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Background: The incidence of nonfunctional pancreatic neuroendocrine neoplasms (NF-pNENs) has been increasing annually. This study is aimed at investigating the clinicopathological characteristics and high-risk factors of NF-pNENs and the influence of surgical treatment on the prognosis of NF-pNEN patients with liver metastases., Methods: pNEN patients in this study were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. This study analyzed patients diagnosed with NF-pNENs from 2000 to 2017 who met the inclusion criteria. A retrospective analysis of the clinicopathological characteristics of NF-pNEN patients was conducted. Kaplan-Meier method was used to calculate the survival time. A multivariate Cox regression model was used to analyze the survival outcomes and risk factors., Results: From 2000 to 2017, the SEER database registered 10576 patients with pNENs and 1774 patients with liver metastases. Cox analysis revealed that age, sex, primary site, grade, tumor stage, surgery, tumor size, and liver metastasis were risk factors of prognosis, with grade being the most influential index. Patients with NF-pNENs with liver metastasis and no metastasis had different primary site, grade, and tumor size. In general, a higher grade was associated with a larger tumor and a greater risk of liver metastasis. Meanwhile, patients with liver metastasis showed that those with tumors originated from the tail of the pancreas had better prognoses than those with tumors originated from other parts. Surgical treatment can improve the prognosis of patients with liver metastases, despite the tumor grade., Conclusions: The incidence of pNENs has been increasing annually, and the liver has been the most common site of metastasis. Liver metastasis in patients with NF-pNENs, related to tumor size and grade, affected their long-term survival. Surgery significantly improved the prognosis of patients with liver metastases secondary to NF-pNENs with different grades., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Abuduhaibaier Sadula et al.)

Objectives: This study aimed to investigate the pharmacokinetic characteristics of siponimod in healthy volunteers and patients with MS based on aggregated data from published clinical trials, and to explore the factors influencing siponimod exposure. Methods: A total of 476 siponimod plasma concentrations aggregated from 28 dosage groups (corresponding to 294 healthy volunteers and 207 patients with MS) were collected from published clinical trials. Population pharmacokinetic (PPK) analysis was performed using a nonlinear, mixed-effect modeling approach. The pharmacokinetic properties of siponimod in healthy volunteers and patients with MS were compared, and the influence of covariates on siponimod exposure was evaluated using both PPK analysis and noncompartmental analysis (NCA). Results: A one-compartment model with first-order absorption and elimination adequately described siponimod pharmacokinetics. The typical population parameter estimates of clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) were 3.17 L/h, 112.70 L, and 0.38 h -1 , respectively. An 11.85% lower siponimod clearance was estimated for patients with MS relative to healthy volunteers. Subgroup analyses using NCA assessments revealed that siponimod presented an accumulation index of approximately 2 after multiple administration. Compared with nonobese participants, obese participants had a relatively lower dose-corrected area under the concentration-time curve (AUC 0-∞ /D) (0.31 vs. 0.42 h/L) and V/F (120.95 vs. 133.75 L), and a relatively higher CL/F (3.25 vs. 3.21 L/h). Participants with CYP2C9*2/*3, *1/*3, and *3/*3 genotypes experienced an increased (1.3- and 3.4-fold, respectively) AUC 0-∞ /D and a decreased (0.7- and 0.3-fold, respectively) CL/F compared with those in participants with the CYP2C9*1/*1, *1*2, and *2*2 genotypes. Fluconazole combination led to a decrease in CL/F (approximately 0.5 times) and an increase in AUC 0-∞ /D (approximately 1.3 times). Conclusion: Siponimod pharmacokinetic properties in healthy volunteers and patients with MS were explored using complementary model-based meta-analysis (MBMA) and NCA approaches. A slightly lower siponimod clearance was observed in patients with MS than in healthy volunteers. The dosage regimen, body mass index, CYP2C9 genetic polymorphism and fluconazole combination may had influences on siponimod pharmacokinetics. Such model paves the road to more population-based analyses in different patient populations with MS to quantify the effect of any influencing factors on siponimod pharmacokinetics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaoyang, Xiu, Ran, Lingyun, Simiao, Ruoming, Enyao, Ying, Yimin and Zhenming.)

This study aimed to delineate changes in the patterns of prolonged grief severity in widowed adults following group bereavement interventions and to identify the predictive factors impacting these patterns. We performed a secondary analysis of data from a randomized trial of 125 Chinese widowed older adults who participated in either LOGBI or DPGBI. Self-ratings of prolonged grief symptoms via Inventory of Complicated Grief (ICG) were subjected to latent class growth analysis to identify subgroups according to symptomatic changes among baseline, post-treatment, and 8-week follow-up. Multinomial regression analysis examined whether participant classification could be predicted by demographics, loss-related characteristics, and the relationship with the deceased and baseline symptom severity. In the results, intervention sample comprised 96 completers with an attendance greater than 60%. A three-class categorization yielded the best model fit for changes in prolonged grief severity for both randomized and intervention samples: improved class (41.6% in the randomized sample, 42.8% in the intervention sample), partial responded class (48.1%/45.5%), and relapse class (10.3%/11.8%). Older widowed adults experiencing a high level of grief at baseline and bereavement following chronic illness had an elevated risk of symptomatic relapse after the completion of intervention. These findings indicated that Chinese widowed adults experienced different changing patterns of prolonged grief severity following group bereavement interventions. Practically, widowed adults with a higher risk of symptomatic relapse might need more intensive or longer term intervention or follow-up support., (© 2020 John Wiley & Sons, Ltd.)

