ITIH1 suppresses carcinogenesis in renal cell carcinoma through regulation of the NF­κB signaling pathway.

Renal cell carcinoma (RCC) is a common malignancy of the urinary system. Although traditional therapies, such as surgery assisted with chemotherapy have improved the quality of life and survival time of patients with RCC, patients with metastasis or recurrence benefit little from such therapies. At present, little is known about the underlying mechanisms of RCC, rendering treatment selection and implementation challenging. Therefore, investigating the cause and underlying mechanisms of RCC remain of importance to explore potential new avenues for its treatment. Inter-α-trypsin inhibitor heavy chain 1 (ITIH1) is an inflammation-associated gene reported to suppress the progression of liver cancer. However, its role in RCC remains poorly understood. Therefore, the present study aimed to investigate the role and mechanism of ITIH1 in RCC. Based on data obtained from The Cancer Genome Atlas database, ITIH1 expression was demonstrated to be significantly higher in tumor tissues compared with normal tissues, which was in turn negatively associated with the survival of patients with RCC. However, in RCC cells, ITIH1 was shown to be expressed at significantly lower levels compared with those in HK-2 cells. The discrepancy between tissues and cell lines might be due to the different environment of cell growth. ITIH1 knockdown in RCC cells significantly increased cell proliferation and invasion whilst significantly decreasing the apoptosis rate, compared with those in control cells (without ITIH1 knockdown). By contrast, overexpression of ITIH1 significantly inhibited cell proliferation and invasion in RCC cells. In terms of western blotting results, the phosphorylation levels of NF-κB were significantly increased following ITIH1 knockdown. The protein expression level of IκB significantly decreased whereas that of IKK, Cyclin D1, proliferating cell nuclear antigen and α-smooth muscle actin were significantly increased in ITIH1-knockdown cells, compared with those in the control cells (without ITIH1 knockdown). This suggests that the NF-κB pathway may be activated after ITIH1 knockdown. Following treatment with the NF-κB pathway inhibitor JSH-23 in combination with ITIH1 knockdown, RCC cell proliferation and invasion were significantly reduced compared with those after ITIH1 knockdown alone. In summary, results from the present study suggest that ITIH1 can serve an inhibitory role in the progression of RCC, which could potentially be inhibited through the NF-κB signaling pathway.

Integrative multi-omics analysis unravels the host response landscape and reveals a serum protein panel for early prognosis prediction for ARDS.

BACKGROUND: The multidimensional biological mechanisms underpinning acute respiratory distress syndrome (ARDS) continue to be elucidated, and early biomarkers for predicting ARDS prognosis are yet to be identified. METHODS: We conducted a multicenter observational study, profiling the 4D-DIA proteomics and global metabolomics of serum samples collected from patients at the initial stage of ARDS, alongside samples from both disease control and healthy control groups. We identified 28-day prognosis biomarkers of ARDS in the discovery cohort using the LASSO method, fold change analysis, and the Boruta algorithm. The candidate biomarkers were validated through parallel reaction monitoring (PRM) targeted mass spectrometry in an external validation cohort. Machine learning models were applied to explore the biomarkers of ARDS prognosis. RESULTS: In the discovery cohort, comprising 130 adult ARDS patients (mean age 72.5, 74.6% male), 33 disease controls, and 33 healthy controls, distinct proteomic and metabolic signatures were identified to differentiate ARDS from both control groups. Pathway analysis highlighted the upregulated sphingolipid signaling pathway as a key contributor to the pathological mechanisms underlying ARDS. MAP2K1 emerged as the hub protein, facilitating interactions with various biological functions within this pathway. Additionally, the metabolite sphingosine 1-phosphate (S1P) was closely associated with ARDS and its prognosis. Our research further highlights essential pathways contributing to the deceased ARDS, such as the downregulation of hematopoietic cell lineage and calcium signaling pathways, contrasted with the upregulation of the unfolded protein response and glycolysis. In particular, GAPDH and ENO1, critical enzymes in glycolysis, showed the highest interaction degree in the protein-protein interaction network of ARDS. In the discovery cohort, a panel of 36 proteins was identified as candidate biomarkers, with 8 proteins (VCAM1, LDHB, MSN, FLG2, TAGLN2, LMNA, MBL2, and LBP) demonstrating significant consistency in an independent validation cohort of 183 patients (mean age 72.6 years, 73.2% male), confirmed by PRM assay. The protein-based model exhibited superior predictive accuracy compared to the clinical model in both the discovery cohort (AUC: 0.893 vs. 0.784; Delong test, P < 0.001) and the validation cohort (AUC: 0.802 vs. 0.738; Delong test, P = 0.008). INTERPRETATION: Our multi-omics study demonstrated the potential biological mechanism and therapy targets in ARDS. This study unveiled several novel predictive biomarkers and established a validated prediction model for the poor prognosis of ARDS, offering valuable insights into the prognosis of individuals with ARDS.

