Efficacy Assessment of Post-nephrectomy Adjuvant Therapies in Patients with Renal Cell Carcinoma.

OBJECTIVE: The objective of our study was to integrate the efficacy results of post-nephrectomy adjuvant therapies in renal cell carcinoma (RCC) patients with risk of recurrence, and attempt to determine the optimal intervention choice. METHODS: We performed standard meta-analysis procedures in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed, Embase, and Cochrane Library databases were searched from inception to 22 September 2022. Randomized controlled trials reporting overall survival (OS) or disease-free survival (DFS) of adjuvant therapies, including immune checkpoint inhibitors (ICIs) and targeted therapies, in adult post-nephrectomy RCC patients were eligible for inclusion. RESULTS: Seven studies involving 7548 participants were included in our analyses. In contrast with placebo, DFS benefit with ICIs was only observed in female RCC patients and RCC patients with high programmed death-ligand 1 (PD-L1) expression (≥ 1%), sarcomatoid features, and M0 intermediate-high risk. Network meta-analyses demonstrated that pembrolizumab exhibited both DFS and OS benefit compared with placebo, sunitinib, sorafenib, and girentuximab, and only DFS benefit compared with atezolizumab and nivolumab plus ipilimumab. CONCLUSIONS: Our results suggest that post-nephrectomy RCC patients with sarcomatoid differentiation and high PD-L1 expression were more responsive to ICIs. Furthermore, pembrolizumab monotherapy exhibited superior DFS and OS results over other adjuvant therapies.

Mechanism exploration and biomarker identification of glycemic deterioration in patients with diseases of the exocrine pancreas.

The damage to the endocrine pancreas among patients with diseases of the exocrine pancreas (DP) leads to reduced glycemic deterioration, ultimately resulting in diabetes of the exocrine pancreas (DEP). The present research aims to investigate the mechanism responsible for glycemic deterioration in DP patients, and to identify useful biomarkers, with the ultimate goal of enhancing clinical practice awareness. Gene expression profiles of patients with DP in this study were acquired from the Gene Expression Omnibus database. The original study defines DP patients to belong in one of three categories: non-diabetic (ND), impaired glucose tolerance (IGT) and DEP, which correspond to normoglycemia, early and late glycemic deterioration, respectively. After ensuring quality control, the discovery cohort included 8 ND, 20 IGT, and 12 DEP, while the validation cohort included 27 ND, 15 IGT, and 20 DEP. Gene set enrichment analysis (GSEA) employed differentially expressed genes (DEGs), while immunocyte infiltration was determined using single sample gene set enrichment analysis (ssGSEA). Additionally, correlation analysis was conducted to establish the link between clinical characteristics and immunocyte infiltration. The least absolute shrinkage and selection operator regression and random forest combined to identify biomarkers indicating glycemic deterioration in DP patients. These biomarkers were further validated through independent cohorts and animal experiments. With glycemic deterioration, biological processes in the pancreatic islets such as nutrient metabolism and complex immune responses are disrupted in DP patients. The expression of ACOT4, B2M, and ACKR2 was upregulated, whereas the expression of CACNA1F was downregulated. Immunocyte infiltration in the islet microenvironment showed a significant positive correlation with the age, body mass index (BMI), HbA1c and glycemia at the 2-h of patients. It was a crucial factor in glycemic deterioration. Additionally, B2M demonstrated a significant positive correlation with immunocyte infiltration and clinical features. Quantitative real-time PCR (qRT-PCR) and western blotting confirmed the upregulation in B2M. Immunofluorescent staining suggested the alteration of B2M was mainly in the alpha cells and beta cells. Overall, the study showed that gradually increased immunocyte infiltration was a significant contributor to glycemic deterioration in patients with DP, and it also highlighted B2M as a biomarker.

What Happens to a Pyrrole Hemithioindigo Photoswitch Trapped in a Fluorescent Protein?

