Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an extracellular enzyme responsible for hydrolyzing cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), the endogenous agonist for the stimulator of interferon genes (STING) pathway. Inhibition of ENPP1 can trigger STING and promote antitumor immunity, offering an attractive therapeutic target for cancer immunotherapy. Despite progress in the discovery of ENPP1 inhibitors, the diversity in chemical structures and the efficacy of the agents are far from desirable, emphasizing the demand for novel inhibitors. Herein, we describe the design, synthesis, and biological evaluation of a series of ENPP1 inhibitors based on the pyrido[2,3-d]pyrimidin-7-one scaffold. Optimization efforts led to compound 31 with significant potency in both ENPP1 inhibition and STING pathway stimulation in vitro. Notably, 31 demonstrated in vivo efficacy in a syngeneic 4T1 mouse triple negative breast cancer model. These findings provide a promising lead compound with a novel scaffold for further drug development in cancer immunotherapy.

Second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP): the cell autonomous and non-autonomous roles in cancer progression.

Cytosolic double-stranded DNA (dsDNA) is frequently accumulated in cancer cells due to chromosomal instability or exogenous stimulation. Cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, which is activated upon binding to dsDNA to synthesize the crucial second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP) that in turn triggers stimulator of interferon genes (STING) signaling. The canonical role of cGAS-cGAMP-STING pathway is essential for innate immunity and viral defense. Recent emerging evidence indicates that 2'3'-cGAMP plays an important role in cancer progression via cell autonomous and non-autonomous mechanisms. Beyond its role as an intracellular messenger to activate STING signaling in tumor cells, 2'3'-cGAMP also serves as an immunotransmitter produced by cancer cells to modulate the functions of non-tumor cells especially immune cells in the tumor microenvironment by activating STING signaling. In this review, we summarize the synthesis, transmission, and degradation of 2'3'-cGAMP as well as the dual functions of 2'3'-cGAMP in a STING-dependent manner. Additionally, we discuss the potential therapeutic strategies that harness the cGAMP-mediated antitumor response for cancer therapy.

Lean body mass positively associate with blood pressure in Chinese adults: the roles of ages and body fat distribution.

BACKGROUND: The relationship between lean body mass (LBM) and blood pressure (BP) is controversial and limited. This study investigated the associations between LBM indexes and BP in adults of different ages and with varying body fat distribution. METHODS: The data for the present analysis was obtained from a cross-sectional survey of 1,465 adults (50.7% males) aged 18-70 years conducted in Beijing, China. Regional LBM and fat distribution, including fat mass (FM) and android to gynoid fat ratio (AOI), were assessed using a dual-energy X-ray bone densitometer. Generalized Liner Model (GLM) was employed. Confounders, including age, sex, height, weight, smoking, and alcohol use, were evaluated through questionnaires and physical examinations. RESULTS: Males had higher rates of hypertension (11.19% vs. 4.92%) and prehypertension (21.57% vs. 14.59%) than females. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 122.04 mmHg and 76.68 mmHg. There were no significant associations between LBM and DBP (p > 0.05). However, arms LBM (ß = 1.86, 95% CI: 0.77, 2.94) and trunk LBM (ß = 0.37, 95% CI: 0.01, 0.73) were significantly associated with SBP. The association of LBM on DBP was stronger with increasing ages, and stronger in females than in males (p < 0.001). The association between adults' arms LBM and SBP was stronger in the high level FM group (ß = 2.74 vs. ß = 1.30) and high level AOI group (ß = 1.80 vs. ß = 2.08). CONCLUSION: The influence of LBM on SBP increases with age, particularly after the age twenty years in females. For adults with high FM or high AOI, LBM in the arms, showed a stronger positive predictive association with SBP. This suggests that, in addition to controlling fat content, future efforts to improve cardiovascular health in adults should include the management of LBM (especially in the upper body).

Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation.

