Analysis of the impact of ERAS-based respiratory function training on older patients' ability to prevent pulmonary complications after abdominal surgery.

BACKGROUND: In China, as the population grows older, the number of elderly people who have died from respiratory problems has increased. AIM: To investigate whether enhanced recovery after surgery (ERAS)-based respiratory function training may help older patients who had abdominal surgery suffer fewer pulmonary problems, shorter hospital stays, and improved lung function. METHODS: The data of 231 elderly individuals having abdominal surgery was retrospectively analyzed. Based on whether ERAS-based respiratory function training was provided, patients were divided into ERAS group (n = 112) and control group (n = 119). Deep vein thrombosis (DVT), pulmonary embolism (PE), and respiratory tract infection (RTI) were the primary outcome variables. Secondary outcome variables included the Borg score Scale, FEV1/FVC and postoperative hospital stay. RESULTS: The percentage of 18.75% of ERAS group participants and 34.45% of control group participants, respectively, had respiratory infections (P = 0.007). None of the individuals experienced PE or DVT. The ERAS group's median postoperative hospital stay was 9.5 d (3-21 d) whereas the control groups was 11 d (4-18 d) (P = 0.028). The Borg score decreased on the 4th d following surgery in the ERAS group compared to the 2nd d prior (P = 0.003). The incidence of RTIs was greater in the control group than in the ERAS group among patients who spent more than 2 d in the hospital before surgery (P = 0.029). CONCLUSION: ERAS-based respiratory function training may reduce the risk of pulmonary complications in older individuals undergoing abdominal surgery.

Identifying tumor immunity-associated molecular features in liver hepatocellular carcinoma by multi-omics analysis.

Background: Although current immunotherapies have achieved some successes for hepatocellular carcinoma (HCC) patients, their benefits are limited for most HCC patients. Therefore, the identification of biomarkers for promoting immunotherapeutic responses in HCC is urgently needed. Methods: Using the TCGA HCC cohort, we investigated correlations of various molecular features with antitumor immune signatures (CD8+ T cell infiltration and cytolytic activity) and an immunosuppressive signature (PD-L1 expression) in HCC. These molecular features included mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and pathways. Results: We found that the mutations of several oncogenes and tumor suppressor genes significantly correlated with reduced antitumor immune signatures, including TTN, CTNNB1, RB1, ZFHX4, and TP53. It indicates that these genes' mutations may inhibit antitumor immune responses in HCC. Four proteins (Syk, Lck, STAT5, and Caspase-7) had significant positive expression correlations with CD8+ T cell enrichment, cytolytic activity, and PD-L1 expression in HCC. It suggests that these proteins' expression could be useful biomarkers for the response to immune checkpoint inhibitors Similiarly, we identified other types of biomarkers potentially useful for predicting the response to ICIs, including miRNAs (hsa-miR-511-5p, 150-3p, 342-3p, 181a-3p, 625-5p, 4772-3p, 155-3p, 142-5p, 142-3p, 155-5p, 625-3p, 1976, 7702), many lncRNAs, and pathways (apoptosis, cytokine-cytokine receptor interaction, Jak-STAT signaling, MAPK signaling, PI3K-AKT signaling, HIF-1 signaling, ECM receptor interaction, focal adhesion, and estrogen signaling). Further, tumor mutation burden showed no significant correlation with antitumor immunity, while tumor aneuploidy levels showed a significant negative correlation with antitumor immunity. Conclusion: The molecular features significantly associated with HCC immunity could be predictive biomarkers for immunotherapeutic responses in HCC patients. They could also be potential intervention targets for boosting antitumor immunity and immunotherapeutic responses in HCC.

Dynamic metabolic profiles for HBeAg seroconversion in chronic hepatitis B (CHB) patients by gas chromatography-mass spectrometry (GC-MS).

