Sulfonamides as N-Centered Radical Precursors for C-N Coupling Reactions To Generate Amidines.

Nitrogen-centered radicals (NCRs) are valuable intermediates for the construction of C-N bonds. Traditional methods for the generation of NCRs employ toxic radical initiators, transition metal catalysts, photocatalysts, or organometallic reagents. Herein, we report a novel strategy for the generation of NCRs toward the construction of C-N bonds under transition-metal-free conditions. Thus, super-electron-donor (SED) 2-azaallyl anions undergo single-electron transfer (SET) with sulfonamides, forming aminyl radicals (R2N•, R = alkyl) and culminating in the generation of amidines bearing various functional groups (33 examples, up to 96% yield). Broad substrate scope and gram-scale telescoped preparation demonstrate the practicality of this method. Radical clock and electron paramagnetic resonance (EPR) experiments support the proposed radical coupling pathway between the generated N-centered radical and the C-centered 2-azaallyl radical.

CTLs heterogeneity and plasticity: implications for cancer immunotherapy.

Cytotoxic T lymphocytes (CTLs) play critical antitumor roles, encompassing diverse subsets including CD4+, NK, and γδ T cells beyond conventional CD8+ CTLs. However, definitive CTLs biomarkers remain elusive, as cytotoxicity-molecule expression does not necessarily confer cytotoxic capacity. CTLs differentiation involves transcriptional regulation by factors such as T-bet and Blimp-1, although epigenetic regulation of CTLs is less clear. CTLs promote tumor killing through cytotoxic granules and death receptor pathways, but may also stimulate tumorigenesis in some contexts. Given that CTLs cytotoxicity varies across tumors, enhancing this function is critical. This review summarizes current knowledge on CTLs subsets, biomarkers, differentiation mechanisms, cancer-related functions, and strategies for improving cytotoxicity. Key outstanding questions include refining the CTLs definition, characterizing subtype diversity, elucidating differentiation and senescence pathways, delineating CTL-microbe relationships, and enabling multi-omics profiling. A more comprehensive understanding of CTLs biology will facilitate optimization of their immunotherapy applications. Overall, this review synthesizes the heterogeneity, regulation, functional roles, and enhancement strategies of CTLs in antitumor immunity, highlighting gaps in our knowledge of subtype diversity, definitive biomarkers, epigenetic control, microbial interactions, and multi-omics characterization. Addressing these questions will refine our understanding of CTLs immunology to better leverage cytotoxic functions against cancer.

Effect of standard nutritional support therapy based on nutritional risk screening on post-operative nutritional status and quality of life in patients with glioma.

OBJECTIVE: To explore the effect of standard nutritional support based on nutritional risk screening on nutrition conditions and living quality in glioma patients after surgery. METHODS: The clinical information of 100 patients with glioma treated at the Sichuan Provincial People's Hospital from April 2021 to April 2022 was reviewed retrospectively. Among them, 39 patients received routine nutritional support during the perioperative period (routing group) and 61 patients received standard nutritional support (standard group). The relevant clinical data were collected, and the postoperative albumin (ALB) level, prealbumin (PA) level, hemoglobin (Hb) level, patient-generated subjective global assessment (PG-SGA) score, Kanofsky performance score (KPS), and short-term prognosis were compared between the two groups. Finally, factors affecting the efficacy of nutritional support in patients with glioma were analyzed. RESULTS: 14 days after the surgery, the levels of ALB, PA, and Hb of the standard group were significantly higher than those in the routing group (all P < 0.05). The PG-SGA scores of the two groups decreased with time, and the PG-SGA scores of the standard group were significantly lower than those of the routing group at 30 d and 60 d after the operation (intergroup effect: F = 9.077, P = 0.003, time effect: F = 75.28, P < 0.001, and interaction effect: F = 3.111, P = 0.047). The KPS scores of the two groups increased with time, and the KPS scores of the standard group were significantly higher than those of the routing group at 30 d and 60 d after operation (intergroup effect: F = 4.458, P = 0.044, time effect: F = 31.333, P < 0.001, and interaction effect: F = 3.507, P = 0.032). Within 6 months after discharge, the tumor recurrence rate of the standard group was significantly lower than that in the routing group (P < 0.05). After 60 days of the surgery, nutritional support therapy worked well in 32 patients, and the results of the logistic regression analysis displayed that age was an independent factor affecting the efficacy of nutritional support in post-operative glioma patients. CONCLUSION: Standard nutritional support based on nutritional risk screening can improve the nutrition condition and living quality of post-operative glioma patients and is worthy of clinical application.

