MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.

Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

Asymmetric Intramolecular Amination Catalyzed with Cp*Ir-SPDO via Nitrene Transfer for Synthesis of Spiro-Quaternary Indolinone.

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

Clinical outcome and molecular landscape of patients with ARID1A-loss gastric cancer.

Chromatin remodelers are commonly altered in human cancer. The mutation of AT-rich interactive domain 1A (ARID1A) in gastric cancer (GC), a component of the SWI/SNF chromatin remodeling complex, was proven associated with treatment response in our previous study. However, ARID1A loss of function was caused not only by mutations but also copy number deletions. The clinicopathologic, genomic, and immunophenotypic correlates of ARID1A loss is largely uncharacterized in GC. Here, 819 patients with clinicopathological information and sequencing data or formalin-fixed paraffin-embedded tissues from four cohorts, Zhongshan Hospital (ZSHS) cohort (n = 375), The Cancer Genome Atlas (TCGA) cohort (n = 371), Samsung Medical Center (SMC) cohort (n = 53), and ZSHS immunotherapy cohort (n = 20), were enrolled. ARID1A loss was defined by genome sequencing or deficient ARID1A expression by immunohistochemistry. We found that ARID1A mutation and copy number deletion were enriched in GC with microsatellite instability (MSI) and chromosomal-instability (CIN), respectively. In the TCGA and ZSHS cohorts, only CIN GC with ARID1A loss could benefit from fluorouracil-based adjuvant chemotherapy. In the SMC and ZSHS immunotherapy cohorts, ARID1A loss exhibited a tendency of superior responsiveness and indicated favorable overall survival after anti-PD-1 immunotherapy. ARID1A-loss tumors demonstrated elevated mutation burden, neoantigen load, and interferon gamma pathway activation. Moreover, in CIN GC, ARID1A loss was correlated with higher homologous recombination deficiency. ARID1A loss defines a distinct subtype of GC characterized by high levels of genome instability, neoantigen formation, and immune activation. These tumors show sensitivity to both chemotherapy and anti-PD-1 immunotherapy. This study provides valuable insights for precision treatment strategies in GC.

Ab initio determination of melting and sound velocity of neon up to the deep interior of the Earth.

The thermophysical properties and elemental abundances of the noble gases in terrestrial materials can provide unique insights into the Earth's evolution and mantle dynamics. Here, we perform extensive ab initio molecular dynamics simulations to determine the melting temperature and sound velocity of neon up to 370 GPa and 7500 K to constrain its physical state and storage capacity, together with to reveal its implications for the deep interior of the Earth. It is found that solid neon can exist stably under the lower mantle and inner core conditions, and the abnormal melting of neon is not observed under the entire temperature (T) and pressure (P) region inside the Earth owing to its peculiar electronic structure, which is substantially distinct from other heavier noble gases. An inspection of the reduction for sound velocity along the Earth's geotherm evidences that neon can be used as a light element to account for the low-velocity anomaly and density deficit in the deep Earth. A comparison of the pair distribution functions and mean square displacements of MgSiO3-Ne and Fe-Ne alloys further reveals that MgSiO3 has a larger neon storage capacity than the liquid iron under the deep Earth condition, indicating that the lower mantle may be a natural deep noble gas storage reservoir. Our results provide valuable information for studying the fundamental behavior and phase transition of neon in a higher T-P regime, and further enhance our understanding for the interior structure and evolution processes inside the Earth.

Novel insights into the glucose metabolic alterations of freshwater snails: a pathway to molluscicide innovation and snail control strategies.

As ecosystem disruptors and intermediate hosts for various parasites, freshwater snails have significant socioeconomic impacts on human health, livestock production, and aquaculture. Although traditional molluscicides have been widely used to mitigate these effects, their environmental impact has encouraged research into alternative, biologically based strategies to create safer, more effective molluscicides and diminish the susceptibility of snails to parasites. This review focuses on alterations in glucose metabolism in snails under the multifaceted stressors of parasitic infections, drug exposure, and environmental changes and proposes a novel approach for snail management. Key enzymes within the glycolytic pathway, such as hexokinase and pyruvate kinase; tricarboxylic acid (TCA) cycle; and electron transport chains, such as succinate dehydrogenase and cytochrome c oxidase, are innovative targets for molluscicide development. These targets can affect both snails and parasites and provide an important direction for parasitic disease prevention research. For the first time, this review summarises the reverse TCA cycle and alternative oxidase pathway, which are unique metabolic bypasses in invertebrates that have emerged as suitable targets for the formulation of low-toxicity molluscicides. Additionally, it highlights the importance of other metabolic pathways, including lactate, alanine, glycogenolysis, and pentose phosphate pathways, in snail energy supply, antioxidant stress responses, and drug evasion mechanisms. By analysing the alterations in key metabolic enzymes and their products in stressed snails, this review deepens our understanding of glucose metabolic alterations in snails and provides valuable insights for identifying new pharmacological targets.

