Inhibition of the rapamycin-insensitive mTORC1 /4E-BP1 axis attenuates TGF-ß1-induced fibrotic response in human Tenon's fibroblasts.

Subconjunctival fibrosis is the major cause of failure in both conventional and modern minimally invasive glaucoma surgeries (MIGSs) with subconjunctival filtration. The search for safe and effective anti-fibrotic agents is critical for improving long-term surgical outcomes. In this study, we investigated the effect of inhibiting the rapamycin-insensitive mTORC1/4E-BP1 axis on the transforming growth factor-beta 1(TGF-ß1)-induced fibrotic responses in human Tenon's fibroblasts (HTFs), as well as in a rat model of glaucoma filtration surgery (GFS). Primary cultured HTFs were treated with 3 ng/mL TGF-ß1 for 24 h, followed by treatment with 10 µM CZ415 for additional 24 h. Rapamycin (10 µM) was utilized as a control for mTORC1/4E-BP1 signaling insensitivity. The expression levels of fibrosis-associated molecules were measured using quantitative real-time PCR, Western blotting, and immunofluorescence analysis. Cell migration was assessed through the scratch wound assay. Additionally, a rat model of GFS was employed to evaluate the anti-fibrotic effect of CZ415 in vivo. Our findings indicated that both rapamycin and CZ415 treatment significantly reduced the TGF-ß1-induced cell proliferation, migration, and the expression of pro-fibrotic factors in HTFs. CZ415 also more effectively inhibited TGF-ß1-mediated collagen synthesis in HTFs compared to rapamycin. Activation of mTORC1/4E-BP signaling following TGF-ß1 exposure was highly suppressed by CZ415 but was only modestly inhibited by rapamycin. Furthermore, CZ415 was found to decrease subconjunctival collagen deposition in rats post GFS. Our results suggest that rapamycin-insensitive mTORC1/4E-BP1 signaling plays a critical role in TGF-ß1-driven collagen synthesis in HTFs. This study demonstrated that inhibition of the mTORC1/4E-BP1 axis offers superior anti-fibrotic efficacy compared to rapamycin and represents a promising target for improving the success rate of both traditional and modern GFSs.

Ultrasmall Single-Chain Nanoparticles Derived from Amphiphilic Alternating Copolymers.

The collapse or folding of an individual polymer chain into a nanoscale particle gives rise to single-chain nanoparticles (SCNPs), which share a soft nature with biological protein particles. The precise control of their properties, including morphology, internal structure, size, and deformability, are a long-standing and challenging pursuit. Herein, a new strategy based on amphiphilic alternating copolymers for producing SCNPs with ultrasmall size and uniform structure is presented. SCNPs are obtained by folding the designed alternating copolymer in N,N-dimethylformamide (DMF) and fixing it through a photocatalyzed cycloaddition reaction of anthracene units. Molecular dynamics simulation confirms the solvophilic outer corona and solvophobic inner core structure of SCNPs. Furthermore, by adjusting the length of PEG units, precise control over the mean size of SCNPs is achieved within the range of 2.8 to 3.9 nm. These findings highlight a new synthetic strategy that enables enhanced control over morphology and internal structure while achieving ultrasmall and uniform size for SCNPs.

Application of GaS nanotubes as efficient catalysts in photocatalytic hydrolysis: a first principles study.

Photocatalytic hydrogen production is a promising and sustainable technology that converts solar energy into hydrogen energy with the assistance of semiconductor photocatalysts. Herein, we investigated the geometric structure and electronic and photocatalytic properties of single-walled GaS nanotubes under the framework of density functional theory with HSE06 as an exchange-correlation function. This paper presents the first study on the geometric structure, electron, and photocatalytic properties of single-walled GaS nanotubes. The results show that the strain energy and formation energy of GaS nanotubes decrease, while the structure is more stable, with increasing radius. Our study shows that after rolling from the slab, the nanotubes undergo a transition from an indirect band gap to a direct band gap and have appropriate band gaps for absorbing visible light. Moreover, it is speculated that the large disparity between the effective mass of electrons and holes can reduce charge carrier recombination. Among them, the nanotube with a diameter larger than (35, 0) showed promising band edge positions for photocatalytic hydrolysis redox potential with pH values between 0 and 7. Based on these properties, we believe that GaS nanotubes will be promising in photocatalytic hydrolysis.

Alternative splicing of the human rhomboid family-1 gene RHBDF1 inhibits epidermal growth factor receptor activation.