The Median Effective Dose of Dexmedetomidine for the Inhibition of Emergence Delirium in Preschool Children Undergoing Tonsillectomy and/or Adenoidectomy: A Retrospective Dose-response Trial.

The incidence of emergence delirium (ED) is higher in preschool children undergoing tonsillectomy and/or adenoidectomy. The purpose of this study was to determine the median effective dose (ED50) of dexmedetomidine (DEX) for the inhibition of ED in preschool children by using probit regression analysis. A total of 140 anesthesia records were retrieved and divided into seven groups based on the infusion rate of DEX: .2, .25, .3, .35, .4, .45, and .5 µg·kg-1·h-1. The Pediatric Anesthesia Emergence Delirium Scale (PAEDS) was used to assess ED in preschool children, and ED was defined as a PAEDS score ≥ 10. Probit regression analysis revealed that the ED50 and ED95 of DEX were .31 µg·kg-1·h-1 (95% CI: .29-.35) and .48 µg·kg-1·h-1 (95% CI: .44-.56), respectively. Probit(p) = -2.84 + 9.28 × ln (Dose), (χ2 = 1.925, P = .859). The PAEDS score was significantly increased in the ED group, and the rate of bradycardia was significantly decreased in the ED group compared with the without ED group (27.3% vs 54.1%, P = .02). DEX can effectively inhibit the ED in preschool children undergoing tonsillectomy and/or adenoidectomy, however, bradycardia was the main complication.

3,5-diCQA suppresses colorectal cancer cell growth through ROS/AMPK/mTOR mediated mitochondrial dysfunction and ferroptosis.

3,5-diCQA has been shown to have anti-tumor effect by decreasing cancer cell growth. However, the molecular mechanism by which 3,5-diCQA impacts colorectal cancer (CRC) cells is unknown. This study discovered that 3,5-diCQA had a suppressive effect on CRC cells, mainly in the inhibition of proliferation, migration, and the enhancement of apoptosis in HCT116 and SW480 cells. Additionally, 3,5-diCQA was found to cause cell cycle arrest in CRC cells. Meanwhile, we found that 3,5-diCQA activates the AMPK pathway through the generation of ROS, mediates mitochondrial damage, and reduces mitochondrial aerobic glycolysis and oxidative phosphorylation levels. 3,5-diCQA promoted oxidative damage and ferroptosis in CRC cells. Hence, we added ROS inhibitor NAC and found that the NAC reversed the effects of 3,5-diCQA on proliferation, apoptosis, ROS generation, and ferroptosis in CRC cells. Moreover, 3,5-diCQA was also shown to suppress the development of CRC tumor in a tumor-forming model of nude mice. In conclusion, we found that 3,5-diCQA enhances the oxidative damage and ferroptosis while reducing proliferation and migration of CRC cells, depending on mitochondrial dysfunction caused by the ROS/AMPK/mTOR pathway.

ORM1 promotes tumor progression of kidney renal clear cell carcinoma (KIRC) through CALR-mediated apoptosis.

