SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER-to-Golgi Transport and Inducing ER Stress.

Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next-generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26-2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67-4.50) and in a biobank meta-analysis (OR, 1.16; 95% CI, 1.04-1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9-edited HEK293T cell lines show that loss-of-function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/- mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein-stimulated pancreatitis models, Sec16a+/- mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.

[Repetitive transcranial acupuncture stimulation combined with electroacupuncture in treatment of acute facial palsy with retroauricular pain: a randomized controlled trial].

OBJECTIVE: To observe the clinical effect of repetitive transcranial acupuncture stimulation (rTAS) combined with electroacupuncture (EA) in treatment of acute facial palsy with retroauricular pain. METHODS: Sixty-eight patients of acute facial palsy with retroauricular pain were randomly divided into an observation group (34 cases, 3 cases dropped out) and a control group (34 cases, 3 cases dropped out). On the basis of conventional therapy, in the control group, Yangbai (GB 14), Cuanzhu (BL 2), Sibai (ST 2), Quanliao (SI 18), Dicang (ST 4), Yifeng (TE 17), Qianzheng (Extra point) and Taiyang (EX-HN 5) on the affected side, and bilateral Hegu (LI 4) were selected. EA was attached to Yangbai (GB 14) and Cuanzhu (BL 2), and Sibai (ST 2) and Dicang (ST 4), respectively, using intermittent wave. In the observation group, on the basis of the regimen as the control group, rTAS was delivered at Baihui (GV 20) and the 1/5 of the lower motor area on the bilateral sides; EA of dense wave was given at the sites of the mastoidⅠand Ⅱ. The intervention of each group was delivered once a day, 6 times a week as one course for 4 courses and taking a day off every course. Before treatment and at the moment after the first treatment completion, the score of visual analogue scale (VAS) was observed in the two groups and the days of retroauricular pain were recorded. Before and after treatment, the score of Sunnybrook facial grading system (SFGS), the grade of House-Brackmann facial nerve function evaluation system (H-B), the latency and amplitude of the motor conduction from the foramina stylomastoideum to the frontal muscle, the orbicularis oris muscle and the orbicularis oculi muscle on the affected facial nerve, were observed in the patients of two groups and the clinical effect was compared between the two groups after treatment. RESULTS: After treatment, SFGS score was increased (P<0.05), H-B grade was improved (P<0.05), the latency was shortened in the motor conduction from the foramina stylomastoideum to the frontal muscle, the orbicularis oris muscle and the orbicularis oculi muscle on the affected facial nerve (P<0.05) and its amplitude elevated (P<0.05) when compared with those before treatment in the two groups. In the observation group, SFGS score was higher (P<0.05), H-B grade was superior (P<0.05), the latency was shorter in the motor conduction from the foramina stylomastoideum to the frontal muscle, the orbicularis oris muscle and the orbicularis oculi muscle on the affected facial nerve (P<0.05) and its amplitude was higher (P<0.05) when compared with those of the control group after treatment. After the completion of the first treatment, VAS score of either group was reduced in comparison with that before treatment (P<0.05), and the score in the observation group was lower than that of the control group (P<0.05). The duration of retroauricular pain was shortened in the observation group when compared with that of the control group (P<0.05). The total effective rate was 87.1% (27/31) in the observation group, which was higher than 77.4% (24/31) of the control group (P<0.05). CONCLUSION: The rTAS combined with EA is effective for reducing neurologic impairment of acute facial palsy and alleviating retroauricular pain in the patients.

Discovery of Novel N-(Anthracen-9-ylmethyl) Benzamide Derivatives as ZNF207 Inhibitors Promising in Treating Glioma.

Targeting tumor stemness is an innovative approach to cancer treatment. Zinc Finger Protein 207 (ZNF207) is a promising target for weakening the stemness of glioma cells. Here, a series of novel N-(anthracen-9-ylmethyl) benzamide derivatives against ZNF207 were rationally designed and synthesized. The inhibitory activity was evaluated, and their structure-activity relationships were summarized. Among them, C16 exhibited the most potent inhibitory activity, as evidenced by its IC50 values ranging from 0.5-2.5 µM for inhibiting sphere formation and 0.5-15 µM for cytotoxicity. Furthermore, we found that C16 could hinder tumorigenesis and migration and promote apoptosis in vitro. These effects were attributed to the downregulation of stem-related genes. The in vivo evaluation demonstrated that C16 exhibited efficient permeability across the blood-brain barrier and potent efficacy in both subcutaneous and orthotopic glioma tumor models. Hence, C16 may serve as a potential lead compound targeting ZNF207 and has promising therapeutic potential for glioma.