Xanthine dehydrogenase (XDH) is the rate-limiting enzyme in purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. The altered expression and activity of XDH are associated with the development and prognosis of multiple types of cancer, while its role in lung adenocarcinoma (LUAD) remains unknown. Herein, we demonstrated that XDH was highly expressed in LUAD and was significantly correlated with poor prognosis. Though inhibition of XDH displayed moderate effect on the viability of LUAD cells cultured in the complete medium, it significantly attenuated the survival of starved cells. Similar results were obtained in XDH-knockout cells. Nucleosides supplementation rescued the survival of starved LUAD cells upon XDH inhibition, while inhibition of purine nucleoside phosphorylase abrogated the process, indicating that nucleoside degradation is required for the XDH-mediated survival of LUAD cells. Accordingly, metabolic flux revealed that ribose derived from nucleoside fueled key carbon metabolic pathways to sustain the survival of starved LUAD cells. Mechanistically, down-regulation of XDH suppressed unfolded protein response (UPR) and autophagic flux in starved LUAD cells. Inhibition of XDH decreased the level of amino acids produced by autophagic degradation, which was accompanied with down-regulation of mTORC1 signaling. Supplementation of amino acids including glutamine or glutamate rescued the survival of starved LUAD cells upon knockout or inhibition of XDH. Finally, XDH inhibitors potentiated the anti-cancer activity of 2-deoxy-D-glucose that induced UPR and/or autophagy in vitro and in vivo. In summary, XDH plays a crucial role in the survival of starved LUAD cells and targeting XDH may improve the efficacy of drugs that induce UPR and autophagy in the therapy of LUAD.

Sugar-Sweetened Beverages and Depressive and Social Anxiety Symptoms Among Children and Adolescents Aged 7-17 Years, Stratified by Body Composition.

Background: Rare studies investigated the associations between sugar-sweetened beverage (SSB) consumption with depressive and social anxiety symptoms among children and adolescents, particularly in different stratification of body composition, which was our purpose. Methods: A cross-sectional survey of children and adolescents aged 7-17 years was conducted in Beijing, China, in 2020, with an average age of 12.07 (SD: 3.09) years. Children's Depression Inventory (CDI) questionnaires and social anxiety scale for children (SASC) were completed in the baseline questionnaires. SSB consumption and body composition were assessed using child-reported questionnaires and a GE Healthcare Lunar iDXA dual-energy X-ray bone densitometer. Multivariate logistic regression was used to assess the associations between SSB consumption with depressive and social anxiety symptoms. Confounders were evaluated by child-reported and parental questionnaires, including age, sex, parental educational attainment, maternal smoking status, single-child status, BMI, incomes, fruit consumption, physical activity, screen time, and the frequency of fried food consumption. Stratified analyses were performed to explore whether the associations were influenced by body composition. Results: A total of 1,311 children and adolescents, including 658 boys and 653 girls, were included in the final analysis. There were 13.96 and 29.75% of the study population with depressive and social anxiety symptoms, respectively. Overall, about 63.77% of the children and adolescents consumed SSB, and the average SSB intake was 0.35 servings per day. In the fully adjusted model, compared to participants who did not consume SSB each day, SSB consumption of ≥1 servings/day was positively associated with depressive symptoms [odds ratio (OR) = 2.28, 95% CI = 1.30-4.01] and social anxiety (OR = 1.10, 95% CI = 0.69-1.77), though the latter did not reach statistical significance. When individuals had higher body fat or lower fat-free mass (FFM) or muscle, the ORs of depressive symptoms were more evident among children and adolescents who drank SSB for ≥1 servings/day (P < 0.05). Conclusion: Higher consumption of SSB could be associated with increased OR of depressive symptoms in children and adolescents. The association remained robust, especially in groups with higher body fat or lower fat-free mass or muscle.

Association between healthy lifestyle pattern and early onset of puberty: based on a longitudinal follow-up study.