Kidney renal clear cell carcinoma (KIRC) is the most prevalent type of kidney cancer and causes thousands of deaths each year. The prognosis for KIRC is poor. One critical factor is that the mechanism beneath KIRC is unclear. ORM1 is a reactant to acute inflammation. In this study, we demonstrated that methylation of ORM1 promoter was low and ORM1 was expressed significantly higher in KIRC. KIRC with higher ORM1 expression exhibited worse survival probability. Meanwhile, ORM1 was expressed higher in KIRC cell lines. When ORM1 was knocked down, cell proliferation ability was inhibited potently compared to the NC control. Cell migration as well as invasion ability were also suppressed dramatically. At molecular level, the expression of active caspase-3 and Bax was upregulated in ORM1-KD group while Bcl-2 downregulated. Moreover, CALR decreased following ORM1-KD and rescued expression of CALR increased Bcl-2 level but reduced the level of cleaved caspase-3 and Bax. Consistently, the apoptotic rate of 786-O and Caki-2 cells was upregulated in ORM1-KD but downregulated after CALR overexpression. The activity of caspase-3 was also regulated by ORM1-KD. In addition, the inhibition rate of sorafenib was enhanced in ORM1 KD group but reduced after overexpression of ORM1. Conclusively, ORM1 is clinically associated with progression of KIRC and regulates cell proliferation, migration, invasion, and apoptosis in KIRC. Moreover, ORM1 affects the efficiency of sorafenib in KIRC and regulates caspase-3 mediated cascades response through CALR molecule. This study provides us a new way to recognize the development and progression in KIRC.

Quantitative analysis of a novel DNA hypermethylation panel using bronchial specimen for lung cancer diagnosis.

Non-diagnostic findings are common in transbronchial lung biopsy (TBLB) and endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB). One of the challenges is to improve the detection of lung cancer using these techniques. To address this issue, we utilized an 850 K methylation chip to identify methylation sites that distinguish malignant from benign lung nodules. Our study found that a combination of HOXA7, SHOX2 and SCT methylation analysis has the best diagnostic yield in bronchial washing (sensitivity: 74.1%; AUC: 0.851) and brushing samples (sensitivity: 86.1%; AUC: 0.915). We developed a kit comprising these three genes and validated it in 329 unique bronchial washing samples, 397 unique brushing samples and 179 unique patients with both washing and brushing samples. The panel's accuracy in lung cancer diagnosis was 86.9%, 91.2% and 95% in bronchial washing, brushing and washing + brushing samples, respectively. When combined with cytology, rapid on-site evaluation (ROSE), and histology, the panel's sensitivity in lung cancer diagnosis was 90.8% and 95.8% in bronchial washing and brushing samples, respectively, and 100% in washing + brushing samples. Our findings suggest that quantitative analysis of the three-gene panel can improve the diagnosis of lung cancer using bronchoscopy.

The Novel IGF-1R Inhibitor PB-020 Acts Synergistically with Anti-PD-1 and Mebendazole against Colorectal Cancer.

CRC is one of the leading causes of cancer mortality worldwide. Chemotherapy is widely used for the treatment of CRC, but its efficacy remains unsatisfactory, mainly due to drug resistance. Therefore, it is urgent to develop new strategies to overcome drug resistance. Combination therapy that aims to achieve additive or synergistic therapeutic effects is an effective approach to tackle the development of drug resistance. Given its established roles in tumor development, progression and metastasis, IGF-1R is a promising drug target for combination therapy against CRC. In this study, we revealed that the novel IGF-1R inhibitor PB-020 can act synergistically with mebendazole (MBZ) to reduce the viability of CRC cells and block xenograft CRC progression. Moreover, the PB-020/anti-PD-1 combination synergistically blocked CRC propagation in the MC38 murine colon carcinoma model. Both combination therapies potently suppressed the PI3K/AKT signaling pathway genes in CRC that may be associated with the development of drug resistance. Our findings establish a preclinical proof-of-concept for combating CRC using combined multi-target treatment with PB-020 and clinical anticancer drugs, which may provide useful clues for clinical trials to evaluate the efficacy and safety of these drug combinations in CRC patients.

CTSB+ macrophage repress memory immune hub in the liver metastasis site of colorectal cancer patient revealed by multi-omics analysis.

