The sound and surprise: overlapping meta-analyses on the topic of safety and efficacy of PD-1 and PD-L1 inhibitors in the treatment of non-small cell lung cancer.

PURPOSE: To analyze the characteristics of overlapping meta-analyses based on randomized controlled trials (RCTs) which reported PD-1/PD-L1 inhibitors in non-small cell cancer (NSCLC). METHODS: Meta-analyses were identified from English and Chinese databases until January 1, 2022. Differences in characteristics of overlapping meta-analyses that conducted in China and other countries were compared to assess their publication propensity. The corrected covered area (CCA) and coverage of relevant RCTs were analyzed for subtopics according to detailed intervention types. The waste and redundancy of evidence were assessed in the case of PD-1/PD-L1 inhibitor monotherapy for second-line treatment for NSCLC. RESULTS: Fifty-nine meta-analyses published in English and 17 meta-analyses published in Chinese reporting 26 RCTs were identified. Fifty-three (69.74%) meta-analyses were conducted in China. The overlapping meta-analyses in China were more likely to be from hospitals, supported by government funding, integrate first and second-line therapies. Five of the six subtopics had overlapping meta-analyses according to specific types of interventions. The CCA of overlapping meta-analyses ranged from 33.33 to 63.19%, and the coverage of relevant RCTs ranged from 63.64 to 100%. All the conclusions of overlapping meta-analyses have been consistent in the subtopic of PD-1/PD-L1 inhibitor monotherapy for second-line treatment since 2017. CONCLUSION: Overlapping meta-analyses of PD-1/PD-L1 inhibitors in NSCLC hints that meta-analyses under this topic probably exist serious redundancy. Future research should focus on prospective registration of protocols for systematic reviews/meta-analyses, scientific designed PICO, and cumulative meta-analysis to reduce redundant and wasted studies. Journals should strengthen the requirement for reviewing previously published evidence in manuscript review.

Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps.

Xenotransplantation has the potential to solve the shortfall of human organ donors. Genetically modified pigs have been considered as potential animal donors for human xenotransplantation and have been widely used in preclinical research. The genetic modifications aim to prevent the major species-specific barriers, which include humoral and cellular immune responses, and physiological incompatibilities such as complement and coagulation dysfunctions. Genetically modified pigs can be created by deleting several pig genes related to the synthesis of various pig specific antigens or by inserting human complement- and coagulation-regulatory transgenes. Finally, in order to reduce the risk of infection, genes related to porcine endogenous retroviruses can be knocked down. In this review, we focus on genetically modified pigs and comprehensively summarize the immunological mechanism of xenograft rejection and recent progress in preclinical and clinical studies. Overall, both genetically engineered pig-based xenografts and technological breakthroughs in the biomedical field provide a promising foundation for pig-to-human xenotransplantation in the future.

Identification of a novel ferroptosis-related gene signature associated with prognosis, the immune landscape, and biomarkers for immunotherapy in ovarian cancer.

Ferroptosis has been implicated in tumor progression and immunoregulation. Identification of ferroptosis-related prognostic gene is important for immunotherapy and prognosis in ovarian cancer (OV). We assessed the potential predictive power of a novel ferroptosis-related gene (FRG) signature for prognosis and immunotherapy in Asian and Caucasian OV populations. We collected gene expression profiles and clinicopathological data from public databases. The least absolute shrinkage and selection operator Cox regression algorithm was used to construct the FRG signature. Receiver operating characteristic (ROC) curve, Kaplan-Meier method, Cox regression model were used to evaluate the clinical benefits of FRG signature. Gene functional and gene set enrichment analyses were used for functional annotation and immune landscape analysis. A 15-FRG signature was constructed and used to stratify patients into two risk groups. Patients in the high-risk group had significantly worse survival. The risk score was a significant independent risk factor for OS. The area under the ROC curve indicated the good prediction performance of the FRG signature. Notably, the low-risk group showed a significant enrichment in immune-related pathways and a "hot" immune status. The risk score was found to be an efficient and robust predictor of response to immunotherapy. In conclusion, our study identified a novel 15-FRG prognostic signature that can be used for prognostic prediction and precision immunotherapy in Asian and Caucasian OV populations.

Safety and Efficacy of Programmed Cell Death 1 and Programmed Death Ligand-1 Inhibitors in the Treatment of Cancer: An Overview of Systematic Reviews.

