The Impacts of Genetic and Environmental Factors on the Progression of Chronic Pancreatitis.

BACKGROUND & AIMS: Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive. METHODS: A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed. RESULTS: A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P < .001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P < .001) and alcohol consumption (HR, 1.86; P < .001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea. CONCLUSIONS: Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297).

SPINK1 mutations and risk of pancreatic cancer in a Chinese cohort.

OBJECTIVE: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). METHODS: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients' demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. RESULTS: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. CONCLUSIONS: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP.

[Effects of Different Inflammatory Factors on Hepatocyte Kinase Receptors and Ligands in Human Periodontal Ligament Fibroblasts].

Objective To investigate the effects of different inflammatory factors on hepatocyte kinase receptor(Eph)and ligand(ephrin)in human periodontal ligament fibroblasts(hPDLFs).Methods hPDLFs were stimulated with either 10 ng/ml tumor necrosis factor-α(TNF-α)or 10 ng/ml interleukin(IL)-1ß,and then the expressions of Eph and ephrin at both mRNA and protein levels were determined at 0,1,2,6,12,and 24 hours.Results The levels of Eph receptors and ephrin ligand changed in a time-dependent manner in human periodontal ligament fibroblasts after treatment with TNF-α or IL-1ß. The expression of ephrinA2 significantly increased in both groups within 24 hours(all P<0.05). In the TNF-α group,the mRNA expression of ephrinA2 significantly increased at 1 h and was significant higher that in the IL-1ß group at 24 h(P<0.05). EphB4 showed a time-dependent decline after a short period of high expression.Conclusions Both TNF-α and IL-1ß can cause changes in the expressions of Eph receptors and ephrin ligands in hPDLFs. The changes induced by both are consistent,although the effect of TNF-α is more pronounced.

[Regulatory Effects of Erythropoietin-producing Hepatocyte Kinase Receptor and Ephrin Ligand on Bone Remodeling].

During the process of bone remodeling,the bone homeostasis is tightly controlled by the coupling of bone resorption and bone formation,depending upon cellular communication between osteoclasts and osteoblasts. Many studies have identified that the bi-directional transduction of erythropoietin producing hepatocyte kinase receptor and ephrin ligand (Eph/ephrin) is one of signal transduction pathways in bone remodeling. This review focus on the potential role of Eph/ephrin in bone remodeling,especially in alveolar remodeling.

Effects of Force and Inflammatory Factors on the Expressions of Osteogenesis Regulators in Human Periodontal Ligament Cells.

Objective To observe the effects of force signals and inflammatory cytokines on the expressions of functional proteins during the differentiation of periodontal ligament cells(PDLCs) into osteoclasts. Methods The caries-free premolars that needed to be removed for orthodontic treatment were collected,human periodontal ligament cells were cultured in vitro.Human PDLCs were exposed to inflammatory cytokines including interleukin(IL)-1ß,-6,-23,and tumor necrosis factor alpha(TNF-α). Cyclicmechanical tension with a maximum 5% elongation for different durations(0,2,4,8,12,and 24 hours) were applied. Then the expressions of signaling molecules related to osteoclastogenesis(OPG) and receptor activated nuclear factor κB ligand(RANKL) were determined at protein levels by Western blotting. Results Inflammatory cytokines improved the expressions of osteoclastgenesis regulators in hPDLCs,while cyclic-tension force reduced their expressions. However,the combined effect of inflammatory cytokines and cyclic-tension force resulted in high expressions of osteoclastgenesis regulators. Conclusion Inflammatory cytokines can promote the expressions of the osteoclastgenic factors,which can not be offset by cyclic-tension force.

(Acetyl-acetonato-κO,O')bis-[2-(5-methyl-3-phenyl-pyrazin-2-yl-κN)phen-yl-κC]iridium(III).

In the title complex, [Ir(C(17)H(13)N(2))(2)(C(5)H(7)O(2))], the Ir(III) atom is hexa-coordinated in a distorted octa-hedral geometry by two C,N-bidentate 2-(5-methyl-3-phenyl-pyrazin-2-yl)phenyl (mdpp) ligands and one O,O-bidentate acetyl-acetonate ligand. The dihedral angles between the phenyl rings and the pyrazine ring are 9.56 (14) and 58.99 (14)° for one mdpp ligand and 9.34 (14) and 79.94 (15)° for the other.

Noncontact magnetically controlled capsule endoscopy for infection-free gastric examination during the COVID-19 pandemic: a pilot, open-label, randomized trial.

