Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Transhiatal bilateral cervical approach for mediastinoscopy-assisted esophagectomy: A retrospective cohort study.

BACKGROUND: The McKeown minimally invasive esophagectomy (McMIE) procedure has various limitations, including surgical contraindications and a high rate of postoperative pulmonary complications. A novel mediastinoscopic esophagectomy procedure was described in this study by using esophageal invagination and a transhiatal and bilateral cervical approach (EITHBC). METHODS: According to the mode of operation, a total of 259 patients were divided into two groups, among which 106 underwent EITHBC and 153 underwent McMIE. The number of lymph nodes dissected, intraoperative outcomes, and postoperative outcomes were compared between the two groups of patients. RESULTS: The results revealed that the average number of resected lymph node in the EITHBC group was significantly higher in the recL106 and TbL106 stations (recL106: 1.75 vs. 1.51, p = 0.016, TbL106: 1.53 vs. 1.19, p = 0.016) and significantly lower in the 107 stations (1. 74 vs. 2. 07, p < 0.001) than in the McMIE group. The intraoperative blood loss in the EITHBC group was significantly lower than that in the McMIE group (63.30 vs. 80.45 mL, p < 0.001). The incidence of postoperative pulmonary complications in the EITHBC group was lower than that in the McMIE group (14.15% vs. 27.45%, p = 0.008). The incidence of recurrent laryngeal nerve paralysis in the EITHBC group was significantly higher than that in the McMIE group (26.41% vs. 10.46%, p = 0.003). CONCLUSION: Compared with the McMIE procedure, the EITHBC procedure has advantages in terms of removing the upper mediastinal lymph nodes and reducing postoperative pulmonary complications.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Hierarchical surface-modification of nano-Cu toward one pot H-transfer-coupling-cyclization-CO2 fixation tandem reactions.

Fixation of CO2 into dihydroisobenzofuran derivatives has enormous applications in both production of natural products and antidepressant drugs, and reducing the green-house effect. However, the relatively complicated multi-step processes limit the further expansion of such a valuable CO2 conversion strategy. Herein, we hierarchically modify the surface of Cu nanoparticles (NPs) with Ag NPs and the robust metal-organic framework (MOF), ZIF-8, and report the presence of the Cu-Ag yolk-shell nanoalloy based heterogeneous catalysts, Cu@Ag and Cu@Ag@ZIF-8. The latter exhibits a crystalline "raisin bread" structure and specific synergic activity for catalyzing the tandem reactions of intra-molecular H-transfer, C-C and C-O coupling, cyclization, and carboxylation from CO2, leading to the first non-homogeneous preparation of dihydroisobenzofuran derivatives in high yield, selectivity, and recyclability under mild conditions. Theoretical calculations elucidate the tandem reaction pathway synergically catalyzed by Cu@Ag@ZIF-8, which offers insights for designing multiphase catalysts towards both organic synthesis and CO2 fixation through tandem processes in one pot.

Fatty acid metabolism-related lncRNAs are potential biomarkers for survival prediction in clear cell renal cell carcinoma.

Metabolic reprogramming of energy is a newly recognized characteristic of cancer. In our current investigation, we examined the possible predictive importance of long noncoding RNAs (lncRNAs) associated to fatty acid metabolism in clear cell renal cell carcinoma (ccRCC). We conducted an analysis of the gene expression data obtained from patients diagnosed with ccRCC using the Cancer Genome Atlas (TCGA) database and the ArrayExpress database. We performed a screening to identify lncRNAs that are differentially expressed in fatty acid metabolism. Based on these findings, we developed a prognostic risk score model using these fatty acid metabolism-related lncRNAs. We then validated this model using Cox regression analysis, Kaplan-Meier survival analysis, and principal-component analysis (PCA). Furthermore, the prognostic risk score model was successfully validated using both the TCGA cohort and the E-MTAB-1980 cohort. We utilized gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) to determine the correlation between fatty acid metabolism and the PPAR signaling pathway in patients with ccRCC at various clinical stages and prognoses. We have discovered compelling evidence of the interaction between immune cells in the tumor microenvironment and tumor cells, which leads to immune evasion and resistance to drugs. This was achieved by the utilization of advanced techniques such as the CIBERSORT method, ESTIMATE R package, ssGSEA algorithm, and TIMER database exploration. Ultimately, we have established a network of competing endogenous RNA (ceRNA) that is related to fatty acid metabolism. The findings of our study suggest that medicines focused on fatty acid metabolism could be clinically significant for individuals with ccRCC. The utilization of this risk model, which is centered around the lncRNAs associated with fatty acid metabolism, could potentially provide valuable prognostic information and hold immunotherapeutic implications for patients with ccRCC.

