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Background: We conducted a systematic review and meta-analysis to assess the risk of respiratory adverse effects in patients with solid tumors treated with immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 inhibitors) in combination with radiation therapy., Methods: We selected eligible studies through the following databases: PubMed, Embase, Cochrane Library, and Clinicaltrials ( https://clinicaltrials.gov/ ). The data was analyzed by using Rstudio., Results: Among 3737 studies, 26 clinical trials, including 2670 patients, were qualified for the meta-analysis. We evaluated the incidence rates of adverse respiratory events, including cough, pneumonia, upper respiratory tract infections, and others: grades 1-5 cough, 0.176 (95%CI: 0.113-0.274, I2 = 92.36%); grades 1-5 pneumonitis, 0.118 (95%CI: 0.067-0.198, I2 = 88.64%); grades 1-5 upper respiratory tract infection, 0.064 (95%CI: 0.049-0.080, I2 = 0.98%); grades 3-5 cough, 0.050 (95%CI: 0.012-0.204, I2 = 8.90%); grades 3-5 pneumonitis, 0.052 (95%CI: 0.031-0.078, I2 = 83.86%); grades 3-5 upper respiratory tract infection, 0.040 (95%CI: 0.007-0.249, I2 = 45.31%)., Conclusions: Our meta-analysis demonstrated that ICI combined with radiotherapy for solid tumors can produce respiratory adverse effects. ICIs combination treatment, a tumor located in the chest, is more likely to cause adverse reactions, and SBRT treatment and synchronous treatment will bring less incidence of adverse reactions. This study provide insights for clinicians to balance the risks of radiotherapy in the course of treating oncology patients., (© 2024. The Author(s).)

Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts individuals and healthcare systems worldwide. However, the exploration of N6-methyladenosine (m6A)-related aging genes in OA pathogenesis remains largely underexplored. This study aimed to elucidate the role of m6A-related aging genes in OA and to develop a robust diagnostic model based on their expression profiles. Leveraging publicly available gene expression datasets, we conducted consensus clustering to categorize OA into distinct subtypes, guided by the expression patterns of m6A-related aging genes. Utilizing XGBoost, a cutting-edge machine learning approach, we identified key diagnostic genes and constructed a predictive model. Our investigation extended to the immune functions of these genes, shedding light on potential therapeutic targets and underlying regulatory mechanisms. Our analysis unveiled specific OA subtypes, each marked by unique expression profiles of m6A-related aging genes. We pinpointed a set of pivotal diagnostic genes, offering potential therapeutic avenues. The developed diagnostic model exhibited exceptional capability in distinguishing OA patients from healthy controls. To corroborate our computational findings, we performed quantitative real-time polymerase chain reaction analyses on two cell lines: HC-OA (representing adult osteoarthritis cells) and C-28/I2 (representative of normal human chondrocytes). The gene expression patterns observed were consistent with our bioinformatics predictions, further validating our initial results. In conclusion, this study underscores the significance of m6A-related aging genes as promising biomarkers for diagnosis and prognosis, as well as potential therapeutic targets in OA. Although these findings are encouraging, further validation and functional analyses are crucial for their clinical application., (© 2024 Wiley Periodicals LLC.)

Objectives: The objective of this study was to investigate changes in serum tumor markers in type 2 diabetes mellitus (T2DM) with microalbuminuria and analyze the relationship between tumor markers and microalbuminuria., Methods: A total of 956 T2DM patients aged 40-70 years hospitalized in the Department of Endocrinology, Xinhua Hospital, China, affiliated with Shanghai Jiaotong University School of Medicine, were enrolled from January 2018 to December 2020. The sample comprised 313 T2DM patients with microalbuminuria and 643 T2DM patients with normal urinary microalbumin levels. After assessing the changes in serum tumor markers in T2DM with microalbuminuria, we analyzed the risk of microalbuminuria by the serum tumor marker category using multiple logistic regression analysis., Results: Serum CEA, CA199, CA125, CA153, CA211, SCC, CA242, and CA50 levels were significantly higher in T2DM patients with microalbuminuria than in those without microalbuminuria, while serum AFP levels were lower in the microalbuminuria group ( P < 0.05). Following adjustment of confounders, serum CEA, CA211, and SCC were independently associated with microalbuminuria in T2DM. An ROC curve was used to estimate the cutoff point of tumor markers for microalbuminuria. Taking the values under the cutoff points as a reference, values for CEA, CA211, and SCC above the cutoff points indicated a significantly high risk of microalbuminuria. The OR of increased CEA for microalbuminuria was 2.006 (95%CI 1.456-2.765), the OR of increased CA211 for microalbuminuria was 1.505 (95%CI 1.092-2.074), and the OR of increased SCC for microalbuminuria was 1.958 (95%CI 1.407-2.724)., Conclusion: Several serum tumor markers were related to microalbuminuria in T2DM. Serum tumor markers such as CEA, SCC, and CA211 may indicate early diabetic nephropathy, particularly when elevated in combination., 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 Chen, Du, Li, Su, Zhang and Zhang.)