The human rhomboid-5 homolog-1 (RHBDF1) is a multi-transmembrane protein present mainly on the endoplasmic reticulum. RHBDF1 has been implicated in the activation of epidermal growth factor receptor (EGFR)-derived cell growth signals and other activities critical to cellular responses to stressful conditions, but details of this activation mechanism are unclear. Here, we report a RHBDF1 mRNA transcript alternative splicing variant X6 (RHBDF1 X6 or RHX6) that antagonizes RHBDF1 activities. We found that while the RHBDF1 gene is marginally expressed in breast tumor-adjacent normal tissues, it is markedly elevated in the tumor tissues. In sharp contrast, the RHX6 mRNA represents the primary RHBDF1 variant in normal breast epithelial cells and tumor-adjacent normal tissues but is diminished in breast cancer cells and tumors. We demonstrate that, functionally, RHX6 acts as an inhibitor of RHBDF1 activities. We show that artificially overexpressing RHX6 in breast cancer cells leads to retarded proliferation, migration, and decreased production of epithelial-mesenchymal transition-related adhesion molecules. Mechanically, RHX6 is able to inhibit the maturation of TACE, a protease that processes pro-TGFα, a pro-ligand of EGFR, and to prevent intracellular transportation of pro-TGFα to the cell surface. Additionally, we show that the production of RHX6 is under the control of the alternative splicing regulator RNA binding motif protein-4 (RBM4). Our findings suggest that differential splicing of the RHBDF1 gene transcript may have a regulatory role in the development of epithelial cell cancers.

Self-Driven Droplet Motions Below their Icing Points.

Liquid fluidity is a most key prerequisite for a broad range of technologies, from energy, fluid machineries, microfluidic devices, water, and oil transportation to bio-deliveries. While from thermodynamics, the liquid fluidity gradually diminishes as temperature decreases until completely solidified below icing points. Here, self-driven droplet motions are discovered and demonstrated occurring in icing environments and accelerating with both moving distances and droplet volumes. The self-driven motions, including self-depinning and continuous wriggling, require no surface pre-preparation or energy input but are triggered by the overpressure spontaneously established during icing and then continuously accelerated by capillary pulling of frosts. Such self-driven motions are generic to a broad class of liquid types, volumes, and numbers on various micro-nanostructured surfaces and can be facilely manipulated by introducing pressure gradients spontaneously or externally. The discovery and control of self-driven motions below icing points can greatly broaden liquid-related applications in icing environments.

Effect of neoadjuvant therapy on serum transforming growth factor-ß, squamous cell carcinoma associated antigen, and prognosis in patients with locally advanced esophageal cancer.

It was to explore the effect of neoadjuvant therapy (NAT) on serum-related indicators and prognosis of patients with locally advanced esophageal cancer (EC). 400 EC patients were grouped as controls (295 cases, radical EC resection alone) and research group (105 cases, NAT plus radical EC resection). The levels of serum carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), programmed death-1 (PD-1), PD-2, transforming growth factor-ß1 (TGF-ß1), and squamous cell carcinoma (SCC) antigen were detected before and after treatment. The follow-up lasted for 3 years. The quality of life (QoL) was evaluated by QLQ-OES24. The recurrence rate, recurrence time, overall survival rate (SR), disease-free SR, and complication rate were compared. Compared with controls, the levels of serum CA19-9, CEA, CYFRA21-1, PD-1, PD-2, TGF-ß1, and SCC were decreased, the QoL score was increased 3 years post-treatment, and the recurrence time was prolonged in the research group (P<0.05). The R0 resection rate, recurrence rate, 3-year overall SR, and disease-free SR of the two groups were 67.12% vs 85.71%, 21.36% vs 6.67%, 56.27% vs 77.14%, 29.83% vs 45.71%, respectively (P<0.05). The complication rates of the two groups were 32.54% and 29.52%, respectively (P>0.05). NAT plus radical resection of EC can effectively reduce the level of serum oncology markers in patients with locally advanced EC, reduce the postoperative recurrence rate, improve QoL and SR, and has high safety.

Metrnl deficiency retards skin wound healing in mice by inhibiting AKT/eNOS signaling and angiogenesis.

Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.

Oil body extraction from high-fat and high-protein soybeans by laccase cross-linked beet pectin: physicochemical and oxidation properties.