Combining full-length gene assay and SpliceAI to interpret the splicing impact of all possible SPINK1 coding variants.

BACKGROUND: Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. In this study, we aim to harness the well-established full-length gene splicing assay (FLGSA) in conjunction with SpliceAI to prospectively interpret the splicing effects of all potential coding SNVs within the four-exon SPINK1 gene, a gene associated with chronic pancreatitis. RESULTS: Our study began with a retrospective analysis of 27 SPINK1 coding SNVs previously assessed using FLGSA, proceeded with a prospective analysis of 35 new FLGSA-tested SPINK1 coding SNVs, followed by data extrapolation, and ended with further validation. In total, we analyzed 67 SPINK1 coding SNVs, which account for 9.3% of the 720 possible coding SNVs. Among these 67 FLGSA-analyzed SNVs, 12 were found to impact splicing. Through detailed comparison of FLGSA results and SpliceAI predictions, we inferred that the remaining 653 untested coding SNVs in the SPINK1 gene are unlikely to significantly affect splicing. Of the 12 splice-altering events, nine produced both normally spliced and aberrantly spliced transcripts, while the remaining three only generated aberrantly spliced transcripts. These splice-impacting SNVs were found solely in exons 1 and 2, notably at the first and/or last coding nucleotides of these exons. Among the 12 splice-altering events, 11 were missense variants (2.17% of 506 potential missense variants), and one was synonymous (0.61% of 164 potential synonymous variants). Notably, adjusting the SpliceAI cut-off to 0.30 instead of the conventional 0.20 would improve specificity without reducing sensitivity. CONCLUSIONS: By integrating FLGSA with SpliceAI, we have determined that less than 2% (1.67%) of all possible coding SNVs in SPINK1 significantly influence splicing outcomes. Our findings emphasize the critical importance of conducting splicing analysis within the broader genomic sequence context of the study gene and highlight the inherent uncertainties associated with intermediate SpliceAI scores (0.20 to 0.80). This study contributes to the field by being the first to prospectively interpret all potential coding SNVs in a disease-associated gene with a high degree of accuracy, representing a meaningful attempt at shifting from retrospective to prospective variant analysis in the era of exome and genome sequencing.

Hsa_circ_0136666 stimulates gastric cancer progression and tumor immune escape by regulating the miR-375/PRKDC Axis and PD-L1 phosphorylation.

BACKGROUND: Targeted drugs are not quite effective for prolonging the survival of patients with gastric cancer due to off-target effects as well as tumor immune escape mechanisms. Circular RNAs widely exist in tumor regions as biomarkers and can be developed as effective drug targets. METHODS: Western blot, QRT-PCR, fluorescence in situ hybridization, and flow cytometry were used to investigate the function of hsa_circ_0136666 in promoting the proliferation of gastric cancer cells. Tissue immunofluorescence, enzyme-linked immunosorbent assay (ELISA), as well as flow cytometric analysis, was conducted to explore the process of tumor immune evasion in tumor-bearing mice. The differences of circRNA expression in clinical samples were analyzed through tissue microarray FISH. The effect of siRNA on improving the efficacy of anti-PDL1 drugs and suppressing the immune microenvironment was evaluated by the coadministration model. RESULTS: We demonstrated that hsa_circ_0136666 was widely and highly expressed in gastric cancer tissues and cells. Functionally, hsa_circ_0136666 promoted gastric cancer tumor proliferation and tumor microenvironment formation, leading to tumorigenesis immune escape, and this effect was dependent on CD8 + T cells. Mechanistically, we confirmed that hsa_circ_0136666 competitively upregulated PRKDC expression by sponging miR-375-3p, regulating immune checkpoint proteins, prompting phosphorylation of PD-L1 to preventing its degradation, driving PD-L1 aggregation and suppressing immune function, thereby impairing cancer immune responses. In terms of application, we found that LNP-siRNA effectively improved anti-PDL1 drug efficacy and inhibited immune escape. CONCLUSION: Our results reveal an oncogenic role played by hsa_circ_0136666 in gastric cancer, driving PD-L1 phosphorylation via the miR-375/PRKDC signaling axis, prompting immune escape. This work proposes a completely new pathogenic mechanism of gastric cancer, uncovers a novel role for hsa_circ_0136666 as an immune target, and provides a rationale for enhancing the efficacy of anti-PD-L1 therapy for gastric cancer.