Sesquilignans PD from Zanthoxylum nitidum var. tomentosum exerts antitumor effects via the ROS/MAPK pathway in liver cancer cells.

Sesquilignans PD is a natural phenylpropanoid compound that was isolated from Zanthoxylum nitidum var. tomentosum. In this study, we assessed the antitumor effect of PD on SK-Hep-1 and HepG2 cells and the underlying molecular mechanisms. The results revealed that PD markedly inhibited the proliferation and migration of both liver cancer cells. Moreover, PD induced apoptosis, autophagy, and reactive oxygen species (ROS) production in liver cancer cells. Notably, PD increased the protein levels of p-p38 MAPK and p-ERK1/2 in liver cancer cells. This is the first report on the anticancer effect of PD, which is mediated via increased ROS production and MAPK signaling activation.

Effects of Total Intravenous Anesthesia on Circadian Rhythms in Patients Undergoing Cardiac Transcatheter Closure.

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure. Methods Thirty patients undergoing cardiac transcatheter closure under elective intravenous anesthesia were included in this study.Paired t-tests were performed to compare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and muscle ARNT-1 like protein-1(BMAL1),cryptochrome 1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score before and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery. Results The postoperative mRNA level of CLOCK was higher [1.38±1.23 vs.1.90±1.47;MD(95%CI):0.52(0.20-0.84),t=3.327,P=0.002] and the postoperative mRNA levels of CRY1 [1.56±1.50 vs.1.13±0.98;MD(95%CI):-0.43(-0.81--0.05),t=-2.319,P=0.028] and PER2 [0.82±0.63 vs.0.50±0.31;MD(95%CI):-0.33(-0.53--0.12),t=-3.202,P=0.003] were lower than the preoperative levels.One week after surgery,the patients presented advanced sleep chronotype [3∶03±0∶59 vs.2∶42±0∶37;MD(95%CI):-21(-40--1),t=-2.172,P=0.038],shortened sleep latency [(67±64)min vs.(37±21)min;MD(95%CI):-30.33(-55.28--5.39),t=-2.487,P=0.019],lengthened sleep duration [(436±83)min vs.(499±83)min;MD(95%CI):62.80(26.93-98.67),t=3.581,P=0.001],increased sleep efficiency [(87.59±10.35)% vs.(92.98±4.27)%;MD(95%CI):5.39(1.21-9.58),t=2.636,P=0.013],decreased sleep quality score [1.13±0.78 vs.0.80±0.71;MD(95%CI):-0.33(-0.62--0.05),t=-2.408,P=0.023],and declined PSQI total score [6.60±3.17 vs.4.03±2.58;MD(95%CI):-2.57(-3.87--1.27),t=-4.039,P<0.001].Body mass index(BMI)(B=-227.460,SE=95.475,t=-2.382,P=0.025),anesthesia duration(B=-47.079,SE=18.506,t=-2.544,P=0.017),and mRNA level of PER2(B=2815.804,SE=1080.183,t=2.607,P=0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine(B=0.067,SE=0.028,t=2.385,P=0.024)independently influenced the PSQI one week after surgery. Conclusions Total intravenous anesthesia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Complement receptor C5aR1 blockade reprograms tumor-associated macrophages and synergizes with anti-PD-1 therapy in gastric cancer.

