The increase of long noncoding RNA Fendrr in hepatocytes contributes to liver fibrosis by promoting IL-6 production.

Liver fibrosis/cirrhosis is a pathological state caused by excessive extracellular matrix deposition. Sustained activation of hepatic stellate cells (HSC) is the predominant cause of liver fibrosis, but the detailed mechanism is far from clear. In this study, we found that long noncoding RNA Fendrr is exclusively increased in hepatocytes in the murine model of CCl4- and bile duct ligation-induced liver fibrosis, as well as in the biopsies of liver cirrhosis patients. In vivo, ectopic expression of Fendrr aggravated the severity of CCl4-induced liver fibrosis in mice. In contrast, inhibiting Fendrr blockaded the activation of HSC and ameliorated CCl4-induced liver fibrosis. Our mechanistic study showed that Fendrr binds to STAT2 and enhances its enrichment in the nucleus, which then promote the expression of IL-6, and, ultimately, activates HSC in a paracrine manner. Accordingly, disrupting the interaction between Fendrr and STAT2 by ectopic expression of a STAT2 mutant attenuated the pro-fibrotic response inspired by Fendrr in the CCl4-induced liver fibrosis. Notably, the increase of Fendrr in patient fibrotic liver is positively correlated with the severity of fibrosis and the expression of IL-6. Meanwhile, hepatic IL-6 positively correlates with the extent of liver fibrosis and HSC activation as well, thus suggesting a causative role of Fendrr in HSC activation and liver fibrosis. In conclusion, these observations identify an important regulatory crosstalk between hepatocyte Fendrr and HSC activation in the progression of liver fibrosis, which might represent a potential strategy for therapeutic intervention.

A hypotensive protocol of inspiratory muscle strength training: Systematic review and meta-analysis with trial sequential analysis.

The aim of this study was to evaluate the hypotensive effect and optimal protocol of inspiratory muscle resistance training (IMST). Randomized controlled trials using IMST to lower blood pressure (BP) were retrieved from 12 databases as of July 2022. A meta-analysis of BP and heart rate variability (HRV) was performed and a trial sequence analysis was performed using trial sequential analysis (TSA) software. Twelve articles (n = 386 participants) from five countries were included, with a mean quality score of 5.83. IMST achieved significant results in reducing systolic, diastolic, and mean arterial pressure (-7.93 [-12.08, -3.78]; -3.80 [-6.08, -1.53]; -4.90 [-13.76, 3.96]). Furthermore, TSA has shown that the findings for systolic and diastolic BP are conclusive. Finally, considerable variation remained between studies when analyzing HRV. The overall hypotensive effect of IMST was demonstrated by the TSA and was well tolerated in different populations. Of these, two interventions, high resistance or low resistance combined with slow breathing, showed the best efficacy under an 8-week exercise intervention. In addition, the process of lowering BP by modulating sympathetic vagal activity has not been further confirmed in this study. Future long-term interventions, especially those over 3 months, are needed to observe the prolonged antihypertensive effects and modulatory mechanisms; controlling for variables such as respiratory rate and executing more rigorous studies to further explore antihypertensive options.

Patient-reported outcome measures in functional dyspepsia: a systematic review and COSMIN analysis.

BACKGROUND: Functional dyspepsia (FD) as a type of disorders of brain-gut interaction (DBGI), patient self-reporting of its symptoms becomes an important component of clinical outcome assessment. We performed a systematic review using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines to identify the best available patient-reported outcome measure (PROM) of FD. METHODS: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched four databases with no date limit, looking for previously confirmed PROMs for evaluating FD symptoms. An overall rating was then assigned based upon COSMIN guidelines, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the level of evidence for psychometric properties of included PROMs. RESULTS: Thirty articles covering outcome indicators of 24 patient reports were included. The Leuven Postprandial Distress Scale (LPDS) showed adequate content validity and moderate quality evidence of adequate internal consistency to generate an A recommendation. CONCLUSION: LPDS is currently the most recommended PROM for patient self-reported FD symptoms. However, it fails to assess two important areas of cross-cultural validity/ measurement invariance and measurement error. Future research can be continuously improved on this basis.

Interventions for reducing blood pressure in prehypertension: A meta-analysis.

Background: We aimed to address which interventions best control blood pressure (BP) and delay disease progression in prehypertension and to give recommendations for the best option following a quality rating. Methods: A Bayesian network meta-analysis was used to assess the effect of the intervention on BP reduction, delaying hypertension progression and final outcome, with subgroup analyses for time and ethnicity. Recommendations for interventions were finally based on cumulative ranking probabilities and CINeMA. Results: From 22,559 relevant articles, 101 eligible randomized controlled trial articles (20,176 prehypertensive subjects) were included and 30 pharmacological and non-pharmacological interventions were evaluated. Moderate-quality evidence demonstrated that angiotensin II receptor blockers, aerobic exercise (AE), and dietary approaches to stop hypertension (DASH) lowered systolic blood pressure (SBP). For lowering diastolic blood pressure (DBP), AE combined with resistance exercise (RE) or AE alone provided high quality evidence, with calcium channel blockers, lifestyle modification (LSM) combined with drug providing moderate quality evidence. LSM produced the best BP lowering effect at 12 months and beyond of intervention. In Asians, TCD bubble was moderate quality evidence for lowering SBP and RE may have had a BP lowering effect in Caucasians. No recommendation can be given for delaying the progression of hypertension and reducing mortality outcomes because of low to very low quality of evidence. Conclusion: AE combined RE are preferentially recommended for BP control in prehypertension, followed by DASH. Long-term BP control is preferred to LSM. Asians and Caucasians add TCD bubble and RE to this list as potentially effective interventions. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022356302, identifier: CRD42022356302.

Correlation between Macrophage Polarization and PD-L1-Related Tumor Microenvironmental Alteration and Metastasis in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis; nearly 80% patients have regional or distant metastasis when diagnosed. Tumor microenvironment (TME) alteration and epithelial-to-mesenchymal transition (EMT) have been reported to play a key role in cancer metastasis. However, the correlation between TME and EMT was poorly studied in PDAC. This study aims to explore the correlation between EMT markers and TME alteration, mainly including macrophage polarization and PD-L1 expression change, in primary and metastatic PDAC tissues by immunohistochemistry. The results indicated that macrophage polarization was found in metastases with the number of M1 macrophages (CD86+) decreased and M2 (CD163+) increased, though PD-L1 expression did not have a significant alteration. Compared to primary tumors, E-cadherin was significantly lower, while snail was higher, while no difference was found with N-cadherin and ZEB1. Correlation analysis indicated that snail, but not ZEB1, E-cadherin, or N-cadherin, was highly correlated with macrophage polarization. To conclude, the number of CD86+ M1 macrophages was increased while CD163+ M2 macrophages decreased in metastases, with no significant alteration of PD-L1 expression compared to primary tumors. EMT markers-Snail and E-cadherin-but not ZEB1 or N-cadherin, were found to be higher/lower in metastases, which mean that EMT played an important role in PDAC metastasis. Further analysis indicated that snail was highly correlated with M1 to M2 macrophage polarization, which prompted that EMT may be one reason for macrophage polarization induced TME alteration in PDAC metastasis.

Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma: Where Do We Go?

The incidence of pancreatic ductal adenocarcinoma (PDAC) has been on the rise in recent years; however, its clinical diagnosis and treatment remain challenging. Although surgical resection remains the only chance for long-term patient survival, the likelihood of initial resectability is no higher than 20%. Neoadjuvant therapy (NAT) in PDAC aims to transform the proportion of inoperable PDACs into operable cases and reduce the likelihood of recurrence to improve overall survival. Ongoing phase 3 clinical trial aims to validate the role of NAT in PDAC therapy, including prolongation of survival, increased R0 resection, and a higher proportion of negative lymph nodes. Controversies surrounding the role of NAT in PDAC treatment include applicability to different stages of PDAC, chemotherapy regimens, radiation, duration of treatment, and assessment of effect. This review aims to summarize the current progress and controversies of NAT in PDAC.

