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Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polα/primase. At telomeres, Polα/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/primase into an active state that completes telomere replication through fill-in synthesis., Competing Interests: Declaration of interests T.R.C. is a member of the SAB of Storm Therapeutics, Eikon Therapeutics, and SomaLogic, Inc., (Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and the expression and function of an uncharacterized protein RNF214 in HCC are still unknown. Phase separation has recently been observed to participate in the progression of HCC. In this study, we investigated the expression, function, and phase separation of RNF214 in HCC. We found that RNF214 was highly expressed in HCC and associated with poor prognosis. RNF214 functioned as an oncogene to promote the proliferation, migration, and metastasis of HCC. Mechanically, RNF214 underwent phase separation, and the coiled-coil (CC) domain of RNF214 mediated its phase separation. Furthermore, the CC domain was necessary for the oncogenic function of RNF214 in HCC. Taken together, our data favored that phase separation of RNF214 promoted the progression of HCC. RNF214 may be a potential biomarker and therapeutic target for HCC., (© 2024. The Author(s).)

Objective: To evaluate the relationship between amount of NSAID use postpartum and outpatient blood pressure (BP) control., Study Design: This is a prospective, single-site, cohort study of postpartum people diagnosed with HDP from 2018 to 2020 using the American College of Obstetrician and Gynecologists criteria. All participants were provided an electronic BP cuff for daily evaluation after discharge. Those who provided at least 7 days of data within the first 14 days after discharge were included. Standard PP pain management included ibuprofen 600 mg every 6 h as needed. The exposure was self-reported amount of NSAIDs used within the first 14 days after discharge. The primary outcome was median mean arterial pressure (MAP) over the first 14 days after hospital discharge. Secondary outcomes included median and maximum systolic and diastolic BPs and need for PP readmission for HDP. Regression models were created, controlling for a propensity score for highest quartile of NSAID use., Results: 103 participants were approached, of whom 60 met inclusion criteria. Those who had a history of a cesarean delivery were more likely to be in the highest quartile of NSAID use; no other significant differences were noted across quartiles of NSAID use. There was no association between NSAID amount used and median MAP (adjusted β coefficient 0.03, 95% CI: -0.17 to 0.22). There were no significant associations between NSAID amount used and all other secondary outcomes., Conclusion: Out-of-hospital NSAID use is not associated with worsened PP BP control after hospital discharge among people diagnosed with HDP., 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 © 2023 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

It has been known for decades that telomerase extends the 3' end of linear eukaryotic chromosomes and dictates the telomeric repeat sequence based on the template in its RNA. However, telomerase does not mitigate sequence loss at the 5' ends of chromosomes, which results from lagging strand DNA synthesis and nucleolytic processing. Therefore, a second enzyme is needed to keep telomeres intact: DNA polymerase α/Primase bound to Ctc1-Stn1-Ten1 (CST). CST-Polα/Primase maintains telomeres through a fill-in reaction that replenishes the lost sequences at the 5' ends. CST not only serves to maintain telomeres but also determines their length by keeping telomerase from overelongating telomeres. Here we discuss recent data on the evolution, structure, function, and recruitment of mammalian CST-Polα/Primase, highlighting the role of this complex and telomere length control in human disease., (© 2023 Cai and de Lange; Published by Cold Spring Harbor Laboratory Press.)

Background: Sickle cell disease (SCD) results in severe complications, such as anaemia and pain episodes. Hydroxyurea (HU) is efficacious in SCD, yet adherence remains low., Objective: To assess the relationship of HU adherence to health care utilization and patients' characteristics., Methods: This is a 5-year retrospective chart review. Patients' demographics and medical history were collected from the electronic medical record (EMR). HU adherence was evaluated using foetal haemoglobin "HbF%", mean corpuscular volume "MCV", and absolute neutrophil count "ANC". Age groups included children (<12 years), adolescents (12-17 years), and young adults (≥18 years)., Results: A total of 113 SCD patients on HU were included (median age 14 years, IQR 10-20; 50% female; 88% HbSS). Young adults had significantly higher HU adherence compared to adolescents and children, including higher median HbF% (24.2 vs . 12.4 vs . 8.6, p  = .003), MCV (fl) (106.4 vs . 96.2 vs . 95.4, p  = .01) and lower ANC (10 3 /ml) (3.25 vs . 4.9 vs . 4.2, p  = .01), respectively. Patients with chronic pain had lower HU adherence (HbF% 15.3 vs . 10.7, p  = .04; ANC 3.6 vs . 6.3, p  = .002; MCV 102.3 vs . 93.1, p  = .1). Patients with higher HbF or MCV and lower ANC had significantly less frequent emergency room visits (r s =-0.26, p  = .01; r s =-0.23, p  = .01; r s =0.24, p  = .01) and hospitalizations (r s =-0.27, p  = .01; r s =-0.31, p  = .01; r s =0.21, p  = .02) as well as shorter length of stays (r s =-0.27, p  = .0045; r s =-.34, p  = 0.004; r s =0.23, p  = .02), respectively. Similar trends in HU adherence and health care utilization were seen in subgroup analysis of only HbSS patients. There was no significant association of HU adherence to patients' sex, socio-economic status, distance from hospital, and HU duration., Conclusions: Young adults with SCD had significantly higher HU adherence compared to children and adolescents. Patients with lower HU adherence and/or chronic pain had increased health care utilization. Future studies examining barriers to adherence and evaluating interventions to optimize HU adherence in SCD are warranted.KEY MESSAGESYoung adults with SCD had significantly higher HU adherence, as reflected in their laboratory markers, compared to children and adolescents.Patients with higher HU adherence and/or those without chronic pain had lower or less frequent health care utilization.No significant association of HU adherence to patients' sex, socio-economic status and distance from hospital.

Background: The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced a global pandemic of coronavirus disease 2019 (COVID-19), resulting in modifications to public health policies on a universal scale. SARS-CoV-2 vaccine has evolved as the most effective and secure way for protecting healthy individuals against COVID-19. Patients with cancer were excluded from clinical trials due to their increased COVID-19 risk and current immunosuppressing therapy. Safety and effectiveness evidence is insufficient for SARS-CoV-2 vaccination in cancer patients., Aim: To assess the efficacy and safety of two-dose SARS-CoV-2 vaccines in cancer patients., Methods: A multicenter observational study was performed at ten Chinese hospitals between January 1, 2021 and December 31, 2021. Each participant in the research received two doses of vaccination. A total of 215 healthy people were screened and 132 eligible patients with cancer were recruited. In order to verify the safety of the second dose of the vaccine, a side-effect report was compiled. Two weeks following the second vaccination dose, subjects underwent an analogous questionnaire survey. Utilizing a magnetic particle-based chemiluminescence immunoassay, serum levels of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies were measured to determine the effectiveness of vaccination. IgG levels ≥ 10 AU/mL were considered seropositive., Results: All the 347 eligible patients completed the follow-up, and anti-SARS-CoV-2 IgG antibodies were detected. Local pain at the injection location was the most common side effect mentioned by all responders, with an increased incidence in cancer patients than the healthy people after the second dose vaccine (17.2% vs 9.1%; P = 0.035). There was no significant difference in headache, urticaria, or other adverse reactions between patients with cancer and healthy people. In the group of cancer patients, the seropositivity incidence was 83.3%, while it was 96.3% in the group of healthy people. In the group of cancer patients, the seropositivity incidence and antibody levels were significantly lower ( P < 0.001). This analysis showed a poorer response rate in patients on active immunosuppressive treatment and elderly cancer patients., Conclusion: Two-dose Chinese vaccines are effective and safe in cancer patients. However, further research is required on the efficacy in elderly cancer patients and those on active immunosuppressive treatment., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: To compare the efficacy of transarterial embolization (TAE) with polyvinyl alcohol (PVA) particles alone and lipiodol-bleomycin emulsion (LBE) plus PVA particles for patients with unresectable large symptomatic focal nodular hyperplasia (FNH)., Methods: We performed a retrospective analysis of patients who underwent TAE either with PVA particles alone (group A, n = 46) or LBE plus PVA particles (group B, n = 35) for large (≥ 7 cm) symptomatic FNH between January 2002 and February 2019. Propensity score matching (PSM) (1:1) was performed to adjust for potential baseline confounders. Technical success, adverse events (AEs), symptom relief, and changes in the lesion size after TAE were evaluated. Statistical analysis included Wilcoxon rank sum test and χ 2 test., Results: After PSM, no significant differences in baseline characteristics were found between the groups (31 in group A and 31 in group B, with a mean age of 31 years). Technical success was achieved in all patients (100%), without major AEs in both groups. Complete resolution of the abdominal symptoms was reported in 77.4% in group A and 100% in group B (p = 0.037) during a mean follow-up period of 72 months; complete resolution (CR) of the FNH rate was significantly higher in group B than in group A (93.6% vs. 67.7%; p = 0.019)., Conclusion: Compared with the use PVA particles alone, TAE with LBE plus PVA particles in the treatment of patients with large symptomatic FNH had a significantly higher rates of CR of the FNH and complete relief of the symptoms., Key Points: • Transarterial embolization (TAE) with lipiodol-bleomycin emulsion (LBE) plus PVA particles for the large symptomatic FNH yielded better results than with PVA particles alone, in terms of complete resolution of FNH lesions (93.6% vs 67.7%) and complete relief of the abdominal symptoms (100% vs 77.4%) during a mean follow-up period of 72 months (38-170 months). • No major complications were recorded in both groups, and no significant difference in the incidence of postembolization syndrome were observed between the two groups., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