Background: This study aimed to investigate the work status of clinicians in China and their management strategy alteration for patients with hepatocellular carcinoma (HCC) during the COVID-19 pandemic., Methods: A nationwide online questionnaire survey was conducted in 42 class-A tertiary hospitals across China. Experienced clinicians of HCC-related specialties responded with their work status and management suggestions for HCC patients during the pandemic., Results: 716 doctors responded effectively with a response rate of 60.1%, and 664 were included in the final analysis. Overall, 51.4% (341/664) of clinicians reported more than a 60% reduction of the regular workload and surgeons declared the highest proportion of workload reduction. 92.5% (614/664) of the respondents have been using online medical consultation to substitute for the "face-to-face" visits. Adaptive adjustment for the treatment strategy for HCC was made, including the recommendations of noninvasive and minimally invasive treatments such as transcatheter arterial chemoembolization for early and intermediate stage. Targeted therapy has been the mainstay for advanced stage and also as a bridge therapy for resectable HCC., Discussion: During the COVID-19 pandemic, online medical consultation is recommended to avoid social contact. Targeted therapy as a bridge therapy is recommended for resectable HCC considering the possibility of delayed surgery., (Copyright © 2021. Published by Elsevier Ltd.)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Recent evidence has shown that circular RNAs (circRNAs) play important roles in tissue development, gene transcription, signal regulation and tumorigenesis. However, whether circRNAs are involved in HCC progression and encode functional proteins remains largely unknown. In the present study, we aimed to explore the function and molecular mechanism of circRNAs in HCC. First, many circRNAs were found to be differentially expressed in HCC samples and paired adjacent normal liver tissues. The validation of dysregulated circRNAs by qRT-PCR revealed that circEPS15 expression was downregulated in HCC tissues, and the survival curves showed that low circEPS15 levels were associated with poor overall survival in HCC patients. Then, the overexpression of circEPS15 suppressed tumor cell invasion and migration by inhibiting the TJP1/CDH2/VIM signaling pathway and retarded cell cycle progression, which was confirmed by the Transwell culture system, wound healing assays, flow cytometry and western blot assays. After that, the spanning junction open reading frame in circEPS15 driven by IRES was shown to encode a novel protein, which was verified by western blotting with full-length, mutated, and truncated sequences of circEPS15 with a FLAG tag. Moreover, ceRNA analysis and qRT-PCR results suggest a possible circRNA (circEPS15)-miRNA-mRNA network in HCC. Collectively, our study reveals that endogenous circEPS15 plays a novel role in repressing HCC through the ceRNA network and encodes a functional protein., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Tian, Li, Sadula, Xiu, Yuan and Bing.)

A new fluorescence coordination polymer [Zn(Py 2 TTz)(5-OH-IPA)] n (1) (Py 2 TTz = 2,5-bis(4-pyridyl)thiazolo[5,4-d]thiazole, 5-OH-IPA = 5-hydroxyisophthalic acid dianion) was synthesized, which exhibited the characteristics of fluorescence quenching and bathochromic shift toward Hg(II) in aqueous solution at pH 7.00. Mechanism study showed that the interactions between Hg(II) ions and Py 2 TTz ligands in 1 were responsible for the fluorescence emission change. Thanks to the specific interactions between 1 and Hg(II), excellent selectivity was achieved both in aqueous solution and in solid test paper. The detection limit of 1 for Hg(II) sensing was 125.76 nmol L -1 and a linear rang was 1.00-10.00 μmol L -1 . More importantly, satisfactory recovery and accuracy of 1 for Hg(II) sensing were also obtained in buffer-free real water samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Abstract: Plant root secretion can be regarded as signal molecules, which exerts impact on microorganisms in the rhizosphere ecological niche. We obtained gene expression profile of Ralstonia solanacearumPO41 under the root secretions environment of Solanum tuberosum at the time points of 8 hrs, 16 hrs and 24 hrs, respectively, after infection with RNA microarray technology. Bioinformatics tools of differential genes expression analysis, GO functional analysis, cluster analysis and pathway analysis were conducted to find out the pathogenic genes and other related genes. We found that the virulence factors of R. solanacearum mainly focused on the output pathways of toxic protein (Sec pathway, Tat pathway and type III secretion system (T3SS)), the aggregation and transfer of exopolysaccharides and the chemotactic movement and adhesion of flagellum in the potato root secretion ecological niche, while the virulence factors in the atypical output pathway mainly distributed in Sec (secB, secDF, yidc) and Tat (tatA, tatC) pathways to promote the output of folded and unfolded toxic proteins. The fliIATPase was obviously upregulated 8 hrs postinoculation, suggesting that type III secretion system was only active at the early stage of PO41 infection. The upregulated expression of phosphoglucomutase and epimerase showed that the virulence factor of exopolysaccharides (EPS) was synthesized at the early stage of R. solanacearum infection. Chemotactic receptor and motor protein were obviously upregulated within 24 hrs postinoculation. Our study revealed that R. solanacearumPO41 had already colonized to the roots within 24 hrs with the stimulating of root secretion. Some pathogenic genes were upregulated during this period. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the influence of the abdominal incision length on the gastrointestinal function recovery post-operatively. Background: Gut motility recovers more quickly after the minimally invasive laparoscopic surgery compared than after the traditional open surgery; however, whether the minimal abdominal incision contributes to the faster gut motility recovery is controversial and lacks solid clinical evidence. Methods: A registry-based secondary cohort analysis was conducted to evaluate the association between the abdominal incision length and gut motility recovery post-operatively based on a multicenter, prospective, and observational study of the prolonged post-operative ileus (PPOI) incidence and the risk factors in the patients with the major abdominal surgery. The incision length, in the centimeters, was the exposure. The primary outcome measures were the PPOI incidence and its association with the incision length. The secondary outcome included the days to the first passage of flatus and the days to the first passage of stool. Results: Overall, 1,840 patients, including 287 (15.7%) patients with the PPOI, were recruited. The PPOI incidence was 17.6% and 13.3% in the long-incision (>18 cm) and short-incision patients ( ≤ 18 cm), respectively. The incidence of the PPOI increased by 1.1% (1.0-1.1) by each centimeter increment of the incision length after adjusting for the confounding factors. In comparison to the short-incision patients, the long-incision patients had prolonged passage of stool (4.46 vs. 4.95 days, p < 0.001). Each centimeter increment of the incision length contributed to a 2% increased risk of delay in the first bowel movement [hazard ratio (HR) 0.980 (0.967, 0.994)]. Conclusion: A long abdominal incision length independently contributed to the prolonged gut function recovery post-operatively mainly by delaying the time to the first bowel movement, but not influencing the time to first passage of flatus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Song, Yang, Guan, Jin, Yang, Chen, Wan, Li, He, Zhang, Zhu, Chen, Xiu, Tian, Yang, Lou and Zhang.)

