Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation.

Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.

Similarity-Based Method with Multiple-Feature Sampling for Predicting Drug Side Effects.

Drugs can treat different diseases but also bring side effects. Undetected and unaccepted side effects for approved drugs can greatly harm the human body and bring huge risks for pharmaceutical companies. Traditional experimental methods used to determine the side effects have several drawbacks, such as low efficiency and high cost. One alternative to achieve this purpose is to design computational methods. Previous studies modeled a binary classification problem by pairing drugs and side effects; however, their classifiers can only extract one feature from each type of drug association. The present work proposed a novel multiple-feature sampling scheme that can extract several features from one type of drug association. Thirteen classification algorithms were employed to construct classifiers with features yielded by such scheme. Their performance was greatly improved compared with that of the classifiers that use the features yielded by the original scheme. Best performance was observed for the classifier based on random forest with MCC of 0.8661, AUROC of 0.969, and AUPR of 0.977. Finally, one key parameter in the multiple-feature sampling scheme was analyzed.

[Effects of different fluid replenishment methods on internal environment, body thermal regulation response and severe heatstroke of 5-km armed cross-country training soldiers].

OBJECTIVE: To explore the effects of different fluid replenishment methods on the internal environment, body thermal regulatory response and severe heatstroke of 5-km armed cross-country training soldiers. METHODS: A Special Force officers and soldiers who participated in 5-km armed cross-country training (2-3 times a week, 25-30 minutes each time for 3 weeks) during summer training from June to July in 2018 were enrolled, and they were divided into three groups according to the random number table, with 300 trainees in each group. 200 mL of drinking fluids were given to each group 15 minutes before and after each 5-km armed cross-country training: A group with boiled water, B group with purified water, and C group with beverage prepared by pharmaceutical laboratory of the 990th Hospital of PLA Joint Logistics Support Force (100 mL containing 6 g carbohydrates, 42 mg sodium, and 11 mg potassium). The venous blood was collected before and after the last training or during the onset of severe heatstroke to do the following tests: serum cardiac troponin I (cTnI, chemiluminescence), MB isoenzyme of creatine kinase (CK-MB, immunosuppressive), serum creatinine (SCr, enzymatic method), urea nitrogen (BUN, enzymatic method), alanine aminotransferase (ALT, tryptase), aspartate transaminase (AST, tryptase), and Na+, K+, Cl- (electrode method). The heart rate (HR) and core temperature (Tc, anal temperature) were monitored at the same time. The amount of sweat in training and the occurrence of severe heatstroke were also recorded. RESULTS: There was no significant difference in heart, liver, kidney function, electrolyte and body heat regulation reaction among three groups of 5-km armed cross-country trainees before training. Compared with before training, the levels of serum cTnI, CK-MB, SCr, BUN, ALT, AST, HR and Tc were significantly increased after training or during the onset of severe heatstroke in three groups, while the contents of Na+, K+, Cl- were significantly decreased, but the increase or decrease of group C was relatively smaller compared with group A and group B [cTnI (µg/L): 0.9 (0.6, 1.4) vs. 1.1 (0.7, 2.8), 1.0 (0.6, 3.3); CK-MB (U/L): 7.0 (5.0, 11.0) vs. 9.0 (6.0, 14.5), 8.0 (6.0, 15.0); SCr (µmol/L): 92.09±18.64 vs. 102.78±18.77, 103.64±20.07; BUN (mmol/L): 7 (6, 9) vs. 9 (8, 11), 10 (8, 13); ALT (U/L): 27 (22, 34) vs. 36 (30, 43), 34 (27, 43); AST (U/L): 37 (31, 48) vs. 41 (34, 50), 39 (34, 51); HR (bpm): 87.01±17.07 vs. 95.88±21.06, 96.59±22.04; Tc (centigrade): 37.73±0.81 vs. 38.03±1.05, 38.10±1.04; Na+ (mmol/L): 150.14±3.86 vs. 144.18±8.89, 144.04±9.39; K+ (mmol/L): 4.32±0.57 vs. 4.15±0.62, 4.13±0.51; Cl- (mmol/L): 100.43±3.71 vs. 98.42±4.24, 98.41±4.58; all P < 0.01]. The incidence of severe heatstroke in group C was significantly lower than that in group A and group B [1.67% (5/300) vs. 5.00% (15/300), 5.33% (16/300), χ2 = 6.424, P = 0.040]. There was no significant difference in sweating volume in groups A, B, C (g: 370.47±48.71, 370.85±50.66, 370.17±50.21, F = 0.014, P = 0.986). There was no significant difference in the above indexes between group A and group B (all P > 0.05). Bi-classification Logistic regression analysis showed that the increase of HR, Tc and excessive loss of Na+, K+, Cl- were risk factors for severe heatstroke [odds ratio (OR) was 0.848, 0.138, 1.565, 17.996 and 2.328 respectively, all P < 0.01]. CONCLUSIONS: Timely supplementation of carbohydrate, sodium and potassium ions can effectively change the internal environment and body heat regulation reaction of 5-km armed cross-country trainees, so as to reduce the occurrence of severe heatstroke. The increases of HR, Tc and excessive loss of Na+, K+, Cl- are risk factors for severe heatstroke.