The CST-Polα/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-Å resolution cryo-EM structure of human CST-Polα/primase, captured prior to catalysis in a recruitment state stabilized by chemical cross-linking. Our structure reveals an evolutionarily conserved interaction between the C-terminal domain of the catalytic POLA1 subunit and an N-terminal expansion in metazoan CTC1. Cross-linking mass spectrometry and negative-stain EM analysis provide insight into CST binding by the flexible POLA1 N-terminus. Finally, Coats plus syndrome disease mutations previously characterized to disrupt formation of the CST-Polα/primase complex map to protein-protein interfaces observed in the recruitment state. Together, our results shed light on the architecture and stoichiometry of the metazoan fill-in machinery., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: To determine if the use of the Proton Pump Inhibitors (PPI) impacts the clinical efficacy of Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC), a meta-analysis was conducted., Method: Eleven studies from PubMed, EMBASE, Cochrane Library, Web of Science, and other databases up to May 2022, were selected. The pertinent clinical outcomes were assessed by applying the Progression-free survival (PFS), Overall Survival (OS), Hazard Ratio (HR), and 95% Confidence Interval (CI)., Result: This study included eleven articles containing 7,893 NSCLC patients. The result indicated that PPI use was dramatically related to poor OS (HR: 1.30 [1.10-1.54]), and poor PFS (HR: 1.25 [1.09-1.42]) in case of patients treated with ICIs. With regard to the subgroup analysis, PPI use was dramatically associated with poor OS (Europe: HR = 1.48 [1.26, 1.74], Worldwide: HR = 1.54 [1.24, 1.91]), and poor PFS (Europe: HR = 1.36 [1.18, 1.57], Worldwide: HR = 1.34 [1.16, 1.55]) in patients from Europe and multi-center studies across the world, poor OS in patients with age less than or equal to 65 (HR = 1.56 [1.14, 2.15]), poor PFS in patients aged more than 65 (HR = 1.36 [1.18, 1.57]), poor OS for patients receiving with PD-1 (HR = 1.37 [1.04, 1.79]), poor PFS for patients receiving with PD-L1 (HR = 1.33 [1.19, 1.49]), and poor OS (-30: HR = 1.89 [1.29, 2.78], ±30: HR = 1.44 [1.27, 1.64]) and poor PFS (-30: HR = 1.51 [1.11, 2.05], ±30: HR = 1.32 [1.20, 1.45]) for patients who received PPI at 30 days before and/or after starting the ICIs treatment., Conclusion: Our meta-analysis indicated that PPI combined with ICIs in the treatment of NSCLC patients could result in poor OS and PFS. PPI use should be extremely cautious in clinical practices to avoid the impact on the efficacy of the ICIs., Competing Interests: The authors state that the study was conducted without any business or financial relationships that could be interpreted as potential conflicts of interest., (Copyright © 2022 Da-Hai Hu et al.)

The process of protein ubiquitination and deubiquitination plays an important role in maintaining protein stability and regulating signal pathways, and protein homeostasis perturbations may induce a variety of diseases. The deubiquitination process removes ubiquitin molecules from the protein, which requires the participation of deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 15 (USP15) is a DUB that participates in many biological cell processes and regulates tumorigenesis. A dislocation catalytic triplet was observed in the USP15 structure, a conformation not observed in other USPs, except USP7, which makes USP15 appear to be unique. USP15 has been reported to be involved in the regulation of various cancers and diseases, and the reported substrate functions of USP15 are conflicting, suggesting that USP15 may act as both an oncogene and a tumor suppressor in different contexts. The importance and complexity of USP15 in the pathological processes remains unclear. Therefore, we reviewed the diverse biological functions of USP15 in cancers and other diseases, suggesting the potential of USP15 as an attractive therapeutic target.

The mammalian telomeric shelterin complex-comprised of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-blocks the DNA damage response at chromosome ends and interacts with telomerase and the CST complex to regulate telomere length. The evolutionary origins of shelterin are unclear, partly because unicellular organisms have distinct telomeric proteins. Here, we describe the evolution of metazoan shelterin, showing that TRF1 emerged in vertebrates upon duplication of a TRF2-like ancestor. TRF1 and TRF2 diverged rapidly during vertebrate evolution through the acquisition of new domains and interacting factors. Vertebrate shelterin is also distinguished by the presence of an HJRL domain in the split C-terminal OB fold of POT1, whereas invertebrate POT1s carry inserts of variable nature. Importantly, the data reveal that, apart from the primate and rodent POT1 orthologs, all metazoan POT1s are predicted to have a fourth OB fold at their N termini. Therefore, we propose that POT1 arose from a four-OB-fold ancestor, most likely an RPA70-like protein. This analysis provides insights into the biology of shelterin and its evolution from ancestral telomeric DNA-binding proteins., (© 2021 Myler et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Suboptimal adherence to 6-mercaptopurine (6-MP) is prevalent in pediatric acute lymphoblastic leukemia (ALL) and associated with increased risk of relapse. Rapid uptake of personal technology makes mobile health (mHealth) an attractive platform to promote adherence., Objective: Study objectives were to examine access to mobile technology and preferences for an mHealth intervention to improve medication adherence in pediatric ALL., Methods: A cross-sectional survey was administered in oncology clinic to parents of children with ALL as well as adolescents and young adults (AYAs) with ALL receiving maintenance chemotherapy., Results: A total of 49 parents (median age [IQR] 39 [33-42] years; female 76% [37/49]) and 15 patients (median age [IQR] 17 [16-19]; male 80% [12/15]) participated. All parents and AYAs owned electronic tablets, smartphones, or both. Parents' most endorsed mHealth app features included a list of medications (71%, 35/49), information about 6-MP (71%, 35/49), refill reminders (71%, 35/49), and reminders to take 6-MP (71%, 35/49). AYAs' most endorsed features included refill reminders (73%, 11/15), reminders to take 6-MP (73%, 11/15), and tracking 6-MP (73%, 11/15)., Conclusions: Parents and AYAs reported ubiquitous access to mobile technology and strong interest in multiple adherence-specific mHealth app features. Parents and AYAs provided valuable insight into preferred features for a multifunctional behavioral intervention (mHealth app) to promote medication adherence in pediatric ALL., (©Mallorie B Heneghan, Tasmeen Hussain, Leonardo Barrera, Stephanie W Cai, Maureen Haugen, Elaine Morgan, Jenna Rossoff, Joanna Weinstein, Nobuko Hijiya, David Cella, Sherif M Badawy. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 18.02.2021.)