Background: NTMT1, a transfer methylase that adds methyl groups to the N-terminus of proteins, has been identified as a critical player in tumor development and progression. However, its precise function in pan-cancer is still unclear. To gain a more comprehensive understanding of its role in cancer, we performed a thorough bioinformatics analysis., Methods: To conduct our analysis, we gathered data from multiple sources, including RNA sequencing and clinical data from the TCGA database, protein expression data from the UALCAN and HPA databases, and single-cell expression data from the CancerSEA database. Additionally, we utilized TISIDB to investigate the interaction between the tumor and the immune system. To assess the impact of NTMT1 on the proliferation of SNU1076 cells, we performed a CCK8 assay. We also employed cellular immunofluorescence to detect DNA damage and used flow cytometry to measure tumor cell apoptosis., Results: Our analysis revealed that NTMT1 was significantly overexpressed in various types of tumors and that high levels of NTMT1 were associated with poor survival outcomes. Functional enrichment analysis indicated that NTMT1 may contribute to tumor development and progression by regulating pathways involved in cell proliferation and immune response. In addition, we found that knockdown of NTMT1 expression led to reduced cell proliferation, increased DNA damage, and enhanced apoptosis in HNSCC cells., Conclusion: High expression of NTMT1 in tumors is associated with poor prognosis. The underlying regulatory mechanism of NTMT1 in cancer is complex, and it may be involved in both the promotion of tumor development and the inhibition of the tumor immune microenvironment., Competing Interests: The authors declare that they have no competing interests., (© 2023 Tan et al.)

Cancer immunotherapy enhances the body's immunity against tumors by mitigating immune escape. Compared with traditional chemotherapy, immunotherapy has the advantages of fewer drugs, a wider range of action and fewer side effects. B7-H7 (also known as HHLA2, B7y) is a member of the B7 family of costimulatory molecules that was discovered more than 20 years ago. B7-H7 is mostly expressed in organs such as the breast, intestine, gallbladder and placenta and is detected predominantly in monocytes/macrophages in the immune system. Its expression is upregulated after stimulation by inflammatory factors such as lipopolysaccharide and interferon-γ. B7-H7/transmembrane and immunoglobulin domain containing 2 (TMIGD2) and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3)-B7-H7 are the two currently confirmed signaling pathways for B7-H7. An increasing number of studies have demonstrated that B7-H7 is widely present in a variety of human tumor tissues, especially in programmed cell death-1 (PD-L1)-negative human tumors. B7-H7 promotes tumor progression, disrupts T-cell-mediated antitumor immunity, and inhibits immune surveillance. B7-H7 also triggers tumor immune escape and is associated with clinical stage, depth of tumor infiltration, metastasis, prognosis, and survival related to different tumor types. Multiple studies have shown that B7-H7 is a promising immunotherapeutic target. Herein, review the current literature on the expression, regulation, receptors and function of B7-H7 and its regulation/function in tumors., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The cell-cycle checkpoint kinase WEE1 is emerging as a therapeutic target for cancer treatment. However, how its catalytic activity is regulated remains poorly understood, and reliable biomarkers for predicting response to WEE1 inhibitor remain to be identified. Here we identify an evolutionarily conserved segment surrounding its Lys177 residue that inhibits WEE1 activity through an intermolecular interaction with the catalytic kinase domain. Upon DNA damage, CHK1-dependent phosphorylation of WEE1 at Ser642 primes GCN5-mediated acetylation at Lys177, resulting in dissociation of the inhibitory segment from the kinase domain and subsequent activation of WEE1 and cell-cycle checkpoints. Conversely, SIRT1 associates with and deacetylates WEE1, which maintains it in an inactive state. Consequently, SIRT1 deficiency induces WEE1 hyperacetylation and activation, rendering cancer cells resistant to WEE1 inhibition. These results suggest that SIRT1 expression level and abundance of WEE1 Lys177 acetylation in tumor cells can serve as useful biomarkers for predicting WEE1 inhibitor sensitivity or resistance., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Immunoglobulin G4-related disease (IgG4-RD) and immunoglobulin G4-related ophthalmic disease (IgG4-ROD) complicated with nonlymphoid malignancy (NL-malignancy) are rare. No exact relationship between IgG4-RD and NL-malignancies has been established yet, and there have been few reports of different types of IgG4-ROD and related malignancies., Methods: We retrospectively reviewed medical records of patients diagnosed with IgG4-RD and NL-malignancy, whichever occurred first, from January 2015 to March 2021. In addition, the literature on the relationship between IgG4-ROD and NL-malignancy was reviewed., Results: There were 115 patients diagnosed with IgG4-RD, and 10 patients were enrolled in the study with NL-malignancy. Three patients were diagnosed with IgG4-ROD. One patient reported a previous history of cancer, and the other 2 patients developed cancer at or after the diagnosis of IgG4-RD. The 3 patients' cancers were located in the lung, gastrointestinal tract, and thyroid., Conclusions: There may be potential malignancy occurrence during follow-up of IgG4-RD patients, especially among elderly patients. In addition, IgG4-RD could be a paraneoplastic syndrome at or before the diagnosis of malignancy., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)

