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Immunotherapy targeting immune checkpoints (ICPs), such as programmed death‐ligand‐1 (PD‐L1), is used as a treatment option for advanced or metastatic non‐small cell lung cancer (NSCLC). However, overall response rate to anti‐PD‐L1 treatment is limited due to antigen heterogeneity and the immune‐suppressive tumor microenvironment. Human leukocyte antigen‐G (HLA‐G), an ICP as well as a neoexpressed tumor‐associated antigen, is previously demonstrated to be a beneficial target in combination with anti‐PD‐L1. In this study, a nanobody‐based trispecific T cell engager (Nb‐TriTE) is developed, capable of simultaneously binding to T cells, macrophages, and cancer cells while redirecting T cells toward tumor cells expressing PD‐L1‐ and/or HLA‐G. Nb‐TriTE shows broad spectrum anti‐tumor effects in vitro by augmenting cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs). In a humanized immunodeficient murine NSCLC model, Nb‐TriTE exhibits superior anti‐cancer potency compared to monoclonal antibodies and bispecific T cell engagers. Nb‐TriTE, at the dose with pharmacoactivity, does not induce additional enhancement of circulating cytokines secretion from PMBCs. Nb‐TriTE effectively prolongs the survival of mice without obvious adverse events. In conclusion, this study introduces an innovative therapeutic approach to address the challenges of immunotherapy and the tumor microenvironment in NSCLC through utilizing the dual ICP‐targeting Nb‐TriTE. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical trajectories and identify risk factors linked to post‐enucleation urinary incontinence (UI). Patients and Methods: In this prospective study (April 2020 to March 2022) at a single institution, 316 consecutive patients receiving endoscopic enucleation due to benign prostatic enlargement were included. Patient information and perioperative details were collected. Follow‐ups, from 1 to 6 months, assessed postoperative UI using International Consultation on Incontinence Questionnaire–Urinary Incontinence Short Form and a four‐item pad questionnaire, classified per International Continence Society definitions. Logistic regression analysed predictors at 1 week, while generalised estimating equation assessed risk factors from 1 to 3 months postoperatively. Results: Patients with a median prostate volume of 57 mL underwent enucleation, with 22.5% experiencing postoperative UI at 1 week, 5.6% at 3 months, decreasing to 1.9% at 6 months. Multivariable analysis identified age (>80 years), specimen weight (>70 g), en bloc with anteroposterior dissection, and anal tone (Digital Rectal Examination Scoring System score <3) as potential factors influencing UI. Subgroup analysis revealed that specimen weight was associated with both continuous and stress UI. Anal tone was related to both other types and stress UI, while overactive bladder symptoms were associated with urge UI. Conclusion: In summary, our study elucidates transient risk factors contributing to temporary post‐enucleation UI after prostatectomy. Informed decisions and personalised interventions can effectively alleviate concerns regarding postoperative UI. [ABSTRACT FROM AUTHOR]

Simple Summary: Imiquimod (IMQ) is clinically used in the treatment of various skin malignancies. We previously showed that IMQ-induced apoptosis and autophagic cell death in skin cancer cells are ROS-dependent. Additionally, IMQ-induced apoptosis is associated with a decrease in Mcl-1 levels. However, the exact role of Mcl-1 in IMQ-induced apoptosis, including its protective mechanisms and physiological function in cancer cells, remains unclear. This study demonstrated that the overexpression of Mcl-1 or IL-6-induced Mcl-1 upregulation reversed mitochondrial dysfunction, mitochondrial fission, and mitophagy in IMQ-treated cancer cells and protected them from IMQ-induced apoptosis. These results provide significant insights supporting the role of Mcl-1 in mitochondria and suggest that it may be a potential target for cancer research and therapy. Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common malignant glioma. Despite innovative research efforts in tumor therapy, the outcome for most diagnosed patients remains poor; therefore, early diagnosis of GBM is the most effective method for achieving better patient outcomes. In recent years, combined research efforts including cellular, molecular, genetic, and bioinformatics methods have been used to investigate GBM, and the results show that variations in miRNA expression occur in GBM tissues and biological fluids. Some highly stable miRNAs circulate in the blood and cerebrospinal fluid (CSF) of both healthy individuals and diagnosed patients, thus raising the possibility that miRNAs may serve as novel diagnostic markers. In addition, increased understanding of the miRNA and mRNA interactions involved in GBM progression may lead to discovering predictive biomarkers, some of which are clinically relevant for targeted therapy and predicting prognosis. However, as this field is relatively new, some studies have yielded conflicting results. To progress in the field, different advanced techniques must be combined, including bioinformatics methods and molecular and cellular techniques. In addition, we must overcome the various challenges in non-invasive GBM biomarker detection. Here, we discuss the progress and potential of miRNAs as biomarkers for GBM and related signaling pathways. Studying the clinical relevance and applicability of these biomarkers may alter GBM patient diagnosis and treatment.

