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More than 80% of newly diagnosed chronic lymphocytic leukemia (CLL) patients present with asymptomatic, early-stage CLL. Of these, only 30-50% progress to advanced stage with reduced survival, while the rest may never require treatment. According to the 2018 International Workshop on CLL (iwCLL) guidelines, patients who do not meet the criteria for treatment initiation should only be treated within the context of clinical trials, as data demonstrating an overall survival benefit in early-stage CLL are still awaited. Risk stratification through continually advancing prognostic models can assist in identifying high-risk patients for early, risk-adapted treatment within clinical trials. Currently, new targeted therapies with high efficacy and lower toxicity are available in early intervention trials. This review (1) explores the development of prognostic models for identifying high-risk patients, (2) examines the design of early intervention trial, (3) summarizes the outcomes of early intervention trials, particularly in the context of targeted therapies, and (4) highlights ongoing clinical trials involving targeted treatments.

Objective: This article aims to analyze the current status and research hotspots of literature related to perioperative management of patients with Lung Cancer and provide reference for future research directions., Methods: This study conducted a bibliometric analysis of research literature related to perioperative management of Lung Cancer published between 2004 and 2024, retrieved from the Web of Science database. R software and VOSviewer were used for analyzing keyword clusters and research themes, revealing trends and frontiers in this field., Results: A total of 4,942 studies on perioperative management of lung cancer were included. In recent years, research in this area has shown a global upward trend, with particular focus on surgical risk assessment, complication prevention, and postoperative management. Perioperative biomarkers before and after surgery have emerged as a central focus due to their impact on diagnosis and treatment. The application of novel therapies, such as targeted drugs and immunotherapy, in perioperative management is also becoming a significant research hotspot. Additionally, China has been a leading contributor to research output in this field, demonstrating strong performance in international collaborations., Conclusion: Perioperative management is a critical factor influencing the prognosis of Resectable lung cancer patients. Through a systematic analysis of the current status and research hotspots in perioperative management of lung cancer, this study provides valuable references for future clinical practice and research, particularly regarding the integration of novel therapies to optimize patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Wei, Liu, Li, Jiang, Cao, Zhang, Yan and He.)

Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Diabetes nephropathy (DN) is a main risk factor for acute coronary syndrome (ACS), but the molecular mechanism is unknown. This research used bioinformatics approaches to uncover potential molecular mechanisms and drugs for DN and ACS. GSE142153 and GSE19339 were downloaded from the Gene Expression Omnibus (GEO) database. The mutually different expression genes (DEGs) detected in the GSE142153 and GSE19339 datasets were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. After a protein-protein interaction network (PPI) analysis, hub genes and transcriptional regulators were tracked by Cytoscape Soft. Finally, potential therapeutic drugs were predicted by the DGIDB drug database. This study identified 274 mutual DEGs from the DN and ACS datasets. Functional analyses indicated that "RNA polymerase II" and the "IL-17 signaling pathway" might play an important role in DN and ACS. Through PPI network construction, the top ten genes were identified. Hub gene and transcription factor interactions were constructed. Seven drugs targeted at VEGFA, IL6, IL1B, and IL1A were evaluated. Four genes and seven drugs were evaluated that could provide a novel perspective for DN and ACS in the future.

Targeted drug delivery has emerged as a transformative approach in the treatment of periorbital skin malignancies, offering the potential for enhanced efficacy and reduced side effects compared to traditional therapies. This review provides a comprehensive overview of targeted therapies in the context of periorbital malignancies, including basal cell carcinoma, squamous cell carcinoma, sebaceous gland carcinoma, and Merkel cell carcinoma. It explores the mechanisms of action for various targeted therapies, such as monoclonal antibodies, small molecule inhibitors, and immunotherapies, and their applications in treating these malignancies. Additionally, this review addresses the management of ocular and periocular side effects associated with these therapies, emphasizing the importance of a multidisciplinary approach to minimize impact and ensure patient adherence. By integrating current findings and discussing emerging trends, this review aims to highlight the advancements in targeted drug delivery and its potential to improve treatment outcomes and quality of life for patients with periorbital skin malignancies.

High-risk acute myeloid leukemia has been associated with a poor outcome. Hematopoietic stem cell transplantation (HSCT) represents the only curative option for eligible patients. Relapse after HSCT is a dramatic event with poor chances of survival. With the aim of reducing the rate of post-HSCT relapse, maintenance treatment has been investigated in this setting. Results from clinical trials suggest an advantage in the use of a maintenance strategy; however, standardized guidelines are not yet available due to the lack of prospective clinical trials. In this review, we have reported the most important strategies adopted as post-HSCT maintenance, highlighting their efficacy, but the current research also opens questions.

Opinion Statement: Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Inflammatory bowel disease (IBD) is a globally increasing disease. Despite continuous efforts, the clinical application of treatment drugs has not achieved satisfactory success and faces limitations such as adverse drug reactions. Numerous investigations have found that the pathogenesis of IBD is connected with disturbances in bile acid circulation and metabolism. Traditional Chinese medicine targeting bile acids (BAs) has shown significant therapeutic effects and advantages in treating inflammatory bowel disease., Aim of This Review: IThis article reviews the role of bile acids and their receptors in IBD, as well as research progress on IBD therapeutic drugs based on bile acids. It explores bile acid metabolism and its interaction with the intestinal microbiota, summarizes clinical drugs for treating IBD including single herbal medicine, traditional herbal prescriptions, and analyzes the mechanisms of action in treating IBD., Materials and Methods: IThe electronic databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) have been utilized to retrieve relevant literature up to January 2024, using keywords "bile acid", "bile acid receptor", "inflammatory bowel disease", "intestinal microbiota" and "targeted drugs"., Results: IImbalance in bile acid levels can lead to intestinal inflammation, while IBD can disrupt the balance of microbes, result in alterations in the bile acid pool's composition and amount. This change can damage of intestinal mucosa healing ability. Bile acids are vital for keeping the gut barrier function intact, regulating gene expression, managing metabolic equilibrium, and influencing the properties and roles of the gut's microbial community. Consequently, focusing on bile acids could offer a potential treatment strategy for IBD., Conclusion: IIBD can induce intestinal homeostasis imbalance and changes in BA pool, leading to fluctuations in levels of relevant metabolic enzymes, transporters, and nuclear receptors. Therefore, by regulating the balance of BA and key signaling molecules of bile acids, we can treat IBD. Traditional Chinese medicine has great potential and promising prospects in treating IBD. We should focus on the characteristics and advantages of Chinese medicine, promote the development and clinical application of innovative Chinese medicine, and ultimately make Chinese medicine targeting bile acids the mainstream treatment for IBD., Competing Interests: Declaration of competing interest The authors declare that they have no potential competing financial interests or personal relationships that could have appeared to influence the work reportered in this parper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Urological cancers are one of the most prevalent malignancies around the globe. Specifically, bladder cancer severely threatens the health of humans because of its heterogeneous and aggressive nature. Extensive studies have been conducted for many years in order to address the limitations associated with the treatment of solid tumors with selective substances. This article aims to provide a summary of the therapeutic drugs that have received FDA approval or are presently in the testing phase for use in the prevention or treatment of bladder cancer. In this review, FDA-approved drugs for bladder cancer treatment have been listed along with their dose protocols, current status, pharmacokinetics, action mechanisms, and marketed products. The article also emphasizes the novel preparations of these drugs that are presently under clinical trials or are in the approval stage. Thus, this review will serve as a single point of reference for scientists involved in the formulation development of these drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level., (© 2024 Wiley‐VCH GmbH.)