Artificial molecular photoswitches that can be reversibly controlled into different configurations by external light stimulation have broad application prospects in various fields, such as materials and chemical biology. Among them, the pyrrole hemithioindigo (PHT) photoswitch has a geometric structure similar to that of the fluorescent protein chromophore. What happens when the chromophore is replaced by PHT, and does it achieve similar functions to the original one? To answer these questions, we carried out ONIOM(QM/MM) and classical molecular dynamics studies on the photoisomerization mechanism and spectroscopic properties of PHT in the fluorescent protein. The results showed that in the protein environment, the fate of excited PHT is governed by the competition between fluorescence emission and hula-twist isomerization. Due to the strong steric hindrance effects caused by the interlacing residues in the protein that restrict the PHT conformation transformation, the cis-to-trans isomerization process of PHT needs to overcome a barrier of at least 4.9 kcal/mol; thus, fluorescence emission is more dominant in competition. It is also found that the intermolecular interaction between LYS67 and the carbonyl oxygen of PHT has a significant effect on the fluorescence emission. These results revealed the photochemical reaction mechanism of a light-driven molecular switch in the fluorescent protein and provided further theoretical support for the field of chemical biology.

Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism.

ABSTRACT: Long-chain acyl-coenzyme A (CoA) synthase 4 (ACSL4) is an enzyme that esterifies CoA into specific polyunsaturated fatty acids, such as arachidonic acid and adrenic acid. Based on accumulated evidence, the ACSL4-catalyzed biosynthesis of arachidonoyl-CoA contributes to the execution of ferroptosis by triggering phospholipid peroxidation. Ferroptosis is a type of programmed cell death caused by iron-dependent peroxidation of lipids; ACSL4 and glutathione peroxidase 4 positively and negatively regulate ferroptosis, respectively. In addition, ACSL4 is an essential regulator of fatty acid (FA) metabolism. ACSL4 remodels the phospholipid composition of cell membranes, regulates steroidogenesis, and balances eicosanoid biosynthesis. In addition, ACSL4-mediated metabolic reprogramming and antitumor immunity have attracted much attention in cancer biology. Because it facilitates the cross-talk between ferroptosis and FA metabolism, ACSL4 is also a research hotspot in metabolic diseases and ischemia/reperfusion injuries. In this review, we focus on the structure, biological function, and unique role of ASCL4 in various human diseases. Finally, we propose that ACSL4 might be a potential therapeutic target.

Bibliometric and visualized analysis of drug resistance in ovarian cancer from 2013 to 2022.

Objective: As one of the cancers that seriously threatens women's health, ovarian cancer has a high morbidity and mortality rate. Surgery and chemotherapy are the basic treatment strategies for ovarian cancer, and chemotherapy resistance is a significant factor in affecting the prognosis, survival cycle, and recurrence of ovarian cancer. This article aims to analyze articles about ovarian cancer and drug resistance via bibliometric software, offering new ideas and directions for researchers in this field. Methods: Both Citespace and Vosviewer are bibliometric software on the Java platform. Articles were collected on ovarian cancer and drug resistance in the Web of Science Core Collection database from 2013 to 2022. The countries, institutions, journals, authors, keywords, and references were analyzed, and the development status of this field was indicated from multiple perspectives. Results: Studies on ovarian cancer and drug resistance generally showed an increasing trend from 2013 to 2022. The People's Republic of China and Chinese institutions contributed more to this field. Gynecologic Oncology published the most articles, and the journal with the most citations was Cancer Research. Li Li was the author with the most publications, and Siegel RL was the author with the most citations. Through burst detection, it can be found that the research hotspots in this field mainly focused on the in-depth exploration of the drug resistance mechanism of ovarian cancer and the progress of PARP inhibitors and bevacizumab in the treatment of ovarian cancer. Conclusions: Many studies on the mechanism of drug resistance in ovarian cancer have been discovered; however, the deeper mechanism remains to be explored. Compared with traditional chemotherapy drugs, PARP inhibitors and bevacizumab have shown better efficacy, but PARP inhibitors have initially shown drug resistance. The future direction of this field should be to overcome the resistance of existing drugs and actively develop new ones.

Corrigendum: Bibliometric and visualized analysis of drug resistance in ovarian cancer from 2013 to 2022.

[This corrects the article DOI: 10.3389/fonc.2023.1173863.].

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease.

BACKGROUND: The objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). RESULTS: We included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. CONCLUSIONS: Compared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.

Efficacy comparison of immune treating strategies for NSCLC patients with negative PD-L1 expression.