Cancer vaccines are being explored for enhanced cancer immunotherapy and prophylaxis. Some of their prevailing weaknesses, however, such as complicated preparation, poor biocompatibility, and failure to elicit strong cellular immune responses, have limited their further clinical applications. Here, we reported a multifunctional nanovaccine that was prepared in a quick and simple way. During the self-assembly of metal-phenolic networks (MPNs), the antigen ovalbumin (OVA) and immunoreactive chlorogenic acid (CHA) were simultaneously loaded. Owing to its dual pH and reduction sensitivities, the nanovaccine could deliver antigens into the cytoplasm of dendritic cells (DCs) and facilitate the cross-presentation of antigens. Moreover, the results of in vivo immunization assays demonstrated that the nanovaccine significantly excited the antigen presentation of DCs and provoked a robust cellular immune response with the restrained activation of regulatory T cells (Tregs), by targeting lymph nodes and executing the function of CHA. In vivo antitumor assays indicated that the nanovaccine with good biocompatibility afforded conspicuous cancer treatment and prevention effects. Overall, the nanovaccine presented in this study shows a promise for potentiating cancer immunotherapy by the lymph node-targeted delivery. STATEMENT OF SIGNIFICANCE: Cancer nanovaccines can be used for cancer immunotherapy. However, some existing shortcomings, such as cumbersome preparation, poor biocompatibility, and failure to elicit strong immune responses, limit the clinical application of cancer nanovaccines. This study developed a multifunctional nanovaccine that was readily prepared through the self-assembly of metal-phenolic networks. The nanovaccine with dual pH and reduction sensitivities could efficiently promote the antigen lysosome escape and cross-presentation. In vivo, it efficiently delivered antigen into lymph nodes and provoked strong cellular immune responses, and thus it showed significant cancer immunotherapy and prevention effect., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Vaccination shows great promise in cancer immunotherapy. However, the induction of robust and broad therapeutic CD8 T cell immunity against tumors is challenging due to the essential heterogenicity of tumor antigen expression. Recently, bioinspired materials have reshaped the field of cancer nanomedicine. Herein, a bioinspired nanofibrous trivalent peptide hydrogel vaccine was constructed using the spontaneous supramolecular co-assembly of three antigenic epitope-conjugated peptides, which could mimic the fibrillar structure and biological function of the extracellular matrix and naturally occurring protein assembly. The hydrogel vaccine could be accurately and flexibly adjusted to load each antigenic peptide at a defined ratio, which facilitated the antigen presentation of dendritic cells and significantly improved the initiation of CD8 T cell response and the secretion of interferon-γ (IFN-γ). C57BL/6 mice were immunized with the trivalent peptide hydrogel vaccine, where it elicited a high broad-spectrum antitumor CD8 T cell response that significantly inhibited the growth of B16 tumors in the absence of additional immunoadjuvants or delivery systems. In summary, the supramolecular assembly of triple antigenic epitope-conjugated peptides offers a simple, customizable, and versatile approach for the development of cancer vaccines with remarkable therapeutic efficacy, thereby providing a highly versatile platform for the application of personalized multivalent tumor vaccines. STATEMENT OF SIGNIFICANCE: (1) We report a feasible, versatile and bioinspired approach to manufacture a multivalent peptide-based hydrogel cancer vaccine in the absence of additional adjuvants, which closely mimics immune niches, co-delivers antigen epitopes, greatly promotes antigen presentation to DCs and their subsequent homing to dLNs and elicits a broad-spectrum antitumor CD8 T cell response, resulting in significant inhibition of B16 tumor growth. (2) This feasible and efficient co-assembly strategy provides an attractive platform for engineering a range of multivalent vaccines at defined ratios to further enhance antigen-specific T cell responses. This approach may also be used for personalized immunotherapy with neo-epitopes., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Primary osseous sarcoma of the pelvis is rare and has a particularly sinister outcome. This study aims to identify independent prognostic factors of cancer-specific survival (CSS) in patients with primary pelvic sarcoma (PS) and develop a nomogram to predict 3-, 5-, and 10-year probability of CSS in these patients., Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 416 patients with primary PS, who were divided into two groups: a training cohort and a validation cohort. Univariate and multivariate Cox analyses were used to screen independent prognostic factors in patients with primary PS. Based on these independent prognostic factors, a prognostic nomogram was developed to predict 3-, 5-, and 10-year probability of CSS. The nomogram's predictive performance and clinical value were evaluated using the calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Finally, a mortality risk stratification system was developed., Results: Tumor size, tumor stage, histological type, surgery, and chemotherapy were identified as independent prognostic factors for the CSS of primary PS patients. Based on these factors, a nomogram was created to predict the 3-, 5-, and 10-year probability of CSS in these patients. The calibration curve, ROC, and DCA indicated that the nomogram performed well and was appropriate for clinical use, with 3-, 5-, and 10-year areas under ROC curve all higher than 0.800. Furthermore, the nomogram-based mortality risk stratification system could effectively divide these patients into three risk subgroups., Conclusions: The nomogram constructed in this study could accurately predict 3-, 5-, and 10-year probability of CSS in patients with primary PS. Clinicians can use the nomogram to categorize these patients into risk subgroups and provide personalized treatment plans., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Immunotherapy has been increasingly used in the treatment of cancer. Compared with chemotherapy, immunotherapy relies on the autoimmune system with fewer side effects. Small molecule immune-oncological medicines usually have good bioavailability, higher tissue and tumor permeability, and a reasonable half-life. In this work, we summarize the current advances in the field of small molecule approaches in tumor immunology, including small molecules in clinical trials and preclinical studies, containing PD1/PD-L1 small molecule inhibitors, IDO inhibitor, STING activators, RORγt agonists, TGF-β inhibitors, etc. PD-1/DP-L1 is the most attractive target at present. Some small molecule drugs are being in clinical trial studies. Among them, CA-170 has attracted much attention as an oral small molecule drug. IDO is another popular target after PD-1/PDL1. The dual IDO and PD-1 inhibitor can improve the low response of PD-1 and has a good synergistic effect. STING is a protein that occurs naturally in the human body and can enhance the body's immunity. RORγt is mainly expressed in cells of the immune system. It promotes the differentiation of Th17 cells and produces the key factor IL-17, which plays a key role in the development of autoimmune diseases. TGFβ signaling exhibits potent immunosuppressive activity on the coordinate innate and adaptive immunity, impairing the antitumor potential of innate immune cells in the tumor microenvironment. It is worth mentioning that immunotherapy drugs can often achieve better effects when used in combination, which will help defeat cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Although many studies have focused on oncology and therapeutics in cancer, cancer remains one of the leading causes of death worldwide. Due to the unclear molecular mechanism and complex in vivo microenvironment of tumors, it is challenging to reveal the nature of cancer and develop effective therapeutics. Therefore, the development of new methods to explore the role of heterogeneous TME in individual patients' cancer drug response is urgently needed and critical for the effective therapeutic management of cancer. The organ-on-chip (OoC) platform, which integrates the technology of 3D cell culture, tissue engineering, and microfluidics, is emerging as a new method to simulate the critical structures of the in vivo tumor microenvironment and functional characteristics. It overcomes the failure of traditional 2D/3D cell culture models and preclinical animal models to completely replicate the complex TME of human tumors. As a brand-new technology, OoC is of great significance for the realization of personalized treatment and the development of new drugs. This review discusses the recent advances of OoC in cancer biology studies. It focuses on the design principles of OoC devices and associated applications in cancer modeling. The challenges for the future development of this field are also summarized in this review. This review displays the broad applications of OoC technique and has reference value for oncology development., Competing Interests: The authors declare no conflicts of interest.