Effect of doping and defects on the optoelectronic properties of ZrSe2 based on the first principle.

CONTEXT: Based on the first principles under the framework of density functional theory, it calculates the effect of vacancy defects in single Zr and single Se atoms and the replacement of Se atoms in ZrSe2 with O, Se, and Te atoms on the optoelectronic properties of monolayer ZrSe2, including geometry, energy band structure, electronic density of states, and optical properties. The doping of the three non-metallic atoms was n-type doping for the O and S atoms and p-type doping for the Te atom. Defects in the Zr atoms and O-atom doping significantly affect the peak reflectance and absorption coefficient of the ZrSe2 system. METHODS: All Density Functional Theory calculations were carried out using the CASTEP module in the Materials-Studio (MS) software. The generalized gradient approximation plane-wave pseudopotential method and the Perdew-Burke-Ernzerfhof (PBE) generalized function were used for structural optimization and total energy calculation of the defect and doping systems. After convergence tests, the plane wave truncation energy was set to 500 eV, and the Brillouin zone K-point grid was set to 4 × 4 × 1. The atomic energy convergence criterion is 1.0 × 10-6 eV/atom, the interatomic interaction force convergence criterion is 0.02 eV/Å, the maximum atomic displacement convergence criterion is 0.001 Å, and the internal crystal stress convergence criterion is 0.05 GPa. In order to avoid the influence of the interaction forces between the layers, a vacuum layer of 15 Å is placed in the Z-axis direction.

Research on early warning of renal damage in hypertensive patients based on the stacking strategy.

BACKGROUND: Among the problems caused by hypertension, early renal damage is often ignored. It can not be diagnosed until the condition is severe and irreversible damage occurs. So we decided to screen and explore related risk factors for hypertensive patients with early renal damage and establish the early-warning model of renal damage based on the data-mining method to achieve an early diagnosis for hypertensive patients with renal damage. METHODS: With the aid of an electronic information management system for hypertensive out-patients, we collected 513 cases of original, untreated hypertensive patients. We recorded their demographic data, ambulatory blood pressure parameters, blood routine index, and blood biochemical index to establish the clinical database. Then we screen risk factors for early renal damage through feature engineering and use Random Forest, Extra-Trees, and XGBoost to build an early-warning model, respectively. Finally, we build a new model by model fusion based on the Stacking strategy. We use cross-validation to evaluate the stability and reliability of each model to determine the best risk assessment model. RESULTS: According to the degree of importance, the descending order of features selected by feature engineering is the drop rate of systolic blood pressure at night, the red blood cell distribution width, blood pressure circadian rhythm, the average diastolic blood pressure at daytime, body surface area, smoking, age, and HDL. The average precision of the two-dimensional fusion model with full features based on the Stacking strategy is 0.89685, and selected features are 0.93824, which is greatly improved. CONCLUSIONS: Through feature engineering and risk factor analysis, we select the drop rate of systolic blood pressure at night, the red blood cell distribution width, blood pressure circadian rhythm, and the average diastolic blood pressure at daytime as early-warning factors of early renal damage in patients with hypertension. On this basis, the two-dimensional fusion model based on the Stacking strategy has a better effect than the single model, which can be used for risk assessment of early renal damage in hypertensive patients.

