Treatment of Keratosis Lichenoides Chronica With Upadacitinib.

This case report describes a 30-year-old man presenting with 1-year history of nonitchy red papules and patches who was subsequently treated with upadacitinib.

Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Influences of vitiligo-associated characteristics on the occurrence of diabetes mellitus: Interactive analysis of a cross-sectional study.

The risk of diabetes mellitus (DM) in vitiligo patients is higher than that in non-vitiligo population. Our goal was to explore the influencing factors for DM in vitiligo patients. A matched-pair design of 107 cases with DM and 428 controls without DM was conducted among vitiligo patients in Xijing hospital from January 2010 to October 2021. The baseline characteristics of patients were analysed based on standard descriptive statistics. The vitiligo-associated characteristics were analysed by logistic regression to identify influencing factors of DM. Interaction analysis was performed to explore the additive interactions between vitiligo-associated characteristics and baseline characteristics. After adjustment for the baseline characteristics, the severity of vitiligo [odds ratio (OR) = 2.47, 95% confidence interval (CI): 1.47-4.14] and onset age of vitiligo (OR = 0.98, 95% CI: 0.97-0.99) had a significant correlation with occurrence of DM. The severity of vitiligo had additive interaction with family history of diabetes [relative excess risk due to interaction (RERI) = 132.51 (95% CI: 5.51-1100.20), attributable proportion (AP) = 0.91 (95% CI: 0.17-0.95), synergy index (S) = 11.53 (95% CI: 1.32-100.5)] and with smoking history [RERI = 6.54 (95% CI: 0.67-19.83), AP = 0.64 (95% CI: 0.04-0.80), S = 3.48 (95% CI: 1.17-10.36)]. Earlier onset age of vitiligo and greater BSA involvement might be two independent risk factors for DM in vitiligo patients. Interaction assessment identified the severity of vitiligo as additive interaction factors with diabetes family history and with smoking history for the DM occurrence.

Sestrin2 contributes to BRAF inhibitor resistance via reducing redox vulnerability of melanoma cells.

BACKGROUND: Treatment resistance often occurs with BRAF inhibitor (BRAFi) therapy for melanoma, bringing in a great challenge to the treatment of melanoma patients harboring mutant BRAF gene. Recent studies revealed redox vulnerability constitutes a novel opportunity to overcome BRAFi resistance. Previously we found Sestrin2 provided protection to metastatic melanoma cells by detoxifying reactive oxygen species (ROS) induced by anoikis, but its defensive role against redox stimuli elicited by BRAFi was unclear. OBJECTIVE: In-depth explored the role of Sestrin2 in BRAFi-resistant melanoma. METHODS: Vemurafenib-resistant melanoma cells were established using 451Lu and UACC62 cell lines carrying BRAFV600E mutation. Mechanistic studies were subsequently performed by transfection of lentiviral vectors encoding an shRNA against SESN2 or embedded with the coding sequences of SESN2 cDNA. RESULTS: Elevated Sestrin2 expression was found in vemurafenib-resistance melanoma cells. Further mechanistic studies revealed that BRAFi-resistant melanoma cells employ Sestrin2 to adapt to higher oxidative stress under vemurafenib exposure. It was also demonstrated that mTOR signaling was significantly activated following Sestrin2 knockdown. Given the known promoting role of active mTOR signaling in melanoma proliferation and survival, the effects of mTOR blocker and Sestrin2 ablation on BRAFi-resistant melanoma cells were further tested, and the combination was found to result in enhanced inhibition of melanoma cell growth. CONCLUSIONS: Our findings demonstrated the contribution of Sestrin2 to the development of BRAFi resistance and the fact that the combination of mTOR blocker assisted Sestrein2 ablation in eliminating BRAFi resistance of melanoma. Therefore, mTOR and Sestrin2 may be novel combinatorial therapeutic targets to overcome BRAFi resistance of melanoma.

Efficacy and safety of interferon-alpha 1b combined with PD-1 monoclonal antibody in patients with unresectable stage IV melanoma: a retrospective study.

