Genetic interference with HvNotch provides new insights into the role of the Notch-signalling pathway for developmental pattern formation in Hydra.

The Notch-signalling pathway plays an important role in pattern formation in Hydra. Using pharmacological Notch inhibitors (DAPT and SAHM1), it has been demonstrated that HvNotch is required for head regeneration and tentacle patterning in Hydra. HvNotch is also involved in establishing the parent-bud boundary and instructing buds to develop feet and detach from the parent. To further investigate the functions of HvNotch, we successfully constructed NICD (HvNotch intracellular domain)-overexpressing and HvNotch-knockdown transgenic Hydra strains. NICD-overexpressing transgenic Hydra showed a pronounced inhibition on the expression of predicted HvNotch-target genes, suggesting a dominant negative effect of ectopic NICD. This resulted in a "Y-shaped" phenotype, which arises from the parent-bud boundary defect seen in polyps treated with DAPT. Additionally, "multiple heads", "two-headed" and "ectopic tentacles" phenotypes were observed. The HvNotch-knockdown transgenic Hydra with reduced expression of HvNotch exhibited similar, but not identical phenotypes, with the addition of a "two feet" phenotype. Furthermore, we observed regeneration defects in both, overexpression and knockdown strains. We integrated these findings into a mathematical model based on long-range gradients of signalling molecules underlying sharply defined positions of HvNotch-signalling cells at the Hydra tentacle and bud boundaries.

Effects of whaling and krill fishing on the whale-krill predation dynamics: bifurcations in a harvested predator-prey model with Holling type I functional response.

In the Antarctic, the whale population had been reduced dramatically due to the unregulated whaling. It was expected that Antarctic krill, the main prey of whales, would grow significantly as a consequence and exploratory krill fishing was practiced in some areas. However, it was found that there has been a substantial decline in abundance of krill since the end of whaling, which is the phenomenon of krill paradox. In this paper, to study the krill-whale interaction we revisit a harvested predator-prey model with Holling I functional response. We find that the model admits at most two positive equilibria. When the two positive equilibria are located in the region { ( N , P ) | 0 ≤ N < 2 N c , P ≥ 0 } , the model exhibits degenerate Bogdanov-Takens bifurcation with codimension up to 3 and Hopf bifurcation with codimension up to 2 by rigorous bifurcation analysis. When the two positive equilibria are located in the region { ( N , P ) | N > 2 N c , P ≥ 0 } , the model has no complex bifurcation phenomenon. When there is one positive equilibrium on each side of N = 2 N c , the model undergoes Hopf bifurcation with codimension up to 2. Moreover, numerical simulation reveals that the model not only can exhibit the krill paradox phenomenon but also has three limit cycles, with the outmost one crosses the line N = 2 N c under some specific parameter conditions.

Urban vs. rural: colorectal cancer survival and prognostic disparities from 2000 to 2019.

This study aimed to analyze the differences in colorectal cancer (CRC) survival between urban and rural areas over the past 20 years, as well as investigate potential prognostic factors for CRC survival in both populations. Using registry data from Surveillance, Epidemiology, and End Results (SEER) from 2000 to 2019, 463,827 CRC cases were identified, with 85.8% in urban and 14.2% in rural areas. The mortality of CRC surpassed its survival rate by the sixth year after diagnosis in urban areas and the fifth year in rural areas. Furthermore, the 5-year overall survival (OS) of CRC increased by 2.9-4.3 percentage points in urban and 0.6-1.5 percentage points in rural areas over the past two decades. Multivariable Cox regression models identified independent prognostic factors for OS and disease-specific survival (DSS) of CRC in urban and rural areas, including age over 40, Black ethnicity, and tumor size greater than 5 cm. In addition, household income below $75,000 was found to be an independent prognostic factor for OS and DSS of CRC in urban areas, while income below $55,000 was a significant factor for rural areas. In conclusion, this study found a notable difference in CRC survival between rural and urban areas. Independent prognostic factors shared among both rural and urban areas include age, tumor size, and race, while household income seem to be area-specific predictive variables. Collaboration between healthcare providers, patients, and communities to improve awareness and early detection of CRC may help to further advance survival rates.