Background: Various minimally invasive approaches have been described for infected necrotizing pancreatitis. This article describes a modified minimal-access retroperitoneal pancreatic necrosectomy (MARPN) procedure assisted by gas insufflation., Methods: This retrospective, observational study documented patients who had undergone a step-up MARPN between 1 January 2010 and 31 December 2016. A minimum follow-up of 1 year was required for inclusion. The step-up approach involved percutaneous catheter drainage followed by the modified MARPN and necrosectomy. If more than one access site was needed it was categorized as complex MARPN., Results: Of 212 patients with infected necrotizing pancreatitis, 164 (77·4 per cent) underwent a step-up approach. The median number of percutaneous catheter drains and MARPN procedures was 3 (range 1-7) and 1 (1-6) respectively. Ninety patients (54·9 per cent) underwent complex MARPN. For residual necrosis after MARPN, three patients (1·8 per cent) underwent sinus tract gastroscopy, and 11 (6·7 per cent) had sinography combined with a tube change. However, operations in 13 patients (7·9 per cent) required conversion to open surgery. Postoperative complications developed in 103 patients (62·8 per cent). The mortality rate was 6·1 per cent (10 deaths)., Conclusion: A step-up approach using a modified MARPN for infected necrotizing pancreatitis is a reasonable option., (© 2020 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Adherence to oral chemotherapy, including 6-mercaptopurine (6-MP), is suboptimal in pediatric acute lymphoblastic leukemia (ALL), which is associated with increased risk of relapse. Study objectives were to examine self-reported adherence to 6-MP and related barriers to adherence, mapped to the capability, opportunity, motivation, and behavior (COM-B) model for behavior change., Procedure: Forty-nine parents (median, 39 years old; 76% females) and 15 patients (median, 17 years old, 20% females) completed the study survey., Results: Suboptimal adherence was reported in 43% of parents and 73% of patients. Most parents and patients (80% and 90%, respectively) reported ≥1 adherence barrier. Parents reported difficulty helping their child meet others with ALL (43%), contacting community organizations (39%), and meeting other parents (37%). Patients reported difficulty finding out what their medications are (40%), finding out what 6-MP does (47%), and meeting other patients (40%). Using the COM-B, we found that parents and patients endorsed barriers in multiple components, especially physical (55%, 67%) and social opportunity (56%, 47%), highlighting that barriers to adherence may be multifaceted., Conclusions: Our results suggest that parents and patients with ALL face various prevalent barriers to medication adherence and provide insight into the development of behavioral interventions focused on promoting adherence, which is essential to prevent relapse and optimize health outcomes in ALL., (© 2020 Wiley Periodicals, Inc.)

Objective: The RIB43A domain with coiled-coils 2 (RIBC2) encodes an uncharacterized vertebrate protein exhibiting similarity with Chlamydomonas protofilament ribbon proteins, required for ciliary motility. To date, no functional variants capable of triggering a change in the expression of RIBC2 have been reported., Patients and Methods: The genotypes of rs2272804 in 30 individuals were identified with Sanger sequencing to estimate allele frequencies. Dual-Luciferase and mutagenesis assays were carried out to investigate the impact of rs2272804 on transcriptional and translational levels. The microarray data of 7 types of cancer were obtained from the Gene Expression Omnibus (GEO) to explore the role of rs2272804 in those diseases., Results: In this study, we identified a common variant in the 5'UTR of RIBC2, rs2272804, which can create an upstream open reading frame (uORF) in the 5'UTR significantly inhibiting the expression of its host gene. Using Dual-Luciferase constructs, we found that this variant leads to an 85% reduction in translational efficiency, but only a 20% decrease was observed at the transcriptional level. In terms of population studies, mRNA levels of RIBC2 varied according to their rs2272804 genotypes. The "A" allele homozygotes, which created a uORF, showed the lowest transcriptional levels while the transcriptional activity of the "C" allele homozygotes without an uORF was the highest, consistent with the in-vitro studies. Furthermore, we explored its role in 7 types of cancer and identified RIBC2 as a significantly differentially expressed gene (DEG) in breast cancer (BRCA), ovarian serous cystadenocarcinoma (OV), and kidney renal clear cell carcinoma (KIRC). Finally, we showed that the overexpression of RIBC2 enhanced the expression of TRIM37 and down-regulated TRAF2. TRIM37 is a member of the tripartite motif (TRIM) family involved in developmental patterning and oncogenesis while TRAF2 is associated with the signal transduction from members of the TNF receptor superfamily., Conclusions: Our reports identified a common variant that exerts a dramatic impact on expression efficiency and provides further functional insight into RIBC2.

Objective: To examine the effectiveness of non-operative of colonic fistula following acute pancreatitis. Methods: Retrospective analysis of 354 patients with acute pancreatitis who were admitted to Department of Hepatobiliary Surgery of Chinese People's Liberation Army General Hospital from January 2013 to December 2018. Age of the patients was (46±14) years (range: 14-85 years); 249 cases (70.3%) were males. There were 41 cases of acute edematous pancreatitis and 313 cases of acute necrotising pancreatitis. Two hundred and fifteen cases were diagnosed as moderate severe acute pancreatitis and 139 were diagnosed as severe acute pancreatitis. Among 313 cases of acute necrotising pancreatitis, 62 cases underwent non-surgical treatment, 251 cases underwent surgical treatment in which 218 of minimal access retroperitoneal pancreatic necrosectomy underwent percutaneous nephroliguectomy with peripancreatic necrotic tissue removal technique. Results: There were 15 cases of colon fistula following acute necrotising pancreatitis, and the incidence rate was 4.2%(15/354). There were 7 males and 8 females, with age of (39±8) years (range: 27 to 50 years). The median interval between acute pancreatitis onset and diagnosis of colonic fistula was 71 days(27-134) days. Two cases occurred at the hepatic flexure of the colon, 4 cases at transverse colon, and 9 cases at splenic flexure of colon. Of the 354 patients, 39 cases died and the mortality was 11.0%. Two patients underwent laparotomy, and one of them died. The remaining 13 patients underwent non-surgical treatment and were discharged. Conclusion: Acute pancreatitis with colonic fistula can be treated with non-surgical treatment and can achieve good prognosis.

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Acute pancreatitis (AP) is a necro-inflammatory disorder with high mortality rate. With advances in understanding the pathogenesis of AP, microRNAs (miRNAs) have been reported to play an essential role in AP progression. However, the mechanism that allows miR-148a-3p to regulate necrosis in AP remains unclear., Methods: Caerulein treatment was used to induce AP in mice or cells. miR-148a-3p -/- mice or miR-148a-3p inhibition in wild type mice were used to investigate the effect of miR-148a-3p on AP. The expression of miR-148a-3p was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The abundances of phosphatase and tensin homolog (PTEN) and hallmarks of necrosis or apoptosis were measured by qRT-PCR or western blots (WB). Cell necrosis, apoptosis, serum amylase or lipase activity and inflammatory cytokines levels were investigated by commercial assay kit. Inflammatory infiltration was analyzed by immunohistochemistry (IHC). The interaction between miR-148a-3p and PTEN was probed by luciferase activity., Results: miR-148a-3p was highly expressed in AP and knockout of miR-148a-3p inhibited water content, cell necrosis, amylase and lipase activity while inducing PTEN expression. Moreover, miR-148a-3p deletion attenuated inflammatory infiltration and necrosis by promoting apoptosis. In addition, miR-148a-3p knockdown protected against cell necrosis, amylase, and lipase activity in AP. Intriguingly, PTEN was a target of miR-148a-3p and interference of PTEN reversed the effect of miR-148a-3p deficiency on AP in vitro., Conclusion: miR-148a-3p inhibition repressed necrosis by regulating PTEN expression in AP, providing a novel biomarker of therapeutics for AP treatment., Competing Interests: None., (IJCEP Copyright © 2018.)