Background: An influx of systematic reviews (SRs) of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in cancer treatment with or without meta-analysis and with different methodological quality and inconsistent results have been published, confusing clinical decision making. The aim of this study was to comprehensively evaluate and summarize the current evidence of PD-(L)1 inhibitors in the treatment of cancer. Methods: A comprehensive search of SRs, which included meta-analyses of PD-(L)1 inhibitors on cancer, was performed on eight databases with a cutoff date of 1 January 2022. Two authors independently identified SRs, extracted data, assessed the report quality according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, evaluated the methodological quality by the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2), and appraised the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Results: A total of 172 SRs with meta-analysis met the inclusion criteria. The report quality of included SRs was quite good, with 128 (74.42%) SRs of high quality and 44 (25.58%) of moderate quality. The methodological quality was alarming, as only one (0.58%) SR had high quality, five (2.91%) SRs had low quality, and the other 166 (96.51%) SRs had critically low quality. For GRADE, 38 (3.77%) outcomes had high-quality evidence, 288 (28.57%) moderate, 545 (54.07%) low, and 137 (13.59%) critically low-quality evidence. Current evidence indicated that treatment with PD-(L)1 inhibitors were significantly effective in non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, malignant melanoma, renal cell carcinoma, and urothelial carcinoma, breast cancer, and head and neck squamous cell carcinoma with PD-L1 expression level≥1%, whereas the evidence in gastroesophageal and colorectal tumors is still controversial. Monotherapy with PD-(L)1 inhibitors was associated with a lower frequency of any grade and high-grade adverse events (AEs). The incidence of any grade and high-grade AEs caused by PD-(L)1 inhibitors in combination with other therapies was no lower than the controls. However, PD-(L)1 inhibitors were associated with a higher frequency of any grade and high-grade immune-related AEs. Conclusions: PD-(L)1 inhibitors appeared to be effective and safe for cancer treatment, except for gastrointestinal tumors; however, the quality of the evidence is not convincing. Future studies should improve methodological quality and focus on the sequential trial analysis of subgroups and safety. Systematic Review Registration: http://www.crd.york.ac.uk/prospero, identifier CRD42020194260.

Engineering Islets From Stem Cells: The Optimal Solution for the Treatment of Diabetes?

Diabetes is a metabolic disease characterized by insulin deficiency. Bioengineering of stem cells with the aim to restore insulin production and glucose regulation has the potential to cure diabetic patients. In this review, we focus on the recent developments for bioengineering of induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and pancreatic progenitor cells in view of generating insulin producing and glucose regulating cells for ß-cell replacement therapies. Recent clinical trials using islet cells derived from stem cells have been initiated for the transplantation into diabetic patients, with crucial bottlenecks of tumorigenesis, post-transplant survival, genetic instability, and immunogenicity that should be further optimized. As a new approach given high expectations, bioengineered islets from stem cells occupies considerable potential for the future clinical application and addressing the treatment dilemma of diabetes.

Multifaceted regulation and functions of 53BP1 in NHEJ­mediated DSB repair (Review).

The repair of DNA double­strand breaks (DSBs) is crucial for the preservation of genomic integrity and the maintenance of cellular homeostasis. Non­homologous DNA end joining (NHEJ) is the predominant repair mechanism for any type of DNA DSB during the majority of the cell cycle. NHEJ defects regulate tumor sensitivity to ionizing radiation and anti­neoplastic agents, resulting in immunodeficiencies and developmental abnormalities in malignant cells. p53­binding protein 1 (53BP1) is a key mediator involved in DSB repair, which functions to maintain a balance in the repair pathway choices and in preserving genomic stability. 53BP1 promotes DSB repair via NHEJ and antagonizes DNA end overhang resection. At present, novel lines of evidence have revealed the molecular mechanisms underlying the recruitment of 53BP1 and DNA break­responsive effectors to DSB sites, and the promotion of NHEJ­mediated DSB repair via 53BP1, while preventing homologous recombination. In the present review article, recent advances made in the elucidation of the structural and functional characteristics of 53BP1, the mechanisms of 53BP1 recruitment and interaction with the reshaping of the chromatin architecture around DSB sites, the post­transcriptional modifications of 53BP1, and the up­ and downstream pathways of 53BP1 are discussed. The present review article also focuses on the application perspectives, current challenges and future directions of 53BP1 research.