Dynamic and heterogeneous interaction between tumor cells and the surrounding microenvironment fuels the occurrence, progression, invasion, and metastasis of solid tumors. In this process, the tumor microenvironment (TME) fractures cellular and matrix architecture normality through biochemical and mechanical means, abetting tumorigenesis and treatment resistance. Tumor cells sense and respond to the strength, direction, and duration of mechanical cues in the TME by various mechanotransduction pathways. However, far less understood is the comprehensive perspective of the functions and mechanisms of mechanotransduction. Due to the great therapeutic difficulties brought by the mechanical changes in the TME, emerging studies have focused on targeting the adverse mechanical factors in the TME to attenuate disease rather than conventionally targeting tumor cells themselves, which has been proven to be a potential therapeutic approach. In this review, we discussed the origins and roles of mechanical factors in the TME, cell sensing, mechano-biological coupling and signal transduction, in vitro construction of the tumor mechanical microenvironment, applications and clinical significance in the TME., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice possess a broad range of severe adverse effects towards vital organs which emphasizes the importance of the discovery of new therapeutic agents or repurposing of existing drugs for the treatment of human cancers. Pyrimethamine is an antiparasitic drug used for the treatment of malaria and toxoplasmosis with a well-documented excellent safety profile. In the last 5 years, numerous efforts have been made to explore the anticancer potential of pyrimethamine in in vitro and in vivo preclinical models and to repurpose it as an anticancer agent. The studies have demonstrated that pyrimethamine inhibits oncogenic proteins such as STAT3, NF-κB, DX2, MAPK, DHFR, thymidine phosphorylase, telomerase, and many more in a different types of cancer models. Moreover, pyrimethamine has been reported to work in synergy with other anticancer agents, such as temozolomide, to induce apoptosis of tumor cells. Recently, the results of phase-1/2 clinical trials demonstrated that pyrimethamine administration reduces the expression of STAT3 signature genes in tumor tissues of chronic lymphocytic leukemia patients with a good therapeutic response. In the present article, we have reviewed most of the published articles related to the antitumor effects of pyrimethamine in malignancies of breast, liver, lung, skin, ovary, prostate, pituitary, and leukemia in in vitro and in vivo settings. We have also discussed the pharmacokinetic profile and results of clinical trials obtained after pyrimethamine treatment. From these studies, we believe that pyrimethamine has the potential to be repurposed as an anticancer drug., (© 2021 International Union of Biochemistry and Molecular Biology.)

