Pan­cancer analysis on the role of KMT2C expression in tumor progression and immunotherapy.

Histone lysine N-methyltransferase 2C (KMT2C) is involved in transcriptional regulation and DNA damage repair. Mutations in KMT2C have been implicated in the progression, metastasis, and drug resistance of multiple cancer types. However, the roles of KMT2C in the regulation of tumor prognosis, immune cell infiltration and the immune microenvironment in these multiple cancer types remain unclear. Therefore, in the present study, data from The Cancer Genome Atlas and Genotype-Tissue Expression databases were used for KMT2C expression analyses. Kaplan-Meier and univariate Cox regression analyses were also performed to investigate the prognostic role of KMT2C. In addition, Gene Set Enrichment Analysis (GSEA) was conducted to study the KMT2C-related signaling pathways. Tumor immune estimation resource 2 and single-sample GSEA were conducted to investigate the correlation between KMT2C expression and immune cell infiltrations, and Spearman's analysis was conducted to study the correlations among KMT2C, tumor mutational burden, microsatellite instability, immune regulators, chemokines and immune receptors. Immunohistochemistry of patient kidney tumor samples was performed to verify the correlation between KMT2C and programmed death-ligand 1 (PD-L1) expression. Finally, RNA interference, wound healing and colony formation assays were conducted to evaluate the effects of KMT2C expression on cell proliferation and metastasis. The results of the present study demonstrated that KMT2C was highly expressed in multiple cancer types, was a protective factor in kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma, and a risk factor for lung squamous cell carcinoma and uveal melanoma. In addition, KMT2C levels were negatively correlated with immune-activated pathways and the infiltration of immune cells, and positively correlated with inhibitory immune factors and tumor angiogenesis. Patients with low KMT2C expression had higher objective response rates to immunotherapy, and drug sensitivity analysis indicated that topoisomerase, histone deacetylase, DOT1-like histone H3K79 methyltransferase and G9A nuclear histone lysine methyltransferase inhibitors could potentially be used to treat tumors with high KMT2C expression levels. Finally, the KMT2C and PD-L1 expression levels were shown to be positively correlated, and KMT2C knockdown markedly promoted the proliferation and invasion capacities of A549 cells. In conclusion, the present study revealed that low KMT2C expression may be a promising biomarker for predicting the response of patients with cancer to immunotherapy. Conversely, high KMT2C expression was shown to promote tumor angiogenesis, which may contribute to the formation of the immunosuppressive tumor microenvironment.

A case study of a patient with platelet transfusion refractoriness (PTR) combined with human leucocyte antigen (HLA) antibody positivity during hepatic arterial infusion chemotherapy in conjunction with the 'atezolizumab plus bevacizumab' regimen.

Hepatic arterial infusion chemotherapy in conjunction with the combination therapy of atezolizumab (T) and bevacizumab (A) is widely used in hepatocellular carcinoma. Some adverse events such as hypertension, weakness and elevated transaminase levels occurred during treatment, while there is currently no reported case about thrombocytopenia with concomitant HLA antibody-positive PTR. We summarize the critical care nursing experience of a patient with PTR because of HLA antibody positivity during hepatic arterial infusion chemotherapy in conjunction with atezolizumab plus bevacizumab (T + A) regimen. This paper explains the nursing measures for patients with severe thrombocytopenia and proposes nursing measures for situations where conventional treatments are ineffective. Key nursing points include the administration of intravenous immunoglobulin (IVIG) and HLA-compatible platelets, prevention of complications, psychological care, oral care, and skin management. Through systematic treatment and targeted nursing care, the patient's platelet count rebounded after 9 days, leading to a successful recovery and discharge. Subsequent follow-up assessments revealed the patient's sustained well-being. Thrombocytopenia is a potential adverse reaction during the treatment of liver cancer. When platelet transfusion is ineffective, vigilance is necessary for the possibility of HLA positivity, and prompt symptomatic management is warranted.

LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

BACKGROUND: Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. METHODS: The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. RESULTS: In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. CONCLUSION: Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

CPD-002, a novel VEGFR2 inhibitor, relieves rheumatoid arthritis by reducing angiogenesis through the suppression of the VEGFR2/PI3K/AKT signaling pathway.

Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002's targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002's effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway.

mTOR in programmed cell death and its therapeutic implications.

Mechanistic target of rapamycin (mTOR), a highly conserved serine/threonine kinase, is involved in cellular metabolism, protein synthesis, and cell death. Programmed cell death (PCD) assists in eliminating aging, damaged, or neoplastic cells, and is indispensable for sustaining normal growth, fighting pathogenic microorganisms, and maintaining body homeostasis. mTOR has crucial functions in the intricate signaling pathway network of multiple forms of PCD. mTOR can inhibit autophagy, which is part of PCD regulation. Cell survival is affected by mTOR through autophagy to control reactive oxygen species production and the degradation of pertinent proteins. Additionally, mTOR can regulate PCD in an autophagy-independent manner by affecting the expression levels of related genes and phosphorylating proteins. Therefore, mTOR acts through both autophagy-dependent and -independent pathways to regulate PCD. It is conceivable that mTOR exerts bidirectional regulation of PCD, such as ferroptosis, according to the complexity of signaling pathway networks, but the underlying mechanisms have not been fully explained. This review summarizes the recent advances in understanding mTOR-mediated regulatory mechanisms in PCD. Rigorous investigations into PCD-related signaling pathways have provided prospective therapeutic targets that may be clinically beneficial for treating various diseases.

Comprehensive bioinformatics analysis and molecular validation of lncRNAs-mediated ceRNAs network in schizophrenia.

AIMS: The present study aimed to investigate how Schizophrenia (SCZ)-specific long non-coding RNAs (lncRNAs) served as competing endogenous RNAs (ceRNAs) to modulate the biological functions and pathways involved in the pathogenesis of SCZ. MAIN METHODS: Microarray dataset (GSE54913) was obtained from Gene Expression Omnibus (GEO) database. Differently expressed (DE) lncRNAs and mRNAs were identified by "limma" package. The binding miRNAs of lncRNAs and target mRNAs of shared miRNAs were predicted by miRcode, miRDB, miRTarbase and targetscan databases. Following the ceRNAs theory, interaction network was established and visualized with the cytoscape. Functional enrichment analysis uncovered the concentrated functions and signaling pathways that may be associated with SCZ progression. Protein-protein interaction (PPI) analysis was utilized to determine hub genes. Quantitative real-time PCR (qRT-PCR) and receiver operating characteristic curve (ROC) were performed to evaluate the expression and diagnostic value of ceRNAs members, respectively. KEY FINDINGS: DElncRNAs and DEmRNAs were initially screened from GSE54913 to construct the SCZ-related ceRNAs network with 42 nodes and 53 edges. Functional enrichment analysis revealed that ceRNAs members appeared to be highly correlated with transcription factor activation, cell replication and tumor-related pathways. Once validated, a significant ceRNAs subnetwork was proposed as being implicated in the pathogenesis of SCZ. ROC analysis indicated that SCZ-related ceRNAs members may be sensitive diagnostic biomarkers for SCZ. SIGNIFICANCE: The significant SCZ-related ceRNAs subnetworks (lncRNA-C2orf48A/hsa-miR-20b-5p,-17-5p/KIF23, FOXJ2) may represent promising predictive and diagnostic biomarkers and provide novel insights into the mechanism by which lncRNAs act as microRNA sponges and contribute to the pathogenesis of SCZ.

Advances in the regulatory mechanisms of mTOR in necroptosis.