Glycogen synthase kinase 3ß in tumorigenesis and oncotherapy (Review).

Glycogen synthase kinase 3ß (GSK 3ß), a multifunctional serine and threonine kinase, plays a critical role in a variety of cellular activities, including signaling transduction, protein and glycogen metabolism, cell proliferation, cell differentiation, and apoptosis. Therefore, aberrant regulation of GSK 3ß results in a broad range of human diseases, such as tumors, diabetes, inflammation and neurodegenerative diseases. Accumulating evidence has suggested that GSK 3ß is correlated with tumorigenesis and progression. However, GSK 3ß is controversial due to its bifacial roles of tumor suppression and activation. In addition, overexpression of GSK 3ß is involved in tumor growth, whereas it contributes to the cell sensitivity to chemotherapy. However, the underlying regulatory mechanisms of GSK 3ß in tumorigenesis remain obscure and require further in­depth investigation. In this review, we comprehensively summarize the roles of GSK 3ß in tumorigenesis and oncotherapy, and focus on its potentials as an available target in oncotherapy.

RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review).

Necroptosis is a type of programmed cell death with necrotic morphology, occurring in a variety of biological processes, including inflammation, immune response, embryonic development and metabolic abnormalities. The current nomenclature defines necroptosis as cell death mediated by signal transduction from receptor­interacting serine/threonine kinase (RIP) 1 to RIP3 (hereafter called RIP1/RIP3). However, RIP3­dependent cell death would be a more precise definition of necroptosis. RIP3 is indispensable for necroptosis, while RIP1 is not consistently involved in the signal transduction. Notably, deletion of RIP1 even promotes RIP3­mediated necroptosis under certain conditions. Necroptosis was previously thought as an alternate process of cell death in case of apoptosis inhibition. Currently, necroptosis is recognized to serve a pivotal role in regulating various physiological processes. Of note, it mediates a variety of human diseases, such as ischemic brain injury, immune system disorders and cancer. Targeting and inhibiting necroptosis, therefore, has the potential to be used for therapeutic purposes. To date, research has elucidated the suppression of RIP1/RIP3 via effective inhibitors and highlighted their potential application in disease therapy. The present review focused on the molecular mechanisms of RIP1/RIP3­mediated necroptosis, explored the functions of RIP1/RIP3 in necroptosis, discussed their potential as a novel therapeutic target for disease therapy, and provided valuable suggestions for further study in this field.

Xenotransplantation in China: Present status.

The main obstacle to organ transplantation is the shortage of organs from deceased individuals. Especially in China, the ratio of patients on the waiting list versus the transplant recipients is 30:1. Therefore, there is an urgent need for organ donors. Genetically modified pig organs have proved to be a new source for xenotransplantation, and Chinese scientists have made considerable progress in this area during recent years. In this paper, we review four important aspects of the xenotransplantation field in China. First, a large variety of genetically modified pigs have been generated by Chinese scientists: all these genetically modified pigs and the purpose of these modifications will be summarized. Second, the preclinical research in pig-to-nonhuman primate xenotransplantation is outlined. The survival time and major biochemical parameters for the xenografts are summarized. Third, regarding the bench-to-bed approach, more suitable organs have been developed for xenotransplantation in humans, and in particular, pig islet transplantation into diabetic patients as well as pig-to-human cornea and skin transplantation. Fourth, we briefly address the regulations and prospects for recruiting xenotransplantation experts in China. Based on recent progress, we anticipate that genetically modified pigs will offer suitable organs for the treatment of end-stage organ diseases in humans in the near future. Given the recent influx of world-renowned scientists in xenotransplantation to China, our country will definitely become one of the major centers of xenotransplantation research and development in the world.

Anti-neoplastic effect of mangiferin on human ovarian adenocarcinoma OVCAR8 cells via the regulation of YAP.