We designed and realized highly fluorescent nanostructures composed of Eu 3+ complexes under a protein coating. The nanostructured material, confirmed by photo-induced force microscopy (PiFM), includes a bottom fluorescent layer and an upper protein layer. The bottom fluorescent layer includes Eu 3+ that is coordinated by 1,10-phenanthroline (Phen) and oleic acid (O). The complete complexes (OEu 3+ Phen) formed higher-order structures with diameter 40-150 nm. Distinctive nanoscale striations reminiscent of fingerprints were observed with a high-resolution transmission electron microscope (HRTEM). Stable fluorescence was increased by the addition of Eu 3+ coordinated by Phen and 2-thenoyltrifluoroacetone (TTA), and confirmed by fluorescence spectroscopy. A satisfactory result was the observation of red Eu 3+ complex emission through a protein coating layer with a fluorescence microscope. Lanthanide nanostructures of these types might ultimately prove useful for biometric applications in the context of human and non-human tissues. The significant innovations of this work include: (1) the structural set-up of the fluorescence image embedded under protein "skin"; and (2) dual confirmations of nanotopography and unique nanofingerprints under PiFM and under TEM, respectively.

The present study examined Chinese students’ personal value orientations according to the Schwartz value theory in comparison with students from Germany and Russia. The theory postulates 10 value orientations grouped into four higher-order factors: conservation versus openness to change and self-transcendence versus self-enhancement. Schwartz’ value orientations have been extensively investigated in Europe but less in East Asian countries such as China. We hypothesized that Chinese students would score higher on conservation and self-enhancement than German and Russian students, but lower on self-transcendence. Regarding openness to change, a null hypothesis was formulated. Students from China (n = 9,601), Germany (n = 1,118), and Russia (n = 3,890) completed the Portrait Values Questionnaire (PVQ-21). To ensure methodological preconditions for cross-cultural comparison, measurement invariance of the PVQ-21 was tested. In a first step, confirmatory Factor Analysis (CFA) was conducted separately for each country. Due to the high correlation between the 10 values, the four higher-order dimensions were studied separately. Configural, metric, and scalar invariance models were tested using multigroup CFA. Full metric and partial scalar invariance models held for all higher-order factors. Thereafter, latent means of values were compared across samples. As a result, Chinese students scored highest on the four higher-order dimensions when compared with Russian and German samples, thus the hypotheses were only partly confirmed. Results of this study could reflect the value conflicts emerging from various cultural influences in contemporary China: Young people are confronted with daily negotiation between Confucian tradition and the rapid economic development. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to its inefficient diagnosis, rapid progress, and tenacious drug resistance. Here, we aimed to analyze the expressive patterns of proteins and phosphorylation in PDAC tissue samples and compare them to normal pancreatic tissue to investigate the underlying mechanisms and to reveal potential protein targets for diagnosis and drug development. Liquid chromatography coupled to mass spectrometry (LC-MS) based proteomics and phosphoproteomics analyses were performed using 20 pairs of patient-derived PDAC tissue and normal pancreatic tissue samples. Protein identification and quantification were conducted using MaxQuant software. Bioinformatics analysis was used to retrieve PDAC-relevant pathways and gene ontology (GO) terms. 4985 proteins and 3643 phosphoproteins were identified with high confidence; of these, 322 proteins and 235 phosphoproteins were dysregulated in PDAC. Several pathways, including several extracellular matrix-related pathways, were found to be strongly associated with PDAC. Further, the expression levels of filamin A (FLNA), integrin alpha-V (ITGAV), thymidine phosphorylase (TYMP), medium-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADM), short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS), and acetyl-CoA acetyltransferase, mitochondrial (ACAT1) were examined through western blot and immunohistochemistry analysis, and the results confirmed the validity of the proteomics analysis results. These findings provide comprehensive insight into the dysregulated regulative networks in PDAC tissue samples at the protein and phosphorylation levels, and they provide clues for further pathological studies and drug-target development.

Objective: This study aimed to develop an assessment tool measuring comprehensive interdisciplinary competence in end-of-life care (EoLC) and investigate its content, construct validity, reliability, and their correlates., Method: Items of the Comprehensive End-of-Life Care Competence Scale (CECCS) were developed according to a comprehensive core competence framework in EoLC and refined by a multi-disciplinary panel of experts. The psychometric properties were further tested through region-wide surveys of self-administered questionnaires completed by health and social care professionals in Hong Kong., Results: Participants comprised social workers, nurses, physicians, and allied health care professionals (445 participants in 2016, 410 in 2017, and 523 in 2018). Factor analysis validated the construct of the questionnaire which encompassed 26 items describing EoLC core competences in seven domains with satisfactory internal reliability (confirmatory factor analysis: χ2/df = 3.12, GFI = 0.85, TLI = 0.93, CFI = 0.94, RMSEA = 0.07; Cronbach's alphas ranged from 0.89 to 0.97): overarching value & knowledge, communication skills, symptom management, psychosocial and community care, end-of-life decision-making, bereavement care, and self-care. Higher perceived levels in these competences were correlated with a higher level of job meaningfulness and satisfaction (r ranged from 0.17 to 0.39, p < 0.01) and correlated with lower perceived stress (r ranged from -0.11 to -0.28, p < 0.05). Regression analysis found that age and work involvement in EoLC were positively associated with the perceived competences in all domains; professionals working in hospices reported higher levels of competence than workers in other settings; social workers showed lower perceived competences in symptom management, but higher levels in bereavement care than other health care professionals., Significance of Results: The validity and internal reliability of CECCS were demonstrated. The levels of perceived competences working in EoLC were significantly associated with professionals' job-related well-being. Practically, there is still room for improvement in comprehensive competences among health and social care workers in Hong Kong.