Identification of oxeiptosis-associated lncRNAs and prognosis-related signature to predict the immune status in gastric cancer.

As a novel form of cell death, oxeiptosis is mainly caused by oxidative stress and has been defined to contribute to the cellular death program in cancer. However, the precise involvement of oxeiptosis-related long non-coding RNAs (lncRNAs) within gastric cancer (GC) remains elusive. Thus, our study was aimed to elucidate the pivotal effect of hub oxeiptosis-related lncRNAs on GC by comprehensively analyzing lncRNA and gene expression data obtained from The Cancer Genome Atlas (TCGA) database. Subsequently, we constructed a risk signature (risk-sig) using lncRNAs and further evaluated its prognostic significance. We successfully identified thirteen lncRNAs closely related with oxeiptosis that exhibited significant relevance to the prognosis of GC, forming the foundation of our meticulously constructed risk-sig. Notably, our clinical analyses unveiled a strong correlation between the risk-sig and crucial clinical parameters including overall survival (OS), gender, TNM stage, grade, M stage, and N stage among GC patients. Intriguingly, the diagnostic accuracy of this risk-sig surpassed that of conventional clinicopathological characteristics, underscoring its potential as a highly informative prognostic tool. In-depth mechanistic investigations further illuminated a robust association between this risk-sig and fundamental biological processes such as tumor stemness, immune cell infiltration, and immune subtypes. These findings provide valuable insights into the complex interplay between oxeiptosis-related lncRNAs and the intricate molecular landscape of GC. Ultimately, leveraging the risk scores derived from our comprehensive analysis, we successfully developed a nomogram that enables accurate prediction of GC prognosis. Collectively, our study established a solid foundation for the integration of thirteen hub oxeiptosis-related lncRNAs into a clinically applicable risk-sig, potentially revolutionizing prognostic assessment in GC and facilitating the development of innovative therapeutic strategies.

PERSISTENT SUBRETINAL FLUID AFTER VITRECTOMY FOR MACULAR HOLE-ASSOCIATED RETINAL DETACHMENT.

PURPOSE: To evaluate the incidence, associated factors, and outcome of persistent subretinal fluid (SRF) after vitrectomy for macular hole-associated retinal detachment (MHRD). METHODS: A total of 158 eyes from 156 patients with MHRD who achieved macular hole closure after primary vitrectomy were included in the analysis; persistent SRF was defined as the presence of SRF for more than 1 month after first surgery. Preoperative and postoperative parameters were analyzed for their relationship with SRF development. RESULTS: Persistent SRF was observed in 19 eyes (12.0% of 158) postoperatively. Seven eyes (36.8% of 19) with persistent SRF eventually displayed complete absorption during follow-up. Univariate analysis revealed that eyes with persistent SRF were statistically associated with internal limiting membrane inverted flap, duration of symptoms, tamponade (perfluoropropane/silicone oil: 14/5 vs. 35/104, P < 0.001), and MHRD subtype (Type 1/Type 2/Type 3: 15/4/0 vs. 60/40/39, P = 0.003). In multivariate analysis, only internal limiting membrane inverted flap (odds ratio, 15.778, 95% confidence interval, 3.170-78.523; P = 0.001) was positively associated with persistent SRF. There were no significant differences in best-corrected visual acuity improvement ( P = 0.425) between the SRF involved foveal and without involved foveal groups and no significant differences between the SRF complete absorption and incomplete absorption groups. CONCLUSION: Absorption of persistent SRF may be more difficult in MHRD eyes than in ordinary rhegmatogenous retinal detachment eyes. The internal limiting membrane inverted flap in MHRD was associated with a greater likelihood of persistent SRF. The location and incomplete absorption of persistent SRF did not seem to be associated with the final visual outcome.

