First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

[Research progress of celastrol on the prevention and treatment of metabolic associated fatty liver disease].

Metabolic associated fatty liver disease (MAFLD) is a liver disease with hepatocyte steatosis caused by metabolic disorders, which is closely related to obesity, diabetes, metabolic dysfunction, and other factors. Its pathological process changes from simple steatosis, liver inflammation to non-alcoholic steatohepatitis (NASH), and then leads to liver fibrosis, cirrhosis, and liver cancer. At present, no specific therapeutics are available for treatment of MAFLD targeting its etiology. Celastrol is the main active component of the traditional Chinese medicine Celastrus orbiculatus Thunb. In recent years, it has been found that celastrol shows important medicinal value in regulating lipid metabolism, reducing fat and weight, and protecting liver, and then ameliorates MAFLD. This article reviews the related research progress of celastrol in the prevention and treatment of MAFLD, so as to provide a reference for the comprehensive development and utilization of celastrol.

Evolutionary history of a beautiful damselfly, Matrona basilaris, revealed by phylogeographic analyses: the first study of an odonate species in mainland China.

Matrona basilaris Selys, 1853 is a damselfly distributed mainly in mainland China. A total of 423 individuals from 48 populations covering almost the entire range were sampled to explore the genetic diversity, phylogeographic structure, and demographic dynamics of the species using sequences of three mitochondrial genes (COI, COII, and ND1) and a nuclear (ITS1 + 5.8 S + ITS2) gene. Phylogenetic tree, median-joining network, and BAPS analyses indicated a four-group division of the entire population, and the divergence event was estimated to have occurred in the middle Pleistocene. The diverse terrain of mainland China as well as past climatic oscillations were assumed to have shaped the current phylogeographic pattern of M. basilaris. Multiple lines of evidence supported population expansion in Group 1 and Group 2 but not in Group 3 or Group 4. The expansion times corresponded to the transition phase from the LIG (∼0.14-0.12 Mya) to the LGM (∼0.021-0.018 Mya). The pre-LGM expansion model reflected a different pattern affecting the historical dynamics of the population of East Asian species caused by Pleistocene climatic changes. Interestingly, Group 2 exhibited a disjunctive distribution pattern. The possible reasons were introgression caused by female-biased dispersal or human phoresy during construction of the Forbidden City during the Ming Dynasty of China.

NEAT1 contributes to breast cancer progression through modulating miR-448 and ZEB1.

Breast cancer is a kind of common female cancers. Increasing evidence has exhibited that lncRNAs exert a crucial role in breast cancer. So far, the mechanism of lncRNAs in breast cancer is still not well established. In our current study, we focused on the biological role of lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) in breast cancer. We observed that NEAT1 levels were significantly increased in human breast cancer cells including MCF-7, MDA-MB-453, MDA-MB-231, and SKBR3 cells compared to normal mammary epithelial cells MCF-10A while miR-448 was decreased. We found that downregulation of NEAT1 was able to inhibit the growth of breast cancer cells and miR-448 mimic exerted the similar function. Bioinformatics analysis and dual luciferase reporter assays confirmed the negative correlation between NEAT1 and miR-448 in vitro. In addition, ZEB1 was predicted as a novel mRNA target of miR-448. Overexpression of NEAT1 can induce breast cancer cell growth, migration, and invasion by inhibiting miR-448 and upregulating ZEB1. It was demonstrated that NEAT1 can increase ZEB1 levels while miR-448 mimic can repress ZEB1. It was speculated in our study that NEAT1 can serve as a competing endogenous lncRNA (ceRNA) to modulate ZEB1 by sponging miR-448 in breast cancer. To conclude, we uncovered that NEAT1 participated in breast cancer progression by regulating miR-448 and ZEB1. NEAT1 can be provided as a vital biomarker in breast cancer diagnosis and treatment therapy.

[Research advances on preventive and therapeutic effects of hydrogen on cardiovascular and cerebrovascular diseases and underlying mechanisms].

For a long time, hydrogen (H2) has been considered as a physiological inert gas. However, recent studies have demonstrated that molecular H2 exerts significant therapeutic effects on various disease models due to its antioxidative, anti-inflammatory and anti-apoptotic capabilities, which have also been well confirmed in many clinical trials. Cardiovascular and cerebrovascular diseases (CCVDs) are the leading cause of death in the world, constituting a serious threat to human life and public health. In this paper, we reviewed the latest research progress of the biomedical effects of H2 in CCVDs and its possible molecular mechanisms, in the hope of providing new clues for the treatment of some CCVDs.