Objective: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need., Design and Results: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively., Conclusions: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group., Trial Registration: NCT01770431; Post-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The nuclear pore complex (NPC) controls the passage of macromolecules between the nucleus and cytoplasm, but how the NPC directly participates in macromolecular transport remains poorly understood. In the final step of mRNA export, the DEAD-box helicase DDX19 is activated by the nucleoporins Gle1, Nup214, and Nup42 to remove Nxf1•Nxt1 from mRNAs. Here, we report crystal structures of Gle1•Nup42 from three organisms that reveal an evolutionarily conserved binding mode. Biochemical reconstitution of the DDX19 ATPase cycle establishes that human DDX19 activation does not require IP 6 , unlike its fungal homologs, and that Gle1 stability affects DDX19 activation. Mutations linked to motor neuron diseases cause decreased Gle1 thermostability, implicating nucleoporin misfolding as a disease determinant. Crystal structures of human Gle1•Nup42•DDX19 reveal the structural rearrangements in DDX19 from an auto-inhibited to an RNA-binding competent state. Together, our results provide the foundation for further mechanistic analyses of mRNA export in humans.

BACKGROUND The transient receptor potential melastatin 8 (TRPM8) was found to be expressed abnormally in a variety of tumors and is associated with unfavorable prognosis in human cancers. However, its clinical significance in pancreatic cancer (PC) is mostly unknown. MATERIAL AND METHODS qRT-PCR was performed to measure the expression of TRPM8 in 110 pairs of PC tissues and the adjacent non-cancerous tissues. The association of TRPM8 expression with the clinical characters of PC patients was analyzed using the chi-square test. Furthermore, the prognostic value of TRPM8 was determined with Kaplan-Meier survival curve and Cox regression analysis. RESULTS We found that the expression level of TRPM8 was significantly elevated in PC tissues compared to the non-cancerous controls (P<0.001). In addition, a close relationship was observed between elevated TRPM8 expression with large tumor size (P=0.001), advanced TNM (P=0.013), and distant metastasis (P=0.034). Survival analysis suggested that patients with high TRPM8 expression has worse OS (P=0.001) and DFS (P<0.001) than those with low TRPM8 expression. Moreover, TRPM8 was confirmed as a valuable prognostic biomarker for OS (HR=1.913; 95% CI: 1.020-3.589; P=0.043) or DFS (HR=2.374; 95% CI: 1.269-4.443; P=0.007) of PC patients. CONCLUSIONS This study shows that TRPM8 expression is significantly up-regulated in PC and it might be a useful prognostic factor for patients with PC.

Aim: To explore the value of three-dimensional (3D) visualization technology in the minimally invasive treatment for infected necrotizing pancreatitis (INP)., Methods: Clinical data of 18 patients with INP, who were admitted to the PLA General Hospital in 2017, were retrospectively analyzed. Two-dimensional images of computed tomography were converted into 3D images based on 3D visualization technology. The size, number, shape and position of lesions and their relationship with major abdominal vasculature were well displayed. Also, percutaneous catheter drainage (PCD) number and puncture paths were designed through virtual surgery (percutaneous nephroscopic necrosectomy) based on the principle of maximum removal of infected necrosis conveniently., Results: Abdominal 3D visualization images of all the patients were well reconstructed, and the optimal PCD puncture paths were well designed. Infected necrosis was conveniently removed in abundance using a nephroscope during the following surgery, and the median operation time was 102 (102 ± 20.7) min. Only 1 patient underwent endoscopic necrosectomy because of residual necrosis., Conclusion: The 3D visualization technology could optimize the PCD puncture paths, improving the drainage effect in patients with INP. Moreover, it significantly increased the efficiency of necrosectomy through the rigid nephroscope. As a result, it decreased operation times and improved the prognosis., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article.

Acid invertase activities in roots and young seeds of a metalliferous population (MP) of Rumex dentatus were previously observed to be significantly higher than those of a non-metalliferous population (NMP) under Cu stress. To date, no acid invertase gene has been cloned from R. dentatus. Here, we isolated four full-length cDNAs from the two populations of R. dentatus, presumably encoding cell wall (RdnCIN1 and RdmCIN1 from the NMP and MP, respectively) and vacuolar invertases (RdnVIN1 and RdmVIN1 from the NMP and MP, respectively). Unexpectedly, RdnCIN1 and RdmCIN1 most likely encode special defective invertases with highly attenuated sucrose-hydrolyzing capacity. The transcript levels of RdmCIN1 were significantly higher than those of RdnCIN1 in roots and young seeds under Cu stress, whereas under control conditions, the former was initially lower than the latter. Unexpected high correlations were observed between the transcript levels of RdnCIN1 and RdmCIN1 and the activity of cell wall invertase, even though RdnCIN1 and RdmCIN1 do not encode catalytically active invertases. Similarly, the transcript levels of RdmVIN1 in roots and young seeds were increased under Cu stress, whereas those of RdnVIN1 were decreased. The high correlations between the transcript levels of RdnVIN1 and RdmVIN1 and the activity of vacuolar invertase indicate that RdnVIN1 and RdmVIN1 might control distinct vacuolar invertase activities in the two populations. Moreover, a possible indirect role for acid invertases in Cu tolerance, mediated by generating a range of sugars used as nutrients and signaling molecules, is discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Genome editing is a cutting-edge technology that generates DNA double strand breaks at the specific genomic DNA sequence through nuclease recognition and cleavage, and then achieves insertion, replacement, or deletion of the target gene via endogenous DNA repair mechanisms, such as non-homologous end joining, homology directed repair, and homologous recombination. So far, more than 600 human hereditary eye diseases and systemic hereditary diseases with ocular phenotypes have been found. However, most of these diseases are of incompletely elucidated pathogenesis and without effective therapies. Genome editing technology can precisely target and alter the genomes of animals, establish animal models of the hereditary diseases, and elucidate the relationship between the target gene and the disease phenotype, thereby providing a powerful approach to studying the pathogenic mechanisms underlying the hereditary eye diseases. In addition, correction of gene mutations by the genome editing brings a new hope to gene therapy for the hereditary eye diseases. This review introduces the molecular characteristics of 4 major enzymes used in the genome editing, including homing endonucleases, zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9), and summarizes the current applications of this technology in investigating the pathogenic mechanisms underlying the hereditary eye diseases. (Chin J Ophthalmol, 2017, 53: 386-371 ) .