Chronic hepatitis B (CHB) remains a major public health problem globally. HBeAg seroconversion is a vital hallmark for the improvement of CHB. The plasma metabolic profile has not been clear in CHB patients and searching metabolic candidates to represent HBeAg seroconversion is also difficult currently. In this study, CHB patients were recruited, followed and divided into the HBeAg-positive (HBeAg-pos.) group (n = 29) and the HBeAg-negative (HBeAg-neg.) group (n = 29) based on HBeAg seroconversion or not. The plasma metabolic profiles were measured by gas chromatography-mass spectrometry (GC-MS) at 0 week (0w), 24 weeks (24w) and 48 weeks (48w) after administration. The acquired data was analyzed using orthogonal partial least squares discriminate analysis (OPLS-DA) and the differential metabolites were further assessed by self and group comparison. No differences of age, gender and serological characteristics were observed between two groups at 0w and 48w separately. The OPLS-DA score plots depending on administration time displayed robust metabolic differences no matter HBeAg turned to be negative or not. According to VIP> 1.0, a total of 15 differential metabolites were same in the two groups, 7 differential metabolites (glycolic acid, D-talose, L-proline, L-(-)-arabitol, ethyl-alpha-D-glucopyranoside, L-leucine and dihydroxybutanoic acid) were derived from one group alone and considered as metabolic candidates. At 0w versus (vs.) 24w, only 3 of 7 candidates (L-proline, L-(-)-arabitol, dihydroxybutanoic acid) showed nonuniform in the two groups, while at 0w vs. 48w, all of them varied inconsistently. Conclusively the dynamic metabolic profiles assayed by GC-MS were different between CHB patients with and without HBeAg seroconversion. The 7 metabolic candidates probably had the ability to reflect the CHB progression for HBeAg seroconversion and 3 of them showed strong relationship with HbeAg seroconversion early.

lncRNA LUNAR1 accelerates colorectal cancer progression by targeting the miR­495­3p/MYCBP axis.

Colorectal cancer (CRC) is a tumor type characterized by high patient morbidity and mortality. It has been reported that long non­coding (lncRNA) LUNAR1 (LUNAR1) participates in the regulation of tumor progression, such as diffuse large B­cell lymphoma. However, its role and underlying mechanisms in CRC progression have not been elucidated. The present study was designed to investigate the underlying mechanisms by which LUNAR1 regulates CRC progression. RT­qPCR and Pearson's correlation analysis revealed that LUNAR1 was highly expressed and was negatively associated with the overall survival of CRC patients. Moreover, CCK­8, clone formation, wound­healing migration, Transwell chamber and FACs assay analyses showed that LUNAR1 knockdown inhibited CRC cell proliferation, migration and invasion, while accelerating cell apoptosis. Additionally, LUNAR1 was found to function as a sponge of miR­495­3p, which was predicted by TargetScan and confirmed by luciferase reporter assay. Furthermore, functional studies indicated that miR­495­3p overexpression inhibited CRC cell proliferation, migration and invasion, while accelerating cell apoptosis. In addition, bioinformatics and luciferase reporter assays showed that miR­495­3p was found to negatively target Myc binding protein (MYCBP), and functional research showed that LUNAR1 accelerated CRC progression via the miR­495­3p/MYCBP axis. In conclusion, LUNAR1 accelerates CRC progression via the miR­495­3p/MYCBP axis, indicating that LUNAR1 may serve as a prognostic biomarker for CRC patients.

Deciphering ion transporters, kinases and PDZ-adaptor molecules that mediate guanylate cyclase C agonist-dependent intestinal fluid loss in vivo.

BACKGROUND: The molecular basis for heat-stable Escherichia coli enterotoxin (STa) action and its synthetic analogue linaclotide is well understood at the enterocyte level. Pharmacologic strategies to prevent STa-induced intestinal fluid loss by inhibiting its effector molecules, however, have achieved insufficient inhibition in vivo. AIMS AND EXPERIMENTAL APPROACH: To investigate whether the currently discussed effector molecules and signaling mechanisms of STa/linaclotide-induced diarrhea have similar relevance in vivo than at the enterocyte level, we studied the effect of 10-7M of the STa analogue linaclotide on short circuit current (Isc) of chambered isolated jejunal mucosa, and on the in vivo action on fluid transport in a perfused segment of proximal jejunum of anesthetized mice. The selected mice were deficient of transport (NHE3, CFTR, Slc26a3/a6), adaptor (NHERF1-3), or signal transduction molecules [cGMP-dependent kinase II (GKII)] considered to be downstream effectors after STa/linaclotide binding to guanylate cyclase C (GCC). Selective NHE3 inhibition by tenapanor was also employed. KEY RESULTS, CONCLUSIONS AND IMPLICATIONS: The comparison allowed the separation of effectors for stimulation of electrogenic anion secretion and for inhibition of electrolyte/fluid absorption in response to STa/linaclotide. The cGKII-NHERF1-CFTR and cGKII-NHERF2-NHE3 interactions are indeed major effectors of small intestinal fluid loss downstream of GCC activation in vitro and in vivo, but 50% of the linaclotide-induced fluid loss in vivo, while dependent on CFTR activation and NHE3 inhibition, does not involve cGKII, and 30% does not depend on NHERF1 or NHERF2. A combined NHERF1 and NHERF2 inhibition appears nevertheless a good pharmacological strategy against STa-mediated fluid loss.

Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFα treatment in chronic DSS-induced colitis.

Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFα treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFα monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3+ T cells and CD68+ macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1ß and TNFα, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFα treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1ß and TNFα. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFα treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFα treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing. KEY MESSAGES: Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption. In DSS-induced colitis, anti-TNFα treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1ß and TNFα. In DSS-induced colitis, anti-TNFα treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes. In DSS-induced colitis, anti-TNFα treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function.

GSTP1 Ala114Val polymorphism and colorectal cancer risk: a meta-analysis.

Studies investigating the association between cytochrome glutathione S-transferase P1 (GSTP1) Ala114Val polymorphism and colorectal cancer (CRC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine databases. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for GSTP1 polymorphism and CRC were calculated in a fixed effects model (the Mantel-Haenszel method) and a random effects model (the DerSimonian and Laird method) when appropriate. The pooled ORs were performed for co-dominant model (ValVal vs. AlaAla, AlaVal vs. AlaAla), dominant model (ValVal + AlaVal vs. AlaAla), and recessive model (ValVal vs. AlaVal + AlaAla). This meta-analysis included seven case-control studies, which included 3,173 CRC cases and 3,323 controls. Overall, the variant genotypes (ValVal and AlaVal) of the Ala114Val were not associated with CRC risk when compared with the wild-type AlaAla homozygote. Similarly, no associations were found in the dominant and recessive models. When stratifying for ethnicity, Hardy-Weinberg equilibrium in controls, study sample size, and source of controls, a significantly increased risk was observed among Asians (AlaVal vs. AlaAla, OR=1.67, 95 % CI=1.08-2.59; dominant model, OR=1.74, 95 % CI=1.14-2.67). No heterogeneity or publication bias was found in the present study. This meta-analysis suggests that the GSTP1 Ala114Val polymorphism may not be associated with CRC risk, while the observed increase in risk of CRC may be due to small-study bias.

Mining predictive biomarker for neoadjuvant chemotherapy in gastric cancer by proteomics.

BACKGROUND/AIMS: In this study, we applied the SELDI-TOF-MS technique for the identification of gastric cancer-specific protein markers and sample SELDI protein profiling to distinguish gastric cancer patients of the efficacy of neoadjuvant chemotherapy from a no efficacy population. METHODOLOGY: Gastric tissue samples from 8 paired patients with gastric cancer, from whom clinical and histopathological data concerning patients and carcinomas were available, were analyzed. We scanned 8 paired samples (chemotherapy sensitive and insensitive) by SELDI-TOF-MS. RESULTS: The data generated 409 high sensitive and reproducibly peaks. From the distribution of the peaks, most of the detectable peaks are in the range from 3000-7000m/z. One potential protein at 7044m/z is Guanine nucleotide-binding protein (GBG7_Human 060262). CONCLUSIONS: In summary, we present novel differential expressed protein profile for neoadjuvant chemotherapy. This data set will help us to understand the mechanism for the chemotherapy resistance. Our data suggested the presence of GBG7 indicate patient will receive better prognosis of neoadjuvant chemotherapy.

Hepatitis B virus X protein disrupts DNA interstrand crosslinking agent mitomycin C induced ATR dependent intra-S-phase checkpoint.

Chronic infection of hepatitis B virus (HBV) is one of the major causes of hepatocellular carcinoma (HCC) in the world. The hepatitis B virus X protein (HBx) is implicated in HCC development, although its oncogenic role remains controversial. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progress, and DNA repair by directly or indirectly interacting with host factors. We constructed the HBx stably expressing HepG2 cell line to investigate the impact of HBx on intra-S-phase checkpoint induced by mitomycin C (MMC). The HBx transformed HepG2 cells are more sensitive to MMC treatment and showed defective radioresistant DNA synthesis compared to the control cell line transformed with empty vector. With DNA content assay, HBx transformed cells showed defective S phase arrest and a consequent G2/M arrest after MMC treatment. HBx impaired the ATR dependent phosphorylation of Chk1 and monoubiquitination of FANCD2. Overexpression of ATR reverted the MMC induced phenotype of Chk1 and FANCD2 in HBx transformed cells. The defect of intra-S-phase checkpoint resulted in accumulation of genomic instability. In conclusion, HBx disrupts intra-S-phase checkpoint induced by MMC through ATR-Chk1 and ATR-FANCD2 pathways.