Thermal-Assisted Multiscale Patterning of Nonplanar Colloidal Nanostructures for Multi-Modal Anti-Counterfeiting.

Nanotransfer printing of colloidal nanoparticles is a promising technique for the fabrication of functional materials and devices. However, patterning nonplanar nanostructures pose a challenge due to weak adhesion from the extremely small nanostructure-substrate contact area. Here, the study proposes a thermal-assisted nonplanar nanostructure transfer printing (NP-NTP) strategy for multiscale patterning of polystyrene (PS) nanospheres. The printing efficiency is significantly improved from ≈3.1% at low temperatures to ≈97.2% under the glass transition temperature of PS. Additionally, the arrangement of PS nanospheres transitioned from disorder to long-range order. The mechanism of printing efficiency enhancement is the drastic drop of Young's modulus of nanospheres, giving rise to an increased contact area, self-adhesive effect, and inter-particle necking. To demonstrate the versatility of the NP-NTP strategy, it is combined with the intaglio transfer printing technique, and multiple patterns are created at both micro and macro scales at a 4-inch scale with a resolution of ≈2757 pixels per inch (PPI). Furthermore, a multi-modal anti-counterfeiting concept based on structural patterns at hierarchical length scales is proposed, providing a new paradigm of imparting multiscale nanostructure patterning into macroscale functional devices.

How to measure earnings surprises: Based on revised market reaction.

We investigate the robustness of earnings surprise measures in the context of a revised market reaction. While existing literature suggests that financial anomalies may distort cumulative abnormal returns (CAR) during annual announcements, our research proves that a revised market reaction offers a more accurate reflection of investor reactions to earnings correction. Specifically, we introduce an innovative adjustment to CAR using stock price jumps, and prove that the fraction of misses on the same side (FOM) provides a superior measure of earnings surprises. Furthermore, we find that investor trading patterns align with FOM, and the post-earnings announcement drift (PEAD) strategy based on FOM outperforms that based on analysts' forecast error.

Mechanochemical Synthesis of PdO2 Nanoparticles Immobilized over Silica Gel for Catalytic Suzuki-Miyaura Cross-Coupling Reactions Leading to the C-3 Modification of 1H-Indazole with Phenylboronic Acids.

The C-3 modification of 1H-indazole has produced active pharmaceuticals for the treatment of cancer and HIV. But, so far, this transformation has seemed less available, due to the lack of efficient C-C bond formation at the less reactive C-3 position. In this work, a series of silica gel-supported PdO2 nanoparticles of 25-66 nm size were prepared by ball milling silica gel with divalent palladium precursors, and then employed as catalysts for the Suzuki-Miyaura cross-coupling of 1H-indazole derivative with phenylboronic acid. All the synthesized catalysts showed much higher cross-coupling yields than their palladium precursors, and could also be reused three times without losing high activity and selectivity in a toluene/water/ethanol mixed solvent. Although the palladium precursors showed an order of activity of PdCl2(dppf, 1,1'-bis(diphenylphosphino)ferrocene) > PdCl2(dtbpf, 1,1'-bis(di-tert-butylphosphino)ferrocene) > Pd(OAc, acetate)2, the synthesized catalysts showed an order of C1 (from Pd(OAc)2) > C3 (from PdCl2(dtbpf)) > C2 (from PdCl2(dppf)), which conformed to the orders of BET (Brunauer-Emmett-Teller) surface areas and acidities of these catalysts. Notably, the most inexpensive Pd(OAc)2 can be used as a palladium precursor for the synthesis of the best catalyst through simple ball milling. This work provides a highly active and inexpensive series of catalysts for C-3 modification of 1H-indazole, which are significant for the large-scale production of 1H-indazole-based pharmaceuticals.

Vitrectomy for retinal detachment associated with macular hole: Prognostic factor analysis under different axial length conditions.

