Bone Safety Profile of Steroidal Aromatase Inhibitor in Comparison to Nonsteroidal Aromatase Inhibitors in Postmenopausal Women with Breast Cancer: A Network Meta-Analysis

Background and ObjectivesAromatase inhibitors (AIs) provide an alternative to tamoxifen as an adjuvant therapy for postmenopausal patients with breast cancer (BC). Large trials resulted better outcomes with AIs. Adjuvant therapy with AIs reduced the risk of relapse compared with tamoxifen. Systemic therapies for BC can interfere with bone turnover, either by affecting gonadal steroid hormone production or by inhibiting peripheral aromatization into estrogen. We aimed to evaluate the safety profile of bone-related events by comparing 3 AIs with tamoxifen and a placebo.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for network meta-analyses (NMAs). Searches were performed using PubMed, Embase/Medline, Cochrane, and Ovid databases. Randomized controlled trials comparing tamoxifen and placebo or other AIs to steroidal or nonsteroidal AIs in patients with BC reporting bone-related safety events were included in NMA. NMA in a Bayesian approach was performed using R software (ver 3.2), Gemtc package.ResultsSeventeen studies reporting 4 different bone-related endpoints were included. Although there was no statistical significance, treatment with exemestane lowered the incidence of bone pain (odds ratio [OR] vs. anastrozole and letrozole: 0.63, 0.54), fracture episodes (OR vs. anastrozole and letrozole: 0.84, 0.80), and osteoporosis (OR vs. anastrozole and letrozole: 0.85, 0.73) compared with letrozole and anastrozole. Reduction in bone mineral density was lesser in exemestane than in anastrozole (mean reduction in hip: 1.05; lumbar spine: 1.25). Treatment ranking with the surface under the cumulative ranking curve showed that exemestane was found to reduce the incidence of bone-related adverse events.ConclusionA lower incidence of bone-related safety events was observed in patients treated with exemestane.     

Establishment of a novel prognostic prediction model through bioinformatics analysis for prostate cancer based on ferroptosis-related genes and its application in immune cell infiltration

BackgroundFerroptosis-related genes (FRGs) play vital roles in survival and prognosis of prostate cancer (PCa) patients. We establish a ferroptosis-related prediction model through bioinformatics analysis for overall survival (OS) and disease-free survival (DFS), so as to evaluate the clinical survival status through the characteristics of immune cell infiltration (ICI), which could provide information for treatment monitoring.MethodsAt first, 268 FRGs were obtained from previous studies. Differentially expressed FRGs were identified based on The Cancer Genome Atlas (TCGA) database, and FRG enrichment analysis was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We then performed univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to establish OS- and DFS-related prognostic prediction models. The association of the model and clinicopathological features was further analyzed. Subsequently, unique genomic signatures of immune cell subsets were obtained through the KEGG database. Based on specific genes associated with ferroptosis and their association with ICI, immune infiltration was assessed in patients in different risk groups.ResultsWe constructed an OS- and an DFS-prognostic model through bioinformatics analysis. The predicted values of OS and DFS-related models were higher in T3–4 than in T1–2 (P=0.0057, P<0.001), and the predicted value of the DFS model in N0 stage was higher than that in N1 stage (P=0.0136). Results of Single-sample gene set enrichment analysis (ssGSEA) on the basis of the KEGG dataset showed p53 signaling being the most enriched signal in the high-risk group, while endocytosis was the most enriched signal in the low-risk group. M2 macrophages (P=0.007) and neutrophils (P=0.024) were enriched in the high-risk group, and CD4-activated memory T cells were significantly accumulated in the low-risk group (P=0.017).ConclusionsThe OS- and DFS-related model based on FRGs and ICI create new insights into the disease state assessment of PCa patients., which may aid in the development of individualized and precise treatment in the future.     

Fusobacterium nucleatum induces excess methyltransferase‐like 3‐mediated microRNA‐4717‐3p maturation to promote colorectal cancer cell proliferation

Fusobacterium nucleatum infection plays vital roles in colorectal cancer (CRC) progression. Overexpression of microRNA‐4717‐3p (miR‐4717) was reported to be upregulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR‐4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo following F. nucleatum infection. MicroRNA‐4717 suppressed the expression of mitogen‐activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3′‐UTR. Furthermore, we confirmed that methyltransferase‐like 3 (METTL3)‐dependent m⁶A methylation could methylate primary (pri)‐miR‐4717, which further promoted the maturation of pri‐miR‐4717, and METTL3 positively regulated CRC cell proliferation through miR‐4717/MAP2K4 pathways. In conclusion, F. nucleatum‐induced miR‐4717 excessive maturation through METTL3‐dependent m⁶A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.     