Analysis of bioprinting strategies for skin diseases and injuries through structural and temporal dynamics: historical perspectives, research hotspots, and emerging trends.

This study endeavors to investigate the progression, research focal points, and budding trends in the realm of skin bioprinting over the past decade from a structural and temporal dynamics standpoint. Scholarly articles on skin bioprinting were obtained from WoSCC. A series of bibliometric tools comprising R software, CiteSpace, HistCite, and an alluvial generator were employed to discern historical characteristics, evolution of active topics, and upcoming tendencies in the area of skin bioprinting. Over the past decade, there has been a consistent rise in research interest in skin bioprinting, accompanied by an extensive array of meaningful scientific collaborations. Concurrently, diverse dynamic topics have emerged during various periods, as substantiated by an aggregate of 22 disciplines, 74 keywords, and 187 references demonstrating citation bursts. Four burgeoning research subfields were discerned through keyword clustering-namely, #3 'in situbioprinting', #6 'vascular', #7 'xanthan gum', and #8 'collagen hydrogels'. The keyword alluvial map reveals that Module 1, including 'transplantation' etc, has primarily dominated the research module over the previous decade, maintaining enduring relevance despite annual shifts in keyword focus. Additionally, we mapped out the top six key modules from 2023 being 'silk fibroin nanofiber', 'system', 'ionic liquid', 'mechanism', and 'foot ulcer'. Three recent research subdivisions were identified via timeline visualization of references, particularly Clusters #0 'wound healing', #4 'situ mineralization', and #5 '3D bioprinter'. Insights derived from bibliometric analyses illustrate present conditions and trends in skin bioprinting research, potentially aiding researchers in pinpointing central themes and pioneering novel investigative approaches in this field.

Erratum: Overexpression of ZEB1 and YAP1 is related to poor prognosis in patients with gliomas with different IDH1 status.

[This corrects the article on p. 138 in vol. 16, PMID: 37559682.].

Upregulation of proBDNF/p75NTR signaling in immune cells and its correlation with inflammatory markers in patients with major depression.

ProBDNF is the precursor protein of brain-derived neurotrophic factor (BDNF) expressed in the central nervous system and peripheral tissues. Previous studies showed that the blood levels of both proBDNF and p75 neurotrophic receptors (p75NTR) in major depressive disorder (MDD) were increased, but which blood cell types express proBDNF and its receptors is not known. Furthermore, the relationship between proBDNF/p75NTR and inflammatory cytokines in peripheral blood of MDD is unclear. Peripheral blood mononuclear cells (PBMCs) and serum were obtained from depressive patients (n = 32) and normal donors (n = 20). We examined the expression of proBDNF and inflammatory markers and their correlative relationship in patients with major depression. Using flow cytometry analysis, we examined which blood cells express proBDNF and its receptors. Finally, the role of proBDNF/p75NTR signal in inflammatory immune activity of PBMCs was verified in vitro experiments. Inflammatory cytokines in PBMC from MDD patients were increased and correlated with the major depression scores. The levels of IL-1ß and IL-10 were also positively correlated with the major depression scores, while the levels of TNF-α and IL-6 were negatively correlated with the major depression scores. Intriguingly, the levels of sortilin were positively correlated with IL-1ß. Q-PCR and Western blots showed proBDNF, p75NTR, and sortilin levels were significantly increased in PBMCs from MDD patients compared with that from the normal donors. Flow cytometry studies showed that proBDNF and p75NTR were present mainly in CD4+ and CD8+ T cells. The number of proBDNF and p75NTR positive CD4+ and CD8+ T cells from MDD patients was increased and subsequently reversed after therapeutic management. Exogenous proBDNF protein or p75ECD-Fc treatment of cultured PBMC affected the release of inflammatory cytokines in vitro. ProBDNF promoted the expression of inflammatory cytokines, while p75ECD-Fc inhibited the expression of inflammatory cytokines. Given there was an inflammatory response of lymphocytes to proBDNF, it is suggested that proBDNF/p75NTR signaling may upstream inflammatory cytokines in MDD. Our data suggest that proBDNF/p75NTR signaling may not only serve as biomarkers but also may be a potential therapeutic target for MDD.

TGF-ß signaling pathway in spinal cord injury: Mechanisms and therapeutic potential.