BACKGROUND: We intended to compare and grade the proposed immune treating strategies for non-small cell lung cancer (NSCLC) with negative Programmed Cell Death Ligand 1(PD-L1). METHODS: We compared the efficacy of single immune checkpoint inhibitor (ICI), single ICI plus chemotherapy, and doublet ICIs with chemotherapy alone, as well as single ICI plus radiotherapy with single ICI for negative PD-L1 (<1%) NSCLC patients. Hazard Ratio (HR) and 95% confidence interval (CI) of progression-free survival (PFS) and overall survival (OS) were used as outcomes. RESULTS: We included 23 randomized control trials with 4665 patients. Compared with chemotherapy alone, single ICI, single ICI plus chemotherapy and doublet ICIs all showed a better OS (0.84 [0.71, 0.99] ; 0.77 [0.69, 0.85] ; 0.64 [0.53, 0.77])), while single ICI plus chemotherapy and doublet ICIs showed a better PFS (0.68 [0.61, 0.75] ; 0.69 [0.56, 0.85]). Additionally, single ICI plus radiotherapy obtained a greater pooled PFS (0.49 [0.28-0.87]) than single ICI. CONCLUSIONS: Both single ICI plus chemotherapy and doublet ICIs were probably better treatment decisions than chemotherapy alone for negative PD-L1 NSCLC patients. Also, single ICI plus radiotherapy carved out a new strategy.

The addition of oral iron improves chemotherapy-induced anemia in patients receiving erythropoiesis-stimulating agents.

Although many studies have shown that supplementation with iron and erythropoiesis-stimulating agents (ESA) is frequently used for managing chemotherapy-induced anemia (CIA), optimal combination therapy using these agents together to ameliorate anemia is not well characterized. To assess the effects of ESA combined with oral or intravenous (IV) iron on relieving CIA, PubMed, Cochrane Library, Embase and China National Knowledge Infrastructure (CNKI) were searched for articles. Data collected in the articles were meta-analyzed using RevMan 5.3 software with a random-effects model. Our comprehensive search yielded 1666 potentially relevant trials. A total of 41 trials randomizing 4200 patients with CIA fulfilled inclusion criteria, including 34 Chinese articles and 7 English articles. Meta-analysis showed that treatment with both ESA and iron more effectively improved CIA relative to iron supplementation alone, with increased hemoglobin, hematocrit, red blood cell count and hematopoietic response rate. Subgroup analyses revealed iron administration, both oral and IV iron, improved anemia in ESA-treated cancer patients with CIA. Our analysis demonstrates that iron supplementation combined with ESA more effectively ameliorates CIA relative to iron supplementation alone, without regard to whether IV or oral iron was used. Together, our findings may contribute to the clinical treatment of CIA using iron therapy with or without ESA.

Interleukin polymorphisms and protein levels associated with lung cancer susceptibility and phenotypes.

BACKGROUND: We conducted a comprehensive analysis to explore whether multiple interleukin (IL), IL-1ß, IL-4, IL-6, IL-8 and IL-10, polymorphisms and IL proteins (IL-6, IL-10) relate to lung cancer (LC) susceptibility or clinical characteristics. METHODS: We performed the standard meta-analysis procedures according to PRISMA. The odds ratio (OR) and mean difference (MD) were used for analysis. RESULTS: We investigated 11 variants from 43 articles, and found that IL-1ß rs16944 (p = 0.04) and IL-10 rs1800872 (p = 0.003) decreased while IL-10 rs1800896 (p = 0.007) increased LC risks. We also found that IL-1ß rs1143627 decreased NSCLC risks (p = 0.03). The heterozygotes and homozygotes contributed differently. In addition, another 15 articles were involved to explore the relationship between IL proteins and LC. We found that LC patients accounted for higher serum IL-6 of 16.60 pg/mL (p < 0.00001) and higher serum IL-10 of 3.47 pg/mL (p = 0.02) than that of controls. Furthermore, IIIA-Ⅳ LC patients tended to have higher proportion of positive IL-6 staining in lung tumor tissue in contrast with IA-IIB patients by TNM stage (p = 0.0002). CONCLUSIONS: Four variants from IL-1ß and IL-10, and serum IL-6 and IL-10 levels are associated with LC risks.

Flavonoids Regulate Inflammation and Oxidative Stress in Cancer.

Cancer is the second leading cause of death globally. Millions of persons die due to cancer each year. In the last two decades, the anticancer effects of natural flavonoids have become a hot topic in many laboratories. Meanwhile, flavonoids, of which over 8000 molecules are known to date, are potential candidates for the discovery of anticancer drugs. The current review summarizes the major flavonoid classes of anticancer efficacy and discusses the potential anti-cancer mechanisms through inflammation and oxidative stress action, which were based on database and clinical studies within the past years. The results showed that flavonoids could regulate the inflammatory response and oxidative stress of tumor through some anti-inflammatory mechanisms such as NF-κB, so as to realize the anti-tumor effect.