System analysis based on the cancer-immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitors as monotherapies for advanced hepatocellular carcinoma (HCC) fail to achieve satisfying results, while combination therapies show greater efficacy. Therefore, identifying new combined targets for immune checkpoint inhibitors could be promising. METHODS: We combined the cancer-immunity cycle score with weighted gene coexpression network and system analyses to screen immunosuppressive targets in HCC. In vitro and in vivo experiments were used to assess the effect of zinc finger protein 207 (ZNF207) on HCC immunity. RNA sequencing, metabolomic, cytokine array analysis, dual-luciferase reporter gene assay, and ChIP quantitative PCR assay were used to investigate the role of ZNF207 in tumor immunity regulation. RESULTS: The system analysis and experimental verification revealed ZNF207 as an immunosuppressive target in HCC. Hypoxia-induced upregulation of ZNF207 promoted HCC progression in immunocompetent mice while being associated with decreased CD8+ T-cell infiltration and increased exhaustion. Mechanistically, the mitogen-activated protein kinase (MAPK)-chemokine C-X3-C-motif ligand axis was involved in ZNF207-mediated CD8+ T-cell chemotaxis. Furthermore, ZNF207 transcriptionally regulated indoleamine 2,3-dioxygenase 1 and elevated kynurenine levels, leading to the exhaustion of CD8+ T cells. Patients with lower ZNF207 expression were more sensitive to antiprogrammed cell death protein 1 (PD1) therapy, and silencing ZNF207 could be beneficial to anti-PD1 combination therapy. CONCLUSION: Our study implicates ZNF207 in suppressing the HCC microenvironment and showed the feasibility of targeting ZNF207 during anti-PD1 therapy in HCC.

Non-clinical immunogenicity, biodistribution and toxicology evaluation of a chimpanzee adenovirus-based COVID-19 vaccine in rat and rhesus macaque.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 has rapidly expanded into a serious global pandemic. Due to the high morbidity and mortality of COVID-19, there is an urgent need to develop safe and effective vaccines. AdC68-19S is an investigational chimpanzee adenovirus serotype 68 (AdC68) vector-based vaccine which encodes the full-length spike protein of SARS-CoV-2. Here, we evaluated the immunogenicity, biodistribution and safety profiles of the candidate vaccine AdC68-19S in Sprague Dawley (SD) rat and rhesus macaque under GLP conditions. To characterize the biodistribution profile of AdC68-19S, SD rats were given a single intramuscular injection of AdC68-19S 2 × 1011 VP/dose. Designated organs were collected on day 1, day 2, day 4, day 8 and day 15. Genomic DNA was extracted from all samples and was further quantified by real-time quantitative polymerase chain reaction (qPCR). To characterize the toxicology and immunogenicity profiles of AdC68-19S, the rats and rhesus macaques were injected intramuscularly with AdC68-19S up to 2 × 1011vp/dose or 4 × 1011vp/dose (2 and fourfold the proposed clinical dose of 1 × 1011vp/dose) on two or three occasions with a 14-day interval period, respectively. In addition to the conventional toxicological evaluation indexes, the antigen-specific cellular and humoral responses were evaluated. We proved that multiple intramuscular injections could elicit effective and long-lasting neutralizing antibody responses and Th1 T cell responses. AdC68-19S was mainly distributed in injection sites and no AdC68-19S related toxicological reaction was observed. In conclusion, these results have shown that AdC68-19S could induce an effective immune response with a good safety profile, and is a promising candidate vaccine against COVID-19.