PURPOSE: To identify prognostic factors for complete anatomical success (CAS) under different axial length (AL) conditions after vitrectomy plus internal limiting membrane (ILM) peeling for retinal detachment associated with macular hole (MHRD). METHODS: This retrospective study included 243 patients (251 eyes) with MHRD who underwent primary vitrectomy plus ILM peeling. Multivariate logistic regression explored prognostic factors for CAS in AL <30 mm and ≥ 30 mm groups. RESULTS: Overall, 113 eyes (45.0% of 251) exhibited complete CAS after initial surgery. Eyes with CAS had greater best-corrected visual acuity improvement than eyes without CAS (p < 0.001). CAS was more common in eyes with AL < 30 mm (50.3% of 155) than in eyes with AL ≥ 30 mm (36.5%, 35/96; p = 0.032). In the AL < 30 mm group, CAS was associated with ILM insertion (odds ratio [OR], 2.824, 95% confidence interval [CI], 1.189-6.710; p = 0.019), silicone oil (SO)/perfluoropropane (C3F8) tamponade (SO: OR, 0.408, 95% CI, 0.191-0.873; C3F8: OR, 2.448, 95% CI, 1.145-5.234; p = 0.021) and staphyloma (OR, 0.318, 95% CI, 0.143-0.707; p = 0.005). In the AL ≥30 mm group, CAS was associated with ILM insertion (OR, 11.621, 95% CI, 2.557-52.813; p = 0.001), SO /C3F8 tamponade (SO: OR, 5.305, 95% CI, 1.206-23.334; C3F8: OR, 0.188, 95% CI, 0.043-0.829; p = 0.027) and age (OR, 0.928, 95% CI, 0.876-0.983; p = 0.011). CONCLUSION: Vitrectomy plus ILM peeling can effectively treat MHRD but has limited efficacy in eyes with AL ≥ 30 mm. ILM insertion was associated with more frequent CAS at any AL. C3F8 tamponade yielded better outcomes with AL < 30 mm; SO tamponade yielded better outcomes with AL ≥ 30 mm.

Research advances in smart responsive-hydrogel dressings with potential clinical diabetic wound healing properties.

The treatment of chronic and non-healing wounds in diabetic patients remains a major medical problem. Recent reports have shown that hydrogel wound dressings might be an effective strategy for treating diabetic wounds due to their excellent hydrophilicity, good drug-loading ability and sustained drug release properties. As a typical example, hyaluronic acid dressing (Healoderm) has been demonstrated in clinical trials to improve wound-healing efficiency and healing rates for diabetic foot ulcers. However, the drug release and degradation behavior of clinically-used hydrogel wound dressings cannot be adjusted according to the wound microenvironment. Due to the intricacy of diabetic wounds, antibiotics and other medications are frequently combined with hydrogel dressings in clinical practice, although these medications are easily hindered by the hostile environment. In this case, scientists have created responsive-hydrogel dressings based on the microenvironment features of diabetic wounds (such as high glucose and low pH) or combined with external stimuli (such as light or magnetic field) to achieve controllable drug release, gel degradation, and microenvironment improvements in order to overcome these clinical issues. These responsive-hydrogel dressings are anticipated to play a significant role in diabetic therapeutic wound dressings. Here, we review recent advances on responsive-hydrogel dressings towards diabetic wound healing, with focus on hydrogel structure design, the principle of responsiveness, and the behavior of degradation. Last but not least, the advantages and limitations of these responsive-hydrogels in clinical applications will also be discussed. We hope that this review will contribute to furthering progress on hydrogels as an improved dressing for diabetic wound healing and practical clinical application.

Comparisons of nonpharmaceutical analgesia and pharmaceutical analgesia on the labor analgesia effect of parturient women.