The mammalian target of rapamycin (mTOR), an evolutionarily highly conserved serine/threonine protein kinase, plays a prominent role in controlling gene expression, metabolism, and cell death. Programmed cell death (PCD) is indispensable for maintaining homeostasis by removing senescent, defective, or malignant cells. Necroptosis, a type of PCD, relies on the interplay between receptor-interacting serine-threonine kinases (RIPKs) and the membrane perforation by mixed lineage kinase domain-like protein (MLKL), which is distinguished from apoptosis. With the development of necroptosis-regulating mechanisms, the importance of mTOR in the complex network of intersecting signaling pathways that govern the process has become more evident. mTOR is directly responsible for the regulation of RIPKs. Autophagy is an indirect mechanism by which mTOR regulates the removal and interaction of RIPKs. Another necroptosis trigger is reactive oxygen species (ROS) produced by oxidative stress; mTOR regulates necroptosis by exploiting ROS. Considering the intricacy of the signal network, it is reasonable to assume that mTOR exerts a bifacial effect on necroptosis. However, additional research is necessary to elucidate the underlying mechanisms. In this review, we summarized the mechanisms underlying mTOR activation and necroptosis and highlighted the signaling pathway through which mTOR regulates necroptosis. The development of therapeutic targets for various diseases has been greatly advanced by the expanding knowledge of how mTOR regulates necroptosis.

Grisel's syndrome associated with mumps: A case report.

Grisel's syndrome (GS) is defined as atlantoaxial rotatory subluxation/fixation not associated with trauma or bone disease, usually following head and neck infection/inflammation or ear, nose, and throat (ENT) surgery. Many conditions could lead to Grisel's syndrome, of which mumps is rarely to be seen. This report discusses a case of GS in children with Type I atlantoaxial joint subluxation and previously diagnosed mumps. A 6-year-old boy who had cervical pain and torticollis for 2 weeks was admitted to our hospital. There was no trauma and he had not had ENT surgery but was diagnosed with mumps 2 weeks previously due to swelling of the left cheek and cervical lymph node. Physical examination and computed tomography confirmed a diagnosis of Grisel's syndrome with an ADI (atlanto-dens interval) of 1.6 mm. The patient then received occipito-mandibular traction for 6 days and recovered. No recurrence was observed at 1 year follow-up. Physicians should raise awareness of this rare complication of mumps to avoid life-threatening neurological impairments owing to Grisel's syndrome.

[Analysis and Treatment Experience of 25 Cases of Primary Gastric Lymphoma with Acute Upper Gastrointestinal Bleeding as the Primary Manifestation].

Objective: To summarize the clinical characteristics and treatment experience of gastric primary lymphoma with acute upper gastrointestinal bleeding as the primary manifestation, and to provide support for clinical treatment. Methods: Information on gastric primary lymphoma patients admitted to the Department of Gastroenterology, West China Hospital of Sichuan University between January 2010 and March 2021 for acute upper gastrointestinal bleeding was retrospectively collected. Data on endoscopic morphology, tumor staging, pathology typing, severity of bleeding, risks of rebleeding, treatment and inhospital prognosis were documented and analyzed. Results: A total of 25 patients with a mean age of 57.2 years were included in the study, all of whom presented clinically with melena (100%), 9 (36%) had hematemesis, and 6 (24%) was accompanied with abdominal pain. Twenty, or 80%, of the gastric lymphoma patients with bleeding as the primary manifestation showed endoscopically a tumor-forming phenotype (Yao Classification), mostly involving the middle and lower parts of the gastric body (44% and 32%, respectively). After conservative treatment with medication, rebleeding occurred in 4 patients during hospitalization. One of them required endoscopic hemostasis, two required surgical resection to stop the bleeding, and one decided not to undergo any further treatment. Only one patient died from infection and no death resulted directly from severe bleeding. Conclusion: Gastric primary lymphoma presenting acute upper gastrointestinal bleeding as the sole clinical manifestation rarely occurs, but when the condition does occur, it shows a wide range of endoscopic involvement. It has a higher risk of rebleeding, and endoscopic or surgical treatment may be attempted when conservative medication treatment for acute upper gastrointestinal bleeding fails.