Spinal cord injury (SCI) is a highly disabling central nervous system injury with a complex pathological process, resulting in severe sensory and motor dysfunction. The current treatment modalities only alleviate its symptoms and cannot effectively intervene or treat its pathological process. Many studies have reported that the transforming growth factor (TGF)-ß signaling pathway plays an important role in neuronal differentiation, growth, survival, and axonal regeneration after central nervous system injury. Furthermore, the TGF-ß signaling pathway has a vital regulatory role in SCI pathophysiology and neural regeneration. Following SCI, regulation of the TGF-ß signaling pathway can suppress inflammation, reduce apoptosis, prevent glial scar formation, and promote neural regeneration. Due to its role in SCI, the TGF-ß signaling pathway could be a potential therapeutic target. This article reported the pathophysiology of SCI, the characteristics of the TGF-ß signaling pathway, the role of the TGF-ß signaling pathway in SCI, and the latest evidence for targeting the TGF-ß signaling pathway for treating SCI. In addition, the limitations and difficulties in TGF-ß signaling pathway research in SCI are discussed, and solutions are provided to address these potential challenges. We hope this will provide a reference for the TGF-ß signaling pathway and SCI research, offering a theoretical basis for targeted therapy of SCI.

DNMT3a-mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF-κB pathway.

Intervertebral disc degeneration (IVDD) is a common chronic musculoskeletal disease that causes chronic low back pain and imposes an immense financial strain on patients. The pathological mechanisms underlying IVDD have not been fully elucidated. The development of IVDD is closely associated with abnormal epigenetic changes, suggesting that IVDD progression may be controlled by epigenetic mechanisms. Consequently, this study aimed to investigate the role of epigenetic regulation, including DNA methyltransferase 3a (DNMT3a)-mediated methylation and peroxisome proliferator-activated receptor γ (PPARγ) inhibition, in IVDD development. The expression of DNMT3a and PPARγ in early and late IVDD of nucleus pulposus (NP) tissues was detected using immunohistochemistry and western blotting analyses. Cellularly, DNMT3a inhibition significantly inhibited IL-1ß-induced apoptosis and extracellular matrix (ECM) degradation in rat NP cells. Pretreatment with T0070907, a specific inhibitor of PPARγ, significantly reversed the anti-apoptotic and ECM degradation effects of DNMT3a inhibition. Mechanistically, DNMT3a modified PPARγ promoter hypermethylation to activate the nuclear factor-κB (NF-κB) pathway. DNMT3a inhibition alleviated IVDD progression. Conclusively, the results of this study show that DNMT3a activates the NF-κB pathway by modifying PPARγ promoter hypermethylation to promote apoptosis and ECM degradation. Therefore, we believe that the ability of DNMT3a to mediate the PPARγ/NF-κB axis may provide new ideas for the potential pathogenesis of IVDD and may become an attractive target for the treatment of IVDD.

A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.

A novel endoscopic nasopharyngectomy by low-temperature plasma radiofrequency ablation in localized recurrent nasopharyngeal carcinoma.

OBJECTIVE: Endoscopic nasopharyngectomy (ENPG) with en bloc resection has been well accepted in resectable localized recurrent nasopharyngeal carcinoma (rNPC), but it is a difficult technique to master for most otorhinolaryngology head and neck surgeons. Ablation surgery is a new and simplified method to remove tumors. We designed a novel method using low-temperature plasma radiofrequency ablation (LPRA) and evaluated the survival benefit. METHODS: A total of 56 localized rNPC patients were explained in detail and retrospectively analyzed. The surgery method was ablated from the resection margin to the center of the tumor. The postmetastatic overall survival (OS), local relapse-free survival (LRFS) rate, progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using the Kaplan-Meier method and compared by the log-rank test. RESULTS: All surgeries were successfully performed without any severe postoperative complications or deaths. The median operation time of ablation and harvested NSFF respectively were 29 min (range, 15-100 min) and 101 min (range, 30-180 min). The average number of hospital days postoperation was 3 days (range, 2-5 days). All cases (100.0%) had radical ablation with negative resection margins. The nasopharyngeal defects were completely re-epithelialized in 54 (96.4%) patients. As of the data cutoff (September 3, 2023), the median follow-up time was 44.3 months (range, 17.1-52.7 months, 95% CI: 40.4-48.2). The 3-year OS, LRFS, PFS and DMFS of the entire cohort were 92.9% (95% CI: 0.862-0.996), 89.3% (95% CI: 0.813-0.973), 87.5% (95% CI: 0.789-0.961), and 92.9% (95% CI: 0.862-0.996), respectively. Cycles of radiotherapy were independent risk factors for OS (p = 0.003; HR, 32.041; 95% CI: 3.365-305.064), LRFS (p = 0.002; HR, 10.762; 95% CI: 2.440-47.459), PFS (p = 0.004; HR, 7.457; 95% CI: 1.925-28.877), and DMFS (p = 0.002; HR, 34.776; 95% CI: 3.806-317.799). CONCLUSION: Radical endoscopic nasopharyngectomy by using low-temperature plasma radiofrequency ablation is a novel, safe and simplified method to master and disseminate for treating resectable rNPC. However, further data and longer follow-up time are needed to prove its efficacy.