Background: Surgical resection is the only potentially curative treatment for pancreatic ductal adenocarcinoma (PDAC). However, most of patients lose the chance of surgery due to the unresectable disease at the time of diagnosis. Despite the improvement of radiological imaging, a portion of patients intended for radical resection were proven to be unresectable at surgical exploration due to occult metastasis., Methods: Patients who were aimed to undergo radical pancreatectomy for PDAC from 2010 to 2019 were reviewed retrospectively. All patients included underwent diagnostic laparoscopic exploration. Patients were divided into two groups depending on whether distant metastasis were encountered during exploration. Univariate and multivariate logistic regression analyses were used to identify risk factors for occult metastasis. A nomogram to predict occult metastasis of PDAC on exploration was developed and evaluated., Results: A total of 273 patients who underwent diagnostic laparoscopic exploration were included in this study. Nineteen (7.0%) patients were found with distant metastasis during exploration. Multivariate logistic regression analysis showed that ALT>40U/L, CA19-9, CA125 and regional nodes enlargement were independent predictors for occult metastasis. Incorporating these four factors, the nomogram achieved concordance index of 0.799, with a well-fitted calibration curve., Conclusions: Occult metastasis is not unusual during surgical exploration in patients with resectable or borderline resectable PDAC. The nomogram could achieve a personal prediction of unexpected distant metastasis on exploration. It may help to sift through patients with PDAC who would benefit from laparoscopic exploration., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-605). The authors have no conflicts of interest to declare., (2021 Gland Surgery. All rights reserved.)

Background: Information on incidence of gastrointestinal stromal tumor (GIST), the most common type of mesenchymal tumor in gastrointestinal tract, was limited in China. This study aimed to estimate the incidence of GIST in urban population from mainland China in 2016., Methods: Urban Employee Basic Medical Insurance (UEBMI) and Urban Residence Basic Medical Insurance (URBMI) in China were used. The denominator of incidence was the total person-years of insured individuals in 2016 in the database, covering approximately 0.43 billion individuals. The numerator was the number of incident GIST cases in 2016., Results: The crude incidence in 2016 was 0.40 per 100,000 person-years (95% CI, 0.06-1.03). Male incidence was higher than female incidence (0.44 vs. 0.36, rate ratio: 1.22, p < 0.001). The mean age at diagnosis was 55.20 years (SD = 14.26) and the incidence among those aged 50 years or older was 2.63 times (0.84 vs. 0.32, p < 0.001) higher than those aged under 50. The highest incidence was observed in East China (2.29, 95% CI: 0.46-5.54)., Conclusions: The incidence of GIST in mainland China was lower than Europe, North America and Korea. The mean age at diagnosis of GIST in China was younger than that of Europe and Canada. This study provides useful information to further research, policy formulating and management of GIST., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pancreatic cancer (PC) is a highly aggressive and refractory disease, with disappointing 5-year survival rates. Regarding the wide application of neoadjuvant treatment in patients with PC, how the post-neoadjuvant Carbohydrate antigen 19-9 (CA19-9) response could translate into a survival benefit is not clearly understood. We aimed to evaluate the correlation of the CA19-9 response with overall survival (OS) in patients with PC receiving neoadjuvant therapy., Methods: An extensive electronic search in PubMed, Embase, and the Cochrane Library was performed to identify relevant articles, from which data relevant to independent correlations of the CA19-9 response with overall survival (OS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs)., Results: Altogether, 17 eligible studies were identified in the systematic review. Pooled analysis showed that CA19-9 response > 50% (HR, 0.43; 95% CI 0.29-0.56; P < 0.001) and normalization of CA19-9 (HR, 0.52; 95% CI 0.42-0.63; P < 0.001) after neoadjuvant treatment are significantly associated with promising overall survival. The results also showed that optimal CA19-9 response after neoadjuvant treatment was significantly related to a favorable prognosis (HR = 0.49, 95% CI 0.42-0.55, P < 0.001; I2 = 45.1%, P = 0.04). Subgroup analysis revealed there were no prognostic difference between CA19-9 > 50% and normalization of CA19-9 after neoadjuvant treatment (P = 0.338), but the duration of neoadjuvant chemotherapy over 4 months was significantly associated with expanded postoperative survival (P = 0.013)., Conclusions: Serum CA19‑9 is valuable in determining the effect of neoadjuvant treatment in patients with PC. Post-neoadjuvant CA19-9 response > 50% or CA19-9 normalization was related to a more promising overall survival, suggesting that optimal CA19-9 response may be a suitable prognostic index to guide treatment decisions.

Background: Surgical resection has been proposed for curable gallbladder cancer (GBCA); however, optimal preoperative evaluation and resection planning methods remain unestablished. The aim of this study was to establish the types of CT tumour radiological appearances in GBCA with a focus on its association with clinicopathologic features and its prognostic impact in curable GBCA., Methods: In all, 118 patients surgically treated for GBCA were identified and CT tumour radiological appearances were reviewed. Models were established and internally validated. Clinicopathologic variables and prognostic impact were analysed for correlation with tumour radiological appearance., Results: The classification and distribution of tumour radiological appearance in these patients was Type 1 (n = 14), Type 2 (n = 60), Type 3 (n = 21), Type 4 (n = 18), and undetermined (n = 5). Among the 113 patients, a higher tendency of T stage and incidence of lymph node metastasis was observed from Type 1 to Type 4. Most Type 1 patients were T1 stage, they have no lymph node involvement or recurrence. With a median follow-up of 25 months (range, 1-135 months), a clear prognostic difference was observed among the 4 types after surgical treatment (p < 0.001). Type 1 patients showed 100% 5-year survival rate. Among the 66 T2 tumours, both tumour location and tumour radiological appearance effectively stratified patient prognosis (p < 0.001, p = 0.007). Introducing tumour radiological appearance into tumour location enabled further prognostic stratification of the 35 T2h tumours (p < 0.001)., Conclusions: Type of CT tumour radiological appearance is a predictor of tumour biology. It may improve preoperative evaluation and resection planning., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs., Methods: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821., Findings: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression., Interpretation: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population., Funding: Hutchison MediPharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs., Methods: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing., Findings: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure)., Interpretation: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population., Funding: Hutchison MediPharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Traditional Chinese art practices such as brush painting and calligraphy are thought to promote self-development through holistically engaging both physical and mental health. This pilot study investigated the beneficial effects of a community-based self-help group incorporating Chinese art practices as a culturally adapted bereavement intervention. Twenty-six Chinese parents aged over 49 years and who had lost their only child participated in a 20-session Chinese brush painting group over a 6-month period. Ten bereaved parents from the same community who did not participate in the art course but received living support were recruited as a control group. Compared with the control group, the art practice group exhibited a pre-post intervention effect in terms of promoting positive affect and preventing deterioration of prolonged grief symptoms, particularly through the improvement of accessory grief symptoms (e.g., "emotional numbness due to the loss", and "feeling that life is unfulfilling, empty or meaningless after the loss"). No effect was found on negative affect. These findings indicate that a culturally adapted community-based art group may be an effective means of improving grief-related health.