The development of a novel simultaneous in vitro dissolution - in situ perfusion system as a potential tool for studying the absorption of solid oral formulation in rat.

The aim of this work is to develop a novel simultaneous in vitro dissolution - in situ perfusion system (SDPS) as a potential tool to evaluate the in vivo performance of solid oral formulation in rat. The innovative nitrendipine (NTD) tablet of Bayotensin mite® made in Germany was used as reference listed drug (RLD), and five generic products from Chinese market were compared with RLD using the in vitro dissolution test method specified by the orange book and the SDPS method developed in this study. Four self-prepared NTD tablets with different proportions of microcrystalline cellulose/starch were employed to investigate the discriminatory ability of the SDPS for formulation. In addition, the predictivity of the SDPS in relation to data from in vivo pharmaceutics studies was evaluated. The 45-min dissolution test and multiple-pH dissolution profiles of generic product 1 and 2 have no difference compared with the RLD, but their dissolution profiles from the SDPS showed statistically significant differences. A biexponential formula successfully described the concentration profiles of self-prepared formulations in SDPS experiments. The kdis (0.08 ± 0.01 ∼ 0.2 ± 0.03 min-1) and ka (about 2.30 × 10-3 min-1) values calculated by the formulas of F1-F3 suggested that the used excipients had no effect on the intestinal absorption of NTD, and it might be the property of active pharmaceutical ingredient that led to the difference among the generics. Furthermore, the in vivo rat pharmacokinetics study results of F1-F3 showed a good correlation (R2 = 0.99) with the SDPS data. In summary, the SDPS is a promising tool to detect the unexpected quality changes of pharmaceutical products in weakly regulated markets, facilitate formulation screening, and potentially reduce animal testing for estimating the in vivo absorption behavior of solid oral formulations. The absorption performance of generic drugs in vivo should be further investigated.

Molecularly engineered dual-network photothermal hydrogel delivery system with enhanced mechanical properties, antibacterial ability and angiogenic effect for accelerating wound healing.

Bacterial infection caused by trauma and chronic wounds in the most mobile area remains a challenge in clinic. It is difficult to achieve the synergistic effects of antibacterial capacity and skin regeneration using conventional therapeutic methods. Developing a multi-functional hydrogel dressing that can cope with the complex wound environment will contribute to the healing and therapeutic effects. In this work, a novel Cur@PAM/TA-Cu photothermal hydrogel delivery system was prepared by engineering tannic acid (TA) into covalent cross-linked polyacrylamide (PAM) on which the chelating tannic acid-copper metal-polyphenolic network (TA-Cu MPN) was imposed to form dual-crosslinked networks, and the natural medicine curcumin was loaded eventually. The molecularly engineered dual-crosslinked networks resulted in enhanced mechanical properties including bio-adhesion, tensile strength and self-healing, which made the hydrogel suitable for dynamic wound and various application scenarios. In addition, the excellent photothermal capacity, antioxidant effect and biocompatibility of the hydrogel were demonstrated. Notably, this curcumin loaded photothermal hydrogel exhibited superior antibacterial capacity (almost 100% killing ratio to E. coli and S. aureus) under 808 nm laser irradiation. Meanwhile, the in vivo wound healing experiment results revealed that the anti-inflammation and proangiogenic effect of Cur@PAM/TA-Cu hydrogel successfully shortened the healing time of wound and the reconstruction of skin structure and function. Thus, this dual-crosslinked multi-functional hydrogel delivery system is a promising wound dressing for accelerating wound healing.

Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment.

As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.

Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual. METHODS: Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. RESULTS: A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial. CONCLUSIONS: As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

Effects of Different Delignification and Drying Methods on Fiber Properties of Moso Bamboo.

Bamboo has become an important kind of fibrous raw material in the world due to its fast-growing property and abundance of natural fiber. During the purification and utilization of bamboo fiber, the removal of lignin is vital and it is affected by the chemical treatment system and drying method. In this paper, the effects of three different delignification chemical systems and three drying methods (air drying, drying and freeze drying) on the physical and chemical properties of bamboo fiber were comparatively studied. The results prove that all three delignification techniques can effectively remove lignin from wood, and by utilizing peroxyformic acid and alkaline sodium sulfite, hemicellulose can be removed to a certain extent. With the selective removal of amorphous hemicellulose and lignin and the hydrolysis of cellulose molecular chains in amorphous regions, all three treatments contributed to an increase in the relative crystallinity of cellulose (ranging from 55% to 60%). Moreover, it was found that the drying methods exerted a certain influence on the mechanical properties of fiber. For instance, drying or air drying would improve the tensile strength of fiber significantly, approximately 2-3.5 times that of original bamboo fiber, and the tensile strength of the drying group reached 850-890 MPa. In addition, the alkaline sodium sulfite treatment had little effect on the thermal stability of bamboo fiber, resulting in high thermal stability of the prepared samples, and the residual mass reached 25-37%. On the contrary, the acetic acid/hydrogen peroxide method exerted great influence on the thermal stability of bamboo fiber, giving rise to a relatively poor thermal stability of prepared fibers, and the residual mass was only about 15%. Among the three drying methods, samples under air drying treatment had the highest residual mass, while those under freeze drying had the lowest. To summarize, the alkaline sodium sulfite method is more suitable for preparing bamboo fiber with higher tensile strength and thermal stability.

Identification and validation of novel biomarkers affecting bladder cancer immunotherapy via machine learning and its association with M2 macrophages.

Background: Immunotherapy has shown promising results in bladder cancer therapy options. Methods: Analysis of open-access data was conducted using the R software. Open-access data were obtained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and IMvigor210 databases. Immunofluorescence and co-culture systems were utilized to validate the effect of PTHLH on M2 macrophage polarization. Results: Here, through the combined (TCGA, GSE128959, GSE13507, and GSE83586) and IMvigor210 cohorts, we comprehensively investigated the biological and immune microenvironment differences in patients with diverse immunotherapy responses. Meanwhile, we found that M2 macrophage could affect bladder cancer immunotherapy sensibility. Moreover, based on the machine learning algorithm (LASSO logistics regression), PTHLH, BHMT2, and NGFR were identified, which all have good prediction abilities for patient immunotherapy. Then, a logistics regression model was established based on PTHLH, BHMT2, and NGFR, and each patient was assigned a logistics score. Subsequently, we investigated the difference in patients with high low logistics scores, including biological enrichment, immune microenvironment, and genomic characteristics. Meanwhile, data from the Human Protein Atlas database indicated a higher protein level of PTHLH in bladder cancer tissue. Immunofluorescence indicated that the knockdown of PTHLH in bladder cancer cells can significantly inhibit the M2 polarization of co-culture M0 macrophages. Conclusions: Our study investigated the difference between bladder cancer immunotherapy responders and non-responders. Meanwhile, the PTHLH was identified as a novel biomarker for bladder cancer immunotherapy.

TCR Coexpression Signature Predicts Immunotherapy Resistance in NSCLC.