Objective: To investigate the characteristics of spectrum and drug resistance of pathogens causing sepsis in patients with severe acute pancreatitis(SAP). Methods: The clinical data of 63 SAP patients with sepsis admitted in Department of Hepatobiliary, People's Liberation Army General Hospital from January 2014 to December 2015 were retrospectively studied. There were 47 males and 16 females, aged from 22 to 73 years, with an average age of (52±11)years. Samples were collected mainly from: (1)pancreatic and peripancreatic necrosis and abdominal drainage; (2)bile; (3) blood or deep venous catheter; (4) sputum and tracheal catheter and thoracic drainage; (5) urine. Strain identification and drug-resistance test were preformed on positive specimens. Results: Of 244 pathogenic isolates, mainly derived from abdominal cavity(36.0%), blood stream (14.0%), central venous catheter(11.8%), necrotic tissue(9.1%) and sputum(8.1%); 154(63.1%) were gram-negative bacteria, 68 cases(27.9%) were gram-positive bacteria and 22 cases(9.0%) were fungi respectively. The top six common pathogens isolated were E . coli(16.0%), E .faecium and faecalis(15.2%), P .aeruginosa(10.7%), K .pneumonia(9.8%), Acinetobacter baumanni(8.2%), Stenotrophomonas maltophilia(5.3%)respectively. The detection rate of E . coli and K . pneumonia extended-spectrum β-lactamases(ESBL) was 84.6%(33/39) and 70.8%(17/24), the resistance rate to imipeniem was 12.8% and 25.0%, to cefperazone-sulbactam was 28.2% and 29.2%. As to P . aeruginosa and Acinetobacter bacillus, the resistance rate to imipeniem was 50.0% and 75.0%, to cefperazone-sulbactam was 42.3% and 70.0%; Stenotrophomonas maltophilia was completely resistant to cefperazone-sulbactam, but sensitive to minocycline, SMZ-TMP with the resistance rate less than 40.0%. Gram-positive bacterium strains mainly included E . faecium(38.2%, 26/68), E .faecalis(16.2%, 11/68) and Staphylococcus(35.3%, 24/68) which maintained high sensitivity to vancomycin, teicoplanin and linezolid, there was only one isolate resistant to vancomycin. Candida were the sole pathogens of fungal infections, sensitive to common antifungal drugs overall. Conclusions: The gram-negative bacteria are the predominant pathogens mainly including ESBL-producing isolates( E .coli and K . pneumonia) and non-fermentation bacteria( P .aeruginosa and Acinetobacter bacillus) causing sepsis in SAP. The infection rate and drug-resistance rate of these two kinds of pathogens are relatively higher.

Objective: To explore the experience of minimal-access video-assisted retroperitoneal debridement in treatment of infected pancreatic necrosis(IPN). Methods: A retrospective review was performed on 12 patients with IPN who underwent minimal-access video-assisted retroperitoneal debridement between June 2008 and June 2013 in People's Liberation Army General Hospital and First Affiliated Hospital of People's Liberation Army General Hospital, respectively.There were 10 male patients and 2 female patients aging from 33 to 55 years with mean age of(43±8)years.Pancreas infective necrosis, the serious complications of severe acute pancreatitis occurred in all of the patients among which there were 2 patients with infection after percutaneous catheter drainage(PCD)in early phase of disease, and 12 patients with spontaneous during the late phase. The technical strategies of the minimally invasive treatment mainly included PCD, minimal-access video-assisted retroperitoneal debridement, and irrigation. Results: Ten patients received PCD and the median time from onset of acute necrotizing pancreatitis to PCD was mean of 24 days(range 8-86 days). Minimal-access video-assisted retroperitoneal debridement was performed after 18 days(range 3-29 days) after PCD.Three patients died after surgery.Five patients had hemorrhage complication and 3 had colonic fistula.Pancreatic fistula occurred in 2 patients. Conclusions: The technique of minimal-access video-assisted retroperitoneal debridement has advantage and some minor disadvantage.Delayed minimal-access video-assisted retroperitoneal debridement is recommended.

Background: Anatomic liver resection is widely accepted as the optimal surgical treatment for hepatocellular carcinoma (HCC); however, the complexity of conventional operative methods limits their use. To explore the possibility of using modern techniques to achieve a simpler approach, we have evaluated ultrasound-guided segmental radiofrequency ablation (RFA) of the Glissonian pedicle before liver resection in a porcine model and in HCC patients., Methods: This study had 2 stages. First, we piloted anatomic liver resection using ultrasound-guided RFA of the segmental Glissonian pedicle in 6 Bama miniature pigs. Having found this technique safe and effective, we selected 21 HCC patients to treat with the same approach., Results: The pigs had no postoperative mortality or morbidity. Demarcation areas were apparent in all targeted segments. The mean length of segmental portal, arterial, and biliary tract branches ablated was 1.7, 1.4, and 1.6 cm, respectively. Human HCC operations consisted of 8 subsegmentectomies, 8 segmentectomies, and 5 multisegmentectomies. The procedure was feasible in all patients, with no mortality, morbidity, or need for blood transfusions. A demarcation area was apparent in all patients within 157 seconds of RF application for each target feeding vessel. The mean number of target feeding vessels was 2 (range, 1-7)., Conclusion: Our study demonstrates that ultrasound-guided RFA ablation of the segmental Glissonian pedicle is expedient, safe, and effective, and is suitable for resection of any hepatic segments or subsegments, from segments 2 to 8., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The effect of antigen specific immunotherapy (SIT) on asthma is supposed to be improved. Published data indicate that administration of probiotics alleviates allergic diseases. B cells play important roles in the pathogenesis of allergic diseases. This study aims to modulate antigen specific B cell property by the administration of Clostridium butyrate (CB) in combination with SIT. The results showed that after a 3-month treatment, the total asthma clinical score and serum specific IgE were improved in the patients treated with SIT, which was further improved in those treated with both SIT and CB, but not in those treated with CB alone. Treatment with SIT and CB increased p300 and STAT3 activation, up regulated the IL-10 gene transcription and increased the frequency of peripheral antigen specific B cells. In conclusion, administration with SIT in combination with CB converts Der p 1 specific B cells to regulatory B cells in asthma patients allergic to Der p 1. The data suggest a potential therapeutic remedy in the treatment of allergic diseases.

Background: This study aims to explore the morbidity and risk factors of delayed gastric emptying (DGE) following pancreaticoduodenectomy., Methods: Between 1 January 2013 and 31 December 2013, data from 196 consecutive patients who underwent pancreaticoduodenectomy in the Chinese PLA General Hospital were recorded retrospectively. A total of 17 factors were examined with univariate analysis, and multivariate logistic regression analysis was used to estimate relative risks., Results: DGE occurred in 71 patients (36.2%). The incidence rates of grade A, grade B and grade C DGE were 22.4% (44/196), 6.1% (12/196) and 7.7% (15/196), respectively. There were three post-operative deaths for the entire series, with an overall mortality rate of 1.5%. Braun enteroenterostomy, clinically relevant post-operative pancreatic fistula (CR-POPF) and intra-abdominal collection correlated with DGE rates significantly in univariate analysis, whereas CR-POPF and intra-abdominal collection were independent risk factors in multivariate logistic regression analysis. Body mass index ≥25 kg/m(2) , CR-POPF and intra-abdominal collection correlated with clinically relevant DGE rates significantly and were independent risk factors in univariate analysis and multivariate regression., Conclusion: Only post-operative complications instead of operative methods were associated with DGE. Early diagnosis and timely treatment for pancreatic fistula and intra-abdominal collection were helpful to decrease morbidity and promote recovery of DGE., (© 2014 The Authors ANZ Journal of Surgery published by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Surgeons.)