Rectal indometacin to prevent pancreatitis after extracorporeal shock wave lithotripsy (RIPEP): a single-centre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Pancreatitis is the most common complication of pancreatic extracorporeal shock wave lithotripsy (ESWL). There has been little research into effective prevention of post-ESWL pancreatitis. Therefore, we aimed to assess the efficacy of prophylactic rectal indometacin in preventing post-ESWL pancreatitis. METHODS: In this double-blind, randomised, placebo-controlled trial done at Changhai Hospital (Shanghai, China), patients aged 18 years or older with chronic pancreatitis and pancreatic stones (>5 mm in diameter) who were eligible for treatment with ESWL were randomly allocated using a computer-generated randomisation table, in a 1:1 ratio, to receive 100 mg rectal indometacin or identical glycerin (placebo) suppositories 30 min before ESWL. Patients, endoscopists, and outcome assessors were masked to group allocation. The primary outcome was the incidence of post-ESWL pancreatitis within 24 h of ESWL, analysed by the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT02797067. FINDINGS: Between May 31, 2016, and June 26, 2019, 1370 patients were enrolled, with 685 patients randomly assigned to the rectal indometacin group and 685 patients to the placebo group. All patients received their allocated intervention and completed final follow-up, and were included in the intention-to-treat analysis. Post-ESWL pancreatitis occurred in 60 (9%) patients in the rectal indometacin group and 84 (12%) patients in the placebo group (relative risk 0·71, 95% CI 0·52-0·98; p=0·042). Transient adverse events occurred in 235 (34%) patients in the rectal indometacin group and 252 (37%) patients in the placebo group, with asymptomatic hyperamylasaemia being the most common (189 [28%] patients vs 197 [29%] patients). No difference was noted between groups in the incidence of other complications and transient adverse events. INTERPRETATION: Pre-procedural administration of rectal indometacin is an efficacious and safe means of reducing the incidence of post-ESWL pancreatitis. FUNDING: Programs of Shanghai Municipal Government and the "Ten Thousand Plan"-National High Level Talents Special Support Plan.

Hepatic interferon regulatory factor 8 expression mediates liver ischemia/reperfusion injury in mice.

Hepatic ischemia/reperfusion (I/R) injury is an inevitable complication of hepatic surgery occasioned by liver transplantation and resection. The progression from liver ischemia to reperfusion injury is accompanied by abnormal metabolism, Kupffer cell activation, neutrophil recruitment and the release of cytokines. Activation of several interferon regulatory factors (IRFs) has been reported to either enhance or restrict I/R progression, but the role of IRF8 in the regulation of I/R injury progression is still unknown. In this study, we explore the IRF8 function in the I/R-mediated liver injury using overexpressed hepatic IRF8 and knockout mice. According to our results, IRF8 knockout mice had significantly lower inflammatory cells infiltration, inflammatory cytokines release and serum aspartate aminotransferase/alanine aminotransferase levels that improved the necrotic injury after I/R, unlike the control mice. Conversely, the overexpression of IRF8 in WT mice markedly aggravated the liver structure damage and its abnormal function. We further showed that IRF8-mediated inflammatory cells infiltration were partly dependent on early autophagy and NF-κΒ signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-κΒ signal pathway inhibitor secukinumab could drastically reverse the IRF8-mediated increase of neutrophil infiltration and chemokine release at different degrees. This work uncovered a critical role of IRF8 in the modulation of the hepatic microenvironment and as a potential target in the initial treatment of I/R injury.

IL-6 deficiency promotes colitis by recruiting Ly6Chi monocytes into inflamed colon tissues in a CCL2-CCR2-dependent manner.

Interleukin 6 (IL-6) is a pleiotropic cytokine that is elevated in inflammatory bowel disease. However, the role of IL-6 deficiency in colitis is not well-defined. Some IL-6 and IL-6 receptor antagonists are associated with severe gastrointestinal immune adverse effects, but the mechanisms of the effects are not clear. This study aimed to investigate the effect of IL-6 in ulcerative colitis in Il6-/- mice. Results indicated that physiological deficiency of IL-6 promoted the development of colitis. Moreover, IL-6 deficiency significantly increased the mRNA levels of monocytes chemokine Ccl2 and its receptor Ccr2 in colon tissues. Similarly, the percentage of Ly6Chigh monocytes and neutrophils were increased in the colon of Il6-/- mice. Intestinal crypts more strongly increased the migration of Il6-/- macrophages than wild-type ones. Moreover, Il6-/- macrophages promoted the migration of neutrophils. Most importantly, RS102895, an antagonist of CCR2, diminished chemotaxis of macrophages and inhibited colitis in Il6-/- mice. Collectively, these results indicate that Il6-/- macrophages migrate to inflamed colon tissues and recruit neutrophils, thereby promoting the effect of Il6-/- on colitis. This study expands our understanding on the effect of IL-6 deficiency in colitis and the development of gastrointestinal immune adverse effects.