Chaetocin is a natural metabolite product with various biological activities and pharmacological functions isolated from Chaetomium species fungi belonging to the thiodiketopyrazines. Numerous studies have demonstrated a wide range of antitumor activities of chaetocin in vitro and in vivo. Several studies have demonstrated that chaetocin suppresses the growth and proliferation of various tumour cells by regulating multiple signalling pathways related to tumour initiation and progression, inducing cancer cell apoptosis (intrinsic and extrinsic), enhancing autophagy, inducing cell cycle arrest, and inhibiting tumour angiogenesis, invasion, and migration. The antitumor effects and molecular mechanisms of chaetocin are reviewed and analysed in this paper, and the prospective applications of chaetocin in cancer prevention and therapy are also discussed. This review aimed to summarize the recent advances in the antitumor activity of chaetocin and to provide a rationale for further exploring the potential application of chaetocin in overcoming cancer in the future., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The aims of this study were to evaluate the associations of metabolic abnormalities with incident diabetic kidney disease (DKD) and to explore whether dyslipidaemia, particularly high fasting triglyceride (TG), was associated with the development of DKD., Methods: In total, 11 142 patients with new-onset type 2 diabetes with baseline estimated glomerular filtration rates (eGFR) ≥60 mL/min/1.73 m 2 were followed up during 2011-2016. Incident DKD was defined as eGFR <60 mL/min/1.73 m 2 at follow-up. Multiple logistic regression analysis was conducted to explore the relationship of metabolic abnormalities at baseline and at follow-up with risks of DKD. High TG was defined by TG ≥1.70 mmol/L. Low high-density lipoprotein cholesterol (HDL-c) was defined by HDL-c <1.0 mmol/L for men or <1.3 mmol/L for women., Results: Participants who developed DKD had higher levels of waist circumference and systolic blood pressure, and lower levels of HDL-c at both baseline and follow-up visits. The DKD group also had higher levels of post-load plasma glucose and TG at follow-up. Multivariate logistic regression analysis revealed that both high TG at baseline [odds ratio (OR) = 1.37, p = .012) and high TG at follow-up (OR = 1.71, p < .001) were significantly associated with increased risks of DKD. Patients with high TG levels at both baseline and follow-up had higher risk of DKD compared with constantly normal TG (OR = 1.65, p < .001) after adjustment for covariates., Conclusions: In a large population of patients with new-onset type 2 diabetes, a high TG level was an independent risk factor for the development of DKD. Tight TG control might delay the occurrence of DKD., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Sufficient energy generation based on effective transport of nutrient via abundant blood vessels in tumor tissue and subsequent oxidative metabolism in mitochondria is critical for growth, proliferation and migration of tumor. Thus the strategy to cut off this transport pathway (blood vessels) and simultaneously close the power house (mitochondria) is highly desired for tumor treatment. Herein, we fabricated a bionic nanocarrier with core-shell-corona structure to give selective and effective tumor therapy via stepwise destruction of existed tumor vessel, inhibition of tumor angiogenesis and dysfunction of tumor mitochondria. The core of this bionic nanocarrier consists of combretastatin A4 phosphate (CA4P) and vitamin K 2 (VK 2 ) co-loaded mesoporous silica nanoparticle (MSNs), which is in charge of the vasculature destruction and mitochondrial dysfunction after cargos release. The N-tert-butylacrylamide (TBAM) and tri-sulfated N-acetylglucosamine (TSAG) shell served as artificial affinity reagent against vascular endothelial growth factor (VEGF) for angiogenesis inhibition. As to guarantee that these actions only happened in tumor, the hyaluronic acid (HA) corona was introduced to endow the nanocarrier with tumor targeting property and stimuli-responsiveness for accurate therapy. Both in vitro and in vivo results indicated that the CA4P/VK 2 -MSNs-TBAM/TSAG-HA (CVM MG H for short) nanocarrier combined well-controllable manipulation of tumor vasculature and tumor mitochondria to effectivly cut off the tumorigenic energy supply, which performed significant inhibition of tumor growth, demonstrating the great candidate of our strategy for effective tumor therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nanovaccine can elicit antigen-specific immune responses against tumor cells expressing homologous antigens and has attracted enormous attention in cancer immunotherapy. However, tumor heterogeneity remarkably hinders the development of nanovaccines. Here we demonstrate that PTT-induced in situ vaccination cancer therapy can elicit potent antitumor immunity against disseminated and metastatic tumors. Gold nanorods (AuNRs) covalently coupled with amphiphilic polyTLR7/8a and MMP-2-sensitive R9-PEG conjugate (AuNRs-IMQD-R9-PEG) were developed as a new biocompatible PTT agent with favorable photothermal efficiency and stability. Importantly, AuNRs-IMQD-R9-PEG can effectively absorb tumor-derived protein antigens, forming nanovaccines directly in vivo and enhance the activation of host dendritic cells (DCs), thereby amplifying adaptive antitumor T-cell responses, triggering effector memory immune responses, and activating innate antitumor immunity. Remarkably, peri-tumoral administration of low-dose multifunctional AuNRs followed by non-invasive near-infrared (NIR) laser irradiation enables efficient tandem PTT-vaccination treatment modality that can inhibit local as well as untreated distant and metastatic tumors in mice inoculated with poorly immunogenic, highly metastatic 4T1 tumors. Our findings indicate that AuNRs-IMQD-R9-PEG-mediated in situ cancer vaccination provides a powerful immunotherapy characterized by markedly increased infiltration of effector CD8 + T, natural killer T (NKT) cells in tumors and long-term animal survival, thus, offering a promising therapeutic strategy for advanced, disseminated cancers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The exploration of an intelligent multifunctional imaging-guided therapeutic platform is of great significance because of its ideal delivery efficiency and controlled release. In this work, a tumor microenvironment (TME)-responsive nanocarrier (denoted as MB@MSP) is designed for on-demand, sequentially release of a short D-peptide antagonist of programmed cell death-ligand 1 (named as P D PPA-1) and a photosensitizer methylene blue (MB). Fe 3 O 4 -Au located in the core of MB@MSP is used as a magnetic resonance imaging and micro-computed tomography imaging contrast agent for noninvasive diagnosis of solid tumors and simultaneous monitoring of drug delivery. The P D PPA-1 coated on MB@MSP can be shed due to the cleavage of the peptide substrate by matrix metalloproteinase-2 (MMP-2) that is highly expressed in the tumor stroma, and disulfide bonding is further broken when it encounters high levels of glutathione (GSH) in TME, which finally leads to significant size reduction and charge-reversal. These transitions facilitate penetration and uptake of nanocarriers against tumors. Noticeably, the released P D PPA-1 can block the immune checkpoint to create an environment that favors the activation of cytotoxic T lymphocytes and augment the antitumor immune response elicited by photodynamic therapy, thus significantly improving therapeutic outcomes. Studies of the underlying mechanisms suggest that the designed MMP-2 and GSH-sensitive delivery system not only induce apoptosis of tumor cells but also modulate the immunosuppressive tumor microenvironment to eventually augment the suppression tumor metastasis effect of CD8 + cytotoxic T cells. Overall, the visualization of the therapeutic processes with comprehensive information renders MB@MSP an intriguing platform to realize the combined treatment of metastatic tumors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to quantitatively summarize the available evidence on the association of breastfeeding with the risk of childhood cancer., Methods: A literature search of PubMed and Embase databases was performed to identify eligible observational studies published from inception to July 17, 2020. The categorical and dose-response meta-analysis was conducted by pooling relative risk (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression and stratification analysis. Sensitivity analysis and publication bias test were also carried out., Results: Forty-five articles involving 475,579 individuals were included in the meta-analysis. Among the thirty-three studies on the association between breastfeeding and risk of childhood leukemia, the pooled risk estimates were 0.77 (95% CI, 0.65-0.91) and 0.77 (95% CI 0.63-0.94) for ever versus non/occasional breastfeeding and longest versus shortest breastfeeding duration group, respectively. There was clear indication for non-linear dose-response relationship between breastfeeding duration and the risk of childhood leukemia (P non-linear < 0.001). The most protective effect (OR, 0.66, 95% CI 0.62-0.70) was observed at a breastfeeding duration of 9.6 months. Four studies examined, the association between breastfeeding and risk of childhood neuroblastoma, and significant inverse associations were consistently observed in both the comparisons of ever breastfeeding versus non/occasional breastfeeding (OR = 0.59, 95% CI 0.44-0.81) and longest versus shortest breastfeeding (OR = 0.61, 95% CI 0.44-0.83). However, no associations of breastfeeding with risk of other cancers were found., Conclusions: Our study supports a protective role of breastfeeding on the risk of childhood leukemia, also suggesting a non-linear dose-response relationship. Further studies are warranted to confirm the association between breastfeeding and risk of childhood neuroblastoma.