Aim: To determine the potential protective role of adiponectin in intestinal ischemia reperfusion (I/R) injury., Methods: A rat model of intestinal I/R injury was established. The serum level of adiponectin in rats with intestinal I/R injury was determined by enzyme-linked immunosorbent assay (ELISA). The serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were also measured by ELISA. Apoptosis of intestinal cells was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The production of malondialdehyde (MDA) and superoxide dismutase (SOD) and villous injury scores were also measured., Results: Adiponectin was downregulated in the serum of rats with intestinal I/R injury compared with sham rats. No significant changes in the expression of adiponectin receptor 1 and adiponectin receptor 2 were found between sham and I/R rats. Pre-treatment with recombinant adiponectin attenuated intestinal I/R injury. The production of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, in rats with intestinal I/R injury was reduced by adiponectin pre-treatment. The production of MDA was inhibited, and the release of SOD was restored by adiponectin pre-treatment in rats with intestinal I/R injury. Adiponectin pre-treatment also inhibited cell apoptosis in these rats. Treatment with the AMP-activated protein kinase (AMPK) signaling pathway inhibitor, compound C, or the heme oxygenase 1 (HO-1) inhibitor, Snpp, attenuated the protective effects of adiponectin against intestinal I/R injury., Conclusion: Adiponectin exhibits protective effects against intestinal I/R injury, which may involve the AMPK/HO-1 pathway.

Objective: Pancreatic neuroendocrine tumors (PanNETs) are a small subgroup of tumors with a variety of biological behaviors., Materials and Methods: We sought to identify the specially expressed genes and characterize significant pathways in PanNETs compared with non-neoplastic samples. Gene expression profile GSE43795 was obtained from Gene Expression Omnibus database, which included 6 PanNETs and 5 non-neoplastic samples. The differentially expressed genes (DEGs) were identified using Limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions and pathways of DEGs. Transcription factors (TFs) and tumor-associated genes (TAGs) were also identified. Finally, a protein-protein interaction (PPI) network was constructed, and hub proteins and functional module were screened out., Results: Total of 821 DEGs (421 down-regulated, 400 up-regulated) were selected. GO and KEGG enrichment analyses showed that up-regulated DEGs were related to several pathways, including type 2 diabetes mellitus, Ca2+ signaling pathway, long-term potentiation, and long-term depression pathways. Down-regulated DEGs were enriched in several pathways, such as pancreatic secretion, protein digestion and absorption, and metabolic pathway. Interferon-stimulated gene protein 15 (ISG15), somatostatin (SST), and synaptosomal-associated protein 25 kDa (SNAP25) were identified as hub proteins., Conclusions: The genes involved in type 2 diabetes mellitus pathway may play important roles in the development of PanNETs. SNAP25, SST, and ISG15 may be used as potential targets for treatment of PanNETs.

Aim: To establish a scoring system to predict clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD)., Methods: The clinical records of 921 consecutive patients who underwent PD between 2008 and 2013 were reviewed retrospectively. Postoperative pancreatic fistula (POPF) was defined and classified by the international study group of pancreatic fistula (ISGPF). We used a logistic regression model to determine the independent risk factors of CR-POPF and developed a scoring system based on the regression coefficient of the logistic regression model. The optimal cut-off value to divide the risk strata was determined by the Youden index. The patients were divided into two groups (low risk and high risk). The independent sample t test was used to detect differences in the means of drain amylase on postoperative day (POD) 1, 2 and 3. The optimal cut-off level of the drain amylase to distinguish CR-POPF from non-clinical POPF in the two risk strata groups was determined using the receiver operating characteristic (ROC) curves., Results: Grade A POPF occurred in 106 (11.5%) patients, grade B occurred in 57 (6.2%) patients, and grade C occurred in 32 (3.5%) patients. A predictive scoring system for CR-POPF (0-6 points) was constructed using the following four factors: 1 point for each body mass index ≥ 28 [odds ratio (OR) = 3.86; 95% confidence interval (CI): 1.92-7.75, P = 0.00], soft gland texture (OR = 4.50; 95%CI, 2.53-7.98, P = 0.00), and the difference between the blood loss and transfusion in operation ≥ 800 mL (OR = 3.45; 95%CI, 1.92-7.75, P = 0.00); and from 0 points for a 5 mm or greater duct diameter to 3 points for a less than 2 mm duct (OR = 8.97; 95%CI: 3.70-21.77, P = 0.00). The ROC curve showed that the area under the curve of this score was 0.812. A score of 3 points was suggested to be the best cut-off value (Youden index = 0.485). In the low risk group, a drain amylase level ≥ 3600 U/L on POD3 could distinguish CR-POPF from non-clinical POPF (the sensitivity and specificity were 75% and 85%, respectively). In the high risk group, the best cut-off was a drain amylase level of 1600 (the sensitivity and specificity were 77 and 63%, respectively)., Conclusion: A 6-point scoring system accurately predicted the occurrence of CR-POPF. In addition, a drain amylase level on POD3 might be a predictor of this complication.

Objective: To compare compensatory sweating after lowering or restricting the level of sympathectomy., Method: A systematic review and meta-analysis were conducted of all randomized controlled trials published in English that compared compensatory sweating after lowering or restricting the level of sympathectomy. The Cochrane collaboration tool was used to assess the risk of bias, and the Mantel-Haenszel odds ratio method was used for the meta-analysis., Results: A total of 11 randomized controlled trials were included, including a total of 1079 patients. Five of the randomized controlled trials studied restricting the level of sympathectomy, and the remaining six studied lowering the level of sympathectomy., Conclusions: The compiled randomized controlled trial results published so far in the literature do not support the claims that lowering or restricting the level of sympathetic ablation results in less compensatory sweating.

Background: The aim of this study was to evaluate the safety, feasibility, and efficacy of a new segmental hepatectomy (SH) approach using intraoperative ultrasound (IOUS) guided infusion of a reversible thermosensitive gel into the portal vein branch in pigs;, Materials and Methods: Poloxamer 407 aqueous solution (20%, W/V) was mixed with indocyanine green (P407-ICG) in this study to make it green, and it remained liquid at room temperature and turned into a firm gel upon reaching body temperature. In experiment I, six pigs were used to detect the outcome of infusing the mixture into the biliary tract, liver parenchyma, and hepatic vein for a safety study. In experiment II, another 12 pigs were randomly segmented into two groups [SH group and partial hepatectomy (PH) group] to investigate the feasibility and efficacy of the new approach using IOUS-guided infusion of the mixture into the portal branch;, Results: No thermosensitive gel-induced abnormal changes were observed in the safety study. In the SH group, IOUS-guided infusion of the P407-ICG solution was effective in occluding the portal blood temporarily and demarcating the target liver segment to achieve precise SH. The blood loss in the SH group was significantly less than that of the PH group;, Conclusions: SH assisted by IOUS-guided infusion of the reversible thermosensitive gel into the feeding portal vein branches is feasible, safe, simple, and effective.

Previously known as a first-response protein upon viral infection and other stress signals, double-stranded RNA-dependent protein kinase (PKR, also termed EIF2AK2) has been found to be differentially expressed in multiple types of tumor, including hepatocellular carcinoma, suggesting that PKR may be involved in tumor initiation and development. However, whether and how PKR promotes or suppresses the development of hepatocellular carcinoma remains controversial. In the present study, PKR expression was investigated using qPCR and western blot analysis, which revealed that PKR expression was upregulated in liver tumor tissues, when compared to that of adjacent normal tissues, which were obtained from four primary liver cancer patients. Furthermore, in vitro cellular assays revealed that PKR exerts a key role in maintaining the proliferation and migration of HepG2 human hepatocellular carcinoma cells. Mouse models with xenograft transplantations also confirmed a tumorigenic role of PKR in HepG2 cells. Furthermore, a transcription factor, signal transducer and activator of transcription 3 (STAT3), was revealed to mediate the tumor-promoting function of PKR in HepG2 cells, as shown by in vitro cellular proliferation and migration assays. In conclusion, the results suggested a tumorigenic role of PKR in liver cancer and a detailed mechanism involving an oncogenic transcription factor, STAT3, is described. Therefore, PKR may present a potential novel therapeutic target for the treatment of liver cancer.