Nrf2/PHB2 alleviates mitochondrial damage and protects against Staphylococcus aureus-induced acute lung injury.

Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA-induced ALI (SA-ALI) remains unclear. In this study, serum samples were collected from SA-sepsis patients, and a SA-ALI mouse model was established by grouping WT and Nrf2-/- mice after 6 h of intraperitoneal injection. A cell model simulating SA-ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA-sepsis patients, negatively correlated with the severity of ALI. In SA-ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation-induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA-ALI. The p-Nrf2/total-Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA-treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual-luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA-ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients.

BACKGROUND: Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis. The frequency of LGMD subtypes varies among regions in China and ethnic populations worldwide. Here, we analyzed the prevalence of LGMD subtypes, their corresponding clinical manifestations, and molecular data in a cohort of LGMD patients in Southeast China. METHODS: A total of 81 consecutive patients with clinically suspected LGMDs from 62 unrelated families across Southeast China were recruited for targeted next-generation sequencing and whole-exome sequencing from July 2017 to February 2020. RESULTS: Among 50 patients (41 families) with LGMDs, the most common subtypes were LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%). Dystroglycanopathies (including LGMD-R9/LGMD2I, LGMD-R11/LGMD2K, LGMD-R14/LGMD2N and LGMD-R20/LGMD2U) were the most common childhood-onset subtypes and were found in 12.2% of the families. A total of 14.6% of the families had the LGMD-R7/LGMD2G subtype, and the mutation c.26_33dupAGGTGTCG in TCAP was the most frequent (83.3%). The only patient with the rare subtype LGMD-R18/LGMD2S had TRAPPC11 mutations; had a later onset than those previously reported, and presented with proximal‒distal muscle weakness, walking aid dependency, fatty liver disease and diabetes at 33 years of age. A total of 22.0% of the patients had cardiac abnormalities, and one patient with LMNA-related muscular dystrophy/LGMD1B experienced sudden cardiac death at 37 years of age. A total of 15.4% of the patients had restrictive respiratory insufficiency. Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B. CONCLUSION: We determined the prevalence of different LGMD subtypes in Southeast China, described the detailed clinical manifestations and distinct muscle MRI patterns of these LGMD subtypes and reported the frequent mutations and the cardiorespiratory involvement frequency in our cohort, all of which might facilitate the differential diagnosis of LGMDs, allowing more timely treatment and guiding future clinical trials.

Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy.

BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, BET inhibitors represent a novel form of epigenetic anticancer treatment. Although preliminary clinical trials have shown the anticancer potential of BET inhibitors, it appears that these drugs have limited effectiveness when used alone. Therefore, given the limited monotherapeutic activity of BET inhibitors, their use in combination with other drugs warrants attention, including the meaningful variations in pharmacodynamic activity among chosen drug combinations. In this paper, we review the function of BET proteins, the preclinical justification for BET protein targeting in cancer, recent advances in small-molecule BET inhibitors, and preliminary clinical trial findings. We elucidate BET inhibitor resistance mechanisms, shed light on the associated adverse events, investigate the potential of combining these inhibitors with diverse therapeutic agents, present a comprehensive compilation of synergistic treatments involving BET inhibitors, and provide an outlook on their future prospects as potent antitumor agents. We conclude by suggesting that combining BET inhibitors with other anticancer drugs and innovative next-generation agents holds great potential for advancing the effective targeting of BET proteins as a promising anticancer strategy.

[Diurnal differences in acute gout attacks: A clinical study of male gout patients].