Transcriptome analysis of Ruditapes philippinarum hepatopancreas provides insights into immune signaling pathways under Vibrio anguillarum infection.

The Manila clam, Ruditapes philippinarum, is one of the most economically important aquatic clams that are harvested on a large scale by the mariculture industry in China. However, increasing reports of bacterial pathogenic diseases have had a negative effect on the aquaculture industry of R. philippinarum. In the present study, the two transcriptome libraries of untreated (termed H) and challenged Vibrio anguillarum (termed HV) hepatopancreas were constructed and sequenced from Manila clam using an Illumina-based paired-end sequencing platform. In total, 75,302,886 and 66,578,976 high-quality clean reads were assembled from 101,080,746 and 99,673,538 raw data points from the two transcriptome libraries described above, respectively. Furthermore, 156,116 unigenes were generated from 210,685 transcripts, with an N50 length of 1125 bp, and from the annotated SwissProt, NR, NT, KO, GO, KOG and KEGG databases. Moreover, a total of 4071 differentially expressed unigenes (HV vs H) were detected, including 903 up-regulated and 3168 down-regulated genes. Among these differentially expressed unigenes, 226 unigenes were annotated using KEGG annotation in 16 immune-related signaling pathways, including Toll-like receptor, NF-kappa B, MAPK, NOD-like receptor, RIG-I-like receptor, and the TNF and chemokine signaling pathways. Finally, 20,341 simple sequence repeats (SSRs) and 214,430 potential single nucleotide polymorphisms (SNPs) were detected from the H and HV transcriptome libraries. In conclusion, these studies identified many candidate immune-related genes and signaling pathways and conducted a comparative analysis of the differentially expressed unigenes from Manila clam hepatopancreas in response to V. anguillarum stimulation. These data laid the foundation for studying the innate immune systems and defense mechanisms in R. philippinarum.

Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance.

BACKGROUND: In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival. CONCLUSION: This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.

TQB2450 in patients with advanced malignant tumors: results from a phase I dose-escalation and expansion study.

Background: Immune checkpoint inhibitor therapy has demonstrated impressive clinical benefits in multiple tumor types. TQB2450, a novel monoclonal antibody targeting programmed cell death ligand 1, has shown safety and efficacy in preclinical studies. Objectives: This first-in-human study aimed to evaluate the safety/tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of TQB2450 in patients with advanced malignant tumors. Design and methods: In this phase I study, eligible patients with advanced malignant tumors received intravenous TQB2450 once every 3 weeks. This study consisted of a 3 + 3 dose-escalation phase (1-30 mg/kg) and a specific dose-expansion phase (1200 mg). The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety. The secondary endpoints were PK, immunogenicity, and investigator-assessed response rate. Results: Between April 2018 and February 2020, 40 patients were enrolled (22 in the dose-escalation phase and 18 in the dose-expansion phase). No DLT was reported and the MTD was not reached. Grade ⩾3 or worse treatment-related treatment-emergent adverse events (AEs) occurred in 11 (27.50%) patients, with the most frequent being aspartate aminotransferase increased (5.00%), leukopenia (5.00%), and anemia (5.00%). Treatment-related serious AEs were reported in six patients, the most common of which was decompensated liver function (5.00%). No treatment-related death was reported. The maximum serum concentration of TQB2450 increased in a dose-proportional manner. Treatment-induced anti-drug antibodies were detected in 31.58% (12/38) of patients. The investigator assessed the objective response rate as 5.00% and the disease control rate was 52.50%, including 2 partial responses and 19 stable diseases. The median progression-free survival was 2.69 (95% confidence interval, 2.07-6.14) months. Conclusion: TQB2450 has a manageable safety profile with favorable PK and immunogenicity and has shown early evidence of clinical activity in advanced malignant tumors. ClinicalTrialsgov identifier: NCT03460457.

The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors.

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Quantitative assessment of the association between XRCC6 C1310G polymorphism and cancer risk.