Nutrient Deprivation Coupled with High Light Exposure for Bioactive Chrysolaminarin Production in the Marine Microalga Isochrysis zhangjiangensis.

Chrysolaminarin, a kind of water-soluble bioactive ß-glucan produced by certain microalgae, is a potential candidate for food/pharmaceutical applications. This study identified a marine microalga Isochrysis zhangjiangensis, in which chrysolaminarin production was investigated via nutrient (nitrogen, phosphorus, or sulfur) deprivations (-N, -P, or -S conditions) along with an increase in light intensity. A characterization of the antioxidant activities of the chrysolaminarin produced under each condition was also conducted. The results showed that nutrient deprivation caused a significant increase in chrysolaminarin accumulation, though this was accompanied by diminished biomass production and photosynthetic activity. -S was the best strategy to induce chrysolaminarin accumulation. An increase in light intensity from 80 (LL) to 150 (HL) µE·m-2·s-1 further enhanced chrysolaminarin production. Compared with -N, -S caused more suitable stress and reduced carbon allocation toward neutral lipid production, which enabled a higher chrysolaminarin accumulation capacity. The highest chrysolaminarin content and concentration reached 41.7% of dry weight (%DW) and 632.2 mg/L, respectively, under HL-S, with a corresponding productivity of 155.1 mg/L/day achieved, which exceeds most of the photoautotrophic microalgae previously reported. The chrysolaminarin produced under HL-N (Iz-N) had a relatively competitive hydroxyl radical scavenging activity at low concentrations, while the chrysolaminarin produced under HL-S (Iz-S) exhibited an overall better activity, comparable to the commercial yeast ß-glucan, demonstrating I. zhangjiangensis as a promising bioactive chrysolaminarin producer from CO2.

ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma.

This study aimed to clarify the role of Orosomucoid 1 (ORM1) in the development and therapy resistance in hepatocellular carcinoma (HCC). The mRNA expression level of ORM1 was analyzed via integrative analysis of Gene Express Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The protein expression level of ORM1 in our cohort was determined using immunohistochemistry. Correlation analysis was used to investigate the relationship between ORM1 expression and clinical parameters. The Cell Counting Kit-8 assay was used to clarify the role of ORM1 in HCC malignant behaviors, including cell growth and sorafenib sensitivity, in vitro. The results indicated that ORM1 was significantly downregulated in the hepatic cancer cells compared to that in the non-cancerous cells. However, it was upregulated in microvascular invasion samples, especially in the cancer embolus compared to that in the surrounding tumor cells. Though Kaplan-Meier analysis did not show an association of ORM1 expression with the overall survival rates of HCC patients, univariate analysis indicated that ORM1 expression was highly correlated with tumor grade and stage. An in vitro assay also revealed that downregulation of ORM1 led to the suppression of tumor growth and enhancement of sorafenib sensitivity without epithelial-to-mesenchymal transition (EMT) alteration, which was consistent with our bioinformatic analysis. Hence, ORM1 played a key role in HCC tumorigenesis and may serve as a potential target for the development of therapeutics against HCC in the future.

Safety and efficacy of S1 monotherapy or combined with nab-paclitaxel in advanced elderly pancreatic cancer patients: A meta-analysis.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of S1 monotherapy or combination with nab-paclitaxel for the treatment of elderly patients with metastatic or locally advanced pancreatic adenocarcinoma. METHOD: PubMed, Embase, Cochrane Central Library, China Biology Medicine, and China National Knowledge Infrastructure databases were searched without time limits according to the inclusion criteria. RevMan (Version 5.3) software was used for data extraction and meta-analysis. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate therapeutic effects while side effects including leukopenia, thrombocytopenia, neurotoxicity, vomit, and alopecia were extracted for evaluation. There was no need for ethical review in this study because no ethical experiments were conducted and all data used were public data. All relevant data are within the paper and its Supporting Information files. RESULTS: Four retrospective studies comprising 308 elderly patients with metastatic or locally advanced pancreatic adenocarcinoma were included in the analysis. One hundred fifty-one patients underwent S1 monotherapy and 157 received S1 combined nab-paclitaxel. Meta-analysis indicated that compared with S1 monotherapy, S1 combined with nab-paclitaxel had higher ORR (OR 2.25, 95% CI: 1.42-3.55; P = .0005) and DCR (OR 2.94, 95% CI: 1.55-5.58; P = .0009). The adverse reaction of leukopenia was higher in the combined therapy group (OR 1.85, 95% CI: 1.09-3.13, P = .02), but no significant difference was found in thrombocytopenia, neurotoxicity, vomiting, and alopecia between the 2 groups (P > .05). CONCLUSION: Nab-paclitaxel plus S1 was more efficient in terms of ORR and DCR than S1 monotherapy in elderly pancreatic ductal adenocarcinoma patients while the side effect was controllable with a higher probability of leukopenia. Thus, combined nab-paclitaxel and S1 could be safely used in elderly patients.