HLA‐G is considered as an immune checkpoint protein and a tumor‐associated antigen. In the previous work, it is reported that CAR‐NK targeting of HLA‐G can be used to treat certain solid tumors. However, the frequent co‐expression of PD‐L1 and HLA‐G) and up‐regulation of PD‐L1 after adoptive immunotherapy may decrease the effectiveness of HLA‐G‐CAR. Therefore, simultaneous targeting of HLA‐G and PD‐L1 by multi‐specific CAR could represent an appropriate solution. Furthermore, gamma‐delta T (γδT) cells exhibit MHC‐independent cytotoxicity against tumor cells and possess allogeneic potential. The utilization of nanobodies offers flexibility for CAR engineering and the ability to recognize novel epitopes. In this study, Vδ2 γδT cells are used as effector cells and electroporated with an mRNA‐driven, nanobody‐based HLA‐G‐CAR with a secreted PD‐L1/CD3ε Bispecific T‐cell engager (BiTE) construct (Nb‐CAR.BiTE). Both in vivo and in vitro experiments reveal that the Nb‐CAR.BiTE‐γδT cells could effectively eliminate PD‐L1 and/or HLA‐G‐positive solid tumors. The secreted PD‐L1/CD3ε Nb‐BiTE can not only redirect Nb‐CAR‐γδT but also recruit un‐transduced bystander T cells against tumor cells expressing PD‐L1, thereby enhancing the activity of Nb‐CAR‐γδT therapy. Furthermore, evidence is provided that Nb‐CAR.BiTE redirectes γδT into tumor‐implanted tissues and that the secreted Nb‐BiTE is restricted to the tumor site without apparent toxicity. [ABSTRACT FROM AUTHOR]

Novel hormonal agents (NHAs) have significantly improved outcomes in men with advanced prostate cancer. However, it remains unclear whether NHAs are associated with subsequent cognitive impairment. Thus, we sought to perform a network meta‐analysis to compare the risk of cognitive impairment across NHA types. Databases (PubMed, Embase, Scopus, and Web of Science), trial registries (Clinicaltrial.gov), the European Medicines Agency, and the US Food and Drug Administration drug safety reports were searched from inception through July 30, 2021. Eligible studies were clinical trials evaluating the risk of cognitive impairment between NHAs and placebo/standard care. Two independent investigators extracted the data and performed quality assessments using the Cochrane Risk of Bias Tool and ROBINS‐I. We estimated the risk ratios by the frequentist approach and calculated the ranking probabilities of all treatments with the surface under the cumulative ranking probabilities. The primary outcome and secondary outcome were odds ratio (OR) and incidence rate ratio of cognitive impairment, respectively. We identified 15 trials with 14,723 participants comparing HNAs with placebo/standard care. Treatments associated with cognitive impairment, from the most to the least, were enzalutamide (OR, 3.66; 95% confidence interval [CI], 2.84–4.73), apalutamide (OR, 1.76; 95% CI, 1.08–2.87), abiraterone acetate (OR, 1.64; 95% CI, 1.01–2.45), and darolutamide (OR, 1.11 95% CI, 0.51–2.39). After adjustment of treatment time duration, enzalutamide still had the highest risk of cognitive impairment with an incidence rate ratio of 2.17 (95% CI, 1.65–2.78). These findings suggest that NHAs, especially enzalutamide, may increase the risk of cognitive impairment compared with placebo/standard care. [ABSTRACT FROM AUTHOR]