X-ray cross-complementing group 6 (XRCC6) plays an important role in the DNA double-strand breaks repair and the maintenance of genomic integrity. XRCC6 C1310G polymorphism may be involved in the development of cancer through increasing genomic damages. However, studies investigating the relationship between XRCC6 C1310G polymorphism and cancer risk yielded contradictory results. To shed some light on these inconsistent findings, a meta-analysis was performed to clarify the effect of XRCC6 C1310G polymorphism on the susceptibility of cancer. A systemic literature search of PubMed, EMBASE, and China National Knowledge Infrastructure databases was conducted from their inception to September 26, 2012. The association between XRCC6 C1310G and cancer risk was assessed by the pooled odds ratio (OR) with 95 % confidence intervals (95 % CI) calculated by meta-analysis. A total of 15 eligible studies (4,642 cancer cases and 6,059 controls) were identified. Overall, there was obvious evidence for an association between XRCC6 C1310G polymorphism and increased risk of cancer under two genetic comparisons (GG vs. CC: fixed-effect OR 1.35, 95 % CI 1.10-1.66, I (2) = 17.0 %; GG vs. CG/CC: fixed-effect OR 1.25, 95 % CI 1.02-1.53, I (2) = 0.0 %). Subgroup analysis indicated that the association was significant in Asians (G vs. C: random-effect OR 1.13, 95 % CI 1.01-1.26, I (2) = 51.3 %; GG vs. CC: fixed-effect OR 1.43, 95 % CI 1.14-1.81, I (2) = 0.0 %; GG vs. CG/CC: fixed-effect OR 1.37, 95 % CI 1.09-1.72, I (2) = 0.0 %), but not in Europeans. Data from the current meta-analysis support the existence of an association between XRCC6 C1310G polymorphism and cancer risk in Asians. Studies with larger sample size are needed to further evaluate the influence of XRCC6 C1310G polymorphism on susceptibility of various cancers.

The protective effects of α-lipoic acid on kidneys in type 2 diabetic Goto-Kakisaki rats via reducing oxidative stress.

To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg-1 intraperitoneal injections. Four healthy Wistar rats served as normal controls. Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured. The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR. Pathological changes in renal tissue were evaluated by light and electron microscopy. There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group. Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group. All the parameters above were improved in the α-lipoic acid-treated diabetic group. Oxidative stress is increased in the kidney of type 2 diabetic GK rats. It is associated with the progression of diabetic nephropathy. α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity.

Therapeutic outcomes of mycophenolate mofetil and glucocorticoid in thyroid-associated ophthalmopathy patients.

Objective: To analyze the efficacy of mycophenolate mofetil (MMF) and glucocorticoid administration in patients with thyroid-associated ophthalmopathy (TAO). Methods: Sixty patients with moderate to severe TAO treated in Jingzhou Central Hospital from January 2022 to June 2022 were selected and enrtolled in this study. The subjects were divided into experimental group (n=30) and control group (n=30) based on the random number table method. Glucocorticoid pulse therapy was provided in the control group, while MMF was given in the experimental group on the basis of Control group. Clinical activity score (CAS), quality of life (QOL), visual acuity, eyelid fissure width, intraocular pressure, and degree of exophthalmos were observed at the time of admission and at the 12th week and 24th post-treatment weeks. We compared the immune function (TRAb, IL-6, and CD4+/CD8+) of the two groups pre-treatment and 24 weeks post-treatment, and evaluated the clinical therapeutic effect. Results: The clinical effective rates at 12 and 24 weeks in the experimental group were higher (73.3% and 83.3%) than those in the control group (46.7% and 60.0%) (P <0.05). After 12 weeks of treatment, patients' CAS scores, and bilateral lid fissure width decreased and right eye visual acuity increased in the control group compared with those before treatment (P < 0.05); further, after 24 weeks of treatment, patients' QOL scores and bilateral visual acuity increased and CAS scores, bilateral lid fissure width and proptosis decreased compared with those before treatment, and patients' QOL scores, CAS scores and bilateral proptosis improved more than those at 12 weeks of treatment (P <0.05). Additionally, greater improvements were observed in the patients' QOL and CAS scores, and proptosis after 24-week treatment than after 12-week treatment (P<0.05). In the experimental group, the QOL score and binocular visual acuity increased, whereas the CAS score, intraocular pressure, lid width, and proptosis decreased after 12 weeks of treatment as compared to the values of these parameters in the pre-treatment period (P < 0.05); after 24 weeks of treatment, greater improvements were established in the ocular-related indexes improved compared to the pre-treatment period and after 12 weeks of treatment (P < 0.05). After 12 weeks of treatment, the patients in the experimental group had more considerable improvements in the right visual acuity, right intraocular pressure, and left lid fissure width than the control group (P < 0.05); at 24 weeks of treatment, patients in the experimental group had greater improvements in the QOL score, bilateral visual acuity, intraocular pressure, bilateral lid fissure width, and bilateral proptosis than the control group (P < 0.05). No significant differences were found in the values of TRAb, IL-6, and CD4+/CD8+ between the two groups before treatment (P>0.05); the values of TRAb, IL-6, and CD4+/CD8+ in the experimental group was significantly lower than those before treatment and in the control group after 24weeks of treatment. (P>0.05). No statistically significant difference was observed in the incidence of liver damage and menstrual disorders between the two groups during the 24 weeks of treatment (P>0.05). Conclusion: The combination of oral MMF and glucocorticoid shock therapy is an effective drug for the treatment of patients with moderately active TAO.