In gastric cancer (GC), the therapeutic response of immune checkpoint blockade (ICB) remains suboptimal. Targeting myeloid cell checkpoints might be feasible as adjuvant to current ICB regimens. We sought to evaluate the crucial role of C5aR1+ TAMs in regulating antitumor immunity and the efficacy of combinatorial treatment with antiprogrammed cell death protein-1 (PD-1) and C5aR1 blockade. Here, we found that C5aR1 was predominantly expressed on macrophages and high level of C5aR1+ TAMs infiltration could predict poor prognosis and inferior chemotherapeutic response. The flow cytometry (FCM) and single-cell RNA-seq (scRNA-seq) data revealed that C5aR1+ TAMs exhibited immunosuppressive property which might contribute to CD8+ T cell dysfunction. Blockade of C5aR1 could diminish the immunosuppressive function of TAMs and led to reinvigorated CD8+ T cells mediated antitumor immunity. Moreover, using in vitro intervention experiment based on fresh GC surgical specimens, we discovered that C5aR1 blockade exert a synergistic effect when combined with PD-1 inhibitor for tumor clearance. Our study demonstrated that C5aR1 is a critical myeloid checkpoint and plays a crucial role in regulating the immunosuppressive property of TAMs and CD8+ T cell immune tolerance. C5aR1 blockade reprograms TAMs and reinvigorated the cytotoxicity of CD8+ T cells, thus improving the efficacy of anti-PD-1 therapy for tumor eradication in GC.

C-type lectin receptor Dectin-1 blockade on tumour-associated macrophages improves anti-PD-1 efficacy in gastric cancer.

BACKGROUND: This study aimed to investigate the expression and clinical significance of Dendritic cell-associated C-type lectin-1 (Dectin-1) in gastric cancer (GC), and to explore the mechanism of Dectin-1 regulating tumour-associated macrophage (TAM)-mediated immune evasion in GC. METHODS: The association of Dectin-1+ cells with clinical outcomes was inspected by immunohistochemistry on tumour microarrays. Flow cytometry and RNA sequencing were applied to detect characteristics of T cells, phenotypic and transcriptional features of Dectin-1+ TAMs. The effect of Dectin-1 blockade was evaluated using an in vitro intervention experiment based on fresh GC tissues. RESULTS: High infiltration of intratumoral Dectin-1+ cells predicted poor prognosis in GC patients. Dectin-1+ cells were mainly composed of TAMs, and the accumulation of Dectin-1+ TAMs was associated with T-cell dysfunction. Notably, Dectin-1+ TAMs exhibited an immunosuppressive phenotype. Furthermore, blockade of Dectin-1 could reprogramme Dectin-1+ TAMs and reactivate anti-tumour effects of T cells, as well as enhanced PD-1 inhibitor-mediated cytotoxicity of CD8+ T cells against tumour cells. CONCLUSIONS: Dectin-1 could affect T-cell anti-tumour immune response by regulating the immunosuppressive function of TAMs, leading to poor prognosis and immune evasion in GC patients. Blockade of Dectin-1 can be used alone or in combination with current therapeutic strategies in GC.

The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration.

BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Somatic ARID1A mutation stratifies patients with gastric cancer to PD-1 blockade and adjuvant chemotherapy.

BACKGROUND: AT-rich interaction domain 1A (ARID1A) encodes a vital component of switch/sucrose non-fermentable chromatin-remodeling complex. Given its association with genomic instability, we conducted this study to determine whether ARID1A mutation status had an impact on therapeutic responsiveness in gastric cancer (GC), especially combinatory chemo-immunotherapy. METHODS: We retrospectively enrolled a total of 1162 patients from five independent cohorts. ZSHS Cohort and TCGA Cohort were designed to inform chemotherapeutic relevance and immunobiology of ARID1A-mutant GC based on tissue samples and sequencing data, respectively. MSKCC Cohort, mGC Cohort, and Melanoma Cohort were utilized to interrogate the predictive efficacy of ARID1A mutation to programmed cell death protein 1 (PD-1) blockade. RESULTS: ARID1A mutation was enriched in EBV-positive, hypermutated-single nucleotide variant and microsatellite-unstable subtype GC, and was predictive of responsiveness to both fluorouracil-based chemotherapy and PD-1 blockade. Specifically, ARID1A mutation score was a highly sensitive indicator (91%) of response to pembrolizumab. Mechanistically, ARID1A mutation correlated with extensive DNA damage repair deficiency and immunogenic tumor microenvironment (TME) featured by elevated activated subsets of CD8+ T cells, CD4+ T cells, and NK cells. Type 17T helper cells were typically abundant in ARID1A-mutant GC and might be a precondition for chemosensitivity conferred by ARID1A mutation. Furthermore, ARID1A mutation indicated elevated expression of VEGFA and CLDN18, as well as over-representation of ERBB2 and FGFR2 signaling pathway. CONCLUSIONS: ARID1A-mutant GC displayed immunogenic TME and might be a candidate for both monotherapy and the combination of frontline chemotherapy and PD-1 blockade.