The development and use of HER2-targeted drugs has improved the prognosis of HER2-positive cancer patients. However, in addition to improved survival rates, treatment-induced adverse events and nontumor-related deaths have increased. We sought to assess the incidence of cardiovascular adverse events when HER2-targeted drugs are combined with other drugs. We systematically searched the literature on the cardiotoxicity of anti-HER2 drugs in electronic databases, including PubMed, Web of Science, Cochrane Library, OVID and CNKI, from their inception to April 2022. The Cochrane Collaboration's tool for assessing risk of bias and the Jadad scale were used to evaluate the risk of bias and quality of the studies, respectively. For each included trial, we calculated the incidence of cardiovascular adverse effects (CAEs) and 95% confidence intervals (95% CIs) and performed a meta-analysis using a random effects model (REM). The meta-analysis was performed using R 4.2.1. We included 41 randomized clinical trials (RCTs) in the meta-analysis, consisting of 56 groups and 31,934 patients. The meta-analysis revealed the following: (1) The incidence of cardiotoxicity in groups given monoclonal antibody treatment was 14% for single therapy (95% CI: 2-34%) and 10%, 11%, and 12% for adjuvant therapy combined with combined therapy (95% CI: 6-13%), chemotherapy (95% CI: 8-13%) and endocrine therapy (95% CI: 7-18%), respectively. However, in the groups treated with the antibody‒drug conjugates (ADCs), the percentage of patients treated with the combination therapy was 1% (95% CI: 0-2%) and 5% (95% CI: 4-7%), respectively, with a significant difference (P < 0.01). The heterogeneity among the included studies was significant (I 2  = 94%, p < 0.01). (2) When monoclonal antibodies were combined with chemotherapy, the incidence of cardiotoxicity under anthracycline-containing therapy (10.3%) was significantly greater than that under nonanthracycline-containing therapy (8.8%). (3) Significant differences were found between subgroups, except for the endocrine group versus some others, although this difference might result from the different inclusion criteria of the original trials. (1) When anti-HER2 drugs are administered in combination with anthracycline-containing chemotherapy, the incidence of cardiotoxicity is greater than with other drugs. (2) Safety benefits can be achieved by replacing traditional monoclonal antibodies with ADCs. The comprehensive use of these drugs necessitates collaboration between oncologists and cardiologists., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The study purpose was to explore the causal association between pyruvate metabolism and breast cancer (BC), as well as the molecular role of key metabolic genes, by using bioinformatics and Mendelian randomization (MR) analysis., Methods: We retrieved and examined diverse datasets from the GEO database to ascertain differentially acting genes (DAGs) in BC via differential expression analysis. Following this, we performed functional and pathway enrichment analyses to ascertain noteworthy molecular functions and metabolic pathways in BC. Employing MR analysis, we established a causal association between pyruvate metabolism and the susceptibility to BC. Additionally, utilizing the DGIdb database, we identified potential targeted medications that act on genes implicated in the pyruvate metabolic pathway and formulated a competing endogenous RNA (ceRNA) regulatory network in BC., Results: We collected the datasets GSE54002, GSE70947, and GSE22820, and identified a total of 1127 DEGs between the BC and NC groups. GO and KEGG enrichment analysis showed that the molecular functions of these DEGs mainly included mitotic nuclear division, extracellular matrix, signaling receptor activator activity, etc. Metabolic pathways were mainly concentrated in PI3K-Akt signaling pathway, Cytokine-cytokine receptor binding and Pyruvate, Tyrosine, Propanoate and Phenylalanine metabolism, etc. In addition, MR analysis demonstrated a causal relationship between pyruvate metabolism and BC risk. Finally, we constructed a regulatory network between pathway genes (ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C) and targeted drugs, as well as a ceRNA (lncRNA-miRNA-mRNA) regulatory network for BC, further revealing their interactions., Conclusions: Our research revealed a causal association between pyruvate metabolism and BC risk, found that ADH1B, ACSS2, ACACB, ADH1A, ALDH2, and ADH1C takes place an important part in the development of BC in the molecular mechanisms related to pyruvate metabolism, and identified some potential targeted small molecule drugs., (© 2024. The Author(s).)

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Qiu, Deng and Wan.)

Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non-immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials., (© 2024 Wiley-VCH GmbH.)