Chronic stress is well-known to cause physiological distress that leads to body balance perturbations by altering signaling pathways in the neuroendocrine and sympathetic nervous systems. This increases allostatic load, which is the cost of physiological fluctuations that are required to cope with psychological challenges as well as changes in the physical environment. Recent studies have enriched our knowledge about the role of chronic stress in disease development, especially carcinogenesis. Stress stimulates the hypothalamic-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS), resulting in an abnormal release of hormones. These activate signaling pathways that elevate expression of downstream oncogenes. This occurs by activation of specific receptors that promote numerous cancer biological processes, including proliferation, genomic instability, angiogenesis, metastasis, immune evasion and metabolic disorders. Moreover, accumulating evidence has revealed that β-adrenergic receptor (ADRB) antagonists and downstream target inhibitors exhibit remarkable anti-tumor effects. Psychosomatic behavioral interventions (PBI) and traditional Chinese medicine (TCM) also effectively relieve the impact of stress in cancer patients. In this review, we discuss recent advances in the underlying mechanisms that are responsible for stress in promoting malignancies. Collectively, these data provide approaches for NextGen pharmacological therapies, PBI and TCM to reduce the burden of tumorigenesis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitochondria are highly dynamic organelles that provide energy for oxidative phosphorylation in cells. Equally, they are the major sites for the metabolism of amino acids, lipids and iron. When cells become cancerous, the morphology, cellular location and metabolic mode of the mitochondria change accordingly. These mitochondrial changes can have two opposing effects on cancer: procancer and anticancer effects. Specifically, mitochondria play roles in the fight against cancer by participating in processes such as ferroptosis, mitophagy and antitumor immunity. Contrastingly, cancer cells can also enslave mitochondria to give them the conditions necessary for growth and metastasis. Moreover, through mitochondria, cancer cells can escape from immune surveillance, resulting in their immune escape and enhanced malignant transformation ability. At present, cancer-related studies of mitochondria are one-sided; therefore, we aim to provide a comprehensive understanding by systematically reviewing the two-sided cancer-related properties of mitochondria. Mitochondrial-targeted drugs are gradually emerging and showing significant advantages in cancer treatment; thus, our in-depth exploration of mitochondria in cancer will help to provide theoretical support for the future provision of efficient and low-toxicity cancer treatments.

Autophagy, which is a conserved biological process and essential mechanism in maintaining homeostasis and metabolic balance, enables cells to degrade cytoplasmic constituents through lysosomes, recycle nutrients, and survive during starvation. Autophagy exerts an anticarcinogenic role in normal cells and inhibits the malignant transformation of cells. On the other hand, aberrations in autophagy are involved in gene derangements, cell metabolism, the process of tumor immune surveillance, invasion and metastasis, and tumor drug-resistance. Therefore, autophagy-targeted drugs may function as anti-tumor agents. Accumulating evidence suggests that flavonoids have anticarcinogenic properties, including those relating to cellular proliferation inhibition, the induction of apoptosis, autophagy, necrosis, cell cycle arrest, senescence, the impairment of cell migration, invasion, tumor angiogenesis, and the reduction of multidrug resistance in tumor cells. Flavonoids, which are a group of natural polyphenolic compounds characterized by multiple targets that participate in multiple pathways, have been widely studied in different models for autophagy modulation. However, flavonoid-induced autophagy commonly interacts with other mechanisms, comprehensively influencing the anticancer effect. Accordingly, targeted autophagy may become the core mechanism of flavonoids in the treatment of tumors. This paper reviews the flavonoid-induced autophagy of tumor cells and their interaction with other mechanisms, so as to provide a comprehensive and in-depth account on how flavonoids exert tumor-suppressive effects through autophagy.

The correlation between G388R or V10I polymorphisms of fibroblast growth factor receptor (FGFR) 4 gene and the risk of carcinoma has been investigated previously, but the results are contradictory. Odds ratios (ORs) with 95% confidence intervals (95%CIs), in silico tools, and immunohistochemical staining (IHS) were adopted to assess the association. In total, 13,793 cancer patients and 16,179 controls were evaluated in our pooled analysis. Summarization of all the studies showed that G388R polymorphism is associated with elevated susceptibility to cancer under homozygous comparison (OR = 1.21, 95%CI = 1.03-1.43, P = 0.020) and a recessive genetic model (OR = 1.21, 95%CI = 1.04-1.41, P = 0.012). In the stratification analysis by cancer type and ethnicity, similar findings were indicated for prostate cancer, breast cancer, and individuals of Asian descendant. Polyphen2 bioinformatics analysis showed that the G388R mutation is predicted to damage the protein function of FGFR4. IHS analysis indicated that FGFR4 expression is increased in advanced prostate cancer. These findings may guide personalized treatment of certain types of cancers. Up-regulation of FGFR4 may be related to a poor prognosis in prostate cancer.