In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives.

Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6.

Effect of Percutaneous Endovascular Angioplasty Combined with Negative Pressure Drainage on the "One-Stop" Treatment of Ischemic Diabetic Foot Ulcer.

BACKGROUND: To explore the therapeutic effect, safety, and economic benefit of a "one-stop" diagnosis and treatment mode of vascular surgery for ischemic diabetic foot (DF) ulcer and to analyze the associated and independent factors that affect ulcer healing. METHODS: In a prospective, single-center study, patients with ischemic DF ulcers from January 2017 to July 2021 were treated with either percutaneous endovascular angioplasty combined with negative pressure closed drainage (PTA-VSD) or percutaneous endovascular angioplasty combined with depuration (PTA-UD). The effectiveness and economic benefits of the 2 measures were compared, and independent factors affecting ulcer healing were explored via univariate and logistic regression analyses. RESULTS: Fifty patients with ischemic DF ulcer (25 patients in the PTA-VSD group and 25 patients in the PTA-UD group; 40 males and 10 females) were included, with an average age of 67.74 ± 10.71 years. No difference was observed in the demographic data. The findings showed that the ulcer healing time in the PTA-VSD group was significantly shorter than that in the PTA-UD group (154.79 vs. 238.31 days), and the ulcer healing rate at 180 days post surgery was significantly greater in the PTA-VSD group (52% vs. 12%) (P = 0.002, < 0.05). The ulcer score in the PTA-VSD group decreased significantly at 3, 6, and 12 months post surgery. The duration of hospitalization in the PTA-VSD group was greater (P = 0.002, <0.05), but no significant difference in hospitalization frequency and cost was observed between the 2 groups. During follow-up, there was 1 death and 1 amputation in the PTA-UD group, but no death or amputation in the PTA-VSD group. Arterial occlusion was primarily located in the femoral-popliteal artery and the inferior knee artery in the 2 groups, and PTA intervention effectively opened the outflow tract of the affected limb. Two to three outflow tracts were opened in 41 patients. The ankle-brachial index (ABI) after surgery was significantly higher in both groups than before. Univariate and multivariate logistic regression analyses revealed that the Wagner grade and number of outflow channels and therapies (PTA-VSD) could be independent factors affecting ulcer healing. CONCLUSIONS: The severity of DF ulcers is an important factor affecting the quality of life of patients. A multidisciplinary "one-stop" treatment strategy based on percutaneous endovascular angioplasty combined with negative pressure-sealing drainage can rapidly and effectively restore the blood flow to the affected limb and promote ulcer healing without increasing medical costs.

Involvement of a AS3MT/c-Fos/p53 signaling axis in arsenic-induced tumor in human lung cells.

Arsenite methyltransferase (AS3MT) is an enzyme that catalyzes the dimethylation of arsenite (+3 oxidation state). At present, the studies on arsenic carcinogenicity mainly focus on studying the polymorphisms of AS3MT and measuring their catalytic activities. We recently showed that AS3MT was overexpressed in lung cancer patients who had not been exposed to arsenic. However, little is known about the molecular mechanisms of AS3MT in arsenite-induced tumorigenesis. In this study, we showed that AS3MT protein expression was higher in the arsenic-exposed population compared to the unexposed population. AS3MT was also overexpressed in human lung adenocarcinoma (A549) and human bronchial epithelial (16HBE) cells exposed to arsenic (A549: 20-60 µmol/L; 16HBE: 2-6 µmol/L) for 48 h. Furthermore, we investigated the effects of AS3MT on cell proliferation and apoptosis using siRNA. The downregulation of AS3MT inhibited the proliferation and promoted the apoptosis of cells. Mechanistically, AS3MT was found to specifically bind to c-Fos, thereby inhibiting the binding of c-Fos to c-Jun. Additionally, the siRNA-mediated knockdown of AS3MT enhanced the phosphorylation of Ser392 in p53 by upregulating p38 MAPK expression. This led to the activation of p53 signaling and the upregulated expression of downstream targets, such as p21, Fas, PUMA, and Bax. Together, these studies revealed that the inorganic arsenic-mediated upregulation of AS3MT expression directly affected the proliferation and apoptosis of cells, leading to arsenic-induced toxicity or carcinogenicity.

