overweight and obese people. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn, registration number ChiCTR1800016786.

Processing of high-salt-containing protein A eluate using mixed-mode chromatography in purifying an aggregation-prone antibody.

We previously developed a method that can significantly improve Protein A chromatography's capability of removing antibody aggregates. That particular method requires polyethylene glycol (PEG) and 400 mM or more of calcium chloride/sodium chloride to be added to wash and elution buffers. Consequently, Protein A chromatography performed using this method has relatively high concentration of salt in its eluate. The high salt content prevents the neutralized eluate from binding to ion exchange columns without conductivity adjustment. In the current study we demonstrated that mixed-mode chromatography can be used as a subsequent step to Protein A chromatography with high-salt-containing eluate. As mixed-mode ligand mediates salt-tolerant adsorption, it allows the neutralized Protein A eluate to be directly loaded without the need of conductivity adjustment, and thus enables a smooth and convenient connection between capture and polishing steps. In this work we also showed that the mixed-mode chromatography, performed in bind-elute mode, removed most of PEG in the Protein A eluate.

[Synthesis and anti-tumor activity of ursolic acid derivatives].

Structure of natural product-ursolic acid was modified for increasing its antitumor activity. Ursolic acid was acylated, esterified, hydrolized or oxidized to obtain target pentacyclic triterpenoid compounds with different substitutes. Sixteen derivatives of ursolic acid were designed and synthesized including eleven new compounds. Anti-tumor activities of ursolic acid and these derivatives against HeLa, SKOV3 and BGC-823 cells in vitro were investigated by MTT assay. The results indicated that compounds 7a and 8a were found to have stronger cell growth inhibitory than ursolic acid on HeLa cells and SKOV3 cells separately, and are worth to be intensively studied further.

The synthesis of ursolic acid derivatives with cytotoxic activity and the investigation of their preliminary mechanism of action.

Nineteen ursolic acid derivatives (15 novel compounds) modified at the C-3 and the C-28 positions were synthesized. The cytotoxic activity of the derivatives was evaluated against HeLa, BGC-823 and SKOV3 cells by MTT assay. Inducing apoptosis and affecting cell cycle distribution by the derivatives in HeLa cells were assessed by flow cytometry and DNA fragmentation. Compounds 10b and 11b were particularly active to inhibit HeLa cells growth through inducing apoptosis and arresting cell cycle progression. The typical 'sub-G1 peak' and DNA ladder formation were checked and cell cycle was arrested at the S phase in a dose-dependent manner.