Tumor-tagging by oncolytic viruses: A novel strategy for CAR-T therapy against solid tumors.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising immunotherapies in the past decade. It brings hope for cure to patients with previously refractory hematological malignancies. However, when translating this strategy into non-hematologic malignancies, the antitumor activity from multiple clinical studies seemed to be subtle or transient. The less satisfying efficacy in solid tumors might at least due to antigen heterogeneity, suboptimal CAR-T cell trafficking and tumor immunosuppressive environment. Here, we will review the updating strategies to challenge the therapeutic impediments of CAR-T therapy in non-hematologic malignancies. We mainly focus on the combination with oncolytic viruses (OV), the born allies for CAR-T cells. In addition to previously reported OVs-arming strategy, we discuss recently proposed tumor-tagging concept by OVs as CAR-T targets, as well as the possible improvements. Overall, tumor-tagging strategy by OVs combination with CAR-T would be a novel and promising solution for the heterogeneity and immunosuppressive microenvironment of solid tumors.

Prevalence and Risk Factors for Osteopathy in Chronic Pancreatitis.

BACKGROUND AND AIMS: The high incidence of osteopathy among patients with chronic pancreatitis (CP) has garnered increased attention over recent years. The aims of this study were to assess the prevalence and risk factors for osteopathy in Chinese patients with CP. METHODS: This was a cross-sectional study of CP patients from a large center in China; patients were recruited between 31 January 2017 and 31 January 2018. Bone density and laboratory tests, including bone-related biochemical, inflammatory, and hormone parameters, were assessed prospectively. Differences between patients with and without osteopathy were analyzed. Logistic regression analysis was used to investigate associations between variables. RESULTS: In total, 104 CP patients were enrolled in this study (68.3% idiopathic and 31.7% alcoholic). According to the M-ANNHEIM classification, 87.5% of the patients were at an early stage (0-II). Osteopenia was diagnosed in 30.8% of patients and osteoporosis in 5.8%; thus, a total of 36.5% of patients presented with osteopathy. In multivariate analysis, the independent risk factors for osteopathy in CP patients were age (OR = 1.04; 95% CI = 1.00-1.08; P = 0.030), BMI (OR = 0.72; 95% CI = 0.58-0.89; P = 0.003), and PTH (OR = 0.96; 95% CI = 0.93-1.00; P = 0.022). CONCLUSIONS: This study is the first to report the prevalence of osteopathy in Chinese patients with CP. It found that age and low BMI are significant risk factors for osteopathy. Low PTH (but within the normal range) showed a weak association with osteopathy, which warrants further exploration.

Hypoxia-induced myeloid derived growth factor promotes hepatocellular carcinoma progression through remodeling tumor microenvironment.

Purpose: Exploring and studying the novel target of hepatocellular carcinoma (HCC) has been extremely important for its treatment. The principal objective of this project is to investigate whether myeloid derived growth factor (MYDGF) could accelerate the progression of HCC, and how it works. Methods: Cell proliferation, clonal formation, sphere formation and xenograft tumor experiments were used to prove the critical role of MYDGF in HCC progression. Tumor angiogenesis, immune cell infiltration, macrophage chemotaxis and inflammatory cytokines detection were utilized to clarify how MYDGF remodeled the tumor microenvironment (TME) to accelerate the progress of HCC. Results: Here, we reported a secretory protein MYDGF, which could be induced by hypoxia, was significantly upregulated in HCC and associated with poor clinical outcomes. Using bioinformatics and experimental approaches, we found that MYDGF promotes cell proliferation in vitro and in vivo through a mechanism that might involve enhanced self-renewal of liver CSCs. Furthermore, MYDGF can also promote tumor angiogenesis, induce macrophages to chemotaxis into tumor tissue, and then release various inflammatory cytokines, including IL-6 and TNF-α, which ultimately aggravate inflammation of tumor microenvironment and accelerate HCC progression. Conclusions: We provided evidence that MYDGF could directly affect the self-renewal of liver CSCs, and indirectly aggravate the inflammatory microenvironment to accelerate the progression of HCC.

Effect of Combined Statin and Antihypertensive Therapy in Patients with Hypertension: A Systematic Review and Meta-Analysis.