Background/aims: Colorectal cancer (CRC) is one of the most common malignancies, and liver metastasis is one of the major causes of death of CRC. This study aimed to compare the genetic difference between metachronous lesions (MC) and synchronous lesions (SC) and explore the molecular pathology of CRC metastasis., Methodology: Microarray expression profile data (GSE10961) including 8 MC and 10 SC was downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between the two groups were identified based on T test. Furthermore, GO enrichment analysis was performed for the down-regulated DEGs using DAVID. Finally, Classify validation of known CRC genes based on previous studies between MC and SC samples was conducted., Results: Total of 36 DEGs including 35 down-regulated DEGs and 1 up-regulated DEGs were identified. The expressional differences of the 5 informative oncogenes: EGFr, PIK3R1, PTGS2 (COX-2), PTGS1 (COX1), and ALOX5AP between SC and MC were really tiny., Conclusions: Some DEGs, such as NFAT5, OLR1, ERAP2, HOXC6 and TWIST1 might play crucial roles in the regulation of CRC metastasis (both SC and MC) and by disrupting some pathways. However, our results indeed demand further research and experiment.

Background: Post-pancreaticoduodenectomy (PD) hemorrhage (PPH) is an uncommon but serious complication. This retrospective study analyzed the risk factors, managements and outcomes of the patients with PPH., Methods: A total of 840 patients with PD between 2000 and 2010 were retrospectively analyzed. Among them, 73 patients had PPH: 19 patients had early PPH and 54 had late PPH. The assessment included the preoperative history of disease, pancreatic status and surgical techniques. Other postoperative complications were also evaluated., Results: The incidence of PPH was 8.7% (73/840). There were no independent risk factors for early PPH. Male gender (OR=4.40, P=0.02), diameter of pancreatic duct (OR=0.64, P=0.01), end-to-side invagination pancreaticojejunostomy (OR=5.65, P=0.01), pancreatic fistula (OR=2.33, P=0.04) and intra-abdominal abscess (OR=12.19, P<0.01) were the independent risk factors for late PPH. Four patients with early PPH received conservative treatment and 12 were treated surgically. As for patients with late PPH, the success rate of medical therapy was 27.8% (15/54). Initial endoscopy was operated in 12 patients (22.2%), initial angiography in 19 (35.2%), and relaparotomy in 15 (27.8%). Eventually, PPH resulted in 19 deaths. The main causes of death were multiple organ failure, hemorrhagic shock, sepsis and uncontrolled rebleeding., Conclusions: Careful and ongoing observation of hemorrhagic signs, especially within the first 24 hours after PD or within the course of pancreatic fistula or intra-abdominal abscess, is recommended for patients with PD and a prompt management is necessary. Although endoscopy and angiography are the standard procedures for the management of PPH, surgical approach is still irreplaceable. Aggressive prevention of hemorrhagic shock and re-hemorrhage is the key to treat PPH.

DNA methylation has an important role in the development of carcinomas. As a metastasis suppressor gene, Raf kinase inhibitory protein (RKIP) suppresses tumor cell invasion and metastasis. In the present study, the associations between RKIP protein expression and promoter methylation with clinicopathological parameters, prognosis and survival rates in gastric adenocarcinoma were investigated. RKIP protein expression and promoter methylation were measured in 135 cases of surgically resected gastric adenocarcinoma specimens and corresponding normal tissues using immunohistochemistry and methylation-specific polymerase chain reaction, respectively. Kaplan-Meier analyses were performed to analyze the patient survival rate. Prognostic factors were determined using multivariate Cox analysis. RKIP promoter methylation was detected in 48.9% of gastric carcinoma tissues and 5.17% of adjacent tissues (P<0.05). RKIP protein expression was detected in 43.0% of gastric carcinoma tissues and 91.1% of adjacent tissues (P<0.05). The protein expression levels and promoter methylation of RKIP were shown to correlate with pathological staging, Union for International Cancer Control-stage, tumor differentiation and lymph node metastasis (P<0.05). In addition, the protein expression of RKIP in gastric carcinomas was demonstrated to be associated with promoter methylation of RKIP. Survival analysis of gastric carcinoma patients revealed that promoter methylation in RKIP-positive tumors correlated with a significantly shorter survival time when compared with RKIP-negative tumors (P=0.0002, using the log-rank test). Using multivariate Cox analysis, promoter methylation of RKIP was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression. Downregulation of RKIP expression was shown to correlate with the incidence and development of gastric carcinomas. Thus, abnormal promoter methylation of RKIP may be a valuable biomarker for estimating gastric carcinoma prognosis.

Objective: To investigate the cytotoxicity of normal CD8(+) T lymphocytes retrovirally transduced with WT1 peptide-specific T-cell receptor (TCR) genes against human lung cancer cells., Methods: HLA-A*2402-restricted and WT1 peptide-specific TCR-α/β genes were cloned from a cytotoxic T lymphocyte clone and inserted into a retroviral TCR expression vector. The cytotoxicity of normal peripheral CD8⁺ T cells transduced with the WT1-TCR genes against human lung cancer cells was evaluated using a standard ⁵¹Cr release assay., Results: The WT1-TCR gene-modified T cells recognized the peptide-pulsed target cells but not the non-pulsed cells. TCR-redirected CD8⁺ T cells lysed WT1-overexpressing human lung cancer cells in an HLA-A*2402-restricted manner, but did not kill normal cells positively expressing HLA-A*2402., Conclusion: These data demonstrate the feasibility of adoptive immunotherapy with TCR-redirected T cell for the treatment of lung cancer.

The current study explored the effects of intensive insulin therapy (IIT) combined with low molecular weight heparin (LMWH) anticoagulant therapy on severe acute pancreatitis (SAP). A total of 134 patients with SAP that received treatment between June 2008 and June 2012 were divided randomly into groups A (control; n=33), B (IIT; n=33), C (LMWH; n=34) and D (IIT + LMWH; n=34). Group A were treated routinely. Group B received continuous pumped insulin, as well as the routine treatment, to maintain the blood sugar level between 4.4 and 6.1 mmol/l. Group C received a subcutaneous injection of LMWH every 12 h in addition to the routine treatment. Group D received IIT + LMWH and the routine treatment. The white blood cell count, hemodiastase, serum albumin, arterial partial pressure of oxygen and prothrombin time were recorded prior to treatment and 1, 3, 5, 7 and 14 days after the initiation of treatment. The intestinal function recovery time, incidence rate of multiple organ failure (MOF), length of hospitalization and fatality rates were observed. IIT + LMWH noticeably increased the white blood cell count, hemodiastase level, serum albumin level and the arterial partial pressure of oxygen in the patients with SAP (P<0.05). It markedly shortened the intestinal recovery time and the length of stay and reduced the incidence rate of MOF, the surgery rate and the fatality rate (P<0.05). It did not aggravate the hemorrhagic tendency of SAP (P>0.05). IIT + LMWH had a noticeably improved clinical curative effect on SAP compared with that of the other treatments.