PURPOSE: The low objective response of immune checkpoint inhibitors (ICIs) remains a great challenge in advanced melanoma therapy. Interferon-alpha has been proven to be a promising combination regimen with ICI in a phase Ib/II trial. Herein, we evaluated the efficacy and safety of interferon-alpha 1b plus PD-1 monoantibody in a real-world Chinese metastatic melanoma cohort. METHODS: Profiles of patients diagnosed with unresectable stage IV (AJCC 8th Edition) between December 1st, 2018 and February 28th, 2022 from the Department of Dermatology, Xijing Hospital were reviewed. All of them received the combination treatment of interferon-alpha 1b (600 µg every other day) plus PD-1 monoantibody (Pembrolizumab 2 mg/kg or Toripalimab 240 mg or Sintilimab 200 mg, every 3 weeks) for at least 12 weeks. The efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST V1.1). The safety data were identified according to Common Terminology Criteria for Adverse Events (CTC AE) V.5.0. RESULTS: In total, 70 patients were included. 50% were females. 52.9% were with ECOG performance status ≥ 1. The fraction of patients receiving Pembrolizumab, Toripalimab, and Sintilimab was 28.6%, 67.1%, and 4.3%, respectively. Acral and mucosal subtypes accounted for 48.6% and 20%. The median follow-up period is 15.1 months. The objective response rate was 32.8%. The median time of overall survival was 18 months (95% CI 14.2-21.8 months), and the median time of PFS was 5.2 months (95% CI 4.2-6.2 months). The incidence of adverse events (any grade) was 98.6%, but only 8.6% of cases experienced grade 3 or 4 adverse reactions. CONCLUSION: The combination of interferon-alpha 1b and PD-1 monoantibody demonstrated promising anti-tumor effects and acceptable toxicity in Chinese metastatic melanoma patients with cutaneous, acral, and mucosal subtypes.

Common Pathogens and Drug Resistance of Neonatal Pneumonia with New Multichannel Sensor.

This study aimed to study the application value of a new multichannel sensor in pathogen detection and drug resistance analysis of neonatal pneumonia. 180 newborns with infectious pneumonia were selected, and a new multichannel piezoelectric sensor was constructed. The traditional Kirby-Bauer (K-B) method and the piezoelectric sensor were adopted to detect the pathogens and drug resistance in newborn samples, respectively. The results showed that the sensitivity and specificity under the K-B method (99.58% and 99.32%) and the multichannel piezoelectric sensor (99.43% and 94.29%) were not statistically different (P > 0.05). The detection time (17.25 h) of the K-B method was significantly longer than that (7.43 h) of the multichannel piezoelectric sensor (P < 0.05). From the results of pathogen detection, it was found that Klebsiella pneumoniae accounted for a relatively high proportion of 25.1%, followed by Staphylococcus aureus and Haemophilus influenzae of 13.4% and 12.33%, respectively. The resistance rate of the Staphylococcus aureus to vancomycin and rifampicin was as high as 100% and that to gentamicin, ciprofloxacin, and erythromycin reached more than 50%. In short, the new multichannel piezoelectric sensor had the high sensitivity and specificity for the pathogens' detection of neonatal pneumonia, and it required a shorter time. The pathogens were mostly Gram-negative bacteria, followed by Gram-positive bacteria and fungi. Klebsiella pneumoniae, Staphylococcus aureus, and Haemophilus influenzae were the main ones. The neonatal pneumonia pathogens had also strong drug resistance against vancomycin, rifampicin, chloramphenicol, meropenem, amikacin sulfate, chloramphenicol, and many other antibacterial drugs.

Acid-regulated boron-nitrogen codoped multicolor carbonized polymer dots and applications for pH sensing and trace water detection.

To obtain multicolor carbonized polymer dots (CPDs), acid-assisted hydrothermal/solvothermal reactions are an effective strategy. However, the long wavelength fluorescence of boron-nitrogen codoped CPDs (BN-CPDs) is rarely reported. In this work, we used concentrated hydrochloric acid to regulate the fluorescence (from green to orange) of BN-CPDs via a solvothermal reaction. Meanwhile, 3-formylphenylboronic acid with a benzene ring structure was employed as the boron source, which helped the formation of the internal conjugated structure of CPDs to obtain long wavelength fluorescent CPDs. The fluorescence properties of BN-CPDs were investigated, which indicated the concentration- and solvent-dependent properties of the BN-CPDs. Based on the experimental results, we assume that the multicolor emission of the BN-CPDs originates from the synergistic effects of the degree of graphitization and surface states. Due to the special fluorescence properties of the BN-CPDs, pH sensing and trace water detection in dichloromethane solution can be effectively achieved. The results of the study reveal the potential of BN-CPDs in sensing applications.