BACKGROUND: Soybean oil bodies (SOB) are droplets of natural emulsified oil. Soybean oil emulsifies well but it is easily oxidized during storage. Beet pectin is a complex anionic polysaccharide, which can be adsorbed on the surface of liposomes to improve their resistance to flocculation. Laccase can covalently cross-link ferulic acid in beet pectin, and its structure is irreversible, which can improve the stability of polysaccharides. RESULTS: At pH 2.5, laccase cross-linked beet pectin high-oil soybean oil body (HOSOB) and high-protein soybean oil body (HPSOB) emulsions showed obvious aggregation and severe stratification, and the oxidation of the emulsions was also high. The flocculation of emulsions decreased with an increase in the pH. The effect of pH on the flocculation of emulsion was confirmed by confocal laser electron microscopy. The ζ potential, emulsification, and rheological shear force increased with increasing pH whereas the particle size and surface hydrophobicity decreased with increasing pH. CONCLUSION: This experiment indicates that the physicochemical stability of the two composite emulsions was strongly affected under acidic conditions but stable under neutral and weakly alkaline conditions. Under the same acid-base conditions, the degree of oxidation of HPSOB composite emulsion changes substantially. The results of this study can provide a basis for the design of very stable emulsions to meet the demand for natural products. © 2023 Society of Chemical Industry.

Carnosol alleviates nonalcoholic fatty liver disease by inhibiting mitochondrial dysfunction and apoptosis through targeting of PRDX3.

Mitochondrial dysfunction is a major factor in nonalcoholic fatty liver disease (NAFLD), preceding insulin resistance and hepatic steatosis. Carnosol (CAR) is a kind of diterpenoid with antioxidant, anti-inflammatory and antitumor activities. Peroxiredoxin 3 (PRDX3), a mitochondrial H2O2-eliminating enzyme, undergoes overoxidation and subsequent inactivation under oxidative stress. The purpose of this study was to investigate the protective effect of the natural phenolic compound CAR on NAFLD via PRDX3. Mice fed a high-fat diet (HFD) and AML-12 cells treated with palmitic acid (PA) were used to detect the molecular mechanism of CAR in NAFLD. We found that pharmacological treatment with CAR notably moderated HFD- and PA- induced steatosis and liver injury, as shown by biochemical assays, Oil Red O and Nile Red staining. Further mechanistic investigations revealed that CAR exerted anti-NAFLD effects by inhibiting mitochondrial oxidative stress, perturbation of mitochondrial dynamics, and apoptosis in vivo and in vitro. The decreased protein and mRNA levels of PRDX3 were accompanied by intense oxidative stress after PA intervention. Interestingly, CAR specifically bound PRDX3, as shown by molecular docking assays, and increased the expression of PRDX3. However, the hepatoprotection of CAR in NAFLD was largely abolished by specific PRDX3 siRNA, which increased mitochondrial dysfunction and exacerbated apoptosis in vitro. In conclusion, CAR suppressed lipid accumulation, mitochondrial dysfunction and hepatocyte apoptosis by activating PRDX3, mitigating the progression of NAFLD, and thus, CAR may represent a promising candidate for clinical treatment of steatosis.

Supercooled melt structure and dynamics of single-chain nanoparticles: A computer simulation study.

By using coarse-grained molecular dynamics simulations, we have investigated the structure and dynamics of supercooled single-chain cross-linked nanoparticle (SCNP) melts having a range of cross-linking degrees ϕ. We find a nearly linear increase in glass-transition temperature (Tg) with increasing ϕ. Correspondingly, we have also experimentally synthesized a series of polystyrene-based SCNPs and have found that the measured Tg estimated from differential scanning calorimetry is qualitatively consistent with the trend predicted by our simulation estimates. Experimentally, an increase in Tg as large as ΔTg = 61 K for ϕ = 0.36 is found compared with their linear chain counterparts, indicating that the changes in dynamics with cross-links are quite appreciable. We attribute the increase in Tg to the enlarged effective hard-core volume and the corresponding reduction in the free volume of the polymer segments. Topological constraints evidently frustrate the local packing. In addition, the introduction of intra-molecular cross-linking bonds slows down the structural relaxation and simultaneously enhances the local coupling motion on the length scales within SCNPs. Consequently, a more pronounced dynamical heterogeneity (DH) is observed for larger ϕ, as quantified by measuring the dynamical correlation length through the four-point susceptibility parameter, χ4. The increase in DH is directly related to the enhanced local cooperative motion derived from intra-molecular cross-linking bonds and structural heterogeneity derived from the cross-linking process. These results shed new light on the influence of intra-molecular topological constraints on the segmental dynamics of polymer melts.