Colorectal cancer (CRC) is a lethal malignant tumor and 25-30% of CRC patients develop liver metastasis (LM) with a worse prognosis, but the metastasis mechanism is yet elucidated. To identify the potential immune regulatory mechanism of CRC liver metastasis, single-cell sequencing and multiplex immunohistochemistry were applied to identify key cell populations of the tumor microenvironment (TME) in the CRC and LM sites. We found memory CD8+ T cells, B cells, and CTSB + macrophages were enriched in the LM site, forming the memory immune hub, which was important for the anti-tumor response against LM. Therefore, our results revealed that memory immune responses were called in the LM sites and probably meditated by CTSB + macrophages.

Anesthetic management of a giant paraganglioma resection: a case report.

BACKGROUND: Patients with pheochromocytomas are often diagnosed with acute myocardial infarction (AMI) due to initial symptoms of palpitations and chest tightness. We describe a case of AMI syndrome where a giant paraganglioma was unexpectedly identified. The anesthetic management of the paraganglioma resection was challenging and complex. CASE PRESENTATION: A 66-year-old woman was admitted to the emergency department for complaints of palpitations, chest tightness and vomiting. A laboratory test revealed that troponin I and N-terminal pro-brain natriuretic peptide levels were dramatically increased. Emergency percutaneous coronary angiography (CAG) showed normal coronary arteries. In addition, the serum levels of free catecholamines were increased, and computed tomography and magnetic resonance imaging revealed a heterogenous mass lesion in the right retroperitoneal. All of this ultimately confirmed the diagnosis of pheochromocytoma. After three weeks of careful preoperative preparation by a multidisciplinary team, and an anesthesiologist team develops detailed perianesthesia management strategies to maintain hemodynamics and blood glucose stability and regulate acid-base balance, pheochromocytoma resection was performed successfully. About 2 weeks later, the patient was discharged healthy. A postoperative pathology test confirmed paraganglioma. CONCLUSIONS: To our knowledge, giant pheochromocytoma resection is a complex challenge for the anesthesiologists, this clinical case may supply a thoughtful experience for anesthetic management in the resection of giant pheochromocytomas. Adequate preoperative evaluation and prudent perianesthesia management by anesthesiologists are important guarantees for patients to obtain a good prognosis and discharge healthily.

Osthole-Mediated Inhibition of Neurotoxicity Induced by Ropivacaine via Amplification of the Cyclic Adenosine Monophosphate Signaling Pathway.

Background: Ropivacaine is widely used for clinical anesthesia and postoperative analgesia. However, the neurotoxicity induced by ropivacaine in a concentration- and duration-dependent manner, and it is difficult to prevent neurotoxicity. Osthole inhibits phosphodiesterase-4 activity by binding to its catalytic site to prevent cAMP hydrolysis. The aim of this present study is to explore the precise molecular mechanism of osthole-mediated inhibition of neurotoxicity induced by ropivacaine. Methods: SH-SY5Y cell viability and apoptosis were measured in different concentration and duration. Protein concentration was determined in each signaling pathway. The molecular mechanism of osthole-mediated inhibition of ropivacaine-caused neurotoxicity was evaluated. Results: The study demonstrated that osthole inhibits SH-SY5Y cells neurotoxicity in a duration- and concentration-dependent manner. Moreover, ropivacaine significantly increased the expression of caspase-3 by promoting the phosphorylation of p38. Osthole-induced upregulation of cAMP activated cAMP-dependent signaling pathway, sequentially leading to elevated cyclic nucleotide response element-binding protein levels, which inhibits P38-dependent signaling and decreases apoptosis of SH-SY5Y. Conclusions: This study display the evidence confirmed the molecular mechanism by which osthole amplification of cAMP-dependent signaling pathway, and overexpression of cyclic nucleotide response element-binding protein inhibits P38-dependent signaling and decreases ropivacaine-induced SH-SY5Y apoptosis.

Long-term immune responses in patients with confirmed novel coronavirus disease-2019: a 9-month prospective cohort study in Shanghai, China.