Purpose: The study adopted a randomized controlled trial to compare the effect of culturally compatible psychosocial interventions on multiple aspects of quality of life (QoL) for family caregivers of lung cancer patients., Methods: 157 Chinese informal caregivers of lung cancer patients were recruited together with the family members for whom they were providing care, and randomly assigned to either integrative body-mind-spirit intervention (I-BMS) or cognitive behavioral therapy (CBT). Patient-caregiver dyads attended the same arm of intervention in separate groups for 8 weeks. Assessments of generic QoL, anxiety, depression, perceived stress, insomnia, and caregiving burden were measured before intervention (T 0 ), within 1-week (T 1 ), 8-week (T 2 ), and 16-week (T 3 ) post-intervention., Results: Adopting the intention-to-treat analysis, family caregivers in receipt of both I-BMS and CBT exhibited a statistically significant improvement in generic QoL immediately following intervention and at follow-up assessments, with moderate effect size. Improvement of insomnia was found at T 1 for both modes, which deteriorated at follow-up; both modes reduced anxiety and perceived stress at follow-up. No intervention effect was observed in depression and domains of caregiving burden. There was no significant interaction effect between intervention type and time. No main or interaction effect between sample background variables and intervention type was found to predict symptomatic changes at T 1 and T 3 ., Conclusions: Culturally attuned I-BMS and CBT exhibited equivalent effectiveness in improving psychological distress and generic QoL for family caregivers of lung cancer patients. To improve the evaluation of outcomes, future study could benefit from incorporating a usual care control.

Purpose: Our animal studies have demonstrated the safety and feasibility of end-to-end intestinal anastomosis using a stent for laparoscopic colonic surgery. Therefore, we designed a non-inferiority trial to investigate the outcomes of stent anastomosis (SA) vs. those of conventional hand-sewn anastomosis (CA)., Methods: A multicenter randomized controlled trial was conducted between December, 2016 and April, 2018. The primary outcome was the healing condition of the anastomoses, evaluated by endoscopy 6 months postoperatively. The secondary outcomes were the anastomotic completion time, anastomotic leak, intestinal obstruction, peritoneal effusion, and bleeding. Quality of life (QOL) was evaluated by questionnaires., Results: The subjects of this study were 60 patients, randomly divided into a SA group (n = 30) and a CA group (n = 30). There were no differences in anastomotic healing conditions (P = 1.00). The stent procedure was associated with a significantly shorter anastomosis time than the hand-sewn anastomosis (13.517 ± 4.281 vs. 20.333 ± 2.998 min, respectively; P < 0.001). There were no significant differences in anastomotic leakage, intestinal obstruction, peritoneal effusion, or bleeding between the groups. Questionnaires revealed almost no discrepancy between baseline QOL scores and those assessed 2, 4, 8, 12, and 24 weeks postoperatively in either group., Conclusions: Intestinal anastomosis with a stent is a non-inferior strategy for laparoscopic colonic surgery, which requires less time for the anastomosis.