Design and optimization of integrated flexure mounts for unloading lateral gravity of a lightweight mirror for space application.

This paper presents an integrated flexure mount (IFM) to unload the lateral gravity of a lightweight mirror. The significance of the position relationship between the plane of mirror centroid and the center of flexure pivot is analyzed using the coupling kinematic stiffness model of the flexure mounts derived in this paper. Based on the analysis, an IFM with S-type flexure hinges was designed, and the structure and assembly are described. Then, the optimal position and size parameters of an S-type flexure hinge were obtained by optimization. The optimization results attained by finite element analysis (FEA) indicate that the optimization objectives and constraints were satisfied. Moreover, the degradation of the mirror's optical performance caused by lateral gravity was minimized, and the effects of temperature variation and assembly tolerance were reduced. The IFMs were fabricated based on the optimization results and assembled with a mirror prototype for a pointing precision test and sine-frequency sweep test. A FEA and test results for the IFMs confirm the validity and feasibility of the flexure mounts model and structure design, and we believe the IFM meets the requirements of a lightweight mirror for space application.

KIT ligand produced by limbal niche cells under control of SOX10 maintains limbal epithelial stem cell survival by activating the KIT/AKT signalling pathway.

Homeostasis and function of limbal epithelial stem cells (LESCs) rely on the limbal niche, which, if dysfunctional, leads to limbal epithelial stem cell deficiency (LSCD) and impaired vision. Hence, recovery of niche function is a principal therapeutic goal in LSCD, but the molecular mechanisms of limbal niche homeostasis are still largely unknown. Here, we report that the neural crest transcription factor SOX10, which is expressed in neural crest-derived limbal niche cells (LNCs), is required for LNCs to promote survival of LESCs both in vivo and in vitro. In fact, using mice with a Sox10 mutation and in vitro coculture experiments, we show that SOX10 in LNCs stimulates the production of KIT ligand (KITL), which in turn activates in LESCs the KIT-AKT signalling pathway that protects the cells against activated CASPASE 3-associated cell death. These results suggest that SOX10 and the KITL/KIT-AKT pathway play key roles in limbal niche homeostasis and LESC survival. These findings provide molecular insights into limbal niche function and may point to rational approaches for therapeutic interventions in LSCD.

Nivolumab in Advanced Hepatocellular Carcinoma: Safety Profile and Select Treatment-Related Adverse Events From the CheckMate 040 Study.

BACKGROUND: CheckMate 040 assessed the efficacy and safety of nivolumab in patients with advanced hepatocellular carcinoma (HCC). Understanding the safety profile of nivolumab is needed to support the management of treatment-related adverse events (TRAEs). This analysis assessed the safety of nivolumab monotherapy in the phase I/II, open-label CheckMate 040 study. MATERIALS AND METHODS: Select TRAEs (sTRAEs; TRAEs with potential immunologic etiology requiring more frequent monitoring) occurring between first dose and 30 days after last dose were analyzed in patients in the dose-escalation and -expansion phases. Time to onset (TTO), time to resolution (TTR), and recurrence of sTRAEs were assessed, and the outcome of treatment with immune-modulating medication (IMM) was evaluated. RESULTS: The analysis included 262 patients. The most common sTRAE was skin (35.5%), followed by gastrointestinal (14.5%) and hepatic (14.1%) events; the majority were grade 1/2, with 10.7% of patients experiencing grade 3/4 events. One patient had grade 5 pneumonitis. Median (range) TTO ranged from 3.6 (0.1-59.9) weeks for skin sTRAEs to 47.6 (47.1-48.0) weeks for renal sTRAEs. Overall, 68% of sTRAEs resolved, with median (range) TTR ranging from 3.7 (0.1-123.3+) weeks for gastrointestinal sTRAEs to 28.4 (0.1-79.1) weeks for endocrine sTRAEs. Most gastrointestinal and all hepatic events resolved with treatment in accordance with established toxicity management algorithms. In 57 patients (40%), sTRAEs were managed with IMM. Reoccurrence of sTRAEs was uncommon following rechallenge with nivolumab. CONCLUSION: Nivolumab demonstrated a manageable safety profile in this analysis of patients with advanced HCC. A majority of sTRAEs resolved with treatment. IMPLICATIONS FOR PRACTICE: Nivolumab is a viable treatment option for patients with previously treated advanced hepatocellular carcinoma as it has demonstrated durable tumor responses and promising survival. Nivolumab has a manageable safety profile. The most common select treatment-related adverse events (sTRAEs) in this analysis were skin related (35%). Gastrointestinal and hepatic sTRAEs were observed in approximately 14% of patients. The majority of sTRAEs resolved (68%). Safety events are easier to manage if addressed early. Patient education on signs and symptoms to watch out for and the importance of early reporting and consultation should be emphasized.