Background and study aims Endoscopists have been at increased risk because of their direct contact with patients during the COVID-19 pandemic. For patients, being diagnosed with and monitored for gastrointestinal cancer and digestive diseases in timely fashion has been challenging, given pandemic-related adjustments in endoscopy departments. We developed a novel noncontact magnetically controlled capsule endoscopy (ncMCE) system in our medical center. In the current study, we aimed to evaluate the feasibility and safety of ncMCE for gastric examination. Patients and methods Patients were randomly assigned to groups that received ncMCE or MCE in a 1:1 ratio from March 26, 2020 to April 26, 2020. Primary endpoints were feasibility assessed by completion rate (CR) and safety based on the occurrence of adverse events (AEs) including infection. Secondary endpoints included maneuverability of endoscopists, pre-procedure perception and post-procedure satisfaction of patients, gastric examination time (GET), and diagnostic yield (DY). Results Forty patients were enrolled with 100 % CR in both groups without any AEs. Neither the endoscopist nor the patients were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 14 days after gastric examination. There were no significant differences in maneuverability (19.3 vs. 20.0, P  = 0.179), pre-procedure perception (9 vs. 9, P  = 0.626) and post-procedure satisfaction (45 vs. 44, P =  0.999), ord DY (20 % vs. 30 %, P  = 0.465). Conclusions ncMCE is a feasible and safe method of gastric examination, which has the potential to protect both medical staff and patients from COVID-19 infection while providing serving as an essential endoscopy service.

Erratum: Noncontact magnetically controlled capsule endoscopy for infection-free gastric examination during the COVID-19 pandemic: a pilot, open-label, randomized trial.

[This corrects the article DOI: 10.1055/a-1648-2238.].

Kutkoside-an iridoid glycoside, exerts anti-proliferative effects in drug-resistant human oral carcinoma cells by targeting PI3K/AKT signalling pathway, inducing apoptosis and suppressing cell migration and invasion.

The Editors of JBUON issue an Expression of Concern to ' Kutkoside-an iridoid glycoside, exerts anti-proliferative effects in drug-resistant human oral carcinoma cells by targeting PI3K/AKT signalling pathway, inducing apoptosis and suppressing cell migration and invasion', by Jun-Chi Hou, Xiao-Nan Xu, JBUON 2020;25(1):338-343; PMID: 32277652. Following the publication of the above article, readers drew to our attention that part of the data was possibly unreliable. We sent emails to the authors with a request to provide the raw data to prove the originality, but received no reply. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

Factors associated with prior acute pancreatitis episodes among patients with chronic pancreatitis.

BACKGROUND: The relationship between chronic pancreatitis (CP) and acute pancreatitis (AP) is complex and not well understood. CP could be preceded by antecedent episodes of AP. AIMS: The aim of this study was to explore both genetic and environmental factors associated with AP episodes before the diagnosis of CP. METHODS: This was a cross-sectional study including 1022 patients. Detailed demographic, genetic, and clinical data were collected. Based on the presence of AP episode(s) before diagnosis of CP, patients were divided into AP group (further classified into single episode of AP group and recurrent AP group) and non-AP group. Related factors among these groups were assessed using multivariate logistic regression model. RESULTS: Before diagnosis of CP, 737 patients (72.1%) had a history of AP. Smoking(P = 0.005) and heavy alcohol consumption(P = 0.002) were risk factors for AP while age at CP onset(P < 0.001), harboring the SPINK1 mutation(P < 0.001), diabetes(P < 0.001) and steatorrhea(P < 0.001) were protective factors. Further, alcoholic CP(P = 0.019) was the only independent risk factor for recurrent AP attacks while age at onset of CP(P < 0.001), pancreatic stones(P = 0.024). and pseudocysts(P = 0.018) served as protective factors. CONCLUSIONS: SPINK1 mutations served as protective factor for AP episodes, suggesting SPINK1 mutation might play a pathogenic role in CP occurrence with occult clinical manifestations.

Kutkoside-an iridoid glycoside, exerts anti-proliferative effects in drug-resistant human oral carcinoma cells by targeting PI3K/AKT signalling pathway, inducing apoptosis and suppressing cell migration and invasion.