Phenylethanoid glycosides extract from Cistanche deserticola ameliorates atherosclerosis in apolipoprotein E-deficient mice and regulates intestinal PPARγ-LXRα-ABCA1 pathway.

OBJECTIVES: This study was aimed to evaluate the protective effects of phenylethanoid glycosides extract from Cistanche deserticola against atherosclerosis and its molecular mechanism. METHODS: Total phenylethanoid glycosides were extracted and purified from C. deserticola, and the C. deserticola extract (CDE) was used to treat a mice model of atherosclerosis. KEY FINDINGS: CDE containing 81.00% total phenylethanoid glycosides, with the contents of echinacoside and acteoside being 31.36% and 7.23%, respectively. A 13-week of CDE supplementation (1000 mg/kg body weight/day) significantly reduced atherosclerotic lesions in the aortic sinus and entire aorta in ApoE-/- mice fed with a high-fat diet. In addition, varying doses of CDE (250, 500 and 1000 mg/kg body weight/day) lowered plasma total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels. Transcriptomic analysis of the small intestine revealed the changes enriched in cholesterol metabolic pathway and the activation of Abca1 gene. Further validation using real-time quantitative PCR and western blot confirmed that CDE significantly increased the mRNA levels and protein expressions of ABCA1, LXRα and PPARγ. CONCLUSIONS: Our results demonstrate the beneficial effects of C. deserticola on atherosclerotic plaques and lipid homeostasis, and it is, at least partially, by activating PPARγ-LXRα-ABCA1 pathway in small intestine.

Inhalation of 4% and 67% hydrogen ameliorates oxidative stress, inflammation, apoptosis, and necroptosis in a rat model of glycerol-induced acute kidney injury.

Acute kidney injury (AKI) is the major complication of rhabdomyolysis (RM) clinically, which is usually mimicked by glycerol injection in basic research. Oxidative stress, inflammatory response and apoptosis are recognized to play important roles in development of this disease. Recently, numerous studies have reported the therapeutic effects of molecular hydrogen (H2) on oxidative stress and inflammation-related diseases. Here, the effects of H2 against glycerol-induced AKI and the underlying mechanisms were explored in rats. Low (4%) and high (67%) concentrations of H2 were prepared using a self-made device to investigate the dose-response. After 72 hours of glycerol injection (8 mL/kg), we found that glycerol triggered oxidative stress, inflammatory reactions, and apoptotic events. These caused subsequent renal damage, evidenced by a significant reduction of antioxidases and up-regulation of the relevant damaged biomarkers. H2 inhalation reversed the above alterations and exerted renoprotective effects. Interestingly, for RM/AKI-related factors, no consistent dose-response benefits of H2 were observed. However, higher concentration of H2 inhalation improved histological and morphological changes better. This study suggests that H2 is a potential alternative therapy to prevent or minimize RM induced AKI possibly via its antioxidant, anti-inflammatory, anti-apoptotic and anti-necroptotic properties.

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. In vitro cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. Functionally, PYGL overexpression promotes cell migration and invasion in vitro and facilitates liver metastasis in vivo, while PYGL knockdown has opposite effects. Mechanically, hypoxia induces PYGL expression in a hypoxia inducible factor 1α (HIF1α)-dependent manner and promotes glycogen accumulation. Elevated PYGL mobilizes accumulated glycogen to fuel glycolysis via its activity as a glycogen phosphorylase, thus inducing the EMT process, which could be suppressed by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Clinically, PYGL expression is upregulated in PDAC and correlates with its malignant features and poor prognosis. Collectively, the data from our study reveal that the hypoxia/PYGL/glycolysis-induced EMT promotes PDAC metastasis, which establishes the rational for targeting hypoxia/PYGL/glycolysis/EMT signaling pathway against PDAC.