Synthesis of Polymer Single-Chain Nanoparticle with High Compactness in Cosolvent Condition: A Computer Simulation Study.

Polymeric single-chain nanoparticles (SCNPs) are soft nano-objects synthesized by intramolecular crosslinking of isolated single polymer chains. Syntheses of such SCNPs usually need to be performed in a dilute solution. In such a condition, the bonding probability of the two active crosslinking units at a short contour distance along the chain backbone is much higher than those which are far away from each other. Such a reaction condition often results in local spheroidization and, therefore, the formation of loosely packed structures. How to inhibit the local spheroidization and improve the compactness of SCNPs is thus a major challenge for the syntheses of SCNPs. In this study, computer simulations are performed and the fact that a precollapse of the polymer chain conformation in a cosolvent condition can largely improve the probability of the crosslinking reactions at large contour distances is demonstrated, favoring the formations of closely packed globular structures. As a result, the formed SCNPs can be more spherical and have higher compactness than those fabricated in ultradilute good solvent solution in a conventional way. It is believed this simulation work can provide a insight into the effective syntheses of SCNPs with spherical conformations and high compactness.

Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.

BACKGROUND & AIMS: Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040. METHODS: CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018. RESULTS: There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations. CONCLUSION: Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients. LAY SUMMARY: The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients. Clinical trial number: NCT01658878.

Safety of Nivolumab plus Low-Dose Ipilimumab in Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer.

BACKGROUND: Early detection and management of treatment-related adverse events (TRAEs) in patients receiving immune checkpoint inhibitors may improve outcomes. In CheckMate 142, nivolumab (3 mg/kg) plus low-dose ipilimumab (1 mg/kg) provided durable clinical benefit (objective response rate [ORR] 55%, median duration of response not reached, 12-month overall survival [OS] rate 85%) and manageable safety for previously treated microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). In-depth safety and additional efficacy outcomes from CheckMate 142 are presented. MATERIALS AND METHODS: Safety assessments included frequency of TRAEs, select TRAEs (sTRAEs), and immune-mediated adverse event incidences; time to onset (TTO); time to resolution (TTR); immune-modulating medication (IMM) use; dose delay; and sTRAE occurrence after resuming therapy. Efficacy assessments included ORR and survival analyses in patients with sTRAEs with or without concomitant IMM treatment and patients without sTRAEs. RESULTS: Among 119 patients, 25%, 23%, 19%, 5%, 5%, and 29% experienced an endocrine, gastrointestinal, hepatic, pulmonary, renal, or skin sTRAE, respectively; the majority (57%) were grade 1/2. sTRAEs occurred early (median TTO, 5.2-12.6 weeks). Nonendocrine sTRAEs resolved in most (>71%) patients (median TTR, 1.5-9.0 weeks). IMMs were used to manage sTRAEs in 22%-56% of patients (most resolved). Of patients with dose delay because of sTRAEs, 25 of 29 resumed treatment. Patients with or without sTRAEs had comparable ORR (57% vs. 52%) and 12-month OS rates (93% vs. 75%). Similar results were observed in patients with or without sTRAEs regardless of IMM use (ORR 52% vs. 57%; OS rates 87% vs. 82%). CONCLUSION: The benefit-risk profile of nivolumab plus low-dose ipilimumab provides a promising treatment option for patients with previously treated MSI-H/dMMR mCRC. IMPLICATIONS FOR PRACTICE: Nivolumab (NIVO) plus low-dose (1 mg/kg) ipilimumab (IPI) received U.S. Food and Drug Administration approval for patients with microsatellite instability-high and/or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on results from CheckMate 142. In this safety analysis, the majority of select treatment-related adverse events (sTRAEs) occurred early, were managed using evidence-based treatment algorithms, and resolved. Efficacy outcomes were comparable between patients with or without sTRAEs regardless of the use of concomitant immune-modulating medications. The benefit-risk profile of NIVO + low-dose IPI provides a promising treatment option for MSI-H/dMMR mCRC.

Correction to: Axin gene methylation status correlates with radiosensitivity of lung cancer cells.

Following publication of the original article.