The present study aimed to explore the association between healthy lifestyle pattern and childhood early onset of puberty. Based on a cohort study in Xiamen of China, a total of 1294 children was followed for three and a half years. Children's lifestyles, including dietary behaviour, physical activity, sleep duration, smoking and drinking behaviour and sedentary behaviour, were collected by questionnaires. Healthy lifestyle pattern was determined mainly according to the recommendations by the Dietary Guidelines for Chinese school-age children and Canadian Guidelines for children and youth. The pubertal development was assessed by clinical examination according to Tanner stages. The association between pre-pubertal lifestyle and early onset of puberty was estimated using linear regression and log-binomial regression. We found that children who adhered to a healthy lifestyle had a 0·36-year delay of the age of puberty onset (coef = 0·36, 95 % CI (0·08, 0·65)) and 53 % lower risk of early onset of puberty (risk ratio = 0·47, 95 % CI (0·27, 0·80)), compared with those who had a poor lifestyle. However, the beneficial effect of favourable lifestyles on the early onset of puberty was found only in boys with normal weight. Boys who adhered to active physical activity and low sedentary behaviour had a relatively delayed age of puberty onset (coef = 0·49, 95 % CI (0·26, 0·72)). This is the first time to find that healthy lifestyle pattern was associated with a substantially lower risk of early onset of puberty, especially in boys with normal weight. Advocating an integrated healthy lifestyle is essential for the development of children.

Efficacy of Endoscopic Posterior Nasal Neurectomy in Treating Eosinophilic Chronic Rhinosinusitis.

OBJECTIVES: Recent guidelines have revealed that eosinophilic chronic rhinosinusitis (ECRS) exhibits a strong tendency for recurrence after surgery and impairs quality of life. Neuropeptides play an important neuroimmunological role. The aim of this study was to determine the efficacy of posterior nasal neurectomy (PNN) for the treatment of ECRS by inhibiting type 2 cytokine expression. METHODS: Forty-six patients were divided into group A and group B according to a random number table. Group A underwent conventional functional endoscopic sinusitis surgery (FESS) combined with PNN, and group B underwent conventional FESS alone. The subjective and objective symptoms included a 10-cm visual analog scale (VAS), 22-item SinoNasal Outcome Test (SNOT-22) score, nasal speculum Lund-Kennedy score, and paranasal sinus computed tomography (CT) Lund-Mackay score at the 1-year postoperative follow-up. RESULTS: Postoperative VAS (10.33 ± 2.18 vs. 8.38 ± 2.11, p < 0.01) and Lund-Kennedy score (1.95 ± 1.32 vs. 3.14 ± 1.35, p < 0.01) were significantly improved. The rhinorrhea score (1.76 ± 0.83 vs. 2.90 ± 1.14, p < 0.001) in the VAS and the discharge (0.43 ± 0.51, vs. 0.95 ± 0.67, p < 0.01) and edema (0.57 ± 0.60 vs. 0.95 ± 0.59, p < 0.05) scores in the Lund-Kennedy score were observed to have improved significantly in group A compared with those in group B. CONCLUSIONS: FESS combined with PNN suppresses edema symptoms, which might significantly decrease the surgical recurrence rate of ECRS in the long term.

The double faced role of xanthine oxidoreductase in cancer.

Xanthine oxidoreductase (XOR) is a critical, rate-limiting enzyme that controls the last two steps of purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. It also produces reactive oxygen species (ROS) during the catalytic process. The enzyme is generally recognized as a drug target for the therapy of gout and hyperuricemia. The catalytic products uric acid and ROS act as antioxidants or oxidants, respectively, and are involved in pro/anti-inflammatory actions, which are associated with various disease manifestations, including metabolic syndrome, ischemia reperfusion injury, cardiovascular disorders, and cancer. Recently, extensive efforts have been devoted to understanding the paradoxical roles of XOR in tumor promotion. Here, we summarize the expression of XOR in different types of cancer and decipher the dual roles of XOR in cancer by its enzymatic or nonenzymatic activity to provide an updated understanding of the mechanistic function of XOR in cancer. We also discuss the potential to modulate XOR in cancer therapy.

Parental Adherence to Ideal Cardiovascular Health Status Was Associated With a Substantially Lower Prevalence of Overweight and Obesity in Their Offspring Aged 6-18 Years.