Ferroptosis is a distinct mode of cell death, distinguishing itself from typical apoptosis by its reliance on the accumulation of iron ions and lipid peroxides. Cells manifest an imbalance between oxidative stress and antioxidant equilibrium during certain pathological contexts, such as tumours, resulting in oxidative stress. Notably, recent investigations propose that heightened intracellular reactive oxygen species (ROS) due to oxidative stress can heighten cellular susceptibility to ferroptosis inducers or expedite the onset of ferroptosis. Consequently, comprehending role of ROS in the initiation of ferroptosis has significance in elucidating disorders related to oxidative stress. Moreover, an exhaustive exploration into the mechanism and control of ferroptosis might offer novel targets for addressing specific tumour types. Within this context, our review delves into recent fundamental pathways and the molecular foundation of ferroptosis. Four classical ferroptotic molecular pathways are well characterized, namely, glutathione peroxidase 4-centred molecular pathway, nuclear factor erythroid 2-related factor 2 molecular pathway, mitochondrial molecular pathway, and mTOR-dependent autophagy pathway. Furthermore, we seek to elucidate the regulatory contributions enacted by ROS. Additionally, we provide an overview of targeted medications targeting four molecular pathways implicated in ferroptosis and their potential clinical applications. Here, we review the role of ROS and oxidative stress in ferroptosis, and we discuss opportunities to use ferroptosis as a new strategy for cancer therapy and point out the current challenges persisting within the domain of ROS-regulated anticancer drug research and development., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, essential for cellular communication, orchestrates a myriad of physiological and pathological processes. Recently, the intricate association between the pathway's dysregulation and the progression of malignant tumors has garnered increasing attention. Nevertheless, there is no systematic summary detailing the anticancer effects of molecules targeting the JAK/STAT pathway in the context of tumor progression. This review offers a comprehensive overview of pharmaceutical agents targeting the JAK/STAT pathway, encompassing phytochemicals, synthetic drugs, and biomolecules. These agents can manifest their anticancer effects through various mechanisms, including inhibiting proliferation, inducing apoptosis, suppressing tumor metastasis, and angiogenesis. Notably, we emphasize the clinical challenges of drug resistance while spotlighting the potential of integrating JAK/STAT inhibitors with other therapies as a transformative approach in cancer treatment. Moreover, this review delves into the avant-garde strategy of employing nanocarriers to enhance the solubility and bioavailability of anticancer drugs, significantly amplifying their therapeutic prowess. Through this academic exploration of the multifaceted roles of the JAK/STAT pathway in the cancer milieu, we aim to sketch a visionary trajectory for future oncological interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly lethal malignant disease. The epithelial-mesenchymal transition (EMT) is crucial in promoting ESCC development. However, the molecular heterogeneity of ESCC and the potential inhibitory strategies targeting EMT remain poorly understood. In this study, we analyzed high-resolution single-cell transcriptome data encompassing 209,231 ESCC cells from 39 tumor samples and 16 adjacent samples obtained from 44 individuals. We identified distinct cell populations exhibiting heterogeneous EMT characteristics and identified 87 EMT-associated molecules. The expression profiles of these EMT-associated molecules showed heterogeneity across different stages of ESCC progression. Moreover, we observed that EMT primarily occurred in early-stage tumors, before lymph node metastasis, and significantly promoted the rapid deterioration of ESCC. Notably, we identified SERPINH1 as a potential novel marker for ESCC EMT. By classifying ESCC patients based on EMT gene sets, we found that those with high EMT exhibited poorer prognosis. Furthermore, we predicted and experimentally validated drugs targeting ESCC EMT, including dactolisib, docetaxel, and nutlin, which demonstrated efficacy in inhibiting EMT and metastasis in ESCC. Through the integration of scRNA-seq, RNA-seq, and TCGA data with experimental validation, our comprehensive analysis elucidated the landscape of EMT during the entire course of ESCC development and metastasis. These findings provide valuable insights and a reference for refining ESCC clinical treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work., (© 2024. The Author(s).)

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications., Competing Interests: The authors declared that they have no conflicts of interest to this paper. Figures were created with BioRender software (https://app.biorender.com/)., (© 2024 The Authors.)

Cuproptosis and disulfidptosis, recently discovered mechanisms of cell death, have demonstrated that differential expression of key genes and long non-coding RNAs (lncRNAs) profoundly influences tumor development and affects their drug sensitivity. Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, presently lacks research utilizing cuproptosis and disulfidptosis-related lncRNAs (CDRLRs) as prognostic markers. In this study, we analyzed RNA-seq data, clinical information, and mutation data from The Cancer Genome Atlas (TCGA) on ccRCC and cross-referenced it with known cuproptosis and disulfidptosis-related genes (CDRGs). Using the LASSO machine learning algorithm, we identified four CDRLRs-ACVR2B-AS1, AC095055.1, AL161782.1, and MANEA-DT-that are strongly associated with prognosis and used them to construct a prognostic risk model. To verify the model's reliability and validate these four CDRLRs as significant prognostic factors, we performed dataset grouping validation, followed by RT-qPCR and external database validation for differential expression and prognosis of CDRLRs in ccRCC. Gene function and pathway analysis were conducted using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) for high- and low-risk groups. Additionally, we have analyzed the tumor mutation burden (TMB) and the immune microenvironment (TME), employing the oncoPredict and Immunophenoscore (IPS) algorithms to assess the sensitivity of diverse risk categories to targeted therapeutics and immunosuppressants. Our predominant objective is to refine prognostic predictions for patients with ccRCC and inform treatment decisions by conducting an exhaustive study on cuproptosis and disulfidptosis., (© 2024. The Author(s).)

Background: Lumbar disc degeneration (LDD) is an important pathological basis for the development of degenerative diseases of the lumbar spine. Most clinical patients have low back pain as their main symptom. The deterioration of the biomechanical environment is an important cause of LDD. Although there is a large amount of basic research on LDD, there are fewer reports that correlate biomechanical mechanisms with basic research. Our research aims to identify 304 key genes involved in LDD due to biomechanical deterioration, using a bioinformatics approach. We focus on SMAD3, CAV1, SMAD7, TGFB1 as hub genes, and screen for 30 potential target drugs, offering novel insights into LDD pathology and treatment options., Methods: The Gene Cards, GenCLip3, OMIM and Drugbank databases were explored to obtain genes associated with biomechanics and LDD, followed by making veen plots to obtain both co-expressed genes. GO enrichment analysis and KEGG pathway analysis of the co-expressed genes were obtained using the DAVID online platform and visualised via a free online website. Protein interaction networks (PPI) were obtained through the STRING platform and visualised through Cytoscape 3.9.0. These genes were predicted for downstream interaction networks using the STITCH platform. Then, the GSE56081 dataset was used to validate the key genes. RT-PCR was used to detect mRNA expression of core genes in the degenerated nucleus pulposus (NP) samples and western bolt was used for protein expression. Lastly, the obtained hub genes were searched in the drug database (DGIdb) to find relevant drug candidates., Results: From the perspective of biomechanics-induced LDD, we obtained a total of 304 genes, the GO functional enrichment and KEGG pathway enrichment analysis showed that the functions of these genes are mostly related to inflammation and apoptosis. The PPI network was constructed and four Hub genes were obtained through the plug-in of Cytoscape software, namely SMAD3, CAV1, SMAD7 and TGFB1. The analysis of key genes revealed that biomechanical involvement in LDD may be related to the TGF-β signaling pathway. Validation of the GSE56081 dataset revealed that SMAD3 and TGFB1 were highly expressed in degenerating NP samples. RT-PCR results showed that the mRNA expression of SMAD3 and TGFB1 was significantly increased in the severe degeneration group; Western blot results also showed that the protein expression of TGFB1 and P-SMAD3 was significantly increased. In addition, we identified 30 potential drugs., Conclusion: This study presented a new approach to investigate the correlation between biomechanical mechanisms and LDD. The deterioration of the biomechanical environment may cause LDD through the TGF-β signaling pathway. TGFB1 and SMAD3 are important core targets. The important genes, pathways and drugs obtained in this study provided a new basis and direction for the study, diagnosis and treatment of LDD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: To explore the clinical characteristics, molecular characteristics, treatment and prognosis of pediatric Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) with a therapeutic target., Methods: A total of 27 patients of Ph-like ALL with targeted drug target were initially diagnosed in Children's Hospital of Soochow University from December 2017 to June 2021. The data of age, gender, white blood cell (WBC) count at initial diagnosis, genetic characteristics, molecular biological changes, chemotherapy regimen, different targeted drugs were given, and minimal residual disease (MRD) on day 19, MRD on day 46, whether hematopoietic stem cell transplantation (HSCT) were retrospective analyed, and the clinical characteristics and treatment effect were summarized. Survival analysis was performed by Kaplan-Meier method., Results: The intensity of chemotherapy was adjusted according to the MRD level during induced remission therapy in 27 patients, 10 patients were treated with targeted drugs during treatment, and 3 patients were bridged with HSCT, 1 patient died and 2 patients survived. Among the 24 patients who did not receive HSCT, 1 patient developed relapse, and achieved complete remission (CR) after treatment with chimeric antigen receptors T cells (CAR-T). The 3-year overall survival, 3-year relapse-free survival and 3-year event-free survival rate of 27 patients were (95.5±4.4)%, (95.0±4.9)% and (90.7±6.3)% respectively., Conclusion: Risk stratification chemotherapy based on MRD monitoring can improve the prognosis of Ph-like ALL in children, combined with targeted drugs can achieve complete remission as soon as possible in children whose chemotherapy response is poor, and sequential CAR-T and HSCT can significantly improve the therapeutic effect of Ph-like ALL in children whose MRD is continuously positive during induced remission therapy.