Inhibition of the ubiquitination of HSF1 by FBXW7 protects the intestine against ischemia-reperfusion injury.

Epithelial apoptosis is an important factor in intestinal ischemia-reperfusion (I/R) injury. Heat shock factor 1 (HSF1) is a classical stress response factor that directly regulates the transcription of heat shock proteins (HSPs) under stress conditions. Although HSPs are involved in protecting the intestine against I/R, the mechanism whereby HSF1 is regulated in I/R is poorly understood. Here, we show that the ubiquitin ligase FBXW7 targets HSF1 for ubiquitination and degradation in intestinal I/R. In this study, we found that FBXW7 expression was upregulated at the transcriptional level in intestinal mucosae subjected to I/R. In Caco-2 and IEC-6 cells subjected to hypoxia/reoxygenation (H/R), a high FBXW7 level led to excessive HSF1 ubiquitination and degradation. FBXW7 knockdown attenuated HSF1 ubiquitination and downregulation and accelerated HSPB1 and HSP70 expression. In addition, FBXW7 deletion alleviated the apoptosis of intestinal epithelial cells, as evidenced by decreased activation of caspase-3 and caspase-9. The results suggest that FBXW7 suppression protects against intestinal I/R, at least partly through the HSF1/HSP pathway. These findings indicate that FBXW7 may be a potential therapeutic target for inhibiting intestinal mucosa apoptosis during intestinal I/R.

p0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer.

As a member of the p120-catenin (p120ctn) subfamily, the p0071 study in tumor is very limited. We demonstrated the clinicopathological significance of p0071 in non-small cell lung cancer (NSCLC), as well as E-cadherin. Co-immunoprecipitation was used to detect the interaction of p0071 with E-cadherin in A549 and SPC cells (E-cadherin is mainly expressed in the cytoplasm of these cells). p0071 cytoplasmic expression was knocked down by siRNA in these cells and this effect on the RhoA activity and cell invasion and migration ability were measured. p0071 overexpression in the cytoplasm of tumor cell was correlated with lymphatic metastase and poor prognosis of NSCLC. The patients with both abnormal expression of p0071 and E-cadherin (cytoplasmic expression) had a statistically significant shorter survival than the patients without both abnormal expression (P  < 0.05). There is a significant correlation between cytoplasmic overexpression of p0071 and E-cadherin in NSCLC tissues. p0071 interacted with E-cadherin in the cytoplasm of A549 and SPC cell lines. Treatment with siRNA-p0071 inhibited the invasion and migration ability of NSCLC cells. Above results confirmed that p0071 interacted with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of NSCLC.

Carnosol-mediated Sirtuin 1 activation inhibits Enhancer of Zeste Homolog 2 to attenuate liver fibrosis.

Quiescent hepatic stellate cell (HSC) activation and subsequent conversion into myofibroblasts is the central event in hepatic fibrosis pathogenesis. Epithelial-mesenchymal transition (EMT), another vital participant in liver fibrosis, has the potential to initiate HSC activation, which promotes abundant myofibroblast production. Previous studies suggest that Enhancer of Zeste Homolog 2 (EZH2) plays a significant role in myofibroblast transdifferentiation; however, the underlying mechanisms remain largely unaddressed. Carnosol (CS), a compound extracted from rosemary, displays multiple pharmacological activities. This study aimed to investigate the signaling mechanisms underlying EZH2 inhibition and the anti-fibrotic effect of CS in liver fibrosis. We found that CS significantly inhibited CCl4- and TGFß1-induced liver fibrosis and reduced both HSC activation and EMT. EZH2 knockdown also prevented these processes induced by TGFß1 in HSCs and AML-12 cells. Interestingly, the protective effect of CS was positively associated with Sirtuin 1 (SIRT1) activation and accompanied by EZH2 inhibition. SIRT1 knockdown attenuated the EZH2 inhibition induced by CS and increased EZH2 acetylation, which enhanced its stability. Conversely, upon TGFß1 exposure, SIRT1 activation significantly reduced the level of EZH2 acetylation; however, EZH2 overexpression prevented the SIRT1 activation that primed myofibroblast inhibition, indicating that EZH2 is a target of SIRT1. Thus, SIRT1/EZH2 regulation could be used as a new therapeutic strategy for fibrogenesis. Together, this study provides evidence of activation of the SIRT1/EZH2 pathway by CS that inhibits myofibroblast generation, and thus, CS may represent an attractive candidate for anti-fibrotic clinical therapy.