Background: Parental health status had a potential influence on offspring health. This study aimed to investigate the separate associations between paternal and maternal cardiovascular health statuses and the prevalence of childhood overweight and obesity in the offspring. Methods: Data were from a cross-sectional study conducted in seven provinces or cities of China in 2013. A total of 29,317 children aged 6-18 years old and their parents, making up 9,585 father-offspring pairs and 19,732 mother-offspring pairs, were included in the final analysis. Information on parental cardiovascular health status factors (dietary behaviors, body mass index (BMI), smoking, physical activity, hypertension, and diabetes mellitus) was obtained from the structured self-administrated questionnaires. Based on the health status factors, we then generated an ideal cardiovascular health (iCVH) score. The overweight and obesity of children were defined using age- and sex-specific cutoffs based on the International Obesity Task Force criteria. A multilevel log-binomial regression model was used to assess the association between parental cardiovascular health status and prevalence of childhood overweight and obesity in the offspring. Results: The prevalence of pediatric overweight and obesity was 22.0% in the father-offspring subset and 23.8% in the mother-offspring subset, respectively. Fathers with ideal BMI, non-smoking, and absence of hypertension and diabetes, and mothers with ideal BMI, ideal physical activity, and absence of hypertension and diabetes were found to be associated with lower prevalence of overweight and obesity in the offspring. The prevalence of offspring overweight and obesity was significantly decreased with the parental iCVH scores increased. Each additional increase in paternal and maternal iCVH factor was associated with a 30% and 27% lower prevalence of overweight and obesity in the offspring. Compared with children whose parental iCVH scores ≤ 3, offspring whose fathers or mothers met all six iCVH factors had 67% [prevalence ratio (PR): 0.33, 95%CI: 0.25-0.42] and 58% (PR: 0.42, 95%CI: 0.29-0.62) lower prevalence of overweight and obesity, respectively. Conclusions: Parental adherence to iCVH status was associated with a lower prevalence of pediatric overweight and obesity in offspring. Our findings support the intervention strategy that parents should involve in the obesity intervention program for children.

Development of a novel, fully human, anti-PCSK9 antibody with potent hypolipidemic activity by utilizing phage display-based strategy.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates serum LDL cholesterol (LDL-C) levels by facilitating the degradation of the LDL receptor (LDLR) and is an attractive therapeutic target for hypercholesterolemia intervention. Herein, we generated a novel fully human antibody with favourable druggability by utilizing phage display-based strategy. METHODS: A potent single-chain variable fragment (scFv) named AP2M21 was obtained by screening a fully human scFv phage display library with hPCSK9, and performing two in vitro affinity maturation processes including CDR-targeted tailored mutagenesis and cross-cloning. Thereafter, it was transformed to a full-length Fc-silenced anti-PCSK9 antibody FAP2M21 by fusing to a modified human IgG1 Fc fragment with L234A/L235A/N297G mutations and C-terminal lysine deletion, thus eliminating its immune effector functions and mitigating mAb heterogeneity. FINDINGS: Our data showed that the generated full-length anti-PCSK9 antibody FAP2M21 binds to hPCSK9 with a KD as low as 1.42 nM, and a dramatically slow dissociation rate (koff, 4.68 × 10-6 s-1), which could be attributed to its lower binding energy (-47.51 kcal/mol) than its parent counterpart FAP2 (-30.39 kcal/mol). We verified that FAP2M21 potently inhibited PCSK9-induced reduction of LDL-C uptake in HepG2 cells, with an EC50 of 43.56 nM. Further, in hPCSK9 overexpressed C57BL/6 mice, a single tail i.v. injection of FAP2M21 at 1, 3 and 10 mg/kg, dose-dependently up-regulated hepatic LDLR levels, and concomitantly reduced serum LDL-C by 3.3% (P = 0.658, unpaired Student's t-test), 30.2% (P = 0.002, Mann-Whitney U-test) and 37.2% (P = 0.002, Mann-Whitney U-test), respectively. INTERPRETATION: FAP2M21 with potent inhibitory effect on PCSK9 may serve as a promising therapeutic agent for treating hypercholesterolemia and associated cardiovascular diseases.