Obesity-Associated Anxiety Is Prevalent among College Students and Alleviated by Calorie Restriction

Anxiety is a common disorder among college students, especially those with obesity. Obesity contributes to metabolic disorders and disturbs the neural functions, further leading to anxiety. In this cross-sectional study, we aimed to determine the association between obesity and anxiety among college students and identified the potential factors for obesity-associated anxiety. We evaluated the intervention effects of calorie restriction on anxiety. Self-reported questionnaires were distributed to 1381 college students from January to March in 2021. Anxiety was measured by the State-Trait Anxiety Inventory (STAI). Participants were classified into anxiety and non-anxiety groups according to their STAI scores. Chi-squared test and logistic regression were used to analyze the potential factors. We found that 383 college students exhibited anxiety, accounting for 30.1% among all included college students, which was higher than the global average. The association between anxiety and obesity was observed among college students (p = 0.009), especially in males (p = 0.007). We identified that pre-obesity (p = 0.012), unhealthy calorie intake (p = 0.001), dieting (p = 0.003) and high academic year (p = 0.006) as the risk factors for anxiety and found that the long sleep duration was a protective factor for anxiety (p < 0.001). We found that more obese students showed an improvement of anxiety than the underweight students after calorie restriction (p < 0.001). Collectively, our findings suggest that obesity-associated anxiety is prevalent among the college students and could be alleviated by moderate calorie restriction. It is necessary for students to receive anxiety management in their college life. Additionally, the proper calorie restriction should be promoted to help students protect against obesity and obesity-associated anxiety.     

Safety and effectiveness of neoadjuvant immunotherapy combined with chemotherapy followed by surgical resection in patients with stage I–IIIA small-cell lung cancer: a retrospective single-arm clinical trial

BackgroundImmunotherapy, chemotherapy and surgery all have significant roles in the management of small-cell lung cancer (SCLC). Neoadjuvant immunotherapy combined with chemotherapy followed by surgery has shown encouraging efficacy for resectable SCLC with a good tolerability and considerable survival benefit. However, there are still few data on whether surgery for stage I–IIIA SCLC can be performed after immunotherapy with chemotherapy. Therefore, we investigated the safety and effectiveness of neoadjuvant immunotherapy combined with chemotherapy followed by surgery in patients with stage I–IIIA SCLC in the hope of adding new ideas to the treatment of SCLC.MethodsThe study group comprised 19 patients with stage I–IIIA SCLC who received neoadjuvant immunotherapy and chemotherapy between 2019 and 2021. Patients received 2–4 cycles of immunotherapy combined with platinum-containing dual-drug chemotherapy (platinum + paclitaxel) before surgery. Imaging evaluation was performed every two cycles until surgery. Tumor response to neoadjuvant therapy, neoadjuvant treatment related adverse events, perioperative and postoperative complications, surgical resection rate, and degree of tumor regression were evaluated. We obtained follow-up data from the patients’ regular examination or treatment in hospital. If we can’t complete it, contacting patients by telephone or WeChat would be adopted by us. The follow-up was not terminated until 3 months after surgery.ResultsThe objective response rate (ORR) was 84.2% (16/19), and no patients had progressive disease (PD). Of the 10 patients who underwent surgery, and approximately 9 (90.0%) had R0 resection. There were no perioperative deaths, and 1 case of pyothorax. The rate of pathological complete remission (pCR) and major pathological response (MPR) was 30.0% (3/10), and 40.0% (4/10) respectively. Grade 3–4 adverse reactions comprised 1 case of anemia and 1 case of constipation.ConclusionsNeoadjuvant immunotherapy combined with chemotherapy followed by surgical resection for patients with stage I–IIIA SCLC is effective and safe with a high ORR and MPR rate, as well as a high R0 resection rate and a tolerable toxicity profile. Whether this regimen gives a survival benefit should be confirmed by further follow-up and larger, randomized controlled trials are required to confirm our findings.     

IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB–expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB–targeting approaches for metastasis treatment.     

Effect of thymoquinone on sepsis-induced cardiac damage via anti-inflammatory and anti-apoptotic mechanisms

ObjectiveSepsis is a systemic and deleterious host reaction to severe infection. Cardiac dysfunction is an established serious outcome of multiorgan failure associated with this condition. Therefore, it is important to develop drugs targeting sepsis-induced cardiac damage and inflammation. Thymoquinone (TQ) has anti-inflammatory, anti-oxidant, anti-fibrotic, anti-tumor, and anti-apoptotic effects. This study examined the effects of thymoquinone on sepsis-induced cardiac damage.MethodsMale BALB/c mice were randomly segregated into four groups: control, TQ, cecal ligation and puncture (CLP), and CLP + TQ groups. CLP was performed after gavaging the mice with TQ for 2 weeks. After 48 hours, we estimated the histopathological changes in the cardiac tissue and the serum levels of cardiac troponin-T. We evaluated the expression of factors associated with inflammation, apoptosis, oxidative stress, and the PI3K/AKT pathway.ResultsTQ significantly reduced intestinal histological alterations and inhibited the upregulation of interleukin-6, tumor necrosis factor-α, Bax, NOX4, p-PI3K, and p-AKT. TQ also increased Bcl-2, HO-1, and NRF2 expression.ConclusionThese results suggest that TQ effectively modulates pro-inflammatory, apoptotic, oxidative stress, and PI3K/AKT pathways, making it indispensable in the treatment of sepsis-induced cardiac damage.