Integrative Genomic Profiling Uncovers Therapeutic Targets of Acral Melanoma in Asian Populations.

PURPOSE: Acral melanoma is the major subtype of melanoma seen in Asian patients with melanoma and is featured by its insidious onset and poor prognosis. The genomic study that elucidates driving mutational events is fundamental to the development of gene-targeted therapy. However, research on genomic profiles of acral melanoma in Asian patients is still sparse. EXPERIMENTAL DESIGN: We carried out whole-exome sequencing (WES) on 60 acral melanoma lesions (with 55 primary samples involved), targeted deep sequencing in a validation cohort of 48 cases, RNA sequencing in 37 acral melanoma samples (all from the 60 undergoing WES), and FISH in 233 acral melanoma specimens (54 of the 60 undergoing WES included). All the specimens were derived from Asian populations. RESULTS: BRAF, NRAS, and KIT were discerned as significantly mutated genes (SMG) in acral melanoma. The detected COSMIC signature 3 related to DNA damage repair, along with the high genomic instability score, implied corresponding pathogenesis of acral melanoma. Moreover, the copy number gains of EP300 were associated with the response of acral melanoma to targeted therapy of A485 (a p300 inhibitor) and immune checkpoint blockade treatment. In addition, the temporal order in mutational processes of the samples was reconstructed, and copy-number alterations were identified as early mutational events. CONCLUSIONS: Our study provided a detailed view of genomic instability, potential therapeutic targets, and intratumoral heterogeneity of acral melanoma, which might fuel the development of personalized strategies for treating acral melanoma in Asian populations.

High-Plex Spatial RNA Profiling Reveals Cell Type‒Specific Biomarker Expression during Melanoma Development.

Early diagnosis of melanoma is critical for improved survival. However, the biomarkers of early melanoma evolution and their origin within the tumor and its microenvironment, including the keratinocytes, are poorly defined. To address this, we used spatial transcript profiling that maintains the morphological tumor context to measure the expression of >1,000 RNAs in situ in patient-derived formalin-fixed, paraffin-embedded tissue sections in primary melanoma and melanocytic nevi. We profiled 134 regions of interest (each 200 µm in diameter) enriched in melanocytes, neighboring keratinocytes, or immune cells. This approach captured distinct expression patterns across cell types and tumor types during melanoma development. Unexpectedly, we discovered that S100A8 is expressed by keratinocytes within the tumor microenvironment during melanoma growth. Immunohistochemistry of 252 tumors showed prominent keratinocyte-derived S100A8 expression in melanoma but not in benign tumors and confirmed the same pattern for S100A8's binding partner S100A9, suggesting that injury to the epidermis may be an early and readily detectable indicator of melanoma development. Together, our results establish a framework for high-plex, spatial, and cell type‒specific resolution of gene expression in archival tissue applicable to the development of biomarkers and characterization of tumor microenvironment interactions in tumor evolution.

Cerebral Structural Abnormalities and Their Associations With Peripheral Cytokine Levels in a Group of Untreated Patients With Nasopharyngeal Carcinoma.

The current study is to characterize the alterations of peripheral cytokines and anatomical brain changes, and their relationships in untreated nasopharyngeal carcinoma (NPC) patients with depressive symptoms. Twenty-nine newly diagnosed NPC patients without any treatment and 46 matched healthy comparisons were recruited, scanned with high-resolution T1 images and assessed psychologically using Hamilton Rating Scale for Depression (HAMD). Serum levels of interleukin-1 beta (IL-1ß), IL-2, IL-6, IL-8, IL-10, interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) were measured by quantitative chemiluminescence assay. Inter-group comparisons of anatomical brain measures were performed, and regions with significant inter-group differences were correlated to HAMD scores and cytokines in NPC patients. A subgroup analysis especially within NPC patients with depression was conducted to precisely characterize the associations among serum cytokines, brain changes and depressive symptoms. Relative to healthy subjects, NPC patients showed significantly decreased cortical thickness in the left parahippocampal gyrus, increased surface area in the right superior parietal lobule and precentral gyrus, and increased gray matter volume in the right postcentral gyrus, bilateral caudate nucleus and right thalamus, as well as significantly elevated IL-1ß, IL-2 and IL-10. The elevated IL-2 and IL-10 were negatively correlated with surface area in right superior parietal lobule, whilst IL-1ß level was positively correlated to HAMD scores. In patients with depression, specific brain changes and evaluated IL-1ß were identified, and the IL-1ß interacted with right precentral gyrus to significantly affect the depressive symptoms. Our findings provide novel evidence indicating potential effects of inflammation on brain structure and behavior in NPC patients.