Inorganic arsenic-mediated upregulation of TUG1 promotes apoptosis in human bronchial epithelial cells by activating the p53 signaling pathway.

Exposure to arsenic, an environmental contaminant, is known to cause arsenicosis and cancer. Although considerable research has been conducted to understand the underlying mechanism responsible for arsenic-induced cancers, the precise molecular mechanisms remain unknown, especially at the epigenetic regulation level. Long non-coding RNAs (LncRNAs) that have been shown to mediate various biological processes, including proliferation, apoptosis, necrosis, and mutagenesis. There are few studies on LncRNAs and biological damage caused by environmental pollutants. The LncRNAs taurine upregulated gene 1 (TUG1) regulates cell growth both in vitro and in vivo, and contributes its oncogenic role. However, the precise roles and related mechanisms of arsenic-induced cell apoptosis are still not fully understood owing to controversial findings in the literature. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed higher expression levels of TUG1 in people occupationally exposed to arsenic than in individuals living away from the source of arsenic exosure (N = 25). In addition, the results suggested that TUG1 was involved in arsenic-induced apoptosis. Furthermore, knockdown experiments showed that silencing of TUG1 markedly inhibited proliferation, whereas depletion of TUG1 led to increased apoptosis. The TUG1-small interfering RNA (siRNA) combination with arsenic (3 µM/L) slightly increased apoptosis compared with the TUG1-siRNA. Additionally, the knockdown experiments showed that the silencing of TUG1 by siRNA inhibited proliferation and promoted apoptosis by inducing p53, p-p53 (ser392), FAS, BCL2, MDM2, cleaved-caspase7 proteins in 16HBE cells. These results indicated that arsenic mediates the upregulation of TUG1 and induces cell apoptosis via activating the p53 signaling pathway.

Novel Therapeutic Potential of Retinoid-Related Orphan Receptor α in Cardiovascular Diseases.

The retinoid-related orphan receptor α (RORα) is one subfamily of nuclear hormone receptors (NRs). This review summarizes the understanding and potential effects of RORα in the cardiovascular system and then analyzes current advances, limitations and challenges, and further strategy for RORα-related drugs in cardiovascular diseases. Besides regulating circadian rhythm, RORα also influences a wide range of physiological and pathological processes in the cardiovascular system, including atherosclerosis, hypoxia or ischemia, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, hypertension, and myocardial hypertrophy. In terms of mechanism, RORα was involved in the regulation of inflammation, apoptosis, autophagy, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial function. Besides natural ligands for RORα, several synthetic RORα agonists or antagonists have been developed. This review mainly summarizes protective roles and possible mechanisms of RORα against cardiovascular diseases. However, there are also several limitations and challenges of current research on RORα, especially the difficulties on the transformability from the bench to the bedside. By the aid of multidisciplinary research, breakthrough progress on RORα-related drugs to combat cardiovascular disorder may appear.

Impact of intratumoural CD96 expression on clinical outcome and therapeutic benefit in gastric cancer.

CD96 was identified as a novel immune checkpoint. However, the role of CD96 in the gastric cancer (GC) microenvironment remains fragmentary. This study aimed to probe the clinical significance of CD96 to predict prognosis and therapeutic responsiveness, and to reveal the immune contexture and genomic features correlated to CD96 in GC patients. We enrolled 496 tumor microarray specimens of GC patients from Zhongshan Hospital (ZSHS) for immunohistochemical analyses. Four hundred and twelve GC patients from the Cancer Genome Atlas (TCGA) and 61 GC patients treated with pembrolizumab from ERP107734 published in the European Nucleotide Archive (ENA) were gathered for further analysis of the association between CD96+ cell infiltration and immune contexture, molecular characteristics, and genomic features by CIBERSORT and gene set enrichment analysis. Clinical outcomes were analyzed by Kaplan-Meier curves, the Cox model, interaction testing, and receiver operating characteristic analysis. High CD96+ cell infiltration predicted poor prognosis and inferior survival benefits from fluorouracil-based adjuvant chemotherapy in the ZSHS cohort whereas superior therapeutic responsiveness to pembrolizumab was shown in the ENA cohort. CD96-enriched tumors showed an immunosuppressive tumor microenvironment featured by exhausted CD8+ T-cell infiltration in both the ZSHS and TCGA cohorts. Moreover, in silico analysis for the TCGA cohort revealed that several biomarker-targeted pathways displayed significantly elevated enrichment levels in the CD96 high subgroup. This study elucidated that CD96 might drive an immunosuppressive contexture with CD8+ T-cell exhaustion and represent an independent adverse prognosticator in GC. CD96 could potentially be a novel biomarker for precision medicine of adjuvant chemotherapy, immunotherapy, and targeted therapies in GC.