Background: PTEN and mTOR signaling have many roles, including antiinflammatory, immunosuppressant and cancer., Objective: US patents were retrieved to show the current landscape of the mTOR and PTEN targets., Methods: PTEN and mTOR targets were analyzed by patent analysis. The U.S. granted patents from January 2003 to July 2022 were performed and analyzed., Results: The results showed that the mTOR target was more attractive in drug discovery than the PTEN target. Our findings indicated that most large global pharmaceutical companies focused the drug discovery related to the mTOR target. The present study demonstrated that mTOR and PTEN targets showed more applications in biological approaches compared to BRAF and KRAS targets. The chemical structures of the inhibitors of the mTOR target demonstrated some similar features to those of the inhibitors of KRAS targets., Conclusion: At this stage, the PTEN target may not be an ideal target subjected to new drug discovery. The present study was the first one which demonstrated that the group of O=S=O may play a critical role in the chemical structures of mTOR inhibitors. It was the first time to show that a PTEN target may be suitably subjected to new therapeutic discovery efforts related to biological applications. Our findings provide a recent insight into therapeutic development for mTOR and PTEN targets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To assess the efficacy and safety of camrelizumab plus different targeted drugs in adjuvant therapy after hepatocellular carcinoma (HCC) surgery., Patients and Methods: This retrospective cohort study included HCC patients who, after undergoing failed postoperative adjuvant lenvatinib therapy, received intravenous camrelizumab 200 mg every 3 weeks (C group, n = 97), camrelizumab plus oral apatinib 250 mg daily (C+A group, n = 125), camrelizumab plus oral lenvatinib 12 mg daily (for bodyweight ≥60 kg)/lenvatinib 8 mg daily (for bodyweight <60 kg) (C+L group, n = 120), or camrelizumab plus oral sorafenib 400 mg bi-daily (C+S group, n = 114) between October 2020 and October 2021. The outcomes including the objective response rate (ORR) and disease control rate (DCR) were evaluated by RECIST 1.1 and iRECIST. The median progression-free survival (mPFS), median overall survival (mOS), 6-month OS rate, 12-month OS rate, and adverse events were evaluated., Results: As of 31 May 2022 with last follow-up time, the ORR was 17.2% for the C group, 44.6% for the C+A group, 47.9% for the C+L group, and 36.3% for the C+S group. The DCR was 72.0% for the C group, 81.8% for the C+A group, 85.5% for the C+L group, and 77.9% for the C+S group. The mPFS was 11.0 months (10.1-12.8) for the C group, 14.0 months (12.7-16.5) for the C+A group, 18.0 months (16.9-20.1) for the C+L group, and 12.0 months (9.7-14.4) for the C+S group. The mOS was 13.0 months (11.6-15.3) for the C group, 17.0 months (15.8-19.4) for the C+A group, 19.0 months (17.7-20.2) for the C+L group, and 15.0 months (14.1-17.3) for the C+S group. Grade 3 or 4 treatment-related adverse events occurred in 14 patients (14.4%) for the C group, 10 patients (8.0%) for the C+A group, 5 patients (4.2%) for the C+L group, and 11 patients (9.6%) for the C+S group. The most common adverse events were fatigue and transaminitis., Conclusion: Camrelizumab combined with lenvatinib as adjuvant therapy showed promising efficacy and manageable safety in HCC patients. It might be a potential adjuvant therapy or second-line treatment for these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Cao, Qiu, Ji, Yuan, Wu, Liu, Feng, Ding, Li and Tao.)

Background: In the last decade, Ibrutinib has become the standard of care in the treatment of several lymphoproliferative diseases such as chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphoma. Beyond Bruton tyrosine kinase inhibition, Ibrutinib shows broad immunomodulatory effects that may promote the occurrence of infectious complications, including opportunistic infections. The infectious burden has been shown to vary by disease status, neutropenia, and prior therapy but data focusing on severe infections requiring intensive care unit (ICU) admission remain scarce. We sought to investigate features and outcomes of severe infections in a multicenter cohort of 69 patients receiving ibrutinib admitted to 10 French intensive care units (ICU) from 1 January 2015 to 31 December 2020., Results: Median time from ibrutinib initiation was 6.6 [3-18] months. Invasive fungal infections (IFI) accounted for 19% (n = 13/69) of severe infections, including 9 (69%; n = 9/13) invasive aspergillosis, 3 (23%; n = 3/13) Pneumocystis pneumonia, and 1 (8%; n = 1/13) cryptococcosis. Most common organ injury was acute respiratory failure (ARF) (71%; n = 49/69) and 41% (n = 28/69) of patients required mechanical ventilation. Twenty (29%; n = 20/69) patients died in the ICU while day-90 mortality reached 55% (n = 35/64). In comparison with survivors, decedents displayed more severe organ dysfunctions (SOFA 7 [5-11] vs. 4 [3-7], p = 0.004) and were more likely to undergo mechanical ventilation (68% vs. 31%, p = 0.010). Sixty-three ibrutinib-treated patients were matched based on age and underlying malignancy with 63 controls receiving conventional chemotherapy from an historic cohort. Despite a higher median number of prior chemotherapy lines (2 [1-2] vs. 0 [0-2]; p < 0.001) and higher rates of fungal [21% vs. 8%, p = 0.001] and viral [17% vs. 5%, p = 0.027] infections in patients receiving ibrutinib, ICU (27% vs. 38%, p = 0.254) and day-90 mortality (52% vs. 48%, p = 0.785) were similar between the two groups., Conclusion: In ibrutinib-treated patients, severe infections requiring ICU admission were associated with a dismal prognosis, mostly impacted by initial organ failures. Opportunistic agents should be systematically screened by ICU clinicians in this immunocompromised population., (© 2023. The Author(s).)