BACKGROUND: The duration of antibodies against SARS-CoV-2 in Covid-19 patients remains uncertain. Longitudinal serological studies are needed to prevent disease and transmission of the virus. METHODS: In 2020, 414 blood samples were tested, obtained from 157 confirmed Covid-19 patients, in a prospective cohort study in Shanghai. RESULTS: The seropositive rate of IgM peaked at 40.5% (17/42) within 1 month after illness onset and then declined. The seropositive rate of IgG was 90.6% (58/64) after 2 months, remained above 85% from 2 to 9 months and was 90.9% (40/44) after 9 months. Generalized estimating equations models suggested that IgM (P < 0.001) but not IgG significantly decreased over time. Age ≥ 40 years (adjusted odds ratio [aOR] 4.531; 95% confidence interval [CI] 1.879-10.932), and cigarette smoking (aOR 0.344; 95% CI 0.124-0.951) were associated with IgG, and age ≥ 40 years (aOR 2.820; 95% CI 1.579-5.036) was associated with IgM. After seroconversion, over 90% and 75.1% of subjects were estimated to remain IgG-positive 220 and 254 days, respectively. Of 1420 self-reported symptoms questionnaires, only 5% reported symptoms 9 months after onset. CONCLUSIONS: In patients with a history of natural infection, anti-SARS-CoV-2 IgG is long-lived, being present for at least 9 months after illness onset. The long duration of natural immunity can mitigate and eliminate Covid-19 and the ongoing pandemic.

Association between estimated glomerular filtration rate and 10-year atherosclerotic cardiovascular disease risk among community residents in Shanghai, China.

BACKGROUND AND AIMS: The association between the estimated glomerular filtration rate (eGFR) and atherosclerotic cardiovascular disease (ASCVD) risk is unknown. We aimed to evaluate whether eGFR can be used as a predictor in ASCVD risk assessment. METHODS AND RESULTS: Using baseline data from 28,187 participants from Shanghai Suburban Adult Cohort and Biobank study, we adopted Pooled Cohort Equations (PCEs) and Prediction for ASCVD Risk in China (China-PAR) to estimate 10-year ASCVD risk. Multivariate logistic regression was used to analyze the relationship between 10-year ASCVD risk and eGFR. The receiver operating characteristic (ROC) curve was used to evaluate predictive value of eGFR for 10-year high ASCVD risk. Compared with normal eGFR, both men and women with reduced eGFR had a higher prevalence of ASCVD risk factors. With the decrease of eGFR level, the median of 10-year ASCVD risk gradually increased. For men, the adjusted odds ratios (95% confidence interval (CI)) of 10-year high ASCVD risk by PCEs associated with eGFR (60-74 and <60 mL/min/1.73 m2) were 1.52 (95%CI:1.17-1.99) and 2.51 (95%CI:1.27-4.97). The corresponding result was significant only for eGFR < 60 mL/min/1.73 m2, OR of 1.57 (1.14-2.18) for women. Using China-PAR, the adjusted OR of 10-year high risk associated with eGFR < 60 mL/min/1.73 m2 was 1.82 (1.40-2.38) in men. ROC indicated that eGFR has a good predictive value for 10-year high ASCVD risk. CONCLUSION: eGFR may be an important risk factor in predicting and stratifying ASCVD risk. Consideration should be given to integrating eGFR into existing risk assessment tools to improve predictive performance.

Higher intake of whole grains and dietary fiber are associated with lower risk of liver cancer and chronic liver disease mortality.

The relationship between dietary factors and liver disease remains poorly understood. This study evaluated the associations of whole grain and dietary fiber intake with liver cancer risk and chronic liver disease mortality. The National Institutes of Health-American Association of Retired Persons Diet and Health Study cohort recruited 485, 717 retired U.S. participants in 1995-1996. Follow-up through 2011 identified 940 incident liver cancer cases and 993 deaths from chronic liver disease. Compared with the lowest, the highest quintile of whole grain intake was associated with lower liver cancer risk (Hazard ratio [HR]Q5 vs. Q1 = 0.78, 95% confidence interval [CI]: 0.63-0.96) and chronic liver disease mortality (HRQ5 vs. Q1 = 0.44, 95% CI: 0.35-0.55) in multivariable Cox models. Dietary fiber was also associated with lower liver cancer risk (HRQ5 vs. Q1 = 0.69, 95% CI: 0.53-0.90) and chronic liver disease mortality (HRQ5 vs. Q1 = 0.37, 95% CI: 0.29-0.48). Fiber from vegetables, beans and grains showed potential protective effect. Here, we show that higher intake of whole grain and dietary fiber are associated with lower risk of liver cancer and liver disease mortality.