PURPOSE: The main purpose of the current research work was to investigate the anticancer potential of Kutkoside -a naturally occurring iridoid glycoside, against drug-resistant human oral carcinoma cells along with evaluating its effects on PI3K/AKT signalling pathway, cellular apoptosis, cell migration and cell invasion. METHODS: Cell viability was assessed by using MTT colorimetric assay, while effects on cellular apoptosis were evaluated by acridine orange (AO)/ethidium bromide (EB) as well as by using flow cytometry employing annexin V-FITC. Effects on cell migration and cell invasion were evaluated by in vitro wound healing assay and transwell Matrigel assay. Effects on PI3K/AKT signalling pathway were evaluated by western blot method. RESULTS: Kutkoside led to significant and dose-dependent inhibition of HSC-2 human oral cancer cells using doses of 0, 1.25, 2.5, 5, 10, 20, 40, 80 and 160 µM. Fluorescence microscopy revealed that on increasing the dose of kutkoside, the number of both apoptotic and necrotic cells increased, showing that Kutkoside induces apoptotic cell death in HSC-2 oral cancer cell line in dose-dependent manner. Flow cytometry indicated that the percentage of apoptotic cells at different dose exposures of Kutkoside, namely 0, 8, 16 and 32 µM was 4.9%, 12.18%, 22.18% and 34.10%, respectively. Kutkoside treatment also led to cell migration inhibition and cell invasion inhibition. This molecule upregulated the expression of AKT and PI3K, simultaneously downregulating the expressions of p-AKT and p-PI3K in a dose-dependent manner. CONCLUSION: Kutkoside shows potential anticancer and pro-apoptotic effects in HSC-2 oral carcinoma cells and as such may be developed as a possible anticancer agent provided further studies are performed.

Upfront Cranial Radiotherapy vs. EGFR Tyrosine Kinase Inhibitors Alone for the Treatment of Brain Metastases From Non-small-cell Lung Cancer: A Meta-Analysis of 1465 Patients.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is revolutionizing the management of brain metastases (BMs). This study was to explore the value of upfront cranial radiotherapy (RT) in EGFR-mutated non-small cell lung cancer (NSCLC) with BMs compared with EGFR-TKIs alone. Methods: We searched all topic-related comparative articles in public databases (MEDLINE, EMBASE, Cochrane Library, and Web of Science) and conference proceedings. Outcomes of interest were intracranial objective response rate (ORR), overall survival (OS), and intracranial progression-free survival (PFS). Statistical analyses were calculated using Review Manager 5.3 software. Results: Thirteen comparative studies that included a total of 1,456 patients were eligible. Upfront brain RT had significantly higher OS (HR = 0.78, 95% CI = 0.65-0.93, P = 0.005) than EGFR-TKI alone. Upfront RT plus TKI had superior OS (HR = 0.71, 95% CI = 0.58-0.86, P = 0.0005) and intracranial PFS (HR = 0.69, 95% CI = 0.49-0.99, P = 0.04). The pooled data favored upfront whole brain RT (WBRT) plus TKI in terms of intracranial PFS (HR = 0.64, 95% CI = 0.48-0.85, P = 0.002) and OS (HR = 0.75, 95% CI = 0.57-1, P = 0.05). Upfront stereotactic radiosurgery (SRS) was associated with better OS (HR = 0.37, 95% CI = 0.26-0.54, P < 0.00001). Similar results were observed when analysis was restricted to the use of erlotinib or geftinib. Conclusions: The upfront use of brain RT seemed critical, especially for SRS. Upfront administration of upfront WBRT plus EGFR-TKI had better survival outcomes and seemed superior to EGFR-TKI alone.

Epigallocatechin­3­gallate inhibits the invasion of salivary adenoid cystic carcinoma cells by reversing the hypermethylation status of the RECK gene.

Epigallocatechin­3­gallate (EGCG) is an active and major constituent of green tea. As a non­nucleoside inhibitor of DNA methylation, EGCG is able to inhibit the hypermethylation of newly synthesised DNA, resulting in the reversal of hypermethylation and recovery in expression of the silenced genes. Reversion­inducing cysteine­rich protein with Kazal motifs (RECK) is a novel tumour suppressor gene, which negatively regulates matrix metalloproteinases, and inhibits tumour invasion, angiogenesis and metastasis. The present study aimed to examine the effects of EGCG on the methylation status of the RECK gene and tumour invasion in a salivary adenoid cystic carcinoma (SACC) cell line in vitro. Marked levels of methylated and weak levels of unmethylated RECK promoter were detected in the SACC83 cells, which was determined using methylation­specific polymerase chain reaction (PCR). In addition, the treatment of SACC83 cells with EGCG partially reversed the hypermethylation status of the RECK gene. Western blot analysis and reverse transcription­PCR demonstrated that EGCG significantly enhanced the protein and mRNA expression levels of RECK, and significantly reduced the invasive ability of the SACC83 cells, as determined using a Transwell assay. These results suggested that EGCG possesses novel anti­metastatic therapeutic potential for the treatment of SACC.