OBJECTIVE: We aimed to compare the labor analgesia effects of nonpharmaceutical analgesia and pharmaceutical analgesia on parturient women. METHODS: One hundred and four parturient women with spontaneous births were selected and randomly divided into pharmaceutical and nonpharmaceutical analgesia groups. Before and after analgesia, the Visual Analogue Scale (VAS), parturient satisfaction with analgesia, serum pain stress factors (substance P [SP], neuropeptide Y [NPY], nerve growth factor [NGF], and prostaglandin E2 [PGE2]), duration of labor, vaginal bleeding at 2 h postpartum, postpartum urinary retention and dysuria incidence, Apgar score of 1 min and 5 min after birth, and neonatal cord blood gas analysis (pH, partial pressure of oxygen [PO2 ], partial pressure of carbon dioxide [PCO2 ], and lactate [Lac]) were compared in the two groups. RESULTS: VAS scores were lower and the analgesia satisfaction was higher in the pharmaceutical analgesia group than in the nonpharmaceutical analgesia group (all p < .05). Serum levels of SP, NPY, NGF, and PGE2 in the pharmaceutical analgesia group were lower than those in the nonpharmaceutical analgesia group (all p < .05). The first and second stages of labor were longer and the bleeding volume at 2 h postpartum was greater in the pharmaceutical analgesia group than those in the nonpharmaceutical analgesia group (all p < .05). Reduced Lac and PCO2 levels and increased PO2 level were found in the pharmaceutical analgesia group in comparison to the nonpharmaceutical analgesia group (all p < .05). CONCLUSION: This study demonstrates that the analgesic effect and neonatal condition of the pharmaceutical analgesia are better than the nonpharmaceutical analgesia, but the labor duration and postpartum bleeding volume of the pharmaceutical analgesia are greater than those of the nonpharmaceutical analgesia.

Inter-Metal Interaction of Dual-Atom Catalysts in Heterogeneous Catalysis.

Dual-atom catalysts (DACs) have been a new frontier in heterogeneous catalysis due to their unique intrinsic properties. The synergy between dual atoms provides flexible active sites, promising to enhance performance and even catalyze more complex reactions. However, precisely regulating active site structure and uncovering dual-atom metal interaction remain grand challenges. In this review, we clarify the significance of the inter-metal interaction of DACs based on the understanding of active center structures. Three diatomic configurations are elaborated, including isolated dual single-atom, N/O-bridged dual-atom, and direct dual-metal bonding interaction. Subsequently, the up-to-date progress in heterogeneous oxidation reactions, hydrogenation/dehydrogenation reactions, electrocatalytic reactions, and photocatalytic reactions are summarized. The structure-activity relationship between DACs and catalytic performance is then discussed at an atomic level. Finally, the challenges and future directions to engineer the structure of DACs are discussed. This review will offer new prospects for the rational design of efficient DACs toward heterogeneous catalysis.

Pathogenetic Pathways in Nonalcoholic Fatty Liver Disease: An Incomplete Jigsaw Puzzle.

Nonalcoholic fatty liver disease (NAFLD)-a condition of excess fat accumulation in hepatocytes associated with metabolic dysfunction-has surpassed viral hepatitis to become the most prevalent chronic liver disease worldwide. As of now, only modestly effective pharmacological therapies for NAFLD exist. The uncomplete understanding of the pathophysiology underlying the heterogeneous disease spectrum known as NAFLD remains one of the major obstacles to the development of novel therapeutic approaches. This review compiles current knowledge on the principal signaling pathways and pathogenic mechanisms involved in NAFLD, which are analyzed in relation to its main pathological hallmarks (ie, hepatic steatosis, steatohepatitis, and liver fibrosis).

A phase Ia dose-escalation trial of Ametumumab (a fully human monoclonal antibody against epidermal growth factor receptor) in patients with advanced solid malignancies.