OBJECTIVE: To observe the diurnal difference of acute gout attacks in men, and provide reference for accurate clinical prevention and treatment. METHODS: Using a single-center, cross-sectional study design, the patients diagnosed with gout in the outpatient department of Rheumatology and Immuno-logy of PLA Joint Logistic Support Force No.980 Hospital from October 2021 to April 2022 were selected. The information about the patient's current/last acute gout attacks (less than 2 weeks from visit), date and time of attacks, joint symptoms and signs, medication use, and relevant biochemical tests on the day of visit was recorded. The diurnal time difference of acute gout attacks in male patients was analyzed, and univariate comparison and multivariate Logistic regression analyses were conducted to compare the diurnal difference of acute gout attacks with clinical characteristics and biochemical indicators. RESULTS: A total of 100 male gout patients were included, and 100 acute attacks were recorded. Diurnal distribution of acute gout attacks: morning (6:00~11:59, 18, 18%), afternoon (12:00~17:59, 11, 11%), the first half of the night (18:00~23:59, 22, 22%), the second half of the night (0:00~05:59, 49, 49%); During the day (included morning and afternoon, 29, 29%) and at night (included the first half of the night and the second half of the night, 71, 71%). The rate of acute gout attack was significantly higher at night than in the day (about 2.5 ∶1). No matter the first or recurrent gout, no matter the duration of the disease, the number of acute gout attacks had the difference of less in the day and more in the night. Serum urate (SU) level was higher in the patients with nocturnal attack than in those with daytime attack (P=0.044). Comorbidities were significantly different in the day-night ratio of the number of acute gout attack (P=0.028). Multiple Logistic regression analysis showed that SU level (OR=1.005, 95%CI: 1.001-1.009) and comorbidities (OR=3.812, 95%CI: 1.443-10.144) were the correlative factors of nocturnal acute gout attacks. CONCLUSION: No matter the first or recurrent gout, no matter the duration of the disease, it has a diurnal variation characterized by multiple attacks at night, increased SU level and comorbidities are correlative factors for nocturnal acute attack of gout.

Dual-functional single-atomic Mo/Fe clusters-decorated C3N5 via three electron-pathway in oxygen reduction reaction for tandemly removing contaminants from water.

Inspired by the development of single-atom catalysts (SACs), the fabrication of multimetallic SACs can be a promising technical approach for the in situ electro-Fenton (EF) process. Herein, dual-functional atomically dispersed Mo-Fe sites embedded in carbon nitride (C3N5) (i.e., MoFe/C3N5) were synthesized via a facile SiO2 template method. The atomically isolated bimetallic configuration in MoFe/C3N5 was identified by combining the microscopic and spectroscopic techniques. The MoFe/C3N5 catalyst on the cathode exhibited a remarkable catalytic activity toward the three electron-dominated oxygen reduction reaction in sodium sulfate, leading to a highly effective EF reaction with a low overpotential for the removal of organic contaminants from wastewater. The new catalyst showed a superior performance over its conventional counterparts, owing to the dual functions of the dual-metal active sites. Density functional theory (DFT) analysis revealed that the dual-functional 50-MoFe/C3N5 catalyst enabled a synergistic action of the Mo-Fe dual single atomic centers, which can alter the adsorption/dissociation behavior and decrease the overall reaction barriers for effective organic oxidation during the EF process. This study not only sheds light on the controlled synthesis of atomically isolated catalyst materials but also provides deeper understanding of the structure-performance relationship of the nanocatalysts with dual active sites for the catalytic EF process. Additionally, the findings will promote the advanced catalysis for the treatment of emerging organic contaminants in water and wastewater.

Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma.

The aim of this study was to investigate the clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma. Histopathology, immunohistochemistry, and human epidermal growth factor receptor 2 (HER2) gene testing were conducted for seven cases of gastric pleomorphic giant cell carcinoma. In histomorphological terms, all seven cases involved pleomorphic giant cell carcinoma, accounting for more than 10% of the entire tumor, with pleomorphic spindle cells and giant cells mixed with various histomorphological structures of adenocarcinoma with high, intermediate, and low differentiation. There was large heterogeneity in the HER2 protein expression and HER2 gene amplification in the gastric pleomorphic giant cell carcinoma, and both levels of HER2 were focal in three cases, accounting for 42.9% (3/7). The mismatch repair gene proteins MLH1, MSH2, PMS2, and MSH6 were positive. Routine immunohistochemical markers, i.e., pan-cytokeratin, epithelial membrane antigen, villin, caudal-type homeobox 2, E-cadherin, and p53, were positive in the gastric pleomorphic giant cell carcinoma, while vimentin, calponin, smooth muscle actin, nestin, S-100, cluster of differentiation (CD) 99, desmin, and CD34 were focally expressed in both the spindle and the giant cells, with Ki-67-positive cells accounting for 70-80%. Gastric pleomorphic giant cell carcinoma presents multiple histomorphological features and is easily confused with various tumors. Clarifying the histopathological features of this type of tumor is important for differential diagnosis and precise treatment.