Cancer nanovaccines have been widely explored to enhance immunotherapy efficiency, in which the significant irritation of antigen-specific cytotoxic T cells (CTLs) is the critical point. In this study, we developed a pH and reduction dual-sensitive nanovaccine (PMSN@OVA-MPN) composed of two parts. The inner part was made up of polyethyleneimine (PEI)-modified mesoporous silica nanoparticles (MSNs) loaded with model antigen ovalbumin (OVA) and the outer part was made up of disulfide bond-involved metal-phenolic networks (MPNs) as a protective corona. In vitro release experiments proved that PMSN@OVA-MPN could intelligently release OVA in the presence of reductive glutathione, but not in neutral phosphate-buffered saline (PBS). Moreover, in vitro cell assays indicated that the nanovaccine promoted not only the OVA uptake efficiency by DC2.4 cells but also antigen lysosome escape due to the proton sponge effect of PEI. Furthermore, in vivo animal experiments indicated that PMSN@OVA-MPN induced a large tumor-specific cellular immune response so as to effectively inhibit the growth of an existing tumor. Finally, the immune memory effect caused by the nanovaccine afforded conspicuous prophylaxis efficacy in neonatal tumors. Hence, the multifunctional vaccine delivery system prepared in this work exhibits a great application potential in cancer immunotherapy and offers a platform for the development of nanovaccines.

Immunotherapy in solid tumors is limited by the poor immunogenicity of tumors and limited T-cell immune response, resulting in low patient response rate. To increase the efficiency of cancer immunotherapy, a unique synergistic combination cancer immunotherapy by co-localized delivery of cancer nanomedicine for enhancing the tumor immunogenicity and nanovaccine for augmenting the antitumor T-cell immunity was developed for post-surgical tumor treatment. The thermo-responsive, curcumin-loaded polymer nanoparticles (nanomedicine)-assembled hydrogel enabled the complete coverage of the surgical bed of primary tumor and the spatio-temporal delivery of cognate nanomedicines and encapsulated nanovaccines. Importantly, the nanomedicine efficiently induced the immunogenic cell death (ICD) of residual cancer cells, and consequently enhanced the tumor immunogenicity and sensitized the tumor to antitumor T-cell immunity. The cancer nanovaccine composed of antigenic peptide, CpG-ODN and cationic polymer nanoparticle significantly triggered the maturation of dendritic cells (DCs) and elicited potent vaccine-specific T-cell immune responses. Using highly malignant postoperative breast carcinoma 4T1 models, we found that the combination immunotherapy strategy strikingly amplified the level of systemic host T-cell immunity, promoted the infiltration of CD8 + T lymphocytes in tumor, and thus efficaciously attenuated the local tumor recurrence and pulmonary metastasis. Collectively, this work provided an advanced synergistic combination approach for post-surgical tumor immunotherapy. The self-assembled hydrogel should enable a broader combination of immunomodulating nanomedicines and vaccines for cancer immunotherapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The production and wide use of artificial antigen presenting cells (aAPCs) in the clinic as cancer immunotherapeutics are hindered by the need of identifying immunogenic cancer antigens and production of recombinant patient-specific major histocompatibility complexes (MHC) loaded with these peptides. To overcome these limitations, in this study, we tested the idea of whether peptide-MHCs can directly be captured from cell lysates, including cancer cells using affinity beads, and used to initiate T cell responses. In theory, these affinity beads covered with the unknown peptide-MHC repertoire captured from the cancer cells could interact with a wide range of antigen-specific T cells and promote anti-cancer responses. Indeed, we found that we can successfully pull-down peptide-MHCs from cell lysates and the aAPCs generated using this technique were able to induce antigen-specific cytotoxic effector T cell responses that led to in vitro and in vivo tumor cell killing. In summary, we present here a novel technique to generate patient-specific aAPCs, that might have the potential to revolutionize the field of cancer vaccines, and provide patients with a vaccine in matters of days at minimal costs.

Aim: To systematically review the prophylactic and therapeutic interventions for reducing the incidence or severity of intestinal symptoms among cancer patients receiving radiotherapy. Materials & methods: A literature search was conducted in the PubMed database using various search terms, including 'radiation enteritis', 'radiation enteropathy', 'radiation-induced intestinal disease', 'radiation-induced intestinal damage' and 'radiation mucositis'. The search was limited to in vivo studies, clinical trials and meta-analyses published in English with no limitation on publication date. Other relevant literature was identified based on the reference lists of selected studies. Results: The pathogenesis of acute and chronic radiation-induced intestinal damage as well as the prevention and treatment approaches were reviewed. Conclusion: There is inadequate evidence to strongly support the use of a particular strategy to reduce radiation-induced intestinal damage. More high-quality randomized controlled trials are required for interventions with limited evidence suggestive of potential benefits.