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to optimize the dose of oncology drugs. DROID consists of two seamlessly connected stages. In the first stage, patients are sequentially enrolled and adaptively assigned to investigational doses to establish the therapeutic dose range (TDR), defined as the range of doses with acceptable toxicity and efficacy profiles, and the recommended phase 2 dose set (RP2S). In the second stage, patients are randomized to the doses in RP2S to assess the dose-response relationship and identify the optimal dose. The simulation study shows that DROID substantially outperforms the conventional approach, providing a new paradigm to efficiently optimize the dose of targeted oncology drugs. DROID aligns with the approach of a randomized, parallel dose-response trial design recommended by the FDA in the Guidance on Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases., (© 2023 The International Biometric Society.)

Background: This meta-analysis was conducted to evaluate the efficacy of the treat-repair-treat (TRT) strategy in the treatment of severe pulmonary arterial hypertension with congenital heart disease (PAH-CHD)., Methods: PubMed, EMBASE, Cochrane and Web of Science online databases were searched by two independent investigators for studies that used the TRT strategy for PAH-CHD, and the retrieved studies were reviewed by a third investigator. The main outcomes were pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD), and transcutaneous oxygen saturation (SpO 2 ). The changes were compared between follow-up and baseline. Stata version 14.0 was used for data analysis. A random-effects model was selected for meta-analysis. Subgroup analysis and meta-regression were used to find the source of heterogeneity., Results: A total of 335 patients from 9 single-arm studies were included. Meta-analysis showed significant reductions in PAP and PVR and improvements in 6MWD and SpO 2 (PAP: SMD -2.73 95% CI -2.97, - 2.50 p = < 0.001; PVR: SMD -1.27 95% CI -1.53, - 1.02 p = < 0.001; 6MWD: SMD 1.88 95% CI 1.49, 2.27 p = < 0.001; SpO 2 : SMD 3.72 95% CI 3.13, 4.32 p = < 0.001). Subgroup analysis showed that younger patients had better efficacy, and the change in SpO 2 was an indication for patient selection. The combined mortality rate was 5% at follow-up., Conclusions: In this meta-analysis, we demonstrated that the TRT strategy may have positive effects on haemodynamics and cardiac function in patients with severe PAH-CHD at short-term follow-up. Our analysis suggests that changes in age and SpO 2 may be related to patient prognosis., Trial Registration: The protocol was registered on the PROSPERO website with the registration number CRD42022366552. The relevant registration information can be obtained from the website https://www.crd.york.ac.uk/prospero/#searchadvanced ., (© 2023. The Author(s).)

Tumorigenesis and tumor development are closely related to the abnormal regulation of ubiquitination. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin ligase critical to the ubiquitination process, plays key roles in the regulation of cancer stem cells, as well as tumor cell functions, including cell proliferation, apoptosis, cell cycle regulation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor drug resistance, by controlling subsequent protein degradation through ubiquitination. NEDD4L primarily functions as a tumor suppressor in several tumors but also plays an oncogenic role in certain tumors. In this review, we comprehensively summarize the relevant signaling pathways of NEDD4L in tumors, the regulatory mechanisms of its upstream regulatory molecules and downstream substrates, and the resulting functional alterations. Overall, therapeutic strategies targeting NEDD4L to treat cancer may be feasible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Zhang, Tian, Zhang, Wang, Tang and Zhao.)

Objective: Systemic lupus erythematosus (SLE) patients are at risk during the COVID-19 pandemic, yet the underlying molecular mechanisms remain incompletely understood. This study sought to analyze the potential molecular connections between COVID-19 and SLE, employing a bioinformatics approach to identify effective drugs for both conditions., Methods: The data sets GSE100163 and GSE183071 were utilized to determine share differentially expressed genes (DEGs). These DEGs were later analyzed by various bioinformatic methods, including functional enrichment, protein-protein interaction (PPI) network analysis, regulatory network construction, and gene-drug interaction construction., Results: A total of 50 common DEGs were found between COVID-19 and SLE. Gene ontology (GO) functional annotation revealed that "immune response," "innate immune response," "plasma membrane," and "protein binding" were most enriched in. Additionally, the pathways that were enriched include "Th1 and Th2 cell differentiation." The study identified 48 genes/nodes enriched with 292 edges in the PPI network, of which the top 10 hub genes were CD4, IL7R, CD3E, CD5, CD247, KLRB1, CD40LG, CD7, CR2, and GZMK. Furthermore, the study found 48 transcription factors and 8 microRNAs regulating these hub genes. Finally, four drugs namely ibalizumab (targeted to CD4), blinatumomab (targeted to CD3E), muromonab-CD3 (targeted to CD3E), and catumaxomab (targeted to CD3E) were found in gene-drug interaction., Conclusion: Four possible drugs that targeted two specific genes, which may be beneficial for COVID-19 patients with SLE., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: The association between acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura (aTTP) and systemic lupus erythematosus (SLE) has been studied; however, the underlying molecular causes remain poorly understood. This research aimed to employ bioinformatics approaches to elucidate potential molecular mechanisms contributing to the pathogenesis of SLE and aTTP., Material and Methods: The Gene Expression Omnibus (GEO) database yielded GSE121239 and GSE36418 to get mutual different expression genes (DEGs). Subsequently, DEGs were subjected to process Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, the DEGs were used for protein-protein interaction (PPI) analysis and screened for hub genes and drugs by the DGIDB drug database., Results: A total of 87 DEGs between the SLE and TTP datasets were identified. In the GO and KEGG analyses, DEGs were mainly enriched in the "regulation of transcription by RNA polymerase II" and "signaling pathways regulating pluripotency of stem cells." After a PPI analysis, three hub genes (BMPR2, SMAD5, and ATF2) were identified. Finally, two drugs targeted to ATF2 were predicted by the DGIDB drug database., Conclusions: Three core genes were linked to the molecular pathogenesis of SLE and aTTP, and two drugs may be viable treatments for both diseases., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