Circulating tumor cells: A surrogate to predict the effect of treatment and overall survival in gastric adenocarcinoma.

BACKGROUND: Circulating tumor cells and serum tumor markers have been found significant in predicting outcome for several malignancies. However, their role in gastric cancer is not fully clarified. We conducted a retrospective study to explore the prognostic value of circulating tumor cells and their applicability in assessing the treatment efficacy in gastric cancers. METHODS: From September 2015 to December 2018, 116 patients with newly pathologically diagnosed gastric adenocarcinoma were enrolled. At both baseline and two courses after chemotherapy, the data of circulating tumor cells and serum tumor markers, such as CEA, CA72-4, CA19-9, CA50, and CA242, were collected. The relationships between the change trend of circulating tumor cells and the treatment efficacy were analyzed after chemotherapy, with a paired t-test. Univariate and multivariable analysis were used to find prognostic factors for overall survival (OS). RESULTS: We found there is a significant difference between the circulating tumor cells-positive and circulating tumor cells-negative before and after therapy (mOS 12.6 vs. 31.6 months, P<0.001; mOS 12.4 vs. 24.2 months, P=0.002), respectively. Also, differentiation, pre-therapeutic circulating tumor cells and therapeutic response were independent predictors of overall survival. Following two courses of chemotherapy, the number of circulating tumor cells increased obviously in the progressive disease group (P=0.002), while they decreased in the non-progressive disease group (P=0.02). Thus, the change in the circulating tumor cells count had a close association with the therapeutic response (P=0.004). CONCLUSION: Generally, circulating tumor cells provide a novel tool to evaluate the outcomes of gastric cancer patients. Since the change of circulating tumor cells was highly related to treatment response, it may be an auxiliary to assess the effect of chemotherapy, leading an earlier adjustment of following regimens.

Hsa-miR-140-5p down-regulates LDL receptor and attenuates LDL-C uptake in human hepatocytes.

BACKGROUND AND AIMS: MicroRNAs (miRs) exert important regulatory effects in cholesterol metabolism. Hepatic low density lipoprotein receptor (LDLR) pathway, as the major mechanism for clearing circulating low density lipoprotein cholesterol (LDL-C) in bloodstream, is a pivotal therapeutic target to treat hypercholesterolemia and atherosclerosis. This study aimed to identify novel miRs that regulate LDLR expression. METHODS AND RESULTS: Hsa-miR-140-5p was predicted by bioinformatics analyses to interact with human LDLR mRNA. To evaluate its functional effects in regulating LDLR, hsa-miR-140-5p and anti-miR-140-5p were transfected into human and mouse liver cells, followed by qRT-PCR, western blot, immunofluorescence, flow cytometry, and LDL-C uptake assays. It was observed that hsa-miR-140-5p over-expression dramatically down-regulated LDLR expression and reduced LDL-C uptake, whereas inhibition of hsa-miR-140-5p significantly up-regulated LDLR expression and enhanced LDL-C uptake in human HepG2 and LO2 cells, but not in mouse Hepa1-6 cells. Luciferase reporter assay and site-directed mutagenesis identified that hsa-miR-140-5p interacts with the predicted seed sequence "AAACCACU" in the 3'-UTR of human LDLR mRNA. Hsa-miR-140-5p over-expression attenuated LDL-C uptake and decreased intracellular cholesterol levels in the presence of 50 µg/ml ox-LDL in HepG2 cells. Additionally, palmitic acid and simvastatin suppressed, whereas LDL-C up-regulated the expression of miR-140-5p in HepG2 cells. CONCLUSIONS: Hsa-miR-140-5p is a negative regulator of LDLR expression in human hepatocytes, but not in mouse hepatocytes. Simvastatin inhibits hsa-miR-140-5p expression in human hepatocytes, which is likely to be a novel mechanism for treating hypercholesterolemia with statins in clinic. Antagonism of hsa-miR-140-5p could be a new therapeutic strategy for the treatment of hypercholesterolemia and atherosclerosis.