High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients.

OBJECTIVE: Immediate early response 5 (IER5) plays a core role in cell cycle and response to irradiation. However, its role in glioma remains unclear. We aimed to evaluate its prognostic significance in glioma based on The Cancer Genome Atlas data resource. METHODS: The Kruskal-Wallis test, Wilcoxon signed-rank test, and logistic regression were employed to explore the relationship between IER5 expression and clinicopathological features. Kaplan-Meier and Cox regression analyses were implemented to investigate the relationship of IER5 with prognosis. A nomogram to estimate the impact of IER5 on prognosis was created based on the Cox multivariate data. We performed gene set enrichment analysis (GSEA) to determine the key signaling cascades associated with IER5. Immunohistochemistry was performed to examine IER5 expression in a tissue microarray (TMA) of glioma samples. RESULTS: Immediate early response 5 gene expression was elevated in glioma patients. The level of IER5 was significantly correlated with WHO grade [OR = 6.71 (4.34-10.68) for G4 vs. G2 and G3], IDH (isocitrate dehydrogenase enzyme) status [OR = 13.35 (8.92-20.46) for wild-type (WT) vs. mutated (Mut)], epidermal growth factor receptor status [OR = 8.42 (4.32-18.43) for Mut vs. WT], age [OR = 0.27 (0.18-0.41) for ≤ 60 years vs. >60 years], and histological type [OR = 7.13 (4.63-11.31] for glioblastoma vs. astrocytoma, oligoastrocytoma, and oligodendroglioma). Univariate analyses revealed that high IER5 expression was linked to short overall survival (OS) [hazard ratio (HR): 3.747; 95% confidence interval (CI): 2.847-4.933; and P < 0.001]. High IER5 expression was linked to poor OS in multivariate analyses (HR: 2.474; 95% CI: 1.552-3.943; and P < 0.001). TMA results showed that high IER5 protein levels were related to short OS (HR: 1.84; 95% CI: 1.10-3.07; and P = 0.021) and poor disease-specific survival (HR: 1.82; 95% CI: 1.09-3.04; and P = 0.023). GSEA showed that many tumor related pathways were enriched differentially in the IER5-high expression group. The C-index and calibration plots of the nomogram showed an effective estimation performance in glioma patients. CONCLUSION: Herein, we established that IER5 plays a critical role in glioma progression and prognosis, which might be an important biomarker for the prognosis of glioma patients.

Interferon-α1b for the treatment of metastatic melanoma: results of a retrospective study.

Recombinant human interferon-α1b (IFN-α1b) is the first genetic engineered drug of China and is approved for cancer treatment by Chinese Food and Drug Administration. Although recombinant IFN-α1b is biologically and therapeutically active, its long-term efficacy against advanced melanoma is unknown. Ninety patients who were diagnosed with stage IV melanoma and received recombinant IFN-α1b therapy in our department were included in this study. The safety and efficacy of IFN-α1b were analyzed. IFN-α1b was overall well tolerated, with only 7.8% of the patients showing grade 3 toxicity and none with grade 4 toxicity or treatment-related death. The most common adverse effect was fever (78.9%). Furthermore, increasing the drug dosage showed no increase in the incidence of adverse events. The median overall survival (mOS) of the cohort was 14.1 months (95% confidence interval, 11.3-16.9 months). There was no significant difference of the mOS between samples of various primary sites. In the 42 patients who had not received prior adjuvant interferon therapy, the objective response rate, disease control rate and clinical benefit rate were 7.1, 28.5 and 21.4%, respectively. Our findings suggest that systemic IFN-α1b treatment is a relatively safe therapy and could prolong the survival of patients with unresectable metastatic melanoma.

Clinical Characteristics and Overall Survival Prognostic Nomogram for Oligodendroglioma: A Surveillance, Epidemiology, and End Results Population-Based Analysis.