Background: Lung cancer has the highest morbidity and mortality rate among types of malignant tumors, and as such, research into prolonging the survival time of patients is vital. The emergence of immune checkpoint inhibitors (ICIs) has greatly improved the survival of patients with non-small cell lung cancer (NSCLC), however, the lack of effective biomarkers to predict the prognosis of immunotherapy has made it difficult to maximize the benefits. T cell receptor (TCR) is one of the most important components for recognizing tumor cells, and with this study we aim to clarify the relationship between TCR coexpression and the prognosis of NSCLC patients receiving immunotherapy. Methods: Univariate COX regression, logistics regression, and KM survival analysis were used to evaluate the relationship between TCR coexpression and the prognosis of immunotherapy. Additionally, CIBERSORT, Gene Set Enrichment Analysis (GSEA), and single-sample GSEA (ssGSEA) algorithms were used to evaluate the tumor immune microenvironment (TIME) of NSCLC patients. Results: Univariate Cox regression analysis showed that the TCR coexpression signature can be used as a clinical prognostic indicator for NSCLC patients receiving immunotherapy (p = 0.0205). In addition, those in the NSCLC group with a high TCR coexpression signature had significantly improved progression-free survival (PFS) (p = 0.014). In the ICI treatment cohort (GSE35640). In addition, there was a high infiltration of CD8+T cells, activated memory CD4+T cells, and M1 macrophages in the TIME of those with a high TCR coexpression signature. The results of pathway enrichment analysis showed that patients with a high TCR coexpression signature had significantly activated signal pathways such as lymphocyte proliferation and activation, chemokine binding, and inflammatory cytokine production. Also, we found that patients with a high TCR coexpression signature had an elevated T cell inflammation gene expression profile (GEP). Conclusion: We show that the TCR coexpression signature may be useful as a new biomarker for the prognosis of NSCLC patients undergoing immunotherapy, with high signatures indicating better treatment response. Additionally, we found that patients with a high TCR coexpression signature had tumor immune microenvironments with beneficial anti-tumor characteristics.

Preliminary study on the diagnostic value of cardiac magnetic resonance feature tracking for malignant ventricular arrhythmias in non-ischemic dilated cardiomyopathy.

Background: Patients with nonischemic dilated cardiomyopathy (NIDCM) and malignant ventricular arrhythmia (MVA) often have a poor prognosis and a high risk of sudden cardiac death. Although the diagnosis of MVA is straightforward by electrocardiogram (ECG), the underlying abnormalities of ventricular mechanics in these patients are unknown. This study aims to preliminarily explore the value of cardiac magnetic resonance feature tracking (CMR-FT) for MVA in dilated cardiomyopathy. Methods: In this retrospective study, patients with NIDCM who met inclusion criteria were divided into an MVA group and a non-MVA group (included from January 2018 to September 2021). The interobserver agreement of myocardial strain parameters, including global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS), were tested. The GLS, GCS, GRS, left ventricular ejection fraction (LVEF), Tpeak-Tend interval on ECG and brain natriuretic peptide (BNP) were compared between groups. Single-factor and multifactor receiver operating characteristic (ROC) curve analyses were conducted to calculate the area under the ROC curve (AUC), cut-off point, sensitivity, and specificity of these parameters in predicting MVA in NIDCM. Results: A total of 161 NIDCM patients were included (54 in the MVA group). GLS, GCS, and GRS had good interobserver agreement (all intraclass correlation coefficients >0.80). The absolute GLS and GCS, GRS and LVEF were lower in the MVA group than the non-MVA group (P<0.001), Tpeak-Tend and BNP were higher (P<0.001). Single-factor ROC curve analysis showed that GLS, GCS and GRS had certain diagnostic value for MVA (AUC =0.795, 0.802, and 0.754, respectively). Among them, GCS had higher sensitivity and specificity (GCS 0.796/0.776, GLS 0.778/0.757, GRS 0.741/0.692). Multifactor ROC curve analysis showed the combination of GLS and GCS (AUC =0.810), the combination of GCS and GRS (AUC =0.802), the combination of GLS and GRS (AUC =0.787), the combination of GLS, GCS, and GRS (AUC =0.810). Conclusions: The three-dimensional myocardial strain parameters (especially GLS and GCS) measured by CMR-FT had certain diagnostic value and could reflect the underlying abnormality of ventricular mechanics of NIDCM with MVA.

Single-Cell Analysis Reveals Spatial Heterogeneity of Immune Cells in Lung Adenocarcinoma.