TIM3+ cells in gastric cancer: clinical correlates and association with immune context.

BACKGROUND: T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a crucial immune checkpoint and is considered as an emerging target for cancer treatment. However, the clinical significance and immune-related role of TIM3+ cells in gastric cancer remain unknown. This study aimed to investigate the clinical significance of tumour-infiltrating TIM3+ cells and their association with immune contexture in gastric cancer. METHODS: This study enrolled three cohorts, including 436 tumour tissue microarray specimens and 58 fresh tumour tissues of gastric cancer patients from Zhongshan Hospital, and 330 transcriptional data from The Cancer Genome Atlas. TIM3+ cells and their association with CD8+ T cells were evaluated by immunohistochemistry and flow cytometry analyses. Kaplan-Meier curves, Cox model and interaction test were performed to assess clinical outcomes. RESULTS: Tumour-infiltrating TIM3+ cells' high subgroups experienced poorer overall survival and disease-free survival and predicted inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. TIM3 indicated CD8+ T cell dysfunction, which impeded chemotherapeutic responsiveness. Besides, HAVCR2 messenger RNA expression was associated with specific molecular characteristics. CONCLUSIONS: The abundance of tumour-infiltrating TIM3+ cells could identify an immunoevasive subtype gastric cancer with CD8+ T cell dysfunction, suggesting that TIM3 might serve as a promising target for immunotherapy in gastric cancer.

Intratumoral PD-1+CD8+ T cells associate poor clinical outcomes and adjuvant chemotherapeutic benefit in gastric cancer.

BACKGROUND: Although PD-1 has been reported to be a marker of T-cell exhaustion in several malignancies, the biological role of PD-1+CD8+ T cells in gastric cancer (GC) remains unclear. Herein, we aimed to investigate the role of PD-1+CD8+ T cells in the tumour microenvironment and its clinical significance in GC. DESIGNS: This study included 441 tumour microarray specimens and 60 Flow cytometry specimens of GC patients from Zhongshan Hospital, and 250 GC patients from the Asian Cancer Research Group. RESULTS: Here, we demonstrated that PD-1+CD8+ T cells functioned as an independent adverse prognosticator in GC. In addition, an abundance of intratumoral PD-1+CD8+ T cells indicated worse chemotherapeutic responsiveness to fluorouracil in Stage III GC patients. Mechanistically, PD-1+CD8+ T cell high infiltration indicated an exhausted phenotype of global CD8+ T cells in GC tissues, which was characterised by elevated immune checkpoint expression including CTLA-4 and TIM-3, whereas decreased expression of perforin. Furthermore, PD-1+CD8+ T cell high-infiltration patients with Stage III GC held elevated activity of several therapeutic signal pathways. CONCLUSIONS: Our study highlighted that PD-1+CD8+ T cell abundance predicts inferior prognosis in GC, and may serve as a novel predictive biomarker to guide therapeutic option.

Poor Clinical Outcomes and Immunoevasive Contexture in Intratumoral IL-10-Producing Macrophages Enriched Gastric Cancer Patients.

OBJECTIVE: To investigate the clinical significance of IL-10+ tumor-associated macrophages (TAMs) in gastric cancer. BACKGROUND: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10+ TAMs in gastric cancer remains obscure. METHODS: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10+ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model. RESULTS: Gastric cancer patients with high IL-10+ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10+ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8+ T cell dysfunction. The combinational analysis of IL-10+ TAM and CD8+ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10+ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. CONCLUSIONS: This study revealed that IL-10+ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy, indicating IL-10+ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.