Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin‐33 ...(IL‐33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL‐33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL‐33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)‐treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL‐33. Gene expression analysis was used to identify IL‐33‐dependent regulators of ER stress and autophagy. Both db/db mice and PA‐treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL‐33. Treatment with IL‐33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3‐methyladenine (3‐MA) or wortmannin, abolished the protective effects of IL‐33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin‐like growth factor‐binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL‐33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL‐33. IL‐33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL‐33‐induced ER stress resolution and autophagic enhancement during DCM.
Interleukin‐33 (IL‐33) abates diabetic cardiomyopathy (DCM) by alleviating endoplasmic reticulum (ER) stress and promoting autophagy. Insulin‐like growth factor‐binding protein 3 is essential for IL‐33‐induced ER stress resolution and autophagic enhancement during DCM.
Abstract Underground coal seam mining significantly alters the stress and energy distribution within the overlying rock, leading to eventual structural degradation. Therefore, it is imperative to ...quantitatively identify the temporal and spatial characteristics of stress evolution of overlying rock caused by mining. This paper introduces a novel rock stress model integrating entropy and a spatial–temporal cube. Similar material model tests are used to identify the abrupt entropy changes within the mining rock, and the trend analysis is carried out to describe the spatial–temporal evolution law of stress during mining. Experimental findings indicate elevated stress levels in the unmined rock preceding and following the panel, as well as within specific rock strata above it. Definitively, dynamic stress arches within the surrounding rock of the stope predominantly bear and distribute the load and pressure from the overlying rock, and each stress mutation is accompanied by a sudden stress entropy change. Over time, z-score shows that the noticeable reduction in mining-induced overburden stress becomes increasingly pronounced, especially in the water-conducting fracture zone. The model's bifurcation set serves as the comprehensive criterion for the entropy-induced sudden changes in the rock system, signifying overall failure.
Background
Sodium picosulfate/magnesium citrate (SPMC) is a small-volume bowel cleansing agent with similar efficacy to and better tolerability than polyethylene glycol. However, we found no data on ...which SPMC preparation (same-day vs. split-dose) provides better bowel cleansing efficacy for afternoon colonoscopy.
Aims
To compare bowel cleansing efficacy of different timing of the regimen.
Methods
This randomized, single-center, endoscopist-blinded, noninferior study compared same-day and split-dose SPMC preparations for afternoon colonoscopy in 101 and 96 patients, respectively. We also included a prospective observation group of 100 patients receiving morning colonoscopy to compare bowel preparation between morning and afternoon colonoscopies. Bowel cleansing efficacy was then evaluated by the Aronchick Scale, Ottawa Bowel Preparation Scale (OBPS), Boston Bowel Preparation Scale (BBPS), and the Bubble Scale.
Results
Same-day and split-dose preparations were similar in efficacy in all four scales. In the Aronchick Scale, the success rate (excellent and good cleanliness) was higher in same-day preparation than in split-dose preparation (100% vs. 92.8%). The same-day preparation also obtained a better OBPS score (1.4 vs. 2.1), but BBPS showed no difference between such groups (7.7 vs. 7.4).
Conclusion
Same-day preparation with SPMC is not inferior to split-dose preparation for afternoon colonoscopy.
Chronic hepatitis B (CHB) relapse occurs after the cessation of nucleos(t)ide analogues (NUC) therapy due to the waning of viral suppression. Few studies have investigated the viral relapse rate and ...clinical relapse rate after tenofovir alafenamide (TAF) therapy. We compared the CHB relapse rate between TAF and entecavir therapy. We enrolled patients with chronic hepatitis B who underwent TAF or entecavir therapy. NUC therapy was terminated after HBeAg loss for 1 year in HBeAg-positive patients and after undetectable serum HBV DNA on three separate tests each >6 months apart in HBeAg-negative patients. After cessation of NUC therapy, we followed alanine aminotransferase (ALT) levels at 12, 24, and 48 weeks. Serum HBV DNA levels were checked if patients showed a two-fold elevation from the upper limit of normal ALT levels (41 IU/mL). Clinical relapse (CR) was defined as a two-fold elevation in ALT levels and HBV DNA levels > 2000 IU/mL. We then investigated the CR rate of HBV after cessation of TAF and entecavir therapy at 12, 24, and 48 weeks. Of the 117 patients enrolled, 78 were in the entecavir group and 39 were in the TAF group. At 12 weeks after cessation of NUC therapy, no patients had HBV CR in the entecavir group. However, three patients (CR cumulative rate 7.9%) had CR in the TAF group. At 24 weeks, the CR cumulative rate in the entecavir and TAF groups were 1.3% and 13.2%, respectively (
< 0.05). At 48 weeks, the CR cumulative rates were 9.2% and 24.2%, respectively (
= 0.055). Patients in the TAF group had a higher cumulative rate of CR than those in the entecavir group (log-rank
= 0.023). Furthermore, patients in the TAF group had earlier CR times than those in the entecavir group, especially in the first 24 weeks after cessation of therapies (
< 0.05). The cessation of TAF therapy had significantly earlier and higher CR rates than that of entecavir therapy. Close monitoring of liver function and HBV DNA levels may be necessary, especially within 24 weeks after cessation of TAF therapy.
This study builds a large database from an extensive survey of existing single-lap shear tests on fiber-reinforced polymer (FRP)-concrete interfacial bonds, comprising 969 test results. Twenty ...shear-bond strength models published over the past 20 years have been collected and analyzed. These models take into account the effects of the concrete compressive strength, concrete width, FRP elastic modulus, FRP thickness, FRP width and FRP bond length on the ultimate bond strength of the FRP-concrete interface. This paper evaluates the predictive accuracy of the 20 collected models and finds that these models have limited accuracy. To accurately predict the bond strength of the FRP-concrete interface, this paper employs the back propagation neural networks (BPNN) method to train and test the database and builds an artificial neural networks (ANN) model that consists of weighted values, biases and transfer functions. The ANN model test conducts 84 training iterations and selects the optimal combination of input nodes. The accuracy of the developed ANN model is higher (i.e., lower predictive error) than that of the existing bond strength models in the literature. Furthermore, this paper develops an explicit user-friendly formula based on the trained ANN model. The proposed formula estimates and validates the 969 bond strength results, and the predictions using the explicit equation fit the test data very well with small error. As such, the formula can be easily applied during practical designs instead of the implicit processes in the ANN model.
Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, ...the relationship between radiographic and histopathological response remains unclear.
We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples.
We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy.
In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in ...patients with poor performance status (PS greater than or equai to 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR-mutation-positive (EGFRm+) NSCLC patients with PS greater than or equai to 2. Methods The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients' clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy. Results Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p = 0.044; OS: p = 0.061) and good disease control (p < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis (p = 0.036) and dose modification (reduction/interruption, p = 0.021) were predictors of disease control. Conclusion Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS. Keywords: Lung cancer, Afatinib, EGFR, TKI, Performance status
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via ...whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.
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