The impacts of the tumor microenvironment (TME) on tumor evolvability remain unclear. A challenge for nearly all cancer types is spatial heterogeneity, providing substrates for the emergence and evolvability of drug resistance and leading to unfavorable prognosis. Understanding TME heterogeneity among different tumor sites would provide deeper insights into personalized therapy. We found 9,992 cell profiles of the TME in human lung adenocarcinoma (LUAD) samples at a single-cell resolution. By comparing different tumor sites, we discovered high TME heterogeneity. Single-sample gene set enrichment analysis (ssGSEA) was utilized to explore functional differences between cell subpopulations and between the core, middle and edge of tumors. We identified 8 main cell types and 27 cell subtypes of T cells, B cells, fibroblasts and myeloid cells. We revealed CD4+ naive T cells in the tumor core that express high levels of immune checkpoint molecules and have a higher activity of immune-exhaustion signaling. CD8+ T cell subpopulations in the tumor core correlate with the upregulated activity of transforming growth factor-ß (TGF-ß) and fibroblast growth factor receptor (FGFR) signaling and downregulated T cell activity. B cell subtypes in the tumor core downregulate cytokine production. In this study, we revealed that there was immunological heterogeneity in the TME of patients with LUAD that have different ratios of immune cells and stromal cells, different functions, and various degrees of activation of immune-related pathways in different tumor parts. Therefore, clarifying the spatial heterogeneity of the tumor in the immune microenvironment can help clinicians design personalized treatments.

Analysis of Interleukin-1 Signaling Alterations of Colon Adenocarcinoma Identified Implications for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.

The Impact of NOTCH Pathway Alteration on Tumor Microenvironment and Clinical Survival of Immune Checkpoint Inhibitors in NSCLC.

The treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) has been proven to induce lasting tumor remission. Screening suitable populations for immunotherapy through predictive markers is an important approach to improving the clinical benefits of patients. Evidence has shown that there may be a close connection between NOTCH signaling and the tumor microenvironment (TME). Hence, we explored the impact of the mutation status of NOTCH signaling on the prognosis of NSCLC patients treated with immunotherapy with the aim to apply NSCLC immunotherapy to the greatest extent possible. We examined two clinical cohorts of NSCLC patients receiving ICIs (MSKCC and NG cohorts). The mutation and prognostic data of the ICI-treated cohort were used to evaluate the association between the mutation status of NOTCH signaling and prognosis following immunotherapy. The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to analyze the differences in the immune microenvironment under different NOTCH signaling mutation states. In the ICI-treated cohorts, the univariate and multivariate Cox regression analyses indicated that high-mutated NOTCH signaling could serve as an independent predictor of NSCLC patients receiving ICIs. Patients with high-mutated NOTCH signaling had significantly improved progression-free survival (PFS) (P = 0.03, HR = 0.69; MSKCC cohort) and prolonged overall survival (OS) (P = 0.004, HR = 0.34; NG cohort). Additionally, high-mutated NOTCH signaling was related to the inflammatory immune microenvironment, inflammatory expression profile, and enhanced immunogenicity. According to this study, high-mutated NOTCH signaling may serve as a biomarker for the prediction of the prognosis of NSCLC patients treated with ICIs. A series of prospective clinical studies and molecular mechanism explorations are still needed in the future.

Ras Homolog Family Member F, Filopodia Associated Promotes Hepatocellular Carcinoma Metastasis by Altering the Metabolic Status of Cancer Cells Through RAB3D.