Determination of the Median Effective Dose of Dexmedetomidine for the Prevention of Emergence Agitation in Geriatric Patients Undergoing Major Open Surgery With General Anesthesia: A Prospective, Double-Blinded, Dose-Response Trial.

Dexmedetomidine can effectively decrease the incidences of emergence agitation (EA) in adult patients, but there are major side effects related to increased dose of dexmedetomidine. The purpose of this study was to determine the median effective dose of dexmedetomidine in the prevention of EA among geriatric patients undergoing major open surgery with general anesthesia. A total of 50 geriatric patients were enrolled in this study. Dexmedetomidine 0.5 µg·kg-1·h-1 continuous intravenous infusion was administered to the first patient. The next dose was increased or decreased by .05 depending on the response of the previous patient, according to the Dixon up-and-down method. An "effective" or "ineffective" response was determined based on the Riker sedation-agitation score (RSAS), we defined "effective" as RSAS<5, and "ineffective" as RSAS≥5. The ED50 of dexmedetomidine in prevention of EA was .30 µg·kg-1·h-1 (95% CI, .27-.33) and the predicted ED95 was .42 µg·kg-1·h-1 (95% CI, .38-.51). The incidence of bradycardia was significantly increased in the group without EA compared to the group with EA (57.1% vs 13.6%, P = .002). The ED50 of dexmedetomidine in prevention of EA was .30 µg·kg-1·h-1 (95% CI, .27-.33) and the predicted ED95 was .42 µg·kg-1·h-1 (95% CI, .38-.51). Bradycardia was the main complication.

Prediction of 10-year atherosclerotic cardiovascular disease risk among community residents in Shanghai, China - a comparative analysis of risk algorithms.

BACKGROUND AND AIMS: The accuracy of various 10-year atherosclerotic cardiovascular disease (ASCVD) risk models has been debatable. We compared two risk algorithms and explored clustering patterns across different risk stratifications among community residents in Shanghai. METHODS AND RESULTS: A total of 28,201 residents (aged 40-74 years old) who were free of ASCVD were selected from the Shanghai Survey in China. The 10-year ASCVD risk was estimated by applying the 2013 Pooled Cohort Equations (PCEs) and Prediction for ASCVD Risk in China (China-PAR). The agreement was assessed between PCEs and China-PAR using Cohen's kappa statistics. The mean absolute 10-year ASCVD risk calculated by PCEs and China-PAR was about 10.0% and 6.0%, respectively. PCEs estimated that 44.9% of participants [with a 95% confidence interval (CI):44.0%-45.8%] were at high risk, while China-PAR estimated only 16.7% (95%CI:15.8%-18.0%) were at high risk. In both models, the percentage of high ASCVD risk was higher for participants who were older, men, less educated, current smokers, drinkers and manual workers. Among high-risk individuals, almost all participants (PCEs:90.5%; China-PAR:98.6%) had at least one risk factor; hypertension being the most prevalent. The concordance between PCEs and China-PAR was moderate (kappa:0.428, 95%CI: 0.420-0.434) with a better agreement for women (kappa:0.503,95%CI: 0.493-0.513) than for men (kappa:0.211,95%CI: 0.201-0.221). CONCLUSION: The proportion of participants with a 10-year ASCVD high risk predicted by China-PAR was lower than the results of the PCEs. The risk stratifications of the two algorithms were inconsistent in terms of demographic and life-behaviour characteristics.

Postdiagnostic dairy products intake and colorectal cancer survival in US males and females.