Background: Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody. Objectives: To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ametumumab. Design: A first-in-human phase Ia dose escalation study of Ametumumab in patients with advanced solid malignancies. Methods: An open-label, first-in-human dose escalation study was done in 22 patients with advanced malignancies who received six ascending dosages ranging from 75 to 750 mg/m2. Following a single dosage and a 28-day dose-limiting toxicity (DLT) monitoring period, patients were given repeated doses weekly. Blood samples were taken to determine the PK parameters of Ametumumab and anti-drug antibody concentrations. Every 8 weeks, radiographic tumor evaluations were conducted. Results: In this trial, no DLT was observed, and the maximum tolerated dose was not reached at doses up to 750 mg/m2. There were no severe adverse events but mild and moderate adverse effects, such as headache, proteinuria, and rash. Single-dose PK results demonstrated a straightforward linear relationship with dosage escalation. The medication concentrations accumulated and attained steady-state after four rounds of injections. It was calculated that 10 patients with disease control would be observed in the 22 evaluable patients. The disease control rate was 45.5%. Conclusion: The Ametumumab was well tolerated and safe in patients with advanced solid malignancies, exhibiting minimal immunogenicity, a long half-life, high levels of drug exposure in the blood, and preliminary effectiveness. Registration: The trial was registered with CTR20170343 on 10 April 2017, The China Center for Drug Evaluation.

Novel considerations on EGFR-based therapy as a contributor to cancer cell death in NSCLC.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) represented by gefitinib and erlotinib are widely used in treating non-small cell lung cancer (NSCLC). However, acquired resistance to EGFR-TKI treatment remains a clinical challenge. In recent years, emerging research investigated in EGFR-TKI-based combination therapy regimens, and remarkable achievements have been reported. This article focuses on EGFR-TKI-based regimens, reviews the standard and novel application of EGFR targets, and summarizes the mechanisms of EGFR-TKI combinations including chemotherapy, anti-vascular endothelial growth factor monoclonal antibodies, and immunotherapy in the treatment of NSCLC. Additionally, we summarize clinical trials of EGFR-TKI-based combination therapy expanding indications to EGFR mutation-negative lung malignancies. Moreover, novel strategies are under research to explore new drugs with good biocompatibility. Nanoparticles encapsulating non-coding RNA and chemotherapy of new dosage forms drawn great attention and showed promising prospects in effective delivery and stable release. Overall, as the development of resistance to EGFR-TKIs treatment is inevitable in most of the cases, further research is needed to clarify the underlying mechanism of the resistance, and to evaluate and establish EGFR-TKI combination therapies to diversify the treatment landscape for NSCLC.

Degree of obesity and gastrointestinal adverse reactions influence the weight loss effect of liraglutide in overweight or obese patients with type 2 diabetes.

Background: Liraglutide can effectively reduce the weight of patients with type 2 diabetes. Nonetheless, its weight loss effect was highly heterogeneous in different patients in the clinical practice. Objective: To identify the factors most associated with the weight loss effect of liraglutide in obese or overweight patients with type 2 diabetes with poorly controlled oral medication in northeast China. Design: A prospective study. Methods: A prospective study was performed in subjects with type 2 diabetes who were taking oral medication and had a body mass index (BMI) of ⩾24 kg/m2. Liraglutide was administered for at least 12 weeks, while the original hypoglycemic regimen was kept unchanged (Phase I). Later, liraglutide treatment was continued or stopped as necessary or as subjects thought fit in the 13-52 weeks that followed (Phase II), and the potential factors affecting the effect of weight loss of liraglutide were analyzed. Results: Of the 127 recruited subjects, 90 had comprehensive follow-up data at week 12. In Phase I, the subjects' blood sugar levels and weight decreased significantly(P < 0.001). Among all the significant factors, the gastrointestinal adverse reactions score (GARS) was more correlated with BMI change (ΔBMI; r = 0.43) and waist circumference change (ΔWC; r = 0.32) than the baseline BMI (BMI0) and WC (WC0). At week 12, linear regression showed that BMI0 independently affected ΔBMI and ΔWC, whereas WC0 only affected ΔWC. The GARS was significantly associated with ΔBMI and ΔWC, and this association continued until week 52, even after most subjects had discontinued liraglutide treatment. Conclusion: The degree of obesity and gastrointestinal adverse reactions were the most promising predictors of weight loss in liraglutide treatment.