BACKGROUND AND AIMS: The mechanism by which tumor cells resist metabolic stress remains unclear, but many oncogenes are known to regulate this process. Accordingly, metabolic stress is closely associated with tumor metastasis. In this study, gene chip technology showed that Ras homolog family member F, filopodia associated (RHOF), a member of the Rho guanosine triphosphatase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. Our aim was to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms. APPROACH AND RESULTS: The results showed that compared to expression in adjacent noncancerous tissues, RHOF was frequently up-regulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with tumor-node-metastasis stage, T grade, metastasis status, recurrence, and survival in HCC. RHOF also affected cell morphology and promoted migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cell lines. Analysis of the underlying mechanism showed that RHOF promoted the Warburg effect by up-regulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted a tumor-promoting effect by directly interacting with AMP-activated protein kinase (AMPK) and increasing the phosphorylation of AMPK. This subsequently affected RAB3D mRNA stability and led to elevated RAB3D expression, thereby amplifying the Warburg effect and malignant biological behaviors of HCC cells. CONCLUSIONS: RHOF helps tumor cells resist metabolic stress through modulating the Warburg effect and plays a critical role in promoting HCC cell migration, invasion, and EMT, highlighting its important role in remodeling the metastatic microenvironment and regulating tumor metastasis. RHOF shows potential as a therapeutic target and prognostic biomarker for HCC.

Screening and Identifying Cisplatin-Related Gene Mutations in Lung Squamous Cell Carcinoma.

INTRODUCTION: Platinum-based chemotherapy is the cornerstone of treatment for patients with LUSC, but cisplatin resistance greatly restricts its clinical application. Therefore, it is particularly important to screen the predominant LUSC population using biomarkers. METHODS: Data for 15 LUSC cell lines were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) Project database to screen for mutations related to cisplatin susceptibility. We conducted whole-exome sequencing (WES) of tumors from 58 LUSC patients from Sichuan Provincial People's Hospital of University of Electronic Science and Technology. Subsequently, the clinical prognostic value of these mutations was verified by using The Cancer Genome Atlas (TCGA)-LUSC cohort and our cohort (n=58). RESULTS: Based on the cisplatin sensitivity data of GDSC-LUSC and survival analysis of TCGA-LUSC and Local-LUSC cohorts, we found that only mutation of IGF2R was associated with cisplatin sensitivity, better overall survival [OS; P=0.04, HR (95% CI): 0.42 (0.23-0.78)] and progression-free survival [PFS; P =0.016, HR (95% CI): 0.26 (0.12-0.59)]. However, there were no significant differences in the frequencies of gene mutations between the IGF2R-mutant (IGF2R-MT) and IGF2R-wild-type (IGF2R-WT) groups. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) indicated enhanced intracellular detoxification and decreased abnormal signaling activity to reverse cisplatin tolerance in the IGF2R-MT group. CONCLUSION: The results suggest that IGF2R mutations are a potential biomarker for screening LUSC patients suitable for cisplatin treatment.

The efficacy and safety of moxibustion for chemotherapy-induced gastrointestinal adverse reaction: A protocol for systematic review and meta-analysis.

BACKGROUND: Many cancer patients experience gastrointestinal adverse reaction during chemotherapy. Pharmacological interventions are commonly used to treat chemotherapy-induced gastrointestinal side effects but have various limitations. Clinical trials have indicated that moxibustion may alleviate gastrointestinal dysfunction and improve quality of life (QoL) after chemotherapy. This study aims to assess the efficacy and safety of moxibustion for chemotherapy-induced gastrointestinal adverse reaction through a systematic review and meta-analysis. METHODS: All randomized controlled trials (RCTs) related to moxibution targeting chemotherapy-induced gastrointestinal adverse reaction will be searched in online databases, such as PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database (VIP Database) and WanFang Database from their inception to May 1, 2020. The primary outcome is the incidence and severity of chemotherapy-related gastrointestinal toxicities (nausea and vomiting, diarrhea and constipation). The secondary outcomes include the quality of life, biological parameters' alteration, and adverse events. Study selection, data extraction, and assessment of risk of bias will be performed independently by 2 researchers. The Cochrane Collaboration's Review Manager (RevMan 5.3) software will be used to conduct the direct meta-analysis. RESULTS: This study will provide a comprehensive review of the available evidence for the treatment of chemotherapy-induced gastrointestinal adverse reaction with moxibustion. CONCLUSION: The conclusion of this study will provide evidence to judge whether moxibustion is an effective and safety therapeutic intervention for chemotherapy-induced gastrointestinal adverse reaction. PROSPERO REGISTRATION NUMBER: CRD42020182990.