A Novel Sox9/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis.

Sox9 has been previously characterized as a transcription factor responsible for the extracellular matrix production during liver fibrosis. However, the deregulation and functional role of hepatocyte Sox9 in the progression of liver fibrosis remains elusive. Here, we found a significant increase of Sox9 in the hepatocytes isolated from CCl4-induced fibrotic liver and showed that antisense oligoribonucleotides depletion of Sox9 was sufficient to attenuate CCl4-induced liver fibrosis. Notably, the increase of Sox9 in hepatocyte was associated with the upregulation of long noncoding RNA H19 in both in vitro and in vivo systems. Mechanistic studies revealed that Sox9 induced H19 by binding to a conserved promoter region of H19. In vitro, hepatocyte injury triggered the increase of Sox9/H19 axis, whereas silence of H19 greatly alleviated the H2O2-induced hepatocyte apoptosis, suggesting that H19 functions as a downstream effector of Sox9 signaling and is involved in hepatocyte apoptosis. In animal experiments, inhibition of H19 alleviated the activation of hepatic stellate cells and reduced the extent of liver fibrosis, whereas ectopic expression of H19 abolished the inhibitory effects of Sox9 depletion on liver fibrosis, suggesting that the profibrotic effect of hepatocyte Sox9 depends on H19. Finally, we investigated the clinical relevance of Sox9/H19 axis to liver fibrosis and identified the increase of Sox9/H19 axis in liver cirrhosis patients. In conclusion, our findings link Sox9/H19 axis to the intrinsic mechanisms of hepatocyte apoptosis and may represent a hitherto unknown paradigm in hepatocyte injury associated with the progression of liver fibrosis.

[Anatomic study on perforating branch flap of medial vastus muscle and its clinical application].

OBJECTIVE: To investigate the anatomic features of the perforating branch flap of the medial vastus muscle, so as to provide a new perforating branch flap for repairing the soft tissue defect. METHODS: Six fresh donated lower limb specimens underwent an intra-arterial injection of a lead oxide and lactoprene preparation. The integument of the thigh was dissected to observe the origin, course, size, and location of the perforating branch of the medial vastus muscle by angiography and photography. Based on the anatomic study, the free perforating branch flaps of the medial vastus muscle (14 cm x 6 cm to 20 cm x 5 cm) were used to repair skin and soft tissue defects (8 cm x 6 cm to 12 cm x 8 cm) of the feet in 4 patients between June 2009 and August 2011. RESULTS: The artery of the medial vastus was sent out constantly from the femoral artery, and then descended in the vastus muscle to lateral patella where it anastomosed with the terminal branches of lateral femoral circumflex artery to form prepatellar vascular network. The artery of the medial vastus sent out 3-5 musculocutaneous perforating branches into the deep fascia and then extended superficially to the overlying skin. Four flaps survived after surgery; wounds at the donor site and recipient site healed by first intention. After follow-up of 6-12 months, the flaps had good appearance and texture. All ankles had normal movement range of plantarflexion and dorsiflexion. CONCLUSION: The free perforating branch flaps of the medial vastus muscle can be harvested easily, and have the advantage of good texture and abundant donor site.