INTRODUCTION: This meta-analysis aimed to explore the preventive effects of combined statin and antihypertensive therapy on major cardiovascular outcomes in patients with hypertension. METHODS: PubMed, Embase, and the Cochrane Library databases and reference lists of published studies were systematically searched throughout October 9, 2019. Studies designed as randomized controlled trials and investigating the effects of combined statin and antihypertensive therapy versus antihypertensive therapy alone were included. Data abstraction and quality of included studies were assessed by 2 independent authors. The summary results were calculated using relative risks (RRs) with 95% CIs employing a random-effects model. RESULTS: A total of 8 randomized controlled trials including 38,618 patients were finally enrolled. The summary RRs indicated that the combined therapy significantly reduced the risk of major adverse cardiovascular events compared with antihypertensive therapy alone (RR 0.79; 95% CI 0.71-0.88; p < 0.001). Furthermore, the patients in the combined therapy group also experienced less myocardial infarction (RR 0.67; 95% CI 0.53-0.84; p = 0.001) and stroke risks (RR 0.82; 95% CI 0.72-0.94; p = 0.005), while no significant difference was observed between combined therapy and antihypertensive therapy alone regarding cardiac death (RR 0.96; 95% CI 0.84-1.08; p = 0.465) and all-cause mortality (RR 0.95; 95% CI 0.86-1.04; p = 0.277). CONCLUSION: These findings suggested that combined statin and antihypertensive therapy was associated with more cardiovascular benefits compared with antihypertensive therapy alone.

Adenovirus-mediated specific tumor tagging facilitates CAR-T therapy against antigen-mismatched solid tumors.

Chimeric antigen receptor T (CAR-T) therapy faces at least two major obstacles in solid tumors, including to find specific antigen among the heterogeneous tumor mass and to overcome the inhibitory microenvironment. Developing novel strategies to overcome these difficulties has been the burning issue in immunotherapy. Here we came up with the concept of tagging cancer cells by tumor-targeting adenoviruses (Ad). We constructed recombinant Ads expressing CD19 tag driven by tumor-specific promoters, which could label antigenically different tumors for single anti-CD19 CAR-T recognition. One Ad, namely AdC68-TMC-tCD19 could mediate universal tag expression and functional immunological synapse formation between CAR-T and cancer cells. In premixed mice model, all tagged mice survived after CAR-T infusion and tumor volume were inhibited by 91.78%. Furthermore, we combined the tumor tagging ability with oncolysis and generated the replicative AdC68-Sur-E1A-TMC-tCD19. Oncolytic tagging system could diminish established tumors in vivo and prolong mice survival significantly. Therefore, we suggest the universal oncolytic Ad-tagging system in combination with single target CAR-T cells could be a powerful complement in immunotherapy against antigenically mismatched solid tumors.

Meta-analysis of the impact of the SPINK1 c.194 + 2T > C variant in chronic pancreatitis.

BACKGROUND AND AIMS: The SPINK1 c.194 + 2T > C variant has been increasingly recognized as an important risk factor for chronic pancreatitis (CP). However, there is no clear agreement on its contribution to different ethnicities and CP etiologies. To address this issue, a meta-analysis of literature was performed. METHODS: Studies addressing the presence of the SPINK1 c.194 + 2T > C variant in CP patients and controls were retrieved from the PubMed, EMBASE and Cochrane databases. Initial analysis included all CP patients, followed by subgroup analyses for East Asian and non-East Asian patients, and for idiopathic CP (ICP) and non-ICP. RESULTS: A total of 13 studies were retrieved for analysis, comprising 2097 cases and 4019 controls. There were 126 cases (10.01%) carrying the SPINK1 c.194 + 2T > C variant in cases, while only two controls were carriers (0.05%). Overall, the variant was significantly associated with an increased risk of CP (OR = 25.73). In the subgroup, the variant was significantly associated with increased risk of CP in East Asians (OR = 73.16), and in non-East Asians (OR = 10.21). Further, the contribution of the variant in ICP (OR = 35.31) was found to be higher than in non-ICP (25.75). CONCLUSIONS: The SPINK1 c.194 + 2T > C variant is a strong risk factor for CP, especially in East Asian patients with ICP.