OBJECTIVE: Oligodendroglioma is a rare primary malignant brain tumor that has highly variable clinical outcomes. The aim of this study was to investigate demographics, outcomes, and prognostic factors of all oligodendroglioma cases from the Surveillance, Epidemiology, and End Results database to build a clinical prognosis model to predict survival time of patients with oligodendroglioma. METHODS: Cases diagnosed between 1975 and 2016 were selected from the Surveillance, Epidemiology, and End Results database. Age, sex, race, insurance, year of diagnosis, marital status, tumor location, tumor size, summary stage, surgery method, and use of radiotherapy and chemotherapy were evaluated with respect to overall survival by univariate and multivariate analysis. A nomogram predicting 5- and 10-year survival probability for oligodendroglioma was constructed and validated. RESULTS: After data cleaning, 4568 patients with oligodendroglioma were included. At the time of last follow-up, mean survival times among grade II and grade III oligodendrogliomas were 74 and 39 months, respectively. In multivariate analysis, radiotherapy, age, tumor site, summary stage, and surgery demonstrated independent associations with survival in both cohorts. Race and radiotherapy demonstrated independent associations with survival in grade II oligodendroglioma. Sex and chemotherapy demonstrated independent associations with survival in grade III oligodendroglioma. Independent factors in either cohort were selected to build a clinical nomogram. The C-index for the nomogram was 0.738 (95% confidence interval 0.718-0.757). The calibration curves of 5- and 10-year survival rates showed good agreement between the nomogram predictions and actual observations. CONCLUSIONS: This study was the first to develop a nomogram for predicting overall survival of patients with oligodendroglioma to help clinicians predict patient prognosis accurately and conduct further treatment.

Advances in Imaging Modalities and Contrast Agents for the Early Diagnosis of Colorectal Cancer.

Colorectal cancer is one of the most common gastrointestinal cancers worldwide. The mortality rate of colorectal cancer has declined by more than 20% due to the rapid development of early diagnostic techniques and effective treatment. At present, there are many diagnostic modalities available for the evaluation of colorectal cancer, such as the carcinoembryonic antigen test, the fecal occult blood test, endoscopy, X-ray barium meal, computed tomography, magnetic resonance imaging, and radionuclide examination. Sensitive and specific imaging modalities have played an increasingly important role in the diagnosis of colorectal cancer following the rapid development of novel contrast agents. This review discusses the applications and challenges of different imaging techniques and contrast agents applied to detect colorectal cancer, for the purpose of the early diagnosis and treatment of patients with colorectal cancer.

Hepatoprotective effect and possible mechanism of phytoestrogen calycosin on carbon tetrachloride-induced liver fibrosis in mice.

The study was to explore the hepatoprotective effect and possible mechanism of calycosin on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Hepatic fibrosis was induced by intraperitoneal injection of CCl4 in C57BL/6 male mice. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, superoxide dismutase (SOD) activity, and hydroxyproline (Hyp) and malondialdehyde (MDA) levels were determined by biochemical assays. Liver histopathology was assessed by H&E and Masson trichrome staining. The mRNA expressions of α-smooth muscle actin (α-SMA), collagen-I (Col-I), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined using qRT-PCR. The protein levels of α-SMA, Col-I, estrogen receptor α (ERα), estrogen receptor ß (ERß), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), JAK2, phospho-JAK2 (p-JAK2), STAT3, and phospho-STAT3 (p-STAT3) were detected by Western blotting. The levels of α-SMA and ERß were measured by immunohistochemistry. Calycosin significantly reduced liver index, MDA level, and ALT and AST activity and increased SOD activity. The α-SMA, Col-I, and Hyp of the calycosin group were significantly lower than those of the model group. Calycosin increased MMP-1 and inhibited TIMP-1 expression resulting in the improvement of MMP-1/TIMP-1 ratio. Importantly, calycosin improved ERß protein expression, JAK2 and STAT3 mRNA expressions, p-JAK2/JAK2, and p-STAT3/STAT3 relative protein expressions. However, ERα, JAK2, and STAT3 protein expressions were relatively unchanged. Calycosin significantly inhibits liver fibrosis in mice, and its mechanism may involve the following: calycosin inhibits oxidative stress; calycosin inhibits collagen synthesis and balances MMP-1/TIMP-1 system; calycosin increases ERß expression and activates JAK2-STAT3 pathway.

Survival Prediction in Gallbladder Cancer Using CT Based Machine Learning.