Comparison of Quality of Life and Nutritional Status of Between Roux-en-Y and Billroth-I Reconstruction After Distal Gastrectomy: A Systematic Review and Meta-Analysis.

Background: This paper purports to use a meta-analysis to compare the postoperative quality of life (QoL) and nutritional status of between Roux-en-Y (R-Y) and Billroth-I (B-I) reconstruction after distal gastrectomy.Methods: For this study, the following databases were searched for articles published from inception until December 2018: PubMed, Web of Science, EBSCO, and Cochrane library.Results: A total of 13 eligible studies, covering 3645 patients, were selected for a meta-analysis. The analysis showed that compared with B-I group in term of short-term outcomes, patients undergoing R-Y reconstruction did not only have significantly better physiological function (P = 0.02), but had significantly less pain (P = 0.04). In the long-term outcomes, the dyspnea and constipation in the B-I group were worse than that in the R-Y group (P = 0.004; P = 0.04, respectively). Patients in the B-I group had higher cholesterol than those in the R-Y group at 5 years postoperatively (P = 0.003). There were no significant differences in termof other nutritional indicators including total protein, cholesterol, albumin, hemoglobin and weight in short-term outcomes.Conclusions: The final conclusion was that R-Y may be superior to the B-I reconstruction in some aspects of QoL. Besides, R-Y reconstruction could reduce the patient's cholesterol level for a long time. For the short-term outcomes, there were no significant differences in other common nutritional indicators.

Cytoplasmic p27 is a novel prognostic biomarker and oncogenic protein for nasopharyngeal carcinoma.

Cytoplasmic p27 plays an important role in regulating the cell cycle. Recent studies have revealed p27 protein translocation from the nucleus to the cytoplasm in many tumour cells. The aim of this study was to investigate the role and molecular mechanisms of cytoplasmic p27 in the progression of nasopharyngeal carcinoma (NPC) and to explore its prognostic value. We found increased cytoplasmic p27 expression by immunohistochemistry in NPC tissues, and its expression level was significantly correlated with the T classification and TNM clinical stage of NPC. The survival rate was significantly lower for NPC patients with cytoplasmic p27 immunopositivity than for NPC patients with cytoplasmic p27 immunonegativity, and cytoplasmic p27 was an independent risk factor that affected the prognosis of patients with NPC. Cytoplasmic p27 promoted the proliferation, cell cycle progression, migration, and invasion of NPC cells, increased Bim-1 and Twist1 protein levels, and decreased RhoA-GTP level. Collectively, these findings suggest that cytoplasmic relocalization of p27 is involved in the pathogenesis of NPC and is closely related to the unfavourable prognosis of patients with NPC. Therefore, cytoplasmic p27 might be a useful prognostic factor and potential therapeutic target for patients with NPC.

Clinical Significance of Tumor Deposits in Gastric Cancer: a Retrospective and Propensity Score-Matched Study at Two Institutions.

BACKGROUND: Gastric cancer (GC) treatment is largely determined by tumor stage. Despite improvements in the mode of treatment of various types of advanced disease, staging is still evolving. The role of tumor deposits (TDs) in staging remains debated. The purpose of this research is to investigate the relationship between TDs and prognosis in GC. METHODS: A total of 3098 patients were considered eligible for prognostic analysis (2706 patients in the TDs-negative group and 392 patients in the TDs-positive group). A one-to-one propensity score-matching analysis was performed using a logistic regression mode and the following covariates: age, gender, tumor location, size, differentiation, perineural invasion, lymphovascular invasion, pTNM stage, type of gastrectomy, and the number of lymph nodes retrieved between TDs-negative and TDs-positive group, then 323 patients in each group were analyzed. Univariate and multivariate analyses of prognostic factors were conducted accordingly. The predictive ability of different staging system incorporating TDs was evaluated. RESULTS: TDs were present in 14.5% cases and almost all of the patients (99%) suffered from advanced GC. Multivariate analysis showed that pN stage, chemotherapy, and TDs were the independent prognostic factors. The TDs-positive group showed a lower rate of 5-year disease-free survival compared with the TDs-negative group in all patients, stage II, and stage III patients (p = 0.001, 0.029, and 0.003, respectively). The 5-year disease-free survival for patients with TDs and without TDs was 27.6% and 34.4%, respectively. CONCLUSIONS: Our research shows that TDs are closely associated with prognosis in GC. TDs should be incorporated into the TNM staging system, which could then accurately improve the staging reliability and prognostic assessment.