Introduction: The best approach for choledocholithiasis remains a matter of debate. Choledocholithiasis is usually treated with endoscopic sphincterotomy (EST), laparoscopic common bile duct exploration (LCBDE) or laparoscopic transcystic common bile duct exploration (LTCBDE). Data pertaining to the clinical outcomes of these approaches in the management of patients with cholecysto-choledocholithiasis in China are limited. An analysis of the economic burden associated with these treatments is lacking. The Chinese REgistry Study on the Treatment of Cholecysto-Choledocholithiasis (CREST Choles) was designed to address these issues in a real-world setting., Methods and Analysis: CREST Choles was an ambispective, multicenter, observational, open-cohort study. A total of 2700 patients undergoing one of the three treatments (EST+laparoscopic cholecystectomy (LC), LCBDE+LC and LTCBDE+LC) during the period from 1 January 2013 to 1 December 2018 at participating centres were enrolled in the study. Patients with gallstones and confirmed common bile duct stones were included. Data pertaining to demographics, disease history, procedural details, imaging features and follow-up were collected. Follow-up was conducted at least 6 months after enrolment in the study and annual follow-up will be conducted until December 2020. The primary outcome is the rate of adverse outcomes within 3 years postoperatively. Economic analysis (eg, incremental cost-effectiveness ratio) would be performed to compare expense across treatments., Ethics and Dissemination: Ethical approval was obtained at all participating centres. The registry presented is the first attempt to comprehensively evaluate the cost of treatment for cholecysto-choledocholithiasis in China. Findings are expected to be available in 2020 and will facilitate clinical decision making in such cases., Trial Registration Number: NCT02554097., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: To examine the primary and secondary outcomes of a theory-driven group bereavement intervention for widowed older adults through a cluster-randomized controlled trial., Research Designs and Methods: Twelve community centers providing health and social services for elderly people were randomly assigned to the experimental condition, the dual-process bereavement group intervention-Chinese (DPBGI-C) and to the control condition, the loss-oriented bereavement group intervention-Chinese (LOBGI-C). Both interventions comprised weekly, 2-hr sessions for 7 weeks followed by a 4-hr outing in the eighth week. Of 215 widowed older adults contacted and assessed, 125 eligible participants were interviewed three times-preintervention, postintervention, and at a 16-week follow-up-to assess complicated grief symptoms, anxiety, depression, loneliness, and social support., Results: Using intention-to-treat analysis, both interventions produced improvements in grief, depression, and social support, but effect sizes were larger with the DPBGI-C. The participants in the DPBGI-C condition also reported reduced anxiety, emotional loneliness, and social loneliness, whereas those in the LOBGI-C condition did not. There were interactions between intervention type and time with respect to grief, anxiety, emotional loneliness, and social loneliness., Discussion and Implications: Although traditional LOBGI-C can help to reduce grief and depression in bereaved older adults, the DPBGI-C was found to be superior as it had a greater and more extensive impact on outcomes. This is the first study of the effectiveness of this evidence-based, theory-driven intervention for widowed Chinese older adults and has implications for theory building and practice., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Pancreatic cancer (PC) is one of the most aggressive malignancies, and it's difficult to diagnosis PC at an early stage, which leads to the poor prognosis of PC., Objectives: To identifiy the possible prognosis or dignosis metabolite biomarkers in the serum exosome of PC patients., Methods: We employed LC-DDA-MS based untargeted lipidomic analysis to search for potential candidate biomarkers in the serum exosome of PC patients. Then LC-MRM-MS based targeted lipid quantification was used to validate the trends of the candidate biomarkers in larger sample cohorts., Results: About 270 lipids belonging to 20 lipid species were found significantly dysregulated between the serum exosome of PC patients and healthy controls. 61 of them were validated in larger samples size. We further analysis the correlation between these dysregulated lipids and other PC related factors, and results show that LysoPC 22:0, PC (P-14:0/22:2) and PE (16:0/18:1) are all associated with tumor stage, CA19-9, CA242 and tumor diameter. What's more, PE (16:0/18:1) is also found to be significantly correlated with the patient's overall survival., Conclusion: These data reveal dysregulated lipids in serum exosome of PC patients, which have potential to be biomarkers for diagnosis, or unveil pathological relationship between exosome and PC progress.

Background: Ingestion of jujube pits is a common clinical problem, which can be difficult to diagnose and life-threatening if accompanied with intestinal perforation and peritonitis. In this study, 18 cases of intestinal perforation caused by ingestion of jujube pits were reviewed and summarized to discuss the clinical characteristics, diagnosis and treatments., Methods: From 2012 to 2018, a total of 18 patients diagnosed as intestinal perforation due to ingested pits of jujube in our center were retrospectively reviewed and the manifestations, laboratory tests, imaging examinations and treatment strategies were summarized., Results: The patients comprised of 11 males and 7 females with an average age of 63.5 years. The main clinical manifestation was abdominal pain. Twelve patients (67%) presented to the emergency department with signs of localized peritonitis. CT imaging revealed positive findings in 17 (94%) patients. Conservative treatments were attempted in 3 patients, and the other 15 patients received emergency surgical exploration, where 7 patients had more than one perforation identified during surgery. Five patients were admitted in the surgical intensive care unit after surgery. The average length of stay of all 18 patients was 9.8 days (range 5-24 days)., Conclusion: Ingestion of jujube pits is a common clinical problem and potentially leads to intestinal perforation and peritonitis. CT imaging is the first imaging modality of choice. Patients with milder symptoms might be managed with cautious conservative treatment, and patients with more than one perforation can be identified during surgery.

The aim of the present study was to investigate the function of microRNA-543 on liver cancer cell proliferation and apoptosis, and also to identify whether the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway was a direct target of microRNA-543. When compared with paracarcinoma tissue, microRNA-543 expression in tissue samples from patients with liver cancer was identified to be decreased. Furthermore, overall survival of patients with high microRNA-543 expression was increased compared with patients with low microRNA-543 expression. Inhibition of microRNA-543 expression increased cell proliferation and decreased apoptosis of liver cancer cells. It also activated the protein expression of phosphorylated JAK2, phosphorylated STAT3, c-Myc and B-cell lymphoma 2 (Bcl-2) in liver cancer cells. However, activation of microRNA-543 expression in turn decreased cell proliferation and increased apoptosis of liver cancer cells. The results of the present study highlight the pivotal function of microRNA-543 as an inhibitor in liver cancer cell proliferation by observing JAK2/STAT3/c-Myc/Bcl-2 in liver cancer.

Although genomic instability, epigenetic abnormality, and gene expression dysregulation are hallmarks of colorectal cancer, these features have not been simultaneously analyzed at single-cell resolution. Using optimized single-cell multiomics sequencing together with multiregional sampling of the primary tumor and lymphatic and distant metastases, we developed insights beyond intratumoral heterogeneity. Genome-wide DNA methylation levels were relatively consistent within a single genetic sublineage. The genome-wide DNA demethylation patterns of cancer cells were consistent in all 10 patients whose DNA we sequenced. The cancer cells' DNA demethylation degrees clearly correlated with the densities of the heterochromatin-associated histone modification H3K9me3 of normal tissue and those of repetitive element long interspersed nuclear element 1. Our work demonstrates the feasibility of reconstructing genetic lineages and tracing their epigenomic and transcriptomic dynamics with single-cell multiomics sequencing., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-associated mortality, with a high number of cases caused by metastasis. The early diagnosis of cancer contributes to the successful treatment of patients with lung cancer. The aim of the present study was to analyze the efficacy of marker gene detection and computed tomography (CT) in diagnosing human lung cancer. Lung cancer marker genes, including carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), tissue polypeptide antigen (TPA), pro-gastrin-releasing peptide (ProGRB), cytokeratin fragment 21-1 (Cyfra21-1) and neuron-specific enolase (NSE), were analyzed in patients with lung cancer. The tumor size was evaluated using CT, and the association between lung serum levels of marker gene protein expression and tumor size was investigated. A total of 328 patients with lung cancer were identified, including 204 adenocarcinoma, 75 large cell carcinoma and 49 squamous cell carcinoma cases. All patients were indicated to have a high serum level of CEA, CA125, TPA, ProGRB, Cyfra21-1 and NSE, compared with the normal range. Immunohistochemistry demonstrated higher expression levels of CEA, CA125, TPA, ProGRB, Cyfra21-1 and NSE in lung tumor tissues, compared with the normal range. Results indicated that CT was able to diagnose tumor size for patients with lung cancer. The CEA and CA125 expression levels were associated with CT-diagnosed adenocarcinoma tumor size. Large cell carcinoma tumor size was associated with serum levels of CEA, TPA and ProGRB. Results indicated that Cyfra21-1 and NSE were associated with the squamous cell carcinoma cases, as demonstrated using CT. In conclusion, these results indicated that comprehensive analysis of marker gene detection and CT results may be used to diagnose human lung cancer.