OBJECTIVE: To establish a classifier for accurately predicting the overall survival of gallbladder cancer (GBC) patients by analyzing pre-treatment CT images using machine learning technology. METHODS: This retrospective study included 141 patients with pathologically confirmed GBC. After obtaining the pre-treatment CT images, manual segmentation of the tumor lesion was performed and LIFEx package was used to extract the tumor signature. Next, LASSO and Random Forest methods were used to optimize and model. Finally, the clinical information was combined to accurately predict the survival outcomes of GBC patients. RESULTS: Fifteen CT features were selected through LASSO and random forest. On the basis of relative importance GLZLM-HGZE, GLCM-homogeneity and NGLDM-coarseness were included in the final model. The hazard ratio of the CT-based model was 1.462(95% CI: 1.014-2.107). According to the median of risk score, all patients were divided into high and low risk groups, and survival analysis showed that high-risk groups had a poor survival outcome (P = 0.012). After inclusion of clinical factors, we used multivariate COX to classify patients with GBC. The AUC values in the test set and validation set for 3 years reached 0.79 and 0.73, respectively. CONCLUSION: GBC survival outcomes could be predicted by radiomics based on LASSO and Random Forest.

A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma.

BACKGROUND: The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive. METHODS: The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism. RESULTS: We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden. CONCLUSIONS: Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.

TAK-242 ameliorates DSS-induced colitis by regulating the gut microbiota and the JAK2/STAT3 signaling pathway.

BACKGROUND: The goal of the present study was to investigate the effects of TAK-242 on the gut microbiota and the TLR4/JAK2/STAT3 signaling pathway in mice with dextran sulfate sodium (DSS)-induced colitis. RESULTS: At the phylum level, Bacteroidetes, Firmicutes, Actinobacteria, Cyanobacteria, Epsilonbacteraeota and Proteobacteria were the primary microbiota in the five groups. TAK-242 treatment significantly enhanced Verrucomicrobia and Actinobacteria; significantly decreased Cyanobacteria, Epsilonbacteraeota and Proteobacteria; and particularly promoted the growth of Akkermansia. TAK-242 markedly alleviated DSS-induced colitis symptoms and colonic lesions by promoting IL-10 release, inhibiting IL-17 release, downregulating TLR4 and JAK2/STAT3 mRNA and protein expression and increasing JAK2/STAT3 phosphorylation. CONCLUSION: TAK-242 modulates the structure of the gut microbiota in colitis and may be a novel therapeutic candidate for ulcerative colitis.

Depletion of lncRNA MALAT1 inhibited sunitinib resistance through regulating miR-362-3p-mediated G3BP1 in renal cell carcinoma.

Long non-coding RNA metastasis associated with lung adenocarcinoma transcript 1 (MALAT1) contributes to chemotherapy resistance in some cancers, but the role of MALAT1 in sunitinib (SU) chemoresistance of carcinoma (RCC) is still unknown. In this study, MALAT1 expression in SU-resistance tumor tissues and cells was tested by qRT-PCR. Then, CCK-8, Annexin V-FITC/PI, transwell, and Western blotting assays were used to evaluate cell viability and IC50, apoptosis, cell invasion, and resistance of SU-resistance RCC cells after transfected with small interfering RNA against MALAT1. Further, RNA pull-down and luciferase reporter assay were applied to investigate the underlying mechanism of MALAT1 in SU resistance. The results showed that MALAT1 expression was dramatically upregulated in SU-resistance RCC tissues and cell lines. Knockdown of MALAT1 inhibited proliferation, invasion, and SU chemoresistance, but induced apoptosis in RCC cells. The results of RNA pull-down and luciferase reporter assay indicated that MALAT1 could interact with miR-362-3p and miR-362-3p interact with RasGAP SH3-domain-Binding Protein 1 (G3BP1). Moreover, G3BP1 also played a role in SU chemoresistance of RCC cells, and MALAT1 could perform as a miR-362-3p sponge to modulate G3BP1 expression. Rescue experiments suggested that downregulation of miR-362-3p and overexpression of G3BP1 can reverse the SU chemosensitivity of MALAT1 knockdown in RCC cells. In conclusion, depletion of LncRNA MALAT1 inhibited SU chemoresistance through modulating G3BP1 via sponging miR-362-3p in RCC cells, suggesting that targeting MALAT1 may be a potential therapeutic strategy for SU-resistance RCC.