BACKGROUND: To evaluate the association between postdiagnostic dairy intake and survival among patients with colorectal cancer (CRC). METHODS: This study analyzed data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Postdiagnostic dairy intake and other dietary and lifestyle factors were obtained from validated questionnaires. Individual dairy items including milk, cheese, yogurt, and so on were reported, and total, high-fat, and low-fat dairy intakes were derived. RESULTS: A total of 1753 eligible CRC cases were identified until 2012, from which 703 deaths were documented after a median follow-up time of 8.2 y, and 242 were due to CRC. Overall, when comparing those who consumed 21+ servings/wk with <7 servings/wk, postdiagnostic total dairy intake did not show significant associations with CRC-specific mortality (HR: 1.35; 95% CI: 0.85, 2.13) or overall mortality (HR: 1.28; 95% CI: 0.98, 1.67). However, high-fat dairy, including whole milk and cream cheese, was positively associated with overall mortality (HR: 1.33; 95% CI: 1.08, 1.65) but not significantly with CRC-specific mortality (HR: 1.31; 95% CI: 0.91, 1.90) when comparing those who consumed 10.5+ servings/wk with <3.5 servings/wk. For the same comparison, low-fat dairy, including skim or nonfat milk and cottage cheese, was inversely associated with overall mortality (HR: 0.74; 95% CI: 0.59, 0.92) but not CRC-specific mortality (HR: 0.91; 95% CI: 0.63, 1.29). CONCLUSIONS: Total dairy products intake did not show significant association with CRC-specific or overall mortality. However, high intake of high-fat dairy products was associated with increased mortality, whereas low-fat dairy was associated with lower risk of overall mortality.

Association between APE1 ASP148GLU and colorectal cancer risk: A meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is recognized as one of the most common cancer globally. The association between CRC and apurinic endonuclease 1 (APE1) Asp148Glu polymorphism remains unclear; thus, this meta-analysis aimed to explore whether APE1 Asp148Glu polymorphism is related to CRC risk. METHODS: Embase, PubMed, Cochrane library, CNKI and Wanfang databases were subject to a systematic search until April, 17, 2020 to evaluate the effect of APE1 Asp148Glu polymorphism on CRC risk. The associated strength was used to evaluate with odds ratios (ORs) with 95% confidence intervals (CIs) between Asp148Glu polymorphism and CRC risk. Subgroup analyses were also performed. RESULTS: In total, 11 articles including 8,136 subjects (3,836 cases and 4,300 controls) were included. Five genetic models were analyzed, including the additive model (G vs. T), the heterozygote comparison (TG vs. TT), the homozygote comparison (GG vs. TT), the dominant model (TG+GG vs. TT), and the recessive model (GG vs. TG+TT). In these models, T refers to thymine and G refers to guanine. The APE1 Asp148Glu polymorphism in heterozygote comparison [OR (95%CI) = 1.36 (1.05, 1.75), P=0.019] and dominant model [OR (95%CI) =1.31 (1.07, 1.61), P=0.010] significantly increased CRC risk. No significant association was seen for the additive model [OR (95%CI) = 1.14 (1.00, 1.31), P=0.057], recessive model [OR (95%CI) = 0.97 (0.71, 1.31), P=0.826] or in homozygote comparison [OR (95%CI) = 1.15 (0.88, 1.52), P=0.309]. Moreover, CRC risk indicated a remarkable association with APE1 Asp148Glu polymorphism in the PCR-RFLP additive model, homozygote comparison and recessive model (PG) may be a potential risk factor for CRC.

Cohort profile: protocol and baseline survey for the Shanghai Suburban Adult Cohort and Biobank (SSACB) study.

PURPOSE: The Shanghai Suburban Adult Cohort and Biobank (SSACB) was established to identify environmental, lifestyle and genetic risk factors for non-communicable chronic diseases (NCDs) in adults (20-74 years old) living in a suburban area of Shanghai with rapid urbanisation. PARTICIPANTS: Two of eight suburban district were purposely selected according to participant willingness, health service facilities, population, geographic region and electronic medical record system. From these suburban districts, four communities were selected based on economic level and population size. At stage three, one-third of the committees/villages were randomly selected from each community. All residents aged 20-74 years old were invited as study participants. FINDINGS TO DATE: The baseline data on demographics, lifestyle and physical health-related factors were collected using a face-to-face questionnaire interview. All participants completed physical examinations and had blood and urine tests. Blood and urine samples from these tests were stored in a biobank. From 6 April 2016 through 31 October 2017, we conducted face-to-face interviews and clinical examinations in 44 887 participants: 35 727 from Songjiang District and 9160 from Jiading District. The average age of participants was 56.4±11.2 years in Songjiang and 56.6±10.5 years in Jiading. The prevalence of hypertension, diabetes and dyslipidaemia was 34.0%, 8.2% and 11.1%, respectively. FUTURE PLANS: In-person surveys will be conducted every 5 years. For annual tracking, baseline data was linked to the local health information system, which was composed of an electronic medical record system, a chronic disease management system, a cancer registry system, an infectious disease report system and a death registry system. The data of the SSACB cohort is located in the School of Public Health, Fudan University. International and domestic collaborative research projects are encouraged and inherent in the project.