Gamma-Muricholic Acid Inhibits Nonalcoholic Steatohepatitis: Abolishment of Steatosis-Dependent Peroxidative Impairment by FXR/SHP/LXRα/FASN Signaling.

Nonalcoholic steatohepatitis (NASH) reflects the outcome of steatosis-based peroxidative impairment. Here, the effect and mechanism of γ-muricholic acid (γ-MCA) on NASH were investigated on the basis of its actions in hepatic steatosis, lipid peroxidation, peroxidative injury, hepatocyte apoptosis, and its NAFLD activity score (NAS). The agonist action of γ-MCA on farnesoid X receptor (FXR) upregulated the small heterodimer partner (SHP) expression of hepatocytes. An increase in SHP attenuated the triglyceride-dominated hepatic steatosis which was induced in vivo by a high-fat high-cholesterol (HFHC) diet and in vitro by free fatty acids depending on the inhibition of liver X receptor α (LXRα) and fatty acid synthase (FASN). In contrast, FXR knockdown abrogated the γ-MCA-dependent lipogenic inactivation. When compared to their excessive production in HFHC diet-induced rodent NASH, products of lipid peroxidation (MDA and 4-HNE) exhibited significant reductions upon γ-MCA treatment. Moreover, the decreased levels of serum alanine aminotransferases and aspartate aminotransferases demonstrated an improvement in the peroxidative injury of hepatocytes. By TUNEL assay, injurious amelioration protected the γ-MCA-treated mice against hepatic apoptosis. The abolishment of apoptosis prevented lobular inflammation, which downregulated the incidence of NASH by lowering NAS. Collectively, γ-MCA inhibits steatosis-induced peroxidative injury to ameliorate NASH by targeting FXR/SHP/LXRα/FASN signaling.

Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice.

Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis. We demonstrated that phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in MAFLD progression. Male mice with liver Pck1 deficiency fed a normal diet displayed hepatic lipid disorder and liver injury, whereas fibrosis and inflammation were aggravated in mice fed a high-fat diet with drinking water containing fructose and glucose (HFCD-HF/G). Forced expression of hepatic PCK1 by adeno-associated virus ameliorated MAFLD in male mice. PCK1 deficiency stimulated lipogenic gene expression and lipid synthesis. Moreover, loss of hepatic PCK1 activated the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increasing secretion of platelet-derived growth factor-AA (PDGF-AA), and promoting hepatic stellate cell activation. Treatment with RhoA and AKT inhibitors or gene silencing of RhoA or AKT1 alleviated MAFLD progression in vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA in male mice, highlighting a potential therapeutic strategy for MAFLD.

Identification and validation of anoikis-associated gene SNCG as a prognostic biomarker in gastric cancer.

As a type of cell apoptosis, anoikis is caused by cells detachment from the extracellular matrix and anoikis resistance is central to cancer metastasis. Here, SNCG was identified as hub anoikis-associated gene in GC and associated with prognosis of patients with GC. To screen the hub anoikis-associated genes connected to GC, the database of Cancer Genome Atlas (TCGA) was employed. For further validating these identified genes, the Gene Expression Omnibus (GEO) dataset was applied, and Western blotting and quantitative Real-Time PCR were carried out. To Identify hub genes, we conducted the analyses of univariate Cox regression, differential expression, and weighted gene co-expression network analysis (WGCNA). According to the identified hub genes, we constructed a model of prognosis. Following complex analysis, SNCG was finally identified as hub anoikis-associated gene in GC. Indeed, K-M and receiver operating characteristic analyses suggested that the expression patterns of SNCG can be used as prognostic factors for GC survival. The expression and survival trends of SNCG were verified in the validation cohort and in vitro experimental analyses. The analysis of immune cell infiltration showed that the infiltrated immune cells varied among patients with GC and gene SNCG. Furthermore, due to the significant association of the constructed risk signature with patient age and survival, this risk signature can be used to predict the prognosis of GC. We suggest that SNCG was served as hub anoikis-associated gene in GC. Meanwhile, SNCG may have prognostic potential for overall patient survival.