The roots of metallophytes serve as the key interface between plants and heavy metal-contaminated underground environments. It is known that the roots of metallicolous plants show a higher activity of acid invertase enzymes than those of non-metallicolous plants when under copper stress. To test whether the higher activity of acid invertases is the result of increased expression of acid invertase genes or variations in the amino acid sequences between the two population types, we isolated full cDNAs for acid invertases from two populations of Kummerowia stipulacea (from metalliferous and non-metalliferous soils), determined their nucleotide sequences, expressed them in Pichia pastoris, and conducted real-time PCR to determine differences in transcript levels during Cu stress. Heterologous expression of acid invertase cDNAs in P. pastoris indicated that variations in the amino acid sequences of acid invertases between the two populations played no significant role in determining enzyme characteristics. Seedlings of K. stipulacea were exposed to 0.3µM Cu(2+) (control) and 10µM Cu(2+) for 7 days under hydroponics׳ conditions. The transcript levels of acid invertases in metallicolous plants were significantly higher than in non-metallicolous plants when under copper stress. The results suggest that the expression of acid invertase genes in metallicolous plants of K. stipulacea differed from those in non-metallicolous plants under such conditions. In addition, the sugars may play an important role in regulating the transcript level of acid invertase genes and acid invertase genes may also be involved in root/shoot biomass allocation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (AC) is one of the most deadly malignancies. The disease has a low five-year survival rate; therefore, the identification of novel therapeutic agents is required. This study aimed to investigate the effect of small interfering RNA (siRNA) targeting hypoxia‑inducible factor 1α (HIF‑1α) on the growth of AC A549 cells. A549 cells were transfected with various concentrations of HIF‑1α or control siRNA, and the effect on HIF‑1α expression was analyzed using quantitative polymerase chain reaction and western blot analysis. The effects of HIF-1α siRNA on growth inhibition and apoptosis were then assessed using standard methods. HIF‑1α siRNA treatment significantly reduced HIF‑1α mRNA and protein expression in A549 cells. Furthermore, the downregulation of HIF-1α expression inhibited the growth of A549 cells and induced apoptosis of A549 cells by upregulating caspase-3 expression. The present in vitro study demonstrates that the downregulation of HIF‑1α is capable of suppressing AC A549 cell growth, through the induction of apoptosis. This suggests that HIF‑1α inhibition may represent a promising strategy for the treatment of AC.

Sucrose metabolism in roots of metallophytes is very important for root growth and maintenance of heavy metal tolerance. However, rare researches have been carried out on this topic so far. We tested here a hypothesis that roots of copper-tolerant plants should manifest higher activities of sucrose-cleaving enzymes than non-tolerant plants for maintaining root growth under Cu stress. Plants of two contrasting populations of metallophyte Rumex dentatus, one from an ancient Cu mine (MP) and the other from a non-mine site (NMP), were treated with Cu in controlled experiments. Cu treatment resulted in a higher root biomass and root/shoot biomass ratio in MP compared to NMP. More complicated root system architecture was showed in MP under Cu stress. Activities and transcript levels of acid invertase as well as contents of sucrose and reducing sugar in MP were elevated under Cu treatment, while activities of neutral/alkaline invertase and sucrose synthase showed no significant differences between two populations. The results indicate important roles of acid invertase in governing root growth under Cu stress.

Objective: To evaluate the effectiveness of dynamic SPECT (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy on the assessment of reserve function of cirrhosis liver., Methods: From January 2010 to December 2011, 55 patients with cirrhosis liver were enrolled in this study. The case numbers of male and female were 43 and 12 respectively and the age was (51 ± 9) years (ranging from 35 to 69 years). After routine biochemistry test, CT scan and (99m)Tc-GSA dynamic SPECT scan were performed in turn using a juxtaposed SPECT/CT system. Then the morphologic volume of liver parenchyma (MLV), functional liver volume (FLV) and the hepatic cell absorption rate constant (GSA-K) were calculated. The correlations between GSA-K and routine biochemistry test, Child-Pugh score, indocyanine green clearance rate (ICG-K) were analyzed. The patients were further divided into 3 groups according to whether there was occlusion or stenosis in the main branch of left portal vein (group 1, n = 5), right portal vein (group 2, n = 13) or not (group 3, n = 37) and the regional hepatic functions index of the 3 groups were compared., Results: The value of FLV of the whole, left and right liver was (594 ± 152) ml, (244 ± 119) ml and (356 ± 171) ml, respectively. There were correlations between GSA-K and total bilirubin, prothrombintime, Child-Pugh score and ICG-K (r = -0.730--0.298, P < 0.05). The FLV and MLV ratios of involved hemiliver to uninvolved hemiliver were 0.09 ± 0.06 and 0.30 ± 0.14 in group 1, 0.57 ± 0.43 and 1.08 ± 0.63 in group 2, 0.71 ± 0.30 and 0.71 ± 0.48 in group 3. The difference in MLV-FLV ratio was signifcant between group 1 and group 3, between group 2 and group 3 (P = 0.000)., Conclusions: The dynamic SPCECT (99m)Tc-GSA scintigraphy can not only assess the whole liver function of cirrhosis liver effectively, but also evaluate the variation of regional liver function accurately.

Background: Liver surgery has gone through the phases of wedge liver resection, regular resection of hepatic lobes, irregular and local resection, extracorporeal hepatectomy, hemi-extracorporeal hepatectomy and Da Vinci surgical system-assisted hepatectomy. Taking advantage of modern technologies, liver surgery is stepping into an age of precise liver resection. This review aimed to analyze the comprehensive application of modern technologies in precise liver resection., Data Source: PubMed search was carried out for English-language articles relevant to precise liver resection, liver anatomy, hepatic blood inflow blockage, parenchyma transection, and down-staging treatment., Results: The 3D image system can imitate the liver operation procedures, conduct risk assessment, help to identify the operation feasibility and confirm the operation scheme. In addition, some techniques including puncture and injection of methylene blue into the target Glisson sheath help to precisely determine the resection. Alternative methods such as Pringle maneuver are helpful for hepatic blood inflow blockage in precise liver resection. Moreover, the use of exquisite equipment for liver parenchyma transection, such as cavitron ultrasonic surgical aspirator, ultrasonic scalpel, Ligasure and Tissue Link is also helpful to reduce hemorrhage in liver resection, or even operate exsanguinous liver resection without blocking hepatic blood flow. Furthermore, various down-staging therapies including transcatheter arterial chemoembolization and radio-frequency ablation were appropriate for unresectable cancer, which reverse the advanced tumor back to early phase by local or systemic treatment so that hepatectomy or liver transplantation is possible., Conclusions: Modern technologies mentioned in this paper are the key tool for achieving precise liver resection and can effectively lead to maximum preservation of anatomical structural integrity and functions of the remnant liver. In addition, large randomized trials are needed to evaluate the usefulness of these technologies in patients with hepatocellular carcinoma who have undergone precise liver resection.

Background: In the present study, we compared preservation of the hepatic artery flow during liver blood inflow occlusion with total portal triad blood flow clamping (the Pringle maneuver) to examine their effects on liver regeneration in rats after partial hepatectomy., Materials and Methods: Male Wistar rats were randomized to a control group (without hepatic inflow occlusion), an occlusion of the portal triad (OPT) group (OPT for 30 min under portal blood bypass), and an occlusion of the portal vein (OPV) group (OPV only for 30 min under portal blood bypass). All the rats underwent partial hepatectomy at the end of hepatic blood control. Liver regeneration was assessed on days 3 and 7 after hepatectomy. Liver damage, extracellular signal-regulated kinase-1/2 activation, and cytokine expression of the remnant liver in the first 24 h after hepatectomy were also assessed., Results: Significantly greater liver regeneration, at a level similar to that of the control group, as indicated by the percentage of the initial liver weight, proliferating cell nuclear antigen and Ki-67 labeling indexes, and technetium-99m galactosyl human serum albumin liver uptake, was observed in the OPV group on day 3 after hepatectomy (P < 0.05 versus the OPT group). Liver damage, as represented by alanine aminotransferase and aspartate aminotransferase measurement and histopathologic examination, was substantially alleviated in the OPV group compared with the OPT group. In contrast to the control and OPV groups, the OPT group had markedly increased extracellular signal-regulated kinase-1/2 activation, heat shock protein 70, and interleukin-6 expression in response to ischemia and partial hepatectomy., Conclusions: Our results have indicated that compared with the Pringle maneuver, clamping the portal vein while preserving the hepatic artery flow during partial hepatectomy is better for remnant liver regeneration at an early posthepatectomy stage., (Copyright © 2013 Elsevier Inc. All rights reserved.)