The safety and tolerability of combined immune checkpoint inhibitors (anti-PD-1/PD-L1 plus anti-CTLA-4): a systematic review and meta-analysis.

BACKGROUND: The future of combined immunotherapy (a PD-1/PD-L1 plus a CTLA-4 antagonist) is very bright. However, besides improving efficacy, combined therapy increases treatment-related adverse events (TRAEs). Also, the clinical application is limited in some solid tumors. METHODS: This paper purports to investigate the TRAEs for the combined immunotherapy aiming for a more appropriate utilization of immune checkpoint inhibitors (ICIs) in clinical practice through a meta-analysis. RESULTS: A total of 17 eligible studies covering 2626 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The incidence rates of any grade and grade 3 or higher TRAEs were 88% (95%CI, 84-92%) and 41% (95%CI, 35-47%), respectively. The overall incidence of any grade TRAEs leading to discontinuation of treatment was 20% (95%CI, 16-24%). The incidence rate of treatment related deaths was 4.3‰ (95%CI, 1.4‰-8.4‰). Analysis showed that NIVO1 + IPI3 cohort had higher incidences of grade 3 or higher TRAEs (RR = 1.77, 95%CI, 1.34-2.34, p < 0.0001) and any grade TRAEs leading to discontinuation of treatment (RR = 1.81, 95%CI, 1.08-3.04, P = 0.02), compared with NIVO3 + IPI1 regimen. CONCLUSIONS: The combined therapy had high TRAEs. The TRAEs, especially grade 3 or higher, led to discontinuation of the treatment. Furthermore, the incidence of treatment-related deaths was rare. Moreover, the NIVO3 + IPI1 regimen, regardless of efficacy, is more recommended because of better tolerance and lower adverse events.

Comparison of Long-Term Outcomes of Endoscopic Submucosal Dissection and Surgery for Early Gastric Cancer: a Systematic Review and Meta-analysis.

BACKGROUND: Endoscopic submucosal dissection (ESD) is an endoscopic alternative to surgical resection of early gastric cancer (EGC). Besides offering both diagnostic and therapeutic capability, it has the benefits of reducing post-operative complications and provides fast recovery and better quality of life compared to surgical resection of neoplastic lesions. However, due to limitations of the procedure, its long-term outcomes are rather controversial. METHODS: This study has been carried out to investigate the long-term outcomes of ESD which includes the overall survival (OS), disease-free survival (DFS), and recurrence rate. The following databases were used to search for articles published until February 2018: Medline, Cochrane Library, PubMed, Web of Science, and EBSCO. RESULTS: A total of 13 eligible studies covering 4986 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The difference of OS and disease-specific survival (DSS) between ESD and surgical treatment was not statistically significant (RR = 0.90, 95% CI = 0.68-1.19, p = 0.46; RR = 0.40, 95% CI = 0.15-1.03, p = 0.06, respectively). However, DFS in the ESD group was much lower than that in the surgery group (RR = 3.40, 95% CI = 2.39-4.84, p < 0.001). In terms of the treatment after recurrence, the proportion of patients who could receive radical treatment was significantly higher in the ESD than that in the gastrectomy (OR = 5.27, 95% CI = 2.35-11.79, p < 0.001). CONCLUSIONS: This meta-analysis showed that ESD might be an alternative treatment option to surgery for patients with EGC in Asian countries. But a close surveillance program after ESD is of necessity, considering the higher possibility of tumor recurrence after ESD.

Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a systematic review and meta-analysis.

OBJECTIVE: To analyze the prognostic value of programmed death factor ligand 1 (PD-L1) in colorectal cancer. METHODS: Electronic databases, such as PubMed, Web of Science, Embase, and Cochrane library, were searched to identify studies evaluating the PD-L1 expression and overall survival (OS) in these patients. Afterwards, the relevant data were extracted to perform the meta-analysis. RESULTS: A total of 3481 patients were included in 10 studies. The combined hazard ratio (HR) was 1.22 (95%CI = 1.01-1.48, P = 0.04), indicating that high expression of PD-L1 was significantly correlated with poor prognosis of colorectal cancer. Apropos of clinicopathological features, the merged odds ratio (OR) exhibited that highly expressed PD-L1 was firmly related to lymphatic invasion (OR = 3.49, 95%CI = 1.54-7.90, P = 0.003) and advanced stage (OR = 1.77, 95%CI = 1.41-2.23, P < 0.00001), but not correlative with patients' gender, microsatellite instability, or tumor location. CONCLUSION: The expression of PD-L1 can be utilized as an independent factor in judging the prognosis of colorectal cancer, and patients with advanced cancer or lymphatic invasion are more likely to express PD-L1. This conclusion may lay a theoretical foundation for the application of PD-1/PD-L1 immunoassay point inhibitors but still needs verifying by sizeable well-designed cohort studies.

Gene expression profile in peripheral blood mononuclear cells of postpartum depression patients.

Postpartum depression (PPD) is a common mental health problem that causes maternal suffering and various negative consequences for offspring. The pathogenesis of PPD and the causes of consequences for offspring remain largely unknown. Here, we applied RNA sequencing to sequence the whole transcriptomes of peripheral blood mononuclear cells (PBMCs) from PPD patients (Edinburgh Postnatal Depression Scale [EPDS] score ≥13) and control subjects (EPDS = 0). We found that PPD was positively correlated with multiple genes involved in energy metabolism, neurodegenerative diseases and immune response, while negatively correlated with multiple genes in mismatch repair and cancer-related pathways. Remarkably, genes associated with appetite regulation and nutrient response were differentially expressed between PPD and control subjects. Then, we employed a postnatal growth retardation model by repeated immobilization stress (IS) stimulation to maternal mice. The expression of appetite regulation and nutrient response-related genes in the PBMCs of IS mice and in the hypothalamus of their offspring were also affected. In conclusion, this study provides a comprehensive characterization of the PBMCs transcriptome in PPD and suggests that maternal stress may affect appetite regulation and nutrient response in the hypothalamus of offspring mice.

A Risk-Scoring Model for Predicting Lymph Node Metastasis in Early Gastric Cancer Patients: a Retrospective Study and External Validation.

BACKGROUND: The possibility of lymph node metastasis (LNM) is critical to the assessment of the indication for endoscopic submucosal dissection. Thus, the aim of this study is to identify the risk factors for LNM and construct a risk-scoring model for patients with early gastric cancer to guide treatment. METHODS: A retrospective examination of reports and studies carried out January 2000 and December 2014 was conducted. A risk-scoring model for predicting LNM was developed based on the data thus collected. In addition, the model is subject to verification and validation by three institutions. RESULTS: Of the 1029 patients, 228 patients (22%) had LNM. Multivariate analysis showed that female, depressed type, undifferentiated type, submucosa, tumor size, and lymphovascular invasion were significantly associated with LNM. An 11-point risk-scoring model was used to predict LNM risk. An area under the receiver operating characteristic (AUROC) of the risk-scoring model was plotted using the development set and the AUROC of the model [0.76 (95% CI 0.73-0.80)] to predict LNM risk. After internal and external validation, the AUROC curve for predicting LNM was 0.77 (95% CI 0.68-0.86), 0.82 (95% CI 0.72-0.91), and 0.82 (95% CI 0.70-0.94), respectively. CONCLUSIONS: A risk-scoring model for predicting LNM was developed and validated. It could help with personalized care for patients with EGC.