Hydrogen inhalation ameliorates hepatic inflammation and modulates gut microbiota in rats with high-fat diet-induced non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a multisystem metabolic disease associated with gut microflora dysbiosis and inflammation. Hydrogen (H2) is a novel and effective antiinflammatory agent. The present study was aimed to clarify the effects of 4% H2 inhalation on NAFLD and its mechanism of action. Sprague-Dawley rats were fed a high-fat diet for 10 weeks to induce NAFLD. Rats in treatment group inhaled 4% H2 each day for 2 h. The protective effects on hepatic histopathology, glucose tolerance, inflammatory markers, and intestinal epithelial tight junctions were assessed. Transcriptome sequencing of liver and 16 S-seq of cecal contents were also performed to explore the related mechanisms of H2 inhalation. H2 improved the hepatic histological changes and glucose tolerance, decreased the liver function parameters of plasma alanine aminotransferase and aspartate aminotransferase, and relieved liver inflammation. Liver transcriptomic data suggested that H2 treatment significantly downregulated inflammatory response genes, and the lipopolysaccharide (LPS)/Toll-like receptor (TLR) 4/nuclear transcription factor kappa B (NF-κB) signaling pathway might be involved, and the expressions of critical proteins were further validated. Meanwhile, the plasma LPS level was significantly decreased by the H2 intervention. H2 also improved the intestinal tight junction barrier by enhancing the expressions of zonula occludens-1 and occluding. Based on 16S rRNA sequencing, H2 altered the composition of gut microbiota, improving the relative abundance of Bacteroidetes-to-Firmicutes. Collectively, our data show that H2 could prevent NAFLD induced by high-fat diet, and the anti-NAFLD effect is associated with the modulation of gut microbiota and inhibition of LPS/TLR4/NF-κB inflammatory pathway.

Next-generation sequencing identifies CDKN2A alterations as prognostic biomarkers in recurrent or metastatic head and neck squamous cell carcinoma predominantly receiving immune checkpoint inhibitors.

Background: This study aimed to identify potential biomarkers in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and further probe the prognostic implications of CDKN2A mutations, particularly within a subset receiving immunotherapy. Methods: In this retrospective single-center study, we evaluated the next-generation sequencing (NGS) data from Foundation Medicine (FM) for patients with recurrent or metastatic HNSCC between January 1, 2019, and December 31, 2021. Patients were stratified based on CDKN2A loss-of-function (LOF) versus wild-type (WT) categorizations, with a focused subgroup analysis on those administered immunotherapy. Results: The study encompassed 77 patients, of which 62 had undergone immunotherapy. The median duration of follow-up was 22.6 months. For the CDKN2A LOF group, the median overall survival (OS) was 16.5 months, contrasted with 30.0 months in the CDKN2A WT group (P=0.014). Notably, female gender (hazard ratio [HR]=4.526, 95% confidence interval [CI]: 1.934-10.180, P=0.0003) and CDKN2A LOF (HR=2.311, 95% CI: 1.156-4.748, P=0.019) emerged as independent risk factors for mortality in patients with recurrent or metastatic HNSCC. Within the immunotherapy subset, the median OS was 11.7 months for the CDKN2A LOF group, and 22.5 months for the CDKN2A WT group (P=0.017). Further, the female gender (HR=4.022, 95% CI: 1.417-10.710, P=0.006), CDKN2A LOF (HR=4.389, 95% CI: 1.782-11.460, P=0.002), and a combined positive score below 1 (HR=17.20, 95% CI: 4.134-79.550, P<0.0001) were identified as significant predictors of mortality among patients with recurrent or metastatic HNSCC receiving immunotherapy. Conclusion: Alterations manifesting as LOF in the CDKN2A gene stand as robust indicators of unfavorable survival outcomes in HNSCC patients, including the subset that underwent immunotherapy.

Chinese expert consensus recommendations for the administration of immune checkpoint inhibitors to special cancer patient populations.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442-454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology.

Atorvastatin exerts its anti-atherosclerotic effects by targeting the receptor for advanced glycation end products.

Recent studies demonstrated the beneficial role of atorvastatin in reducing the risk of cardiovascular morbidity and mortality in patients with diabetes mellitus and/or metabolic syndrome. To investigate the mechanisms underlying the anti-atheroscleroic action of atorvastatin, we examined the expression of the receptor for advanced glycation end products (RAGE) and its downstream target gene, monocyte chemoattractant protein-1 (MCP-1) using real-time PCR. In in vitro studies, exposure to high glucose or AGE induced oxidative stress and activation of the AGE/RAGE system in human umbilical vein endothelial cells. Treatment of the cells with atorvastatin significantly released the oxidative stress by restoring the levels of glutathione and inhibited the RAGE upregulation. In diabetic Goto Kakisaki (GK) rats fed with a high-fat diet for 12weeks, RAGE and MCP-1 were upregulated in the aortas, and there was a significant correlation between RAGE and MCP-1 mRNA abundance (r=0.482, P=0.031). Treatment with atorvastatin (20mg/kg qd) significantly downregulated the expression of RAGE and MCP-1. These data thus demonstrate a novel "pleiotropic" activity of atorvastatin in reducing the risk of cardiovascular diseases by targeting RAGE expression.