PARP was an enzyme found in the nucleus of eukaryotic cells that played a crucial role in repairing damaged DNA. Recently, PARP inhibitors have demonstrated great potential in cancer treatment. Thus, the FDA has approved several small-molecule PARP inhibitors for cancer maintenance therapy. The combination of PARP inhibitors and radiotherapy relies on synthetic lethality, taking advantage of the flaws in DNA repair pathways to target cancer cells specifically. Studies conducted prior to clinical trials have suggested that the combination of PARP inhibitors and radiotherapy can enhance the sensitivity of cancer cells to radiation, intensify DNA damage, and trigger cell death. Combining radiotherapy with PARP inhibitors in clinical trials has enhanced the response rate and progression-free survival of diverse cancer patients. The theoretical foundation of PARP inhibitors combined with radiotherapy is explained in detail in this article, and the latest advances in preclinical and clinical research on these inhibitors for tumor radiotherapy are summarized. The problems in the current field are recognized in our research and potential therapeutic applications for tumors are suggested. Nevertheless, certain obstacles need to be tackled when implementing PARP inhibitors and radiotherapies in clinical settings. Factors to consider when using the combination therapy are the most suitable schedule and amount of medication, identifying advantageous candidates, and the probable adverse effects linked with the combination. The combination of radiotherapy and PARP inhibitors can greatly enhance the effectiveness of cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Chu, Song, Liu, Chai, Wang and Liu.)

Objective: The impact of inflammatory response on tumor development and therapeutic response is of significant importance in clear cell renal cell carcinoma (ccRCC). The customization of specialized prognostication approaches and the exploration of supplementary treatment options hold critical clinical implications in relation to the inflammatory response., Methods: In the present study, unsupervised clustering was implemented on TCGA-KIRC tumors using transcriptome profiles of inflammatory response genes, which was then validated in two ccRCC datasets (E-MATB-1980 and ICGC) and two immunotherapy datasets (IMvigor210 and Liu et al.) via SubMap and NTP algorithms. Combining co-expression and LASSO analyses, inflammatory response-based scoring system was defined, which was evaluated in pan-cancer., Results: Three reproducible inflammatory response subtypes (named IR1, IR2 and IR3) were determined and independently verified, each exhibiting distinct molecular, clinical, and immunological characteristics. Among these subtypes, IR2 had the best OS outcomes, followed by IR3 and IR1. In terms of anti-angiogenic agents, sunitinib may be appropriate for IR1 patients, while axitinib and pazopanib may be suitable for IR2 patients, and sorafenib for IR3 patients. Additionally, IR1 patients might benefit from anti-CTLA4 therapy. A scoring system called IRscore was defined for individual ccRCC patients. Patients with high IRscore presented a lower response rate to anti-PD-L1 therapy and worse prognostic outcomes. Pan-cancer analysis demonstrated the immunological features and prognostic relevance of the IRscore., Conclusion: Altogether, characterization of inflammatory response subtypes and IRscore provides a roadmap for patient risk stratification and personalized treatment decisions, not only in ccRCC, but also in pan-cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Small-cell lung cancer (SCLC) has a poor prognosis and can be diagnosed with systemic metastases. Nevertheless, the molecular mechanisms underlying the development of SCLC are unclear, requiring further investigation. The current research aims to identify relevant biomarkers and available drugs to treat SCLC. The bioinformatics analysis comprised three Gene Expression Omnibus datasets (including GSE2149507, GSE6044, and GSE30219). Using the limma R package, we discovered differentially expressed genes (DEGs) in the current work. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were made by adopting the DAVID website. The DEG protein-protein interaction network was built based on the Search Tool for the Retrieval of Interacting Genes/Proteins website and visualized using the CytoHubba plugin in Cytoscape, aiming to screen the top ten hub genes. Quantitative real-time polymerase chain reaction was adopted for verifying the level of the top ten hub genes. Finally, the potential drugs were screened and identified using the QuartataWeb database. Totally 195 upregulated and 167 downregulated DEGs were determined. The ten hub genes were NCAPG, BUB1B, TOP2A, CCNA2, NUSAP1, UBE2C, AURKB, RRM2, CDK1, and KIF11. Ten FDA-approved drugs were screened. Finally, two genes and related drugs screened could be the prospective drug targets for SCLC treatment., Competing Interests: Conflict of interest: The authors declare that there are no conflicts of interest in this work., (© 2023 the author(s), published by De Gruyter.)

Protein homeostasis, an important aspect of cellular fitness that encompasses the balance of production, folding and degradation of proteins, has been linked to several diseases of the human body. Multiple interconnected pathways coordinate to maintain protein homeostasis within the cell. Recently, the role of the protein homeostasis network in tumorigenesis and tumour progression has gradually come to light. Here, we summarize the involvement of the most prominent components of the protein quality control mechanisms (HSR, UPS, autophagy, UPR and ERAD) in tumour development and cancer immunity. In addition, evidence for protein quality control mechanisms and targeted drugs is outlined, and attempts to combine these drugs with cancer immunotherapy are discussed. Altogether, combination therapy represents a promising direction for future investigations, and this exciting insight will be further illuminated by the development of drugs that can reach a balance between the benefits and hazards associated with protein homeostasis interference., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The optimal local treatment for HCC with tumor diameter ≥ 5 cm is not well established. This research evaluated the effectiveness of external beam radiation therapy (EBRT) versus transcatheter arterial chemoembolization (TACE) for HCC with tumor diameter ≥ 5 cm., Methods: A total of 1210 HCC patients were enrolled in this study, including 302 and 908 patients that received EBRT and TACE, respectively. Propensity score matching (PSM) was used to identify patient pairs with similar baseline characteristics. Overall survival (OS) was the primary study endpoint., Results: We identified 428 patients using 1:1 PSM for survival comparison. Compared with the TACE group, the EBRT group had a significantly longer median OS (mOS) before (14.9 vs. 12.3 months, p = 0.0085) and after (16.8 vs. 11.4 months, p = 0.0026) matching. In the subgroup analysis, compared with the TACE group, the EBRT group had a significantly longer mOS for HCC with tumor diameters of 5-7 cm (34.1 vs. 14.3 months, p = 0.04) and 7-10 cm (34.4 vs. 10 months, p = 0.00065), whereas for HCC with tumor diameters ≥ 10 cm, no significant difference in mOS was observed (11.2 vs. 11.2 months, p = 0.83). In addition, the multivariable Cox analysis showed that Child-A, alkaline phosphatase < 125 U/L, and EBRT were independent prognostic indicators for longer survival., Conclusion: EBRT is more effective than TACE as the primary local treatment for HCC with tumor diameter ≥ 5 cm, especially for HCC with tumor diameter of 5-10 cm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Wang, Li, Chi, Zhang, He, Wang, Wen, Song, Chen, Wu, Jiang, Li, Gu, Wang, Li, Liu, Guo, Xu, Guo and Han.)

Pituitary adenoma (PA) is the third most common central nervous system tumor originating from the anterior pituitary, but its pathogenesis remains unclear. The Wnt signaling pathway is a conserved pathway involved in cell proliferation, Self-renewal of stem cells, and cell differentiation. It is related to the occurrence of various tumors, including PA. This article reviews the latest developments in Wnt pathway inhibitors and pathway-targeted drugs. It discusses the possibility of combining Wnt pathway inhibitors with immunotherapy to provide a theoretical basis for the combined treatment of PA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Ma, Zhao, Liu, Ye and Li.)

Introduction: Tumor immunotherapy targeting PD-L1 has emerged as one of the powerful tools for tumor therapy. Numerous studies indicate that tumor-targeted drugs critically have an influence on the interaction between the immune system and tumors by changing the expression of PD-L1, which is beneficial for immunotherapy. Our study provided novel evidence for improving the drug regimen in tumor targeted therapy and immunotherapy., Methods: The expression of PD-L1 on SKBR3, MDA-MB-231, MCF7, 4T1, MC38 and B16 cells was evaluated by flow cytometry after treatment with six preclinical targeted drugs (ARN-509, AZD3514, Galeterone, Neratinib, MLN8237 and LGK974). AURKA was knockdowned by using the specific siRNA or CRISPR-Cas9 technology. In the 4T1-breast tumor and colorectal cancer xenograft tumor models, we determined the number of infiltrated CD3+ and CD8+ T cells in tumor tissues by IHC., Results: We found that AURKA inhibitor MLN8237 promoted the expression of PD-L1 in a time- and concentration-dependent manner while exerted its antitumor effect. Knockdown of AURKA could induce the upregulation of PD-L1 on SKBR3 cells. MLN8237-induced PD-L1 upregulation was mainly associated with the phosphorylation of STAT3. In the 4T1-breast tumor xenograft model, the infiltrated CD3+ and CD8+ T cells decreased after treatment with MLN8237. When treated with MLN8237 in combination with anti-PD-L1 antibody, the volumes of tumor were significantly reduced and accompanied by increasing the infiltration of CD3+ and CD8+ T cells in colorectal cancer xenograft tumor model., Discussion: Our data demonstrated that MLN8237 improved the effect of immunology-related therapy on tumor cells by interacting with anti-PD-L1 antibody, which contributed to producing creative sparks for exploring the possible solutions to overcoming drug resistance to tumor targeted therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Meng, Zhao, Jiang, Xu, Li, Wang, Ma, Li, Liu, Zheng, Peng and Shi.)

The majority of lower-risk myelodysplastic syndromes/neoplasms patients present with anemia. Historically, these patients were treated with erythropoiesis-stimulating agents (ESA), with modest responses. A subset of these patients with del(5q) may do better with lenalidomide. Recently, in randomized trials, luspatercept has shown better responses compared with ESAs in treatment-naive patients and imetelstat in patients refractory to ESAs. Other evaluated novel compounds (fostamatinib, H3B-880, roxadustat, pyruvate kinase receptor activator) have not yet shown meaningful efficacy. More needs to be done to improve outcomes; in pursuance of this, participation in clinical trials evaluating novel therapies should be encouraged. While lower-risk myelodysplastic syndromes/neoplasms tend to have an indolent course, a subset of them has a dismal prognosis. Improving prognostication and serial monitoring will help in identifying high-risk patients for appropriate management.

Objective: To summarize the situation of antineoplastic agents-induced interstitial lung diseases (ILD), provide reference for strengthening clinical management of druginduced interstitial lung diseases (DILD). Methods: We retrospectively investigated the medical records of 12 patients with antineoplastic agents-induced ILD in a hospital between January and December 2020. Data collected included patients' characteristic (gender, age, ECOG PS score, smoking history, primary tumor, concurrent diseases or complications.) and treatment conditions (DILD-causing drugs, clinical symptoms, chest CT, DILD treatment drugs, onset cycle, onset time, severity of DILD, DILD course and prognosis.). Results: The median age of 12 DILD cases was 68%, 66.67% of the patients were male, lung cancer accounted for 58.33% (7/12). DILD was induced by cytotoxicity drugs, targeted drugs and immune checkpoint inhibitors (ICIs), of which ICIs accounted for 66.67% (8/12). Scattered patchy, cord-like, grid-like or flocculent shadows were observed on chest CT, mainly under the pleura of lungs. Once DILD occurs, the suspected antineoplastic agents were stopped and glucocorticoid was given, among which 83.33% (10/12) patients were treated with antibiotics. Finally, 16.67% (2/12) were cured, 33.33% (4/12) were improved, 16.67% (2/12) were not cured and 33.33% (4/12) were dead. Conclusion: Antineoplastic agents-induced ILD is mostly found in elderly male lung cancer patients with smoking history. The clinical symptoms of DILD are diverse and lack of specificity. ICIs-ILD has the characteristic of high incidence and poor prognosis compared with other antineoplastic agents. Comprehensive evaluation before medication, regular review, early and adequate glucocorticoid shock therapy after onset can improve the prognosis of DILD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Gu, Liu, Sun and Sun.)

Background: In patients with hepatocellular carcinoma (HCC), the tumor microenvironment (TME) is resistant to immunotherapy because of its specificity. It is meaningful to explore the role of macrophage, which is one of the most abundant immune cells in the TME, in cellular communication and its effect on the prognosis and immunotherapy of HCC. Methods: Dimensionality reduction and clustering of the single-cell RNA-seq data from the GSE149614 dataset were carried out to identify the cellular composition of HCC. CellChat was used to analyze the communication between different cells. The specifically highly expressed genes of macrophages were extracted for univariate Cox regression analysis to obtain prognostic genes for HCC cluster analysis, and the risk system of macrophage-specifically highly expressed genes was developed by random forest analysis and multivariate Cox regression analysis. Prognosis, TME infiltration, potential responses to immunotherapy, and antineoplastic drugs were compared among molecular subtypes and between risk groups. Results: We found that HCC included nine identifiable cell types, of which macrophages had the highest communication intensity with each of the other eight cell types. Of the 179 specifically highly expressed genes of macrophage, 56 were significantly correlated with the prognosis of HCC, which classified HCC into three subtypes, which were reproducible and produced different survival outcomes, TME infiltration, and immunotherapy responses among the subtypes. In the integration of four macrophage-specifically highly expressed genes for the development of a risk system, the risk score was significantly involved in higher immune cell infiltration, poor prognosis, immunotherapy response rate, and sensitivity of six drugs. Conclusion: In this study, through single-cell RNA-seq data, we identified nine cell types, among which macrophage had the highest communication intensity with the rest of the cell types. Based on specifically highly expressed genes of macrophage, we successfully divided HCC patients into three clusters with distinct prognosis, TME, and therapeutic response. Additionally, a risk system was constructed, which provided a potential reference index for the prognostic target and preclinical individualized treatment of HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Lin, Yu, Chen, He and Ye.)

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1 bar ) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1 bar -A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Accumulating evidence has demonstrated that NEDD4 E3 ubiquitin ligase family plays a pivotal oncogenic role in a variety of malignancies via mediating ubiquitin dependent degradation processes. Moreover, aberrant expression of NEDD4 E3 ubiquitin ligases is often indicative of cancer progression and correlated with poor prognosis. In this review, we are going to address association of expression of NEDD4 E3 ubiquitin ligases with cancers, the signaling pathways and the molecular mechanisms by which the NEDD4 E3 ubiquitin ligases regulate oncogenesis and progression, and the therapies targeting the NEDD4 E3 ubiquitin ligases. This review provides the systematic and comprehensive summary of the latest research status of E3 ubiquitin ligases in the NEDD4 subfamily, and proposes that NEDD4 family E3 ubiquitin ligases are promising anti-cancer drug targets, aiming to provide research direction for clinical targeting of NEDD4 E3 ubiquitin ligase therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The development of targeted drugs in paediatric oncology has been notoriously slow, in part due to the peculiarities of this rare and highly heterogeneous population. To provide therapeutic breakthroughs for the highest risk subgroups of childhood cancer, innovative research solutions have been implemented in the last several years by different international collaborative groups and regulators. Here, we discuss and summarise some of these approaches, as well as challenges and unmet needs that are still being addressed. A wide range of topics were covered in this review including molecular diagnosis optimisation, innovative research methodologies, big data approaches, trial enrolment strategies, and improvements in regulation and preclinical research platforms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Diabetic retinopathy (DR) is the most common retinal vascular disease. Proliferative DR (PDR) is the aggressive stage of DR with angiogenesis as a pathological hallmark, which is the main cause of blindness. There is growing evidence that ferroptosis plays a vital role in diabetics as well as its complications including DR. However, the potential functions and mechanisms of ferroptosis have not been completely elucidated in PDR. The ferroptosis-related differentially expressed genes (FRDEGs) were identified in GSE60436 and GSE94019. Then we constructed a protein-protein interaction (PPI) network and screened ferroptosis-related hub genes (FRHGs). The GO functional annotation and the KEGG pathway enrichment analyses of FRHGs were performed. The miRNet and miRTarbase databases were applied to construct the ferroptosis-related mRNA-miRNA-lncRNA network, and the Drug-Gene Interaction Database (DGIdb) was used for predicting potential therapeutic drugs. Finally, we identified 21 upregulated and 9 downregulated FRDEGs, among which 10 key target genes (P53, TXN, PTEN, SLC2A1, HMOX1, PRKAA1, ATG7, HIF1A, TGFBR1, and IL1B) were recognized with enriched functions, mainly relating to responses to oxidative stress and hypoxia in biological processes of PDR. HIF-1, FoxO and MAPK signalling may be the main pathways that influence ferroptosis in PDR. Moreover, a mRNA-miRNA-lncRNA network was constructed based on the 10 FRHGs and their co-expressed miRNAs. Finally, potential drugs targeting 10 FRHGs for PDR were predicted. Results of the receiver operator characteristic (ROC) curve indicated, with high predictive accuracy in two testing datasets (AUC>0.8), that ATG7, TGFB1, TP53, HMOX1 and ILB1 had the potential to be biomarkers of PDR., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities., (© 2023. The Author(s).)

Potassium channels play an important role in human physiological function. Recently, various molecular mechanisms have implicated abnormal functioning of potassium channels in the proliferation, migration, invasion, apoptosis, and cancer stem cell phenotype formation. Potassium channels also mediate the association of tumor cells with the tumor microenvironment. Meanwhile, potassium channels are important targets for cancer chemotherapy. A variety of drugs exert anti-cancer effects by modulating potassium channels in tumor cells. Therefore, there is a need to understand how potassium channels participate in tumor development and progression, which could reveal new, novel targets for cancer diagnosis and treatment. This review summarizes the roles of voltage-gated potassium channels, calcium-activated potassium channels, inwardly rectifying potassium channels, and two-pore domain potassium channels in tumorigenesis and the underlying mechanism of potassium channel-targeted drugs. Therefore, the study lays the foundation for rational and effective drug design and individualized clinical therapeutics., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

With the in-depth study of the human genome and the increasing popularity of gene sequencing, it has been gradually confirmed that genetics can play a crucial role in infertility. To provide references for clinical treatment, we have focused on genes and drug therapy for genetic infertility. This review recommends adjuvant therapy and drug substitution. Examples of these therapies include antioxidants (such as folic acid, vitamin D, vitamin E, inositol, coenzyme Q10 etc.), metformin, anticoagulants, levothyroxine, dehydroepiandrosterone, glucocorticoids, and gonadotropins etc. Based on the pathogenesis, we provide an overview of the current knowledge, including randomized controlled trials and systematic reviews, and predict potential target genes and signaling pathways, proposing possible future strategies for the use of targeted drugs to treat infertility. Non-coding RNAs are anticipated to become a novel target for the treatment of reproductive illnesses since they have a significant role in controlling the occurrence and development of reproductive diseases.

RET and ROS1 are becoming key targets for targeted therapy. To show current landscape of ROS1 and RET targets, a patent analysis was performed. The present results indicated that inhibitor structures of ROS1 target demonstrated unique elements compared with inhibitor structures of RET or BRAF targets. Our study was the first time to uncover that a number of inhibitor structures of ROS1 target contained sulfur and boron elements. The inhibitors of RET target could be developed for treatment of various cancers, including lung cancer, thyroid cancer, and other solid tumor, while the inhibitors of ROS1 target are virtually developed for treatment of lung cancer. Our findings provide a new insight for drug discovery of ROS1 and RET target.

CLDN6 is a member of the CLDNs family that is specifically and highly expressed in cancers such as ovarian, testicular, endocervical, liver and lung adenocarcinoma, but hardly expressed in adult normal tissues. CLDN6 is able to activate multiple signaling pathways, which take part in the development and progression of cancer, including promoting tumor growth, migration and invasion, and promoting chemoresistance in cancer. In recent years, CLDN6 has received much attention as a novel target for cancer therapeutics. Many types of anticancer drugs targeting CLDN6 have been developed, including antibody-conjugated drugs (ADC), monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T). This paper briefly summarizes the structure, expression and function of CLDN6 in tumors, and reviews the current status and ideas of developing targeted CLDN6 anticancer drugs.