Ovarian cancer is the most malignant gynecologic neoplasm in women and has the worst prognosis of all cancer types in women based on the 5-year survival rates. A previous study indicated that mangiferin exerts an anti-neoplastic effect on human ovarian cancer cells by targeting Notch3. Additionally, it has been demonstrated that Notch signaling is a functionally important downstream effector of Yes-associated protein (YAP), therefore it was hypothesized that YAP may be involved in the antitumor effect of mangiferin. The present study aimed to further reveal the mangiferin-mediated inhibitory effect on ovarian cancer and investigate the molecular anticancer mechanism of mangiferin. Based on the in vitro data, accompanied with the significantly reduced cell proliferation of mangiferin-treated cells compared with mangiferin-treated YAP-overexpressed cells (P<0.05), YAP expression was identified to be substantially downregulated by mangiferin. In contrast, observations of the cell morphology and apoptotic percentages revealed that the antitumor effect of mangiferin may be reversed by YAP overexpression. Furthermore, decreased levels of migration and invasion were observed in mangiferin-treated cells, which may also be abrogated by YAP overexpression. Thus, these data further demonstrated that mangiferin inhibits metastasis by regulating YAP. Additionally, due to the frequent chemoresistance observed in cisplatin-based chemotherapy, the present study evaluated the cisplatin resistance in OVCAR8 cells and elucidated that mangiferin may sensitize the tumor cells to cisplatin; and this improved sensitization was also abolished by YAP overexpression. These results collectively indicated that YAP was not only closely associated with the anticancer effect of mangiferin, but also mediated drug resistance in tumor. Furthermore, the downregulation of downstream TEA domain transcription factor 4 expression was observed in the mangiferin-treated cells, further validating the inhibitory effect of mangiferin on YAP. In addition, OVCAR8 cell xenograft models revealed that through increasing the sensitivity of a tumor to cisplatin, mangiferin inhibited the growth of a tumor and increased the survival time of tumor xenograft mice. Based on these results, it was concluded that mangiferin may inhibit tumor cell growth and enhance cisplatin-sensitivity in OVCAR8 cells via the regulation of the YAP pathway. Altogether, by targeting YAP and enhancing the response to cisplatin treatment, mangiferin potentially functioned as a novel therapeutic agent in the treatment of ovarian cancer.

Mangiferin: An effective therapeutic agent against several disorders (Review).

Mangiferin (1,3,6,7­tetrahydroxyxanthone­C2­ß­D­glucoside) is a bioactive ingredient predominantly isolated from the mango tree, with potent antioxidant activity and multifactorial pharmacological effects, including antidiabetic, antitumor, lipometabolism regulating, cardioprotective, anti­hyperuricemic, neuroprotective, antioxidant, anti­inflammatory, antipyretic, analgesic, antibacterial, antiviral and immunomodulatory effects. Therefore, it possesses several health­endorsing properties and is a promising candidate for further research and development. However, low solubility, mucosal permeability and bioavailability restrict the development of mangiferin as a clinical therapeutic, and chemical and physical modification is required to expand its application. This review comprehensively analyzed and collectively summarized the primary pharmacological actions of mangiferin that have been demonstrated in the literature, to support the potential future development of mangiferin as a novel therapeutic drug.

Mangiferin induces radiosensitization in glioblastoma cells by inhibiting nonhomologous end joining.

Although surgery and high­dose radiotherapy have been the standard treatments for glioblastoma multiforme (GBM), these therapies are palliative, due to the high risk of local relapse. Emerging evidence has demonstrated that DNA double­strand break (DSB) repair serves a critical role in resistance to radiotherapy. Previous studies have revealed that mangiferin possesses anti­neoplastic effects on human lung adenocarcinoma and ovarian cancer. The present study aimed to investigate the role of mangiferin in radio­sensitivity inhuman GBM. Through in vitro experiments, decreased proliferation and increased DNA damage were observed in cells pretreated with mangiferin following radiation. Further study of the repair pathway indicated that mangiferin inhibits the non­homologous end­joining (NHEJ) DSB repair pathway. Furthermore, studies on key proteins in the NHEJ DSB repair pathway revealed that mangiferin inhibited the phosphorylation of serine­protein kinase ATM, TP53­binding protein 1 and γ­histone H2AX (γ­H2AX). In addition, observations on the average percentages of γ­H2AX­positive cells and the average number of γ­H2AX foci per cell suggested that treatment with mangiferin decreased the number of γ­H2AX foci in GBM cells following radiation. However, mangiferin selectively inhibited DSB repair in GBM cells, and was not able to trigger DSB repair inhibition in normal neuronal Schwann cells. Through in vivo tumor­bearing mouse experiments, a smaller tumor volume, decreased tumor weight and prolonged life span were observed in mice treated with mangiferin following radiation. Therefore, xenograft GBM models clearly demonstrated that treatment with mangiferin treatment may increase tumor sensitivity to radiotherapy. Taken together, as demonstrated by in vivo and in vitro data, mangiferin may be a potential novel therapeutic drug for improving the radiation sensitivity of glioblastoma.