Protocadherin10 (PCDH10), a member of the nonclustered protocadherin family, functions as a tumor suppressor in many cancers. The aim of this study was to evaluate the expression level and prognostic value of PCDH10 in hepatocellular carcinoma (HCC) patients.Quantitative real-time polymerase chain reaction was used to analyze the expression level of PCDH10 in HCC tissues and adjacent nontumor tissues. The association of PCDH10 expression with clinicopathological features of patients was evaluated by chi-squared test. Overall survival was estimated using the Kaplan-Meier method. Besides, the patient prognosis was also evaluated by Cox regression analysis.PCDH10 expression was significantly lower in HCC tissues than that in adjacent nontumor tissues (P = .000). Kaplan-Meier curves showed that patients with lower PCDH10 expression had a worse overall survival. Moreover, PCDH10 expression level was associated tumor size (P = .005), tumor node metastasis stage (P = .002), smoking status (P = .000), and drinking status (P = .005). Multivariate analysis showed that the expression of PCDH10 (P = .000; hazard ratio = 4.784; 95% confidence interval: 2.550-8.977) was an independently associated with poor overall survival rates, as well as smoking status and drinking status.Our findings indicated that the decreased expression of PCDH10 was closely associated with poor prognosis of HCC patients. It might be considered as a valuable biomarker for HCC.

A common challenge in systems biology is quantifying the effects of unknown parameters and estimating parameter values from data. For many systems, this task is computationally intractable due to expensive model evaluations and large numbers of parameters. In this work, we investigate a new method for performing sensitivity analysis and parameter estimation of complex biological models using techniques from uncertainty quantification. The primary advance is a significant improvement in computational efficiency from the replacement of model simulation by evaluation of a polynomial surrogate model. We demonstrate the method on two models of mating in budding yeast: a smaller ODE model of the heterotrimeric G-protein cycle, and a larger spatial model of pheromone-induced cell polarization. A small number of model simulations are used to fit the polynomial surrogates, which are then used to calculate global parameter sensitivities. The surrogate models also allow rapid Bayesian inference of the parameters via Markov chain Monte Carlo (MCMC) by eliminating model simulations at each step. Application to the ODE model shows results consistent with published single-point estimates for the model and data, with the added benefit of calculating the correlations between pairs of parameters. On the larger PDE model, the surrogate models allowed convergence for the distribution of 15 parameters, which otherwise would have been computationally prohibitive using simulations at each MCMC step. We inferred parameter distributions that in certain cases peaked at values different from published values, and showed that a wide range of parameters would permit polarization in the model. Strikingly our results suggested different diffusion constants for active versus inactive Cdc42 to achieve good polarization, which is consistent with experimental observations in another yeast species S. pombe., Competing Interests: The authors have declared that no competing interests exist.

Background: Pancreatic duct obstructions are common in patients with pancreaticoduodenectomy. However, it is often neglected in follow up. This study was to review the outcomes of pancreatic duct obstruction and explore the prevention of pancreatic duct obstruction., Methods: A retrospective analysis of 78 patients undergoing pancreaticojejunostomy without reccurence of disease within 24 months between 2004 and 2014. Pancreatic duct obstruction and long-term pancreatic complications were analysed., Results: Twenty-five patients developed pancreatic duct obstruction following pancreaticojejunostomy, 13 of whom were found to have long-term pancreatic complications. The presence of pancreatic duct obstruction and early pancreatic obstruction were associated with long-term pancreatic complications, respectively (p = 0.002, p = 0.002). There are 10 patients with pancreatic duct stent more than 24 months, the postoperative median pancreatic parenchymal thickness in these 10 patients (17.1 mm, range 8.0 to 24.7 mm) was not significantly change than the median in them preoperative (16.4 mm, range 7.2 to 24.7 mm; p = 0.747). All of them have no long-term pancreatic complications, though the difference was not significantly (p = 0.068)., Conclusions: Early pancreatic duct obstruction is associated with postoperative pancreatic long-term complications. Sustained internal pancreatic stent may improve pancreatic duct obstruction.

Background: There were many reports suggesting that different kinds of tumors can express B7-H4; however, the prognostic value in cancer was still unclearly. Therefore, we conducted a meta-analysis to investigate the relationship between overexpression of B7-H4 with the prognostic value in pancreatic cancer patients., Materials and Methods: The Pubmed, Embase, Cochrane Library, Ovid, Web of Science, and Chinese research database (including CBM, CNKI, and WAN FANG) were searched for related literature published until October 12, 2017. The pooled odds ratios (ORs) and/or pooled hazard ratios (HRs) for clinical pathological factors and overall survival (OS) were calculated and analyzed using Stata software. To assess whether an individual study had an impact on the result, sensitivity analysis was performed for all included individual studies using the fixed-effects model. Publication bias was evaluated using Egger's and Begg's tests., Results: Data from 6 observational studies including 442 patients were summarized in this meta-analysis, and each study was eligible for inclusion based on included and exclude criteria. The pooled results indicated that the B7-H4 overexpression could predict the presentation of lymph node metastasis (OR = 3.94, 95% CI: 1.22-12.66, P = .022), advanced TNM stage (T = the extent of the primary tumor, N = regional lymph nodes, M = distant metastases) (III+IV vs I+II; OR = 7.63, 95% CI: 2.46-23.66, P < .001), and the poor OS (HR = 3.00, 95%CI = 2.20-4.10, P < .001) in PC patients., Conclusions: This study reveals that high expression of B7-H4 is an unfavorable prognostic factor for patients with pancreatic cancer. These results may guide the clinical management of this patient population.