Management of medically inoperable and tyrosine kinase inhibitor-naïve early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: a retrospective multi-institutional analysis.

BACKGROUND: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for medically inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations has not yet been determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI treatment alone and combined radiation and TKI treatment on the survival outcomes in this patient subgroup. METHODS: A total of 132 cases of medically inoperable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among these patients, 65 received combined radiation and EGFR-TKI therapy (R + TKI) (49.2%), while 67 received EGFR-TKI (50.8%) treatment alone. All patients were followed until death. RESULTS: For the R + TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < 0.001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups was 24 months and 14.7 months respectively (log-rank p < 0.001). Multivariate analysis showed that R + TKI was independently associated with improved OS (adjusted HR 0.420; 95% CI 0.287 to 0.614; p < 0.001) and PFS (adjusted HR 0.420; 95% CI 0.291 to 0.605; p < 0.001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. CONCLUSIONS: Upfront radiation to primary sites with subsequent TKI treatment is a feasible option for patients with medically inoperable EGFR-mutant non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with those yielded by TKI treatment alone.

Expression of Wip1 in serum of patients with small cell lung cancer and its clinical significance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression of wild type p53 induced phosphatase 1 (Wip1) in small cell lung cancer (SCLC) cells and the serum of SCLC patient and its relationship with clinical prognosis. Methods: Real time quantitative PCR (qPCR) was used to detect the expression of Wip1 in SCLC cells and serum samples. Results: The expression of Wip1 in drug-resistant SCLC cells was significantly higher than that in sensitive cell lines (P<0.01). The expression of Wip1 in serum of SCLC group was significantly higher than that of normal control group (P<0.05); the expression of Wip1 in serum of patients with chemotherapy resistance was significantly higher than that in patients with chemotherapy sensitivity (all P<0.05); the serum Wip1 level was correlated with disease stage, chemotherapy sensitivity and survival status of SCLC patients (all P<0.05). The area under ROC curve of Wip1 predicting the prognosis of SCLC was 0.836 (95%CI:0.8230-0.9600, P<0.01); the expression lever of Wip1 was significantly correlated with progression free survival and overall survival time of SCLC patients (all P<0.05). Disease stage, chemosensitivity and Wip1 expression were independent prognostic factors for SCLC patients (all P<0.05). Conclusion: The expression of Wip1 in serum of SCLC patients may be related to chemotherapy sensitivity and prognosis. Wip1 may be a potential biomarker for therapeutic efficacy and prognosis evaluation of SCLC patients.

HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway.

BACKGROUND: The human ether a-go-go-related gene 1 (HERG1) is involved in tumor progression; however, its role in esophageal squamous cell carcinoma (ESCC) is not well studied. This study investigated HERG1 function in ESCC progression and elucidated the underlying mechanisms. METHODS: The prognostic value of HERG1 was determined by immunohistochemistry in ESCC biopsies. Cell growth and proliferation were analyzed by colony formation and methyl thiazolyl tetrazolium assays. Cell migration and invasion were analyzed by wound healing and Boyden transwell assays. Epithelial-mesenchymal transition (EMT) was evaluated by immunoblotting and quantitative polymerase chain reaction (qPCR). A xenograft mouse model was used to validate the tumorigenic and metastatic roles of HERG1 in vivo. RESULTS: HERG1 expression was overall higher in ESCC tissues compared to adjacent non-tumor tissues. A retrospective analysis of 349 patients with ESCC (stages I-IV) confirmed increased HERG1 expression was associated with disease progression and higher mortality rate. The overall survival of the patients was significantly worse when their tumors displayed higher HERG1 expression. HERG1 knockdown reduced tumor growth and metastasis in athymic mice. HERG1 affected the proliferation, migration, and invasion of two ESCC cell lines (TE-1 and KYSE-30). Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies. Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression. CONCLUSIONS: HERG1 contributes to poor prognosis in patients with ESCC by promoting ESCC cell proliferation, migration, and invasion via TXNDC5 through the PI3K/AKT signaling pathway. Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment.