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Radionuclide therapy (RT) is widely used to advanced local cancers. However, its therapeutic efficacy is limited to the radiation resistance of cancer cells. Combination therapy aims to circumvent tumor resistance, and the combination of RT with photothermal therapy (PTT), photodynamic therapy (PDT), chemotherapy (CMT), and immunotherapy has shown promising treatment outcomes. Nanotechnology holds promise in advancing combination therapy by integrating multiple therapies on a nanostructure platform. This is due to the increased surface area, passive/active targeting capabilities, high payload capacity, and enriched surface of nanomedicines, offering significant advantages in treatment sensitivity and specificity. In the first part of this review, we categorize radionuclide therapy. The second part summarizes the latest developments in combination therapies, specifically focusing on the integration of RT with PTT, PDT, CMT and immunotherapy. The last part provides an overview of the challenges and potential opportunities related to radionuclide-labelled nanoparticles for cancer combination therapy., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: We confirm that the details of any images can be published. Copyright permission is granted. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Hypoxia in solid tumors increases their invasiveness and resistance to therapy, presenting a formidable obstacle in tumor therapy. The hypoxia prodrug banoxantrone (AQ4N) undergoes conversion into its topoisomerase II inhibitor form AQ4 under hypoxic conditions, which inhibits tumor cells while leaving normal cells unharmed. Numerous studies have found that AQ4N significantly enhances the tumor effect while minimizing toxicity to normal tissues when combined with other drugs or therapeutic approaches. Thus, to maximize AQ4N's effectiveness, co-delivery of AQ4N with other therapeutic agents to the tumor site is paramount, leading to the development of multifunctional multicomponent AQ4N nanocomposites thereby emerging as promising candidates for combination therapy in tumor treatment. However, currently there is a lack of systematic analysis and reviews focusing on AQ4N. Herein, this review provides a comprehensive retrospect and analysis of the recent advancements in AQ4N nanocomposites. Specifically, we discuss the synergistic effects observed when AQ4N is combined with chemotherapeutic drugs, radiotherapy, phototherapy, starvation, sonodynamic therapy and immunotherapy in preclinical models. Moreover, the advantages, limitations, and future perspectives of different AQ4N nanocomposites are highlighted, providing researchers from diverse fields with novel insights into tumor treatment.

Natural products, which are compounds extracted and/or refined from plants and microbes in nature, have great potential for the discovery of therapeutic agents, especially for infectious diseases and cancer. In recent years, natural products have been reported to induce multiple cell death pathways to exhibit antitumor effects. Among them, pyroptosis is a unique programmed cell death (PCD) characterized by continuous cell membrane permeability and intracellular content leakage. According to the canonical and noncanonical pathways, the formation of gasdermin-N pores involves a variety of transcriptional targets and post-translational modifications. Thus, tailored control of PCD may facilitate dying cells with sufficient immunogenicity to activate the immune system to eliminate other tumor cells. Therefore, we summarized the currently reported natural products or their derivatives and their nano-drugs that induce pyroptosis-related signaling pathways. We reviewed six main categories of bioactive compounds extracted from natural products, including flavonoids, terpenoids, polyphenols, quinones, artemisinins, and alkaloids. Correspondingly, the underlying mechanisms of how these compounds and their derivatives engage in pyroptosis are also discussed. Moreover, the synergistic effect of natural bioactive compounds with other antitumor therapies is proposed as a novel therapeutic strategy for traditional chemotherapy, radiotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, hyperthermal therapy, and sonodynamic therapy. Consequently, we provide insights into natural products to develop a novel antitumor therapy or qualified adjuvant agents by inducing pyroptosis, which may eventually be applied clinically.

Background: IBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation., Methods: In phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated., Results: As of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months., Conclusions: IBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Qing Zhou reports honoraria from AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol-Myers Squibb, Hengrui. Yi-Long Wu reports honoraria from AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol-Myers Squibb, Hengrui; consulting or advisory role from AstraZeneca, Roche, Boehringer Ingelheim, Takeda; and research funding from Boehringer Ingelheim, Roche, Pfizer, Bristol-Myers Squibb. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Increasing evidence indicates that 2-hydroxyglutarate (2HG) is an oncometabolite that drives tumour formation and progression. Due to mutations in isocitrate dehydrogenase (IDH) and the dysregulation of other enzymes, 2HG accumulates significantly in tumour cells. Due to its structural similarity to α-ketoglutarate (αKG), accumulated 2HG leads to the competitive inhibition of αKG-dependent dioxygenases (αKGDs), such as KDMs, TETs, and EGLNs. This inhibition results in epigenetic alterations in both tumour cells and the tumour microenvironment. This review comprehensively discusses the metabolic pathways of 2HG and the subsequent pathways influenced by elevated 2HG levels. We will delve into the molecular mechanisms by which 2HG exerts its oncogenic effects, particularly focusing on epigenetic modifications. This review will also explore the various methods available for the detection of 2HG, emphasising both current techniques and emerging technologies. Furthermore, 2HG shows promise as a biomarker for clinical diagnosis and treatment. By integrating these perspectives, this review aims to provide a comprehensive overview of the current understanding of 2HG in cancer biology, highlight the importance of ongoing research, and discuss future directions for translating these findings into clinical applications., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microbes are extensively present among various cancer tissues and play critical roles in carcinogenesis and treatment responses. However, the underlying relationships between intratumoral microbes and tumors remain poorly understood. Here, a MIcrobial Cancer-association Analysis using a Heterogeneous graph transformer (MICAH) to identify intratumoral cancer-associated microbial communities is presented. MICAH integrates metabolic and phylogenetic relationships among microbes into a heterogeneous graph representation. It uses a graph transformer to holistically capture relationships between intratumoral microbes and cancer tissues, which improves the explainability of the associations between identified microbial communities and cancers. MICAH is applied to intratumoral bacterial data across 5 cancer types and 5 fungi datasets, and its generalizability and reproducibility are demonstrated. After experimentally testing a representative observation using a mouse model of tumor-microbe-immune interactions, a result consistent with MICAH's identified relationship is observed. Source tracking analysis reveals that the primary known contributor to a cancer-associated microbial community is the organs affected by the type of cancer. Overall, this graph neural network framework refines the number of microbes that can be used for follow-up experimental validation from thousands to tens, thereby helping to accelerate the understanding of the relationship between tumors and intratumoral microbiomes., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

WDFY2 is a protein that may provide valuable insights into the mechanisms underlying human tumors and aid in the development of novel therapies. Despite its potential importance, the role of WDFY2 in pan-cancer has not been systematically investigated. In this study, we comprehensively explored the expression pattern and function of WDFY2 across 33 cancers using various databases, including TCGA, CPTAC and GEO datasets. Our results indicate that WDFY2 is downregulated in most cancer types, including BRCA, KIRP, KICH, LUAD, KIRC, PCPG, PRAD, THCA, ACC, OV, TGCT and UCS, while it is upregulated in CESC, CHOL, COAD, HNSC, LUSC, READ, STAD and UCEC. Prognostic analyses showed that higher levels of WDFY2 were associated with worse disease outcomes in ACC, BLCA, COAD, READ, SARC, MESO and OV. WDFY2 mutations were most frequent in colorectal cancer but were not associated with disease prognosis. We also found that WDFY2 expression correlated with monocyte infiltration status in SKCM, endothelial cell infiltration in COAD, KIRC, MESO, OV and THCA, and cancer-associated fibroblast infiltration in COAD, LUAD and OV. Additionally, functional enrichment analysis revealed that WDFY2 is involved in metabolism. Overall, our comprehensive analysis sheds light on the role of WDFY2 in various cancers, providing a better understanding of its role in tumorigenesis.

Nanozymes, as an emerging class of enzyme mimics, have attracted much attention due to their adjustable catalytic activity, low cost, easy modification, and good stability. Researchers have made great efforts in developing and applying high-performance nanozymes. Recently, transition-metal-based nanozymes have been designed and widely developed because they possess unique photoelectric properties and high enzyme-like catalytic activities. To highlight these achievements and help researchers to understand the research status of transition-metal-based nanozymes, the development of transition-metal-based nanozymes from material characteristics to biological applications is summarized. Herein, we focus on introducing six categories of transition-metal-based nanozymes and highlight their progress in biomarker sensing and catalytic therapy for tumors. We hope that this review can guide the further development of transition-metal-based nanozymes and promote their practical applications in cancer diagnosis and treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: To analyze the 5-year relative survival rate of cancer in Henan province based on cancer registration data. Methods: Cancer survival data were extracted from the cancer registration database of Henan province with the diagnosis date between January 1, 2010 and December 31, 2019 were included. The closing date of follow-up was set as December 31, 2019. The 5-year relative survival rate of cancer was calculated using the period survival analysis method and the Ederer II method in the R package "periodR", and the interest period was between 2015 and 2019. Results: During the period of 2015-2019, the overall 5-year relative survival rate of cancer patients in Henan province was 43.6%, and after age-standardization, it was 40.2%. The overall 5-year relative survival rate showed the characteristics of higher survival rate in females than males (45.9% vs 34.7%, Z =39.60, P ＜0.001) and higher survival rate in urban areas than rural areas (44.9% vs 39.1%, Z =12.97, P ＜0.001). The 5-year relative survival rate for cancer patients among children aged 0-14 was 60.2%, and for adults aged 15 and above, it was 43.5%, which was standardized to 40.2% after age adjustment. There are two types of cancers with a standardized 5-year relative survival rate exceeding 70% (thyroid cancer at 82.2% and breast cancer at 71.6%), and four cancers with a rate below 30% (pancreatic cancer at 18.2%, liver cancer at 19.6%, lung cancer at 24.0%, and gallbladder cancer at 26.6%). Conclusion: The cancer 5-year survival rate in Henan Province is lower than that of the national average, indicating the need for continued enhancement of cancer prevention and control measures.

R-loops are three-stranded nucleic acid structures composed of an RNA-DNA hybrid and a displaced DNA strand. They are widespread and play crucial roles in regulating gene expression, DNA replication, and DNA and histone modifications. However, their regulatory mechanisms remain unclear. As R-loop detection technology advances, changes in R-loop levels have been observed in cancer models, often associated with transcription-replication conflicts and genomic instability. N6-methyladenosine (m6A) is an RNA epigenetic modification that regulates gene expression by affecting RNA localization, splicing, translation, and degradation. Upon reviewing the literature, we found that R-loops with m6A modifications are implicated in tumor development and progression. This article summarizes the molecular mechanisms and detection methods of R-loops and m6A modifications in gene regulation, and reviews recent research on m6A-modified R-loops in oncology. Our goal is to provide new insights into the origins of genomic instability in cancer and potential strategies for targeted therapy., (© 2024. The Author(s).)

A growing percentage of diabetes-related deaths has been attributed to cancer, with environmental factors playing important contributions. Thus, we studied the potential relationship between endocrine disruptors polychlorinated biphenyls (PCBs) and cancer risk in diabetes. We aimed to evaluate the association between serum seven indicator-PCB (PCB-28/52/101/118/138/153/180) levels and incident cancer, and further explore the possible modifying role of lifestyle. A total of 2806 type 2 diabetes mellitus (T2DM) cases were included from the Dongfeng-Tongji cohort at the baseline in 2008 and tracked until December 2018, and 320 incident cancers were identified during about 10-year follow-up. Cox proportional hazards models and competing risk regression models were used to reveal associations of baseline concentrations of PCBs with total cancer and specific cancer, respectively. Lifestyle score was determined by body mass index, waist circumference, physical activity, smoking, alcohol drinking, and diet. Each interquartile range (IQR) increment of non-dioxin-like PCBs (NDL-PCBs) generated an 8%-30% increase in cancer incidence. Individuals in the highest quartile for PCB-52, PCB-101, PCB-138, and lowly chlorinated PCBs had 1.44- to 1.68-fold higher cancer risk compared to those in the lowest quartile. Restricted cubic spline analyses and the quantile g-computation model showed similar results. Significant interactions were found between PCBs and fasting blood glucose or simplified insulin resistance assessment indicators. NDL-PCBs were positively and significantly associated with gastrointestinal cancer and respiratory cancer, especially with liver cancer, colorectal cancer, and lung cancer. Higher PCBs showed a significant increase in total cancer risk among participants with an unhealthy lifestyle, however, no associations were observed in those with a relatively healthy lifestyle (P interaction < 0.05). Our findings indicated an increased cancer risk associated with NDL-PCBs, highlighted the role of a healthy lifestyle in potentially reducing adverse impact, and provided preliminary data for environmental and public health interventions to alleviate the risk of cancer among diabetes., 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. Published by Elsevier Ltd.)

Purpose: To evaluate the impacts of tele-exercise intervention with cancer patients' quality of life, taking into account the influence of the duration of tele-exercise intervention, type of intervention, and gender of cancer patients on quality of life., Methods: The PubMed (MEDLINE), Embase, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and PsycINFO databases were searched from inception to August 21, 2023. The Cochrane Collaboration's risk of bias tool 2 was utilized to estimate the risk of bias, and the Grading of Recommendations, Assessment. For statistical analyses, R Studio was employed., Results: This meta-analysis contained eight trials. When compared to controls, tele-exercise interventions (SMD = 0.41, 95% CI: 0.12 to 0.70, p < .010; I 2  = 54%, p = .030) have a positive influence on boosting the quality of life within cancer patients. Subgroup analyses demonstrated the greater effectiveness of tele-exercise in enhancing the quality of life of cancer patients when the duration was greater than or equal to 10 weeks. Furthermore, tele-exercise was found to have a stronger advantageous effect on quality of life among female cancer. In addition, among the types of interventions for tele-exercise, neither web-based nor telephone-based formats significantly enhanced quality of life among cancer patients., Conclusion: Tele-exercise interventions are a cost-effective and feasible non-pharmacologic complementary way to promote cancer patients' quality of life. Additional large-sample, carefully designed randomized controlled trials are warranted to further validate the impact of tele-exercise concerning cancer patients' quality of life., Registration Number: CRD42023477147., Competing Interests: Conflict of interest No conflict of interest exists in the submission of this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Previous studies have proved that healthy behaviors hinder the onset and progression of tumors. Digital therapeutics (DTx), playing a pivotal role in facilitating behavioral adjustments through educational interventions, lifestyle support, and symptom monitoring, contribute to the goal of tumor prevention. We aim to optimize the evaluation of the feasibility and acceptability of DTx for cancer prevention. This involves assessing AITI's daily activity rates and user feedback, and comparing changes in behavioral habits and differences in SF-36 before and after the intervention. In a 4-week trial with 57 participants engaging actively, we found both the average daily activity rate and 4-week retention rate at 35 (61.4%). The USE Questionnaire scores (validity, ease of use, acquisition, and satisfaction) ranged from 68.06 to 83.10, indicating AITI's user-friendliness and acceptability. Furthermore, positive habit changes were noted among participants in exercise and diet (p < 0.0001), suggesting the effectiveness of the DTx approach in modifying behavioral habits related to physical activity and nutrition. This pilot study underscores the potential of DTx in advancing cancer prevention. However, larger and longer studies are needed to comprehensively assess its impact., (© 2024. The Author(s) under exclusive licence to American Association for Cancer Education.)

Cancer is a major public health problem and represents substantial disparities worldwide. This study reported estimates for 36 cancers across 185 countries by incidence, mortality, 5-year prevalence, mortality-to-prevalence ratio (MPR), and mortality-to-incidence ratio (MIR) to examine its association with human development index (HDI) and gross national income (GNI). Data were collected from the GLOBOCAN 2020. MPR and MIR were calculated by sex, age group, country, and cancer type and then summarized into totals. Segi's population and global cancer spectrum were used to calculate age- and type-standardized ratios. Correlation analyses were conducted to assess associations. Results showed that breast cancer was the most diagnosed cancer globally. Low- and middle-income countries had high MPR and MIR. Cancers of esophagus, pancreas, and liver had the highest ratios. Males and the older population had the highest ratios. HDI and GNI were positively correlated with incidence and mortality but negatively correlated with MPR/MIR. Substantial disparities in cancer burden were observed among 36 cancer types across 185 countries. Socioeconomic development may contribute to narrowing these disparities, and tailored strategies are crucial for regional- and country-specific cancer control., (© 2024. Higher Education Press.)

Interferon Gamma Inducible Protein 30 (IFI30), also known as Gamma-Interferon-Inducible Lysosomal Thiol Reductase (GILT), is predominantly found in lysosomes and the cytoplasm. As the sole enzyme identified to catalyze disulfide bond reduction in the endocytic pathway, IFI30 contributes to both major histocompatibility complex (MHC) class I-restricted antigen cross-presentation and MHC class II-restricted antigen processing by decreasing the disulfide bonds of endocytosed proteins. Remarkably, emerging research has revealed that IFI30 is involved in tumorigenesis, tumor development, and the tumor immune response. Targeting IFI30 may provide new strategies for cancer therapy and improve the prognosis of patients. This review provided a comprehensive overview of the research progress on IFI30 in tumor progression, cellular redox status, autophagy, tumor immune response, and drug sensitivity, with a view to providing the theoretical basis for pharmacological intervention of IFI30 in tumor therapy, particularly in immunotherapy., (© 2024. Springer Nature Switzerland AG.)

Disparities in cancer diagnosis, treatment, and outcomes based on self-identified race and ethnicity (SIRE) are well documented, yet these variables have historically been excluded from clinical research. Without SIRE, genetic ancestry can be inferred using single-nucleotide polymorphisms (SNPs) detected from tumor DNA using comprehensive genomic profiling (CGP). However, factors inherent to CGP of tumor DNA increase the difficulty of identifying ancestry-informative SNPs, and current workflows for inferring genetic ancestry from CGP need improvements in key areas of the ancestry inference process. This study used genomic data from 4274 diverse reference subjects and CGP data from 491 patients with solid tumors and SIRE to develop and validate a workflow to obtain accurate genetically inferred ancestry (GIA) from CGP sequencing results. We use consensus-based classification to derive confident ancestral inferences from an expanded reference dataset covering eight world populations (African, Admixed American, Central Asian/Siberian, European, East Asian, Middle Eastern, Oceania, South Asian). Our GIA calls were highly concordant with SIRE (95%) and aligned well with reference populations of inferred ancestries. Further, our workflow could expand on SIRE by (i) detecting the ancestry of patients that usually lack appropriate racial categories, (ii) determining what patients have mixed ancestry, and (iii) resolving ancestries of patients in heterogeneous racial categories and who had missing SIRE. Accurate GIA provides needed information to enable ancestry-aware biomarker research, ensure the inclusion of underrepresented groups in clinical research, and increase the diverse representation of patient populations eligible for precision medicine therapies and trials., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: To assess the effectiveness of applying digital health palliative care to improve symptoms, mood, and quality of life in patients with advanced cancer., Methods: We searched PubMed, Embase, Web of Science, Cochrane Library (CENTRAL), and CINAHL databases on November 16, 2023, to identify randomized controlled trials of the impact of palliative care applying digital health on patients with advanced cancer. The Cochrane Risk of Bias Tool version 1.0 was used to evaluate the quality of randomized controlled trials., Results: A total of 20 randomized controlled trials were included, of which 18 were meta-analyzed. Compared with usual care, palliative care applying digital health was effective in improving symptoms (SMD = -0.21, 95% CI: -0.37 to -0.06, P = 0.007) and reducing the intensity of pain (SMD = -0.49, 95% CI: -0.85 to -0.13, P = 0.008) in patients with advanced cancer, but no effective improvement in depressive symptoms, anxiety symptoms, or quality of life was found., Conclusions: Our systematic review provides evidence that palliative care applying digital health has great potential to improve symptoms in patients with advanced cancer, but more research is needed to explore its impact on mood and quality of life., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Many solid tumors frequently overexpress Non-SMC Condensin I Complex Subunit H (NCAPH), and new studies suggest that NCAPH may be a target gene for clinical cancer therapy. Numerous investigations have shown that a variety of transcription factors, including as MYBL2, FOXP3, GATA3, and OTC1, can stimulate the transcription of NCAPH. Additionally, NCAPH stimulates many oncogenic signaling pathways, such as β-Catenin/PD-L1, PI3K/AKT/SGK3, MEK/ERK, AURKB/AKT/mTOR, PI3K/PDK1/AKT, and Chk1/Chk2. Tumor immune microenvironment modification and tumor growth, apoptosis, metastasis, stemness, and treatment resistance all depend on these signals. NCAPH has the ability to form complexes with other proteins that are involved in glycolysis, DNA damage repair, and chromatin remodeling. This review indicates that NCAPH expression in most malignant tumors is associated with poor prognosis and low recurrence-free survival., Competing Interests: Declaration of competing interest All other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment., (© 2024 Wiley‐VCH GmbH.)

Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio- N -arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.

Background: Malnutrition commonly occurs in cancer patients, impacting their quality of life and survival duration. The objective of this meta-analysis and systematic review is to assess the effects of nutritional interventions on patients undergoing neoadjuvant chemoradiotherapy., Methods: A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library databases to obtain randomized controlled trials of nutritional interventions in patients with neoadjuvant chemoradiotherapy. Outcomes assessed included toxicity reactions to neoadjuvant therapy, levels of inflammation-related markers, nutritional status, and relevant clinical outcomes. The relative risk (RR) or weighted mean difference (WMD) and 95% confidence interval (CI) were used as effect sizes., Results: A total of 16 studies were included, involving 954 patients. Nutritional intervention significantly reduced the incidence of vomiting (RR = 0.37, 95%CI: 0.21-0.67, P = 0.001) and mucositis (RR = 0.82, 95%CI: 0.67-1.00, P = 0.046) in patients with neoadjuvant chemoradiotherapy. For the nutritional status of cancer patients, nutritional intervention significantly increased the proportion of well-nourished patients (RR = 12.74, 95%CI: 4.43-36.69, P < 0.001). In addition, nutritional intervention also reduced the length of hospital stay in neoadjuvant chemoradiotherapy patients after surgery (WMD =  - 0.82, 95%CI: - 1.61- - 0.02, P = 0.043). However, there was no improvement in nausea (P = 0.534), diarrhea (P = 0.068), febrile neutropenia (P = 0.551), levels of albumin (P = 0.211), prealbumin (P = 0.063), C-reactive protein (P = 0.430), clinical remission (P = 0.148), or postoperative complications (P = 0.098)., Conclusion: Nutritional intervention can reduce the toxicity of neoadjuvant chemoradiotherapy (vomiting and mucositis), improve the nutritional status of patients, and shorten the length of postoperative hospital stay. Well-designed and high-quality studies are necessary to confirm the effect of nutritional interventions on cancer patients, with a specific focus on reaching nutritional goals and providing the right nutrients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Tumor neovascularization is essential for the growth, invasion, and metastasis of tumors. Recent studies have highlighted the significant role of N6-methyladenosine (m 6 A) modification in regulating these processes. This review explores the mechanisms by which m 6 A influences tumor neovascularization, focusing on its impact on angiogenesis and vasculogenic mimicry (VM). We discuss the roles of m 6 A writers, erasers, and readers in modulating the stability and translation of angiogenic factors like vascular endothelial growth factor (VEGF), and their involvement in key signaling pathways such as PI3K/AKT, MAPK, and Hippo. Additionally, we outline the role of m 6 A in vascular-immune crosstalk. Finally, we discuss the current development of m 6 A inhibitors and their potential applications, along with the contribution of m 6 A to anti-angiogenic therapy resistance. Highlighting the therapeutic potential of targeting m 6 A regulators, this review provides novel insights into anti-angiogenic strategies and underscores the need for further research to fully exploit m 6 A modulation in cancer treatment. By understanding the intricate role of m 6 A in tumor neovascularization, we can develop more effective therapeutic approaches to inhibit tumor growth and overcome treatment resistance. Targeting m 6 A offers a novel approach to interfere with the tumor's ability to manipulate its microenvironment, enhancing the efficacy of existing treatments and providing new avenues for combating cancer progression., (© 2024. The Author(s).)

Introduction: Cancer patients not only experience a variety of problems associated with the treatment of their disease but also a range of psychological problems such as anxiety and depression, which may lead to reduced adherence to treatment and a lower quality of life for cancer patients. Telehealth interventions are widely used for cancer patients, and their effectiveness in improving anxiety and depression in cancer patients is variable and still contradictory., Methods: Embase, Pubmed, Web of Science, PsycINFO, CINAHL Complete, and the Cochrane Central Register of Controlled Trials were searched from inception to 19 April 2022. Data synthesis was conducted using STATA 15.0, and scores for anxiety and depression were calculated using standardized mean differences and 95% confidence intervals., Results: A total of 13125 cancer patients from 68 randomized controlled trials were included in the systematic evaluation. The meta-analysis showed that the telehealth intervention had a significant effect on anxiety (standardized mean differences = -0.40, 95% confidence intervals: -0.6 to 0.2, p  < 0.001) and depression (standardized mean differences = -0.48, 95% confidence intervals: -0.67 to 0.28, p  < 0.001) in patients with cancer., Discussion: Telehealth interventions significantly improved anxiety and depression levels in cancer patients compared to traditional care interventions. Breast cancer patients most often received telehealth interventions; electronic device-based and application-based telehealth interventions were more effective than online interventions; short-term interventions were more effective than medium-term and long-term interventions, and different outcome measurement tools led to different intervention outcomes. More high-quality research is needed to explore the effects of telehealth interventions., 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.

Cancer is a serious global public health issue, and a great deal of research has been made to treat cancer. Of these, discovery of promising compounds that effectively fight cancer always has been the main point of interest in pharmaceutical research. Carnosic acid (CA) is a phenolic diterpenoid compound widely present in Lamiaceae plants such as Rosemary (Rosmarinus officinalis L.). In recent years, there has been increasing evidence that CA has significant anti-cancer activity, such as leukaemia, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, lymphoma, prostate cancer, oral cancer, etc. The potential mechanisms involved by CA, including inhibiting cell proliferation, inhibiting metastasis, inducing cell apoptosis, stimulating autophagy, regulating the immune system, reducing inflammation, regulating the gut microbiota, and enhancing the effects of other anti-cancer drugs. This article reviews the biosynthesis, pharmacokinetics and metabolism, safety and toxicity, as well as the molecular mechanisms and signaling pathways of the anticancer activity of CA. This will contribute to the development of CA or CA-containing functional foods for the prevention and treatment of cancer, providing important advances in the advancement of cancer 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With large specific surface area, controllable pore size, increased active sites, and structural stability, two-dimensional metal organic frameworks (2D MOFs) have emerged as promising nanomedicines in cancer therapy. These distinctive features make 2D MOFs particularly advantageous in cancer treatment and the corresponding application has gained considerable popularity, signifying significant application potential. Herein, recent advances in various applications including drug delivery and chemotherapy, photodynamic therapy, sonodynamic therapy, chemodynamic therapy, catalytic therapy, and combined therapy were summarized, with emphasis on the latest progress of new materials and mechanisms for these processes. Moreover, the current challenges, potential solutions, and possible future directions are discussed as well.

Background: To provide reference for clinical development of ADCs in the industry, we analyzed the landscape and characteristics of clinical trials about antibody-drug conjugates (ADCs)., Method: Clinical trials to study ADCs used for the pharmacotherapy of cancers initiated by the sponsor were searched in the Cite line Pharma Intelligence (Trialtrove database), and the landscape and characteristics of these clinical trials were analyzed from multiple perspectives, such as the number, phases, status, indications, and targets of the clinical trials., Result: As of December 31, 2022, a total of 431 clinical trials have been initiated to study ADCs used for the pharmacotherapy of cancers, and the number of the last 10 years was 5.5 times as large as the first 11 years. These clinical trials involved 47 indications, including breast cancer, lymphoma (lymphoma, non-Hodgkin's and lymphoma, Hodgkin's), unspecified solid tumor, bladder cancer and lung cancer (lung, non-small cell cancer and lung, small cell cancer). As for each of these five indications, 50 + clinical trials have been carried out, accounting for as high as 48.50% (454/936). ADCs involve 38 targets, which are relatively concentrated. Among them, ERBB2 (HER2) and TNFRSF8 (CD30) involve in 100 + registered clinical trials, and TNFRSF17 (BCMA), NECTIN4 and CD19 in 10 + trials. The clinical trials for these five targets account for 79.02% (354/448) of the total number. Up to 93.97% (405/431) of these clinical trials explored the correlation between biomarkers and efficacy. Up to 45.91% (292/636) of Lots (lines of treatment) applied in the clinical trials were the second line. Until December 31, 2022, 54.52% (235/431) of the clinical trials have been completed or terminated., Conclusion: ADCs are a hotspot of research and development in oncology clinical trials, but the indications, targets, phases, and Lot that have been registered are seemingly relatively concentrated at present. This study provides a comprehensive analysis which can assist researchers/developer quickly grasp relevant knowledge to assess a product and also providing new clues and ideas for future research., (© 2024. The Author(s).)

Circulating cell-free DNA (cfDNA) in the peripheral blood is a promising biomarker for cancer diagnosis and prognosis. Somatic mutations identified in cancers have been used to detect therapeutic targets for clinical transformation and individualize drug selection, while germline variants can predict a patient's risk of developing cancer and drug sensitivity. However, no platform has been developed to analyze, calculate, integrate, and friendly visualize these pan-cancer cfDNA mutations deeply. In this work, we performed panel sequencing encompassing 1,115 cancer-related genes across 16,659 cancer patients, spanning 27 cancer types. We detected 496 germline variants in leukocytes and 11,232 somatic mutations in the cfDNA of all patients. CPGV (Cancer Peripheral blood Gene Variations), a database constructed from this dataset, is the first pan-cancer cfDNA database that encompasses somatic mutations, germline variants, and further comparative analyses of mutations across different cancer types. It bears great promise to serve as a valuable resource for cancer research., (© 2024. The Author(s).)

Background: The efficacy and toxicity of KRAS G12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent., Methods: Clinical trials evaluating KRAS G12C inhibitors for advanced solid tumors were searched from PubMed, Embase, and Cochrane Library online databases up to 31st December 2023. The characteristics of the studies and the results of objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate, and treatment-related adverse events (trAEs) were extracted., Results: Ten studies with 925 heavily pretreated advanced patients harboring KRAS G12C mutation were included. For total population, the pooled analysis of ORR was 28.6% (95%CI, 21.2-36.6%), DCR was 85.5% (95%CI, 82.2-88.6%), PFS rate at 6 months (PFS6) was 49.6% (95%CI, 41.4-57.9%), PFS rate at 12 months (PFS12) was 26.7% (95%CI, 19.8-34.1%), OS rates at 6 months (OS6) was 76.2% (95%CI, 68.8-82.9%), OS rates at 12 months (OS12) was 47.8% (95%CI, 38.6-57.0%). The pooled analysis of any grade trAEs was 79.3% (95%CI, 66.2-90.0%) and grade three or more trAEs was 24.4% (95%CI, 16.7-32.9%). The median time to response and DoR results from individual data were 1.39 months (95%CI, 1.37-1.41 months) and 10.54 months (95%CI, 7.72-13.36 months). Sotorasib had significantly lower pooled incidences of any trAEs (OR, 0.07, 95%CI, 0.03-0.14) and grade three or more trAES (OR, 0.34, 95%CI, 0.24-0.49) compared with adagrasib., Conclusions: KRAS G12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors; however, most of the pooled results were heterogeneous. Sotorasib has shown better safety results., (© 2024. The Author(s).)

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.

Aim: To determine the effectiveness of brief reminiscence-based psychosocial interventions in alleviating psychological distress in cancer patients., Background: Cancer patients suffer tremendous psycho-spiritual pain, which affects their quality of life. Brief reminiscence-based psychosocial interventions have demonstrated positive effects on the mental health of cancer patients; however, the efficacy of these interventions has been inconsistent., Design: A systematic review and meta-analysis., Methods: This review was conducted and reported in accordance with the PRISMA 2020 checklist provided by the EQUATOR network. The Cochrane Library, Web of Science, PsycINFO, PubMed, Embase, CINAHL and Scopus databases were systematically searched from inception to 27 November 2022 to identify randomised controlled trials (RCTs) published in English., Results: Twenty studies involving 1744 cancer participants were included. The meta-analysis showed statistically significant effects of brief reminiscence-based psychosocial interventions on hope, anxiety and depression at post-intervention. A separate analysis revealed that brief reminiscence-based psychosocial interventions had a sustainable effect on hope, spiritual well-being, anxiety and depression at 1 month after the intervention. However, no statistically significant effect on quality of life was found in our study either immediately after the intervention or at 1 month., Conclusions: Brief reminiscence-based psychosocial interventions can significantly reduce anxiety and depressive symptoms and improve hope and spiritual well-being in cancer patients., Relevance to Clinical Practice: This study further supports that brief reminiscence-based psychosocial interventions should be incorporated into the routine care of cancer patients to address their psychosocial distress., Patient or Public Contribution: All authors of this article contributed to the study conception and design. All authors of the included studies provided original data for this paper., (© 2024 John Wiley & Sons Ltd.)

High-throughput sequencing and multiomics technologies have allowed increasing numbers of biomarkers to be mined and used for disease diagnosis, risk stratification, efficacy assessment, and prognosis prediction. However, the large number and complexity of tumor markers make screening them a substantial challenge. Machine learning (ML) offers new and effective ways to solve the screening problem. ML goes beyond mere data processing and is instrumental in recognizing intricate patterns within data. ML also has a crucial role in modeling dynamic changes associated with diseases. Used together, ML techniques have been included in automatic pipelines for tumor marker screening, thereby enhancing the efficiency and accuracy of the screening process. In this review, we discuss the general processes and common ML algorithms, and highlight recent applications of ML in tumor marker screening of genomic, transcriptomic, proteomic, and metabolomic data of patients with various types of cancers. Finally, the challenges and future prospects of the application of ML in tumor therapy are discussed., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Xingxing Fu drafted the manuscript. Qi Zuo and Wanting Ma searched part of the literature. Xingxing Fu, Yinan Zhao, Yanfei Qi and Shubiao Zhang conceived and designed the work. Xingxing Fu, Yinan Zhao, Yanfei Qi and Shubiao Zhang edited and revised the manuscript. All the authors have read and approved the final manuscript., (Copyright © 2024. Published by Elsevier Inc.)

The protein kinase casein kinase 2 (CK2) exerts its influence on the metabolism of three major cellular substances by phosphorylating essential protein molecules involved in various cellular metabolic pathways. These substances include hormones, especially insulin, rate-limiting enzymes, transcription factors of key genes, and cytokines. This regulatory role of CK2 is closely tied to important cellular processes such as cell proliferation and apoptosis. Additionally, tumor cells undergo metabolic reprogramming characterized by aerobic glycolysis, accelerated lipid β-oxidation, and abnormally active glutamine metabolism. In this context, CK2, which is overexpressed in various tumors, also plays a pivotal role. Hence, this review aims to summarize the regulatory mechanisms of CK2 in diverse metabolic pathways and tumor development, providing novel insights for the diagnosis, treatment, and prognosis of metabolism-related diseases and cancers., (© 2023 International Union of Biochemistry and Molecular Biology.)

Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation., (© 2024. The Author(s).)

Cancer is a complex disease composing systemic alterations in multiple scales. In this study, we develop the Tumor Multi-Omics pre-trained Network (TMO-Net) that integrates multi-omics pan-cancer datasets for model pre-training, facilitating cross-omics interactions and enabling joint representation learning and incomplete omics inference. This model enhances multi-omics sample representation and empowers various downstream oncology tasks with incomplete multi-omics datasets. By employing interpretable learning, we characterize the contributions of distinct omics features to clinical outcomes. The TMO-Net model serves as a versatile framework for cross-modal multi-omics learning in oncology, paving the way for tumor omics-specific foundation models., (© 2024. The Author(s).)

Cell mechanotransduction signals are important targets for physical therapy. However, current physiotherapy heavily relies on ultrasound, which is generated by high-power equipment or amplified by auxiliary drugs, potentially causing undesired side effects. To address current limitations, a robotic actuation-mediated therapy is developed that utilizes gentle mechanical loads to activate mechanosensitive ion channels. The resulting calcium influx precisely regulated the expression of recombinant tumor suppressor protein and death-associated protein kinase, leading to programmed apoptosis of cancer cell line through caspase-dependent pathway. In stark contrast to traditional gene therapy, the complete elimination of early- and middle-stage tumors (volume ≤ 100 mm 3 ) and significant growth inhibition of late-stage tumor (500 mm 3 ) are realized in tumor-bearing mice by transfecting mechanogenetic circuits and treating daily with quantitative robotic actuation in a form of 5 min treatment over the course of 14 days. Thus, this massage-derived therapy represents a quantitative strategy for cancer treatment., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Bispecific antibodies possess exceptional potential as therapeutic agents due to their capacity to bind to two different antigens simultaneously. However, challenges pertain to unsatisfactory stability, manufacturing complexity, and limited tumor penetration hinder their broad applicability. In this study, a versatile technology is presented for the rapid generation of bispecific nanobody-aptamer conjugates with efficient tumor penetration. The approach utilizes microbial transglutaminase (MTGase) and click chemistry to achieve site-specific conjugation of nanobodies and aptamers, which are termed nanotamers. The nanotamers recognize and bind to two types of molecular targets expressed on cancer cells. As a prototype, a bispecific nanotamer is developed that binds both clusters of differentiation 47 (CD47) and mesenchymal epithelial transition receptor (Met) expressed on the tumor cell membrane. This CD47-Met nanotamer demonstrates high affinity and specificity toward tumor cells expressing both targets, exhibits improved receptor functional inhibition through a strong steric hindrance effect. Moreover, its capacity for deep tumor penetration greatly enhances the impact of conventional chemotherapy on antitumor efficacy. The as-developed nanotamer synthesis approach shows promise to customize bispecific molecular probes targeting different cancer types and different therapeutic goals., (© 2024 Wiley‐VCH GmbH.)

Purpose: To synthesise qualitative research on the parental hope experiences for children with cancer and identify the levels of parental hope experiences and psychosocial adjustment during cancer events., Methods: Five electronic databases (Cochrane Library, PubMed, Embase, Web of Science, and CINAHL) and three Chinese databases (CNKI, Wanfang, and VIP) were used to retrieve qualitative studies on the hope experiences of parents of children with cancer from inception to February 2023. The Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) was used to assess the methodological quality of the included studies. Data were synthesised using a thematic analysis., Results: Four analytical themes were identified: the process and way hope exists, sources of hope, positive effects of hope, and obstacles to hope maintenance., Conclusions: Maintaining hope is crucial for parents who are caring for their children with cancer. There are different sources of hope, and targeted interventions can enhance the experience of hope for parents of children with cancer. Families, healthcare providers, and society should pay more attention to the parents of children with cancer and provide them with psychological, social, and financial support to improve their level of hope and quality of care., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The lack of selective release ability in the tumor microenvironment and the limited efficacy of monotherapy are important factors that limit the current use of carbon monoxide (CO) donors for tumor therapy. Herein, inspired by endogenous biochemical reactions in vivo, one kind of CO-releasing nanomotor was designed for the multimodal synergistic treatment of tumor. Specifically, glucose oxidase (GOx) and 5-aminolevulinic acid (5-ALA) were co-modified onto metal-organic framework material (MIL-101) to obtain MIL-GOx-ALA nanomotors (M-G-A NMs), which exhibit excellent biocompatibility and degradation ability in tumor microenvironment. Subsequently, the released 5-ALA generates CO in the tumor microenvironment through an endogenous reaction and further acts on mitochondria to release large amounts of reactive oxygen species (ROS), which directly kill tumor cells. Furthermore, the produced ROS and the degradation products of M-G-A NMs can also provide the reaction substrate for the Fenton reaction, thereby enhancing chemodynamic therapy (CDT) and inducing apoptosis of tumor cells. Both in vitro and in vivo experimental data confirm the successful occurrence of the above process, and the combination of CO gas therapy/enhanced CDT can effectively inhibit tumor growth. This CDT-enhancing agent designed based on endogenous biochemical reactions has good prospects for tumor treatment application., 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 Inc. All rights reserved.)

Background: Accumulating evidence suggests that domestic water hardness is linked to health outcomes, but its association to all-cause and cause-specific cancers warrants investigation., Objective: The aim of this study was to investigate the association of domestic hard water with all-cause and cause-specific cancers., Methods: In the prospective cohort study, a total of 447,996 participants from UK Biobank who were free of cancer at baseline were included and followed up for 16 y. All-cause and 22 common cause-specific cancer diagnoses were ascertained using hospital inpatient records and self-reported data until 30 November 2022. Domestic water hardness, measured by CaCO 3 concentrations, was obtained from the local water supply companies across England, Scotland, and Wales in 2005. Data were analyzed using Cox proportional hazard models, with adjustments for known measured confounders, including demographic, socioeconomic, clinical, biochemical, lifestyle, and environmental factors., Results: Over a median follow-up of 13.6 y (range: 12.7-14.4 y), 58,028 all-cause cancer events were documented. A U-shaped relationship between domestic water hardness and all-cause cancers was observed ( p for nonlinearity < 0.001 ). In comparison with individuals exposed to soft water ( 0 - 60 mg / L ), the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause cancer were 1.00 (95% CI: 0.98, 1.02) for those exposed to moderate hard water ( > 60 - 120 mg / L ), 0.88 (95% CI: 0.84, 0.91) for those exposed to hard water ( > 120 - 180 mg / L ) and 1.06 (95% CI: 1.04, 1.08) for those exposed to very hard water ( > 180 mg / L ). Additionally, domestic water hardness was associated with 11 of 22 cause-specific cancers, including cancers of the esophagus, stomach, colorectal tract, lung, breast, prostate, and bladder, as well as non-Hodgkin lymphoma, multiple myeloma, malignant melanoma, and hematological malignancies. Moreover, we observed a positive linear relationship between water hardness and bladder cancer., Discussion: Our findings suggest that domestic water hardness was associated with all-cause and multiple cause-specific cancers. Findings from the UK Biobank support a potentially beneficial association between hard water and the incidence of all-cause cancer. However, very hard water may increase the risk of all-cause cancer. https://doi.org/10.1289/EHP13606.

The components that comprise the senescence-associated secretory phenotype (SASP) include growth factors, proteases, chemokines, cytokines, and bioactive lipids. It drives secondary aging and disrupts tissue homeostasis, ultimately leading to tissue repair and regeneration loss. It has a two-way regulatory effect on tumor cells, resisting cancer occurrence and promoting its progression. A category of single-stranded circular non-coding RNA molecules known as circular RNAs (circRNAs) carries out a series of cellular activities, including sequestering miRNAs and modulating gene editing and expression. Research has demonstrated that a large number of circRNAs exhibit aberrant expression in pathological settings, and play a part in the onset and progress of cancer via modulating SASP factors. However, the research related to SASP and circRNAs in tumors is still in its infancy at this stage. This review centers on the bidirectional modulation of SASP and the role of circRNAs in regulating SASP factors across different types of tumors. The aim is to present novel perspectives for the diagnosis and therapeutic management of malignancies., Competing Interests: Declaration of Competing Interest All authors disclosed no relevant relationships., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer heterogeneity analysis is essential for precision medicine. Most of the existing heterogeneity analyses only consider a single type of data and ignore the possible sparsity of important features. In cancer clinical practice, it has been suggested that two types of data, pathological imaging and omics data, are commonly collected and can produce hierarchical heterogeneous structures, in which the refined sub-subgroup structure determined by omics features can be nested in the rough subgroup structure determined by the imaging features. Moreover, sparsity pursuit has extraordinary significance and is more challenging for heterogeneity analysis, because the important features may not be the same in different subgroups, which is ignored by the existing heterogeneity analyses. Fortunately, rich information from previous literature (for example, those deposited in PubMed) can be used to assist feature selection in the present study. Advancing from the existing analyses, in this study, we propose a novel sparse hierarchical heterogeneity analysis framework, which can integrate two types of features and incorporate prior knowledge to improve feature selection. The proposed approach has satisfactory statistical properties and competitive numerical performance. A TCGA real data analysis demonstrates the practical value of our approach in analyzing data heterogeneity and sparsity., (© 2024 John Wiley & Sons Ltd.)

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.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity., Competing Interests: Declaration of interests D.E.F. has a financial interest in Soltego. S.M. and D.A.H. are cofounders of TellBio. G.M.B. has sponsored research agreements with Olink Proteomics, Teiko Bio, InterVenn Biosciences, and Palleon Pharmaceuticals; served on advisory boards for Iovance, Merck, Nektar Therapeutics, Novartis, and Ankyra Therapeutics; consults for Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics; and holds equity in Ankyra Therapeutics. M.S.-F. received funding from Calico Life Sciences, Bristol-Myers Squibb, Istari Oncology, and consultants for Galvanize Therapeutics. R.W.J. is a member of the advisory board for/has a financial interest in Xsphera Biosciences Inc. R.W.J. has received honoraria from Incyte (invited speaker), G1 Therapeutics (advisory board), and Bioxcel Therapeutics (invited speaker). R.W.J. has ownership interest in U.S. patents US20200399573A9 and US20210363595A1. A.N.H. has received grants/research support from Amgen, Blueprint Medicines, BridgeBio, Bristol-Myers Squibb, C4 Therapeutics, Eli Lilly, Novartis, Nuvalent, Pfizer, Roche/Genentech, and Scorpion Therapeutics. A.N.H. has served as a compensated consultant for Amgen, Engine Biosciences, Nuvalent, Oncovalent, Pfizer, TigaTx, and Tolremo Therapeutics. M.L.S. is an equity holder and scientific co-founder/advisory board member of Immunitas Therapeutics. C.J.O. received funding from Scorpion Therapeutics, Gilead Sciences, and eFFECTOR Therapeutics. L.B.-P. is a founder/consultant/holds privately held equity in Scorpion Therapeutics. All relationships for investigators have been reviewed/managed by their respective institutions in accordance with their conflict-of-interest policies. M.M., B.H., R.D.W., H.E.M., C.-C.T., G.K., N.B., J.R.N., and B.R.M. are employees of Scorpion Therapeutics and some hold equity., (Copyright © 2024 Elsevier Inc. All rights reserved.)

One of the hallmarks of cancer is metabolic reprogramming in tumor cells, and aerobic glycolysis is the primary mechanism by which glucose is quickly transformed into lactate. As one of the primary rate-limiting enzymes, pyruvate kinase (PK) M is engaged in the last phase of aerobic glycolysis. Alternative splicing is a crucial mechanism for protein diversity, and it promotes PKM precursor mRNA splicing to produce PKM2 dominance, resulting in low PKM1 expression. Specific splicing isoforms are produced in various tissues or illness situations, and the post-translational modifications are linked to numerous disorders, including cancers. hnRNPs are one of the main components of the splicing factor families. However, there have been no comprehensive studies on hnRNPs regulating PKM alternative splicing. Therefore, this review focuses on the regulatory network of hnRNPs on PKM pre-mRNA alternative splicing in tumors and clinical drug research. We elucidate the role of alternative splicing in tumor progression, prognosis, and the potential mechanism of abnormal RNA splicing. We also summarize the drug targets retarding tumorous splicing events, which may be critical to improving the specificity and effectiveness of current therapeutic interventions.

Background: Choline, an indispensable nutrient, plays a pivotal role in various physiological processes. The available evidence regarding the nexus between dietary choline intake and health outcomes, encompassing cardiovascular disease (CVD), cancer, and all-cause mortality, is limited and inconclusive. This study aimed to comprehensively explore the relationship between dietary choline intake and the aforementioned health outcomes in adults aged > 20 years in the U.S., Methods: This study utilized data from the National Health and Nutrition Examination Survey between 2011 and 2018. Dietary choline intake was evaluated using two 24-h dietary recall interviews. CVD and cancer status were determined through a combination of standardized medical status questionnaires and self-reported physician diagnoses. Mortality data were gathered from publicly available longitudinal Medicare and mortality records. The study utilized survey-weighted logistic and Cox regression analyses to explore the associations between choline consumption and health outcomes. Restricted cubic spline (RCS) analysis was used for dose‒response estimation and for testing for nonlinear associations., Results: In our study of 14,289 participants (mean age 48.08 years, 47.71% male), compared with those in the lowest quintile (Q1), the adjusted odds ratios (ORs) of CVD risk in the fourth (Q4) and fifth (Q5) quintiles of choline intake were 0.70 (95% CI 0.52, 0.95) and 0.65 (95% CI 0.47, 0.90), respectively (p for trend = 0.017). Each 100 mg increase in choline intake was associated with a 9% reduced risk of CVD. RCS analysis revealed a linear correlation between choline intake and CVD risk. Moderate choline intake (Q3) was associated with a reduced risk of mortality, with an HR of 0.75 (95% CI 0.60-0.94) compared with Q1. RCS analysis demonstrated a significant nonlinear association between choline intake and all-cause mortality (P for nonlinearity = 0.025). The overall cancer prevalence association was nonsignificant, except for colon cancer, where each 100 mg increase in choline intake indicated a 23% reduced risk., Conclusion: Elevated choline intake demonstrates an inverse association with CVD and colon cancer, while moderate consumption exhibits a correlated reduction in mortality. Additional comprehensive investigations are warranted to elucidate the broader health implications of choline., (© 2024. The Author(s).)

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.