Oxidative stress-induced mitochondrial function and cell apoptosis to osteoblasts, plays a critical role in the pathophysiology of osteoporosis. However, mechanisms underlying such process remain not yet clear. We aims in this study to investigate a possible role of SMAD (the mothers against decapentaplegic homolog 4 (SMAD4) in the oxidative stress-induced apoptosis, in homo sapiens osteoblast hFOB1.19 cells. Results demonstrated that the treatment with more than 100μM H 2 O 2 significantly downregulated the cellular viability, whereas markedly induced apoptosis in hFOB1.19 cells. The SMAD4 was markedly reduced in both mRNA and protein levels in the H 2 O 2 -treated hFOB1.19 cells, along with the reduction of Small ubiquitin-related modifier 1 (SUMO 1) and SUMO 2/3. The immunoprecipitation assay confirmed indicated the interaction between SUMO 1 (or SUMO 2/3) and SMAD4. Moreover, the SMAD4 overexpression markedly ameliorated the H 2 O 2 -resulted viability reduction and apoptosis induction in hFOB1.19 cells. Interestingly, such amelioration was blocked by the knockdown of SUMO 2/3. Taken together, we conclued that SMAD4 inhibits the H 2 O 2 -induced apoptosis in osteoblast hFOB1.19 cells; such inhibition might depend on the SUMOylation by SUMO 2/3. It implies a promising role of SMAD4 in oxidative stress-promoted damage to osteoblasts., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Although laparoscopic treatment of gallbladder cancer (GBC) has been explored in the last decade, long-term results are still rare. This study evaluates long-term results of intended laparoscopic treatment for suspected GBC confined to the gallbladder wall, based on our experience over 10 years., Methods: Between August 2006 and December 2015, 164 patients with suspected GBC confined to the wall were enrolled in the protocol for laparoscopic surgery. The process for GBC treatment was analyzed to evaluate the feasibility of computed tomography (CT) and/or magnetic resonance imaging (MRI) combined with frozen-section examination in identifying GBC confined to the wall. Of 159 patients who underwent the intended laparoscopic radical treatment, 47 with pathologically proven GBC were investigated to determine the safety and oncologic outcomes of a laparoscopic approach to GBC., Results: Among the 164 patients, 5 patients avoided further radical surgery because of unresectable disease and 12 were converted to open surgery; in the remaining 147 patients, totally laparoscopic treatment was successfully accomplished. Extended cholecystectomy was performed in 37 patients and simple cholecystectomy in 10. The T stages based on final pathology were Tis (n=6), T1a (n=2), T1b (n=9), T2 (n=26), and T3 (n=4). Recurrence was detected in 11 patients over a median follow-up of 51 months. The disease-specific 5-year survival rate of these 47 patients was 68.8%, and rose to 85% for patients with a normal cancer antigen 19-9 (CA19-9) level., Conclusions: The favorable long-term outcomes demonstrate the feasibility of combined CT/MRI and frozen-section examination in the selection of patients with GBC confined to the gallbladder wall, confirm the oncologic safety of laparoscopic treatment in selected GBC patients, and favor measurement of preoperative CA19-9 in the selection of GBCs suitable for laparoscopic treatment.

Background: Platelet to lymphocyte ratio (PLR) was recently reported being associated with the prognosis of pancreatic cancer (PC), but the prognostic value of PLR in pancreatic cancer remains inconsistent. We conduct a meta-analysis to evaluate the prognostic role of PLR in patients with PC., Methods: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for eligible studies which investigated the relationship between PLR and clinical outcome of patients with pancreatic cancer. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the prognostic role of PLR in overall survival (OS) and progression-free survival (PFS)/time to progression (TTP)., Results: A total of 16 studies comprising 3028 patients with PC were enrolled in this meta-analysis. Pooled analysis demonstrated that elevated PLR predicted a poor OS (HR = 1.22, 95% CI: 1.09-1.36, P < .001). Prognostic role of PLR on OS were significant in subgroup of Asians (HR = 1.22, 95% CI: 1.11-1.34, P < .001), patients treated with chemotherapy (HR = 1.18, 95% CI: 1.04-1.35, P = .01) and mixed methods (HR = 1.29, 95% CI: 1.07-1.57, P = .009), American joint committee on cancer (AJCC) stage of III-IV (HR = 1.22, 95% CI: 1.09-1.36, P < .001), pathological subtype of pancreatic adenocarcinoma (HR = 1.21, 95% CI: 1.08-1.36, P = .001), and cut-off value of PLR ≥160 (HR = 1.48, 95% CI: 1.25-1.75, P < .001)., Conclusions: An elevated PLR is associated with unfavorable overall survival in patients with pancreatic cancer.

In this paper, we introduce the numerical strategy for mixed uncertainty propagation based on probability and Dempster-Shafer theories, and apply it to the computational model of peristalsis in a heart-pumping system. Specifically, the stochastic uncertainty in the system is represented with random variables while epistemic uncertainty is represented using non-probabilistic uncertain variables with belief functions. The mixed uncertainty is propagated through the system, resulting in the uncertainty in the chosen quantities of interest (QoI, such as flow volume, cost of transport and work). With the introduced numerical method, the uncertainty in the statistics of QoIs will be represented using belief functions. With three representative probability distributions consistent with the belief structure, global sensitivity analysis has also been implemented to identify important uncertain factors and the results have been compared between different peristalsis models. To reduce the computational cost, physics constrained generalized polynomial chaos method is adopted to construct cheaper surrogates as approximations for the full simulation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)