Multifaceted regulation and functions of YAP/TAZ in tumors (Review).

The Hippo pathway, initially identified through screenings for mutant tumor suppressors in Drosophila, is an evolutionarily conserved signaling pathway that controls organ size by regulating cell proliferation and apoptosis. Abnormal regulation of the Hippo pathway may lead to cancer in mammals. As the major downstream effectors of the Hippo pathway, unphosphorylated Yes-associated protein (YAP) and its homolog transcriptional co-activator TAZ (also called WWTR1) (hereafter called YAP/TAZ) are translocated into the nucleus. In the nucleus, in order to induce target gene expression, YAP/TAZ bind to the TEA domain (TEAD) proteins, and this binding subsequently promotes cell proliferation and inhibits apoptosis. In contrast, as key regulators of tumorigenesis and development, YAP/TAZ are phosphorylated and regulated by multiple molecules and pathways including Lats1/2 of Hippo, Wnt and G-protein-coupled receptor (GPCR) signaling, with a regulatory role in cell physiology, tumor cell development and pathological abnormalities simultaneously. In particular, the crucial role of YAP/TAZ in tumors ensures their potential as targets in designing anticancer drugs. To date, mounting research has elucidated the suppression of YAP/TAZ via effective inhibitors, which significantly highlights their application in cancer treatment. In the present review, we focus on the functions of YAP/TAZ in cancer, discuss their potential as new therapeutic target for tumor treatment, and provide valuable suggestions for further study in this field.

Nuclear GSK3ß induces DNA double-strand break repair by phosphorylating 53BP1 in glioblastoma.

Glioblastoma is the most malignant and lethal subtype brain tumors with high risk of recurrence and therapeutic resistance. Emerging evidence has indicated that glycogen synthesis kinase 3 (GSK3)ß plays oncogenic roles in multiple tumor types; however, the underlying mechanisms remain largely unknown. It has also been demonstrated that p53 binding protein 1 (53BP1) plays a central role in DNA double-strand break (DSB) repair. This study aimed to reveal the significance of GSK3ß translocation from the cytoplasm to the nucleus, and to determine whether GSK3ß induces DNA DSB repair in the nuclei of glioblastoma cells via phospho-53BP1. By performing in vitro experiments, we found that GSK3ß translocated from the cytoplasm to the nucleus, and it then bound to 53BP1 following exposure to IR (IR). In addition, 53BP1-mediated DNA DSB repair was observed to be abrogated by the inhibition of GSK3ß. Further experiments on the phosphorylation site of 53BP1 by GSK3ß revealed that the S/T-Q motif may play a critical role. Importantly, our in vivo and in vitro data clearly indicated that GSK3ß induced the phosphorylation of 53BP1 at the Ser166 site. Moreover, brain tumor xenograft models revealed that following exposure to IR plus SB216763, a specific GSK3ß inhibitor, tumor growth was markedly inhibited and the survival of mice markedly increased. Based on these results, we concluded that the phosphorylation of 53BP1 by GSK3ß was indispensable for DNA DSB repair. Our study also suggested that the inhibition of GSK3ß by SB216763 significantly inhibited the proliferation and induced the apoptosis of glioblastoma cells. Taken together, our data indicate that GSK3ß, a key phosphorylation protein for 53BP1, may be a potential target for enhancing the sensitivity of glioblastoma cells to radiation.

PKM2 in carcinogenesis and oncotherapy.

Tumor cell metabolism is characterized by abundant glucose consumption and aerobic glycolysis. And pyruvate kinase M2 (PKM2) plays a decisive role in glycolysis, significantly contributing to the Warburg effect, tumor growth, angiogenesis, cell division, metastasis and apoptosis. To date, researchers have unraveled the potential of pyruvate kinase M2 as an antitumor target, which suggests a new orientation for oncotherapy. Herein, we focus on the role of pyruvate kinase M2 in tumor cell development and its function as a potential new therapeutic target for tumor treatment. Besides, research actuality on pyruvate kinase M2-dependent glycometabolism and signaling pathway in tumors is also summarized, providing valuable suggestions for further study in this field.