Relationship between IL10 and PD-L1 in Liver Hepatocellular Carcinoma Tissue and Cell Lines.

BACKGROUND: Despite the large-scale clinical application of programmed death-ligand 1 (PD-L1) monoclonal antibody, reduction in its clinical response rate has become a gradual problem. As such, use of PD-L1 monoclonal antibody in combination with other anticarcinoma drugs has been the main strategy in improving its efficacy. Interleukin 10 (IL10) is a recognized inflammatory and immunosuppressive factor. Previous studies have suggested that there is a link between PD-L1 and IL10. OBJECTIVE: This study was aimed at clarifying the relationship between PD-L1 and IL10 in liver hepatocellular carcinoma (LIHC) and whether IL10 enhances the efficacy of PD-L1 inhibitor. METHODS: Expression levels of PD-L1 and IL10 in carcinoma and adjacent tissues were tested by immunochemistry, Western blotting, and RT-PCR. Survival duration and follow-up data of each patient were recorded. LIHC cell lines Bel7405 and MHCC 97-H were used for in vitro experiments. Exogenous IL10 and anti-IL10 were added to cell supernatant. Expression level of PD-L1 in the LIHC cell lines was determined using Western blotting and ELISA. CCK8 and transwell assays were adopted to examine the effect of PD-L1 combined with IL10 on proliferation, invasion, and metastasis of LIHC cells. RESULTS: The survival period of patients with low expression of IL10 was longer than that of patients with high expression (P = 0.01). Overexpression of PD-L1 increased the IL10 and Met levels in LIHC tissues and cell lines. IL10 downregulated the expression level of PD-L1 and enhanced the efficacy of crizotinib via the Met signaling pathway in the LIHC cells. CONCLUSIONS: A combination of IL10 and PD-L1 inhibitor holds great promise as an effective treatment for LIHC.

Relationship between IL-10 and PD-L1 in esophageal carcinoma tissues and IL-10 down-regulates PD-L1 expression via Met signaling pathway.

BACKGROUND: Programmed death-ligand 1 (PD-L1) plays a critical role in host immunity in the setting of cancer progression. Interleukin 10 (IL-10) is a multi-cellular, multi-functional cytokine that regulates cell growth and differentiation and participates in inflammatory and immune responses. The purpose of this study was to clarify the relationship between PD-L1 and IL-10 and their clinical importance in esophageal carcinoma (ESCA). METHODS: ESCA patients (n=100) who underwent surgery with preoperative therapy were included in the study. By immuno-histochemical staining, PD-L1, IL-10 and CD8 positive cells were examined in resected specimens. The gene expression levels of PD-L1, IL-10 and Met were detected by qRT-PCR and Western blots, and differentially compared in cancer, adjacent and normal tissues. In cell experiments, the Eca109 and TE-1 cell-lines were incubated with IL-10 or anti-IL-10 antibody, and then PD-L1 and Met expression levels were compared by ELISA and Western blots. The effect of crizotinib and/or IL-10 on the proliferation, invasion and migration of esophageal squamous cell-lines was estimated by CCK8 and transwell assay. RESULTS: In tumor tissues, the mRNA and protein levels of PD-L1, IL-10 and Met were higher than those in adjacent tissues. The high expression levels of PD-L1 and IL-10 indicated a poor prognosis. IL-10 reduced the expression of PD-L1 in esophageal squamous cell-lines via Met signaling. Over-expression of PD-L1 in increased the levels of IL-10, and Met in in ESCA tissue and cell lines. The combination of crizotinib and IL-10 were more effective in inhibiting the proliferation, migration and invasion of esophageal squamous cell lines. CONCLUSIONS: The combination of IL-10 and PD-L1 monoclonal antibody may have therapeutic promise in treating ESCA.