Reprogrammed metabolism is an important hallmark of cancer cells. Pyruvate kinase (PK) is one of the major rate-limiting enzymes in glucose metabolism. The M2 isoform of PK (PKM2), is considered to be an important marker of metabolic reprogramming and one of the key enzymes. Recently, through the continuous development of genome-wide analysis and functional studies, accumulating evidence has demonstrated that long non-coding RNAs (LncRNAs) play vital regulatory roles in cancer progression by acting as either potential oncogenes or tumor suppressors. Furthermore, several studies have shown that up-regulation of PKM2 in cancer tissues is associated with LncRNAs expression and patient survival. Thus, scientists have begun to unveil the mechanism of LncRNA-associated PKM2 in cancer metabolic progression. Based on these novel findings, in this mini-review, we summarize the detailed molecular mechanisms of LncRNA related to PKM2 in cancer metabolism. We expect that this work will promote a better understanding of the molecular mechanisms of PKM2, and provide a profound potential for targeting PKM2 to treat tumors., (© 2019 The Author(s).)

Cancer research has advanced throughout the years with respect to the personalization of the treatments and to targeting cancer-related molecular signatures on different organs. Still, the adverse events of the treatments such as radiotherapy are of high concern as they may increase the mortality rate due to their severity. With the improved efficiency of cancer treatments, patient survival has been increasing. Consequently, the number of patients with adverse effects from radiotherapy is also expected to increase in the forthcoming years. Therefore, approaches for personalized treatments include the elimination of adverse events and decreasing the toxicity in healthy tissues while increasing the efficiency of cancer cytotoxicity. In this context, this paper aims to discuss the recent advances in the field of thorax irradiation therapy and its related toxicities leading to radiation pneumonitis in cancer patients. Molecular mechanisms involved in the radiation-induced lung injury and approaches used to overcome this lung injury are discussed. The discourse covers approaches such as therapeutic administration of natural products, current and prospective radioprotective drugs, and applications of mesenchymal stem cells for radiation-induced lung injury.

Objectives: The objective of this study was to assess risk of neurological toxicities following the use of different immune checkpoint inhibitor (ICI) regimens in solid tumors., Methods: Pubmed, Embase, and ClinicalTrials.gov databases were searched for publications, and data were analyzed using Review Manager 5.3 software to compare the risk of immune-related and nonspecific neurological complications potentially triggered by ICIs to controls., Results: In total 23 randomized clinical trials comprising 11,687 patients were included in this meta-analysis. Patients with PD-L1 (OR, 0.29; 95% confidence interval [CI], 0.18-0.48; P<0.01) or programmed cell-death protein 1 (PD-1) inhibitor (OR, 0.21; 95% CI, 0.14-0.31; P<0.01) were less likely to develop any-grade peripheral neuropathy than chemotherapy, while the risk of grade 3-5 was also smaller for PD-1 inhibitor (OR, 0.16; 95% CI, 0.05-0.54; P=0.003). Combination therapy with CTLA4 and PD-1 inhibitor did not significantly increase the risk of any-grade (OR, 0.83; 95% CI, 0.21-3.32; P>0.05) or grade 3-5 (OR, 1.4; 95% CI, 0.2-9.61; P>0.05) peripheral neuropathy compared to monotherapy with CTLA4 or PD-1 inhibitor. However, difference in risk of immune-related adverse events (irAEs) involving central nervous system did not reach statistical significance in patients with different ICI regimens compared those under chemotherapy. Additionally, risk of experiencing paresthesia was in line with that of peripheral neuropathy (OR, 0.42; 95% CI, 0.28-0.62; P<0.01)., Conclusions: This meta-analysis shows that PD-L1/PD-1 and CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy, while combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.

Aim and Objective: Flap endonuclease-1 (FEN1) plays a central role in DNA replication and DNA damage repair process. In mammals, FEN1 functional sites variation is related to cancer and chronic inflammation, and supports the role of FEN1 as a tumor suppressor. However, FEN1 is overexpressed in multiple types of cancer cells and is associated with drug resistance, supporting its role as an oncogene. Hence, it is vital to explore the multi-functions of FEN1 in normal cell metabolic process. This study was undertaken to examine how the gene expression profile changes when FEN1 is downregulated in 293T cells., Materials and Methods: Using the RNA sequencing and real-time PCR approaches, the transcript expression profile of FEN1 knockdown HEK293T cells have been detected for the next step evaluation, analyzation, and validation., Results: Our results confirmed that FEN1 is important for cell viability. We showed that when FEN1 downregulation led to the interruption of nucleic acids related metabolisms, cell cycle related metabolisms are significantly interrupted. FEN1 may also participate in non-coding RNA processing, ribosome RNA processing, transfer RNA processing, ribosome biogenesis, virus infection and cell morphogenesis., Conclusion: These findings provide insight into how FEN1 nuclease might regulate a wide variety of biological processes, and laid the foundation for understanding the role of other RAD2 family nucleases in cell growth and metabolism., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We performed a systematic review and meta-analysis to determine the risk of immune-related pancreatitis associated with the treatment by immune checkpoint inhibitors (ICIs) for solid tumors. Eligible studies were selected from multiple databases including phase II/III randomized controlled trials (RCTs) with ICIs in solid tumor patients. The data were analyzed with Stata version 12.0 software. After excluding ineligible studies, a total of 15 clinical trials were considered eligible for the meta-analysis, which included 9099 patients. Compared with chemotherapy or placebo, the risk ratio (RR) for all-grade lipase elevation after CTLA-4 inhibitor treatment was 1.05 (95% confidence interval (CI): 1.01-2.24, p = 0.047). However, the risk for pancreatitis after ICI treatment in any subgroup was not significantly higher than that after control therapy. In addition, compared with ipilimumab/nivolumab alone, the RR for all-grade and high-grade lipase elevation under combination treatment of nivolumab and ipilimumab was 6.43 (95% CI: 1.43-28.99, p = 0.015) and 6.44 (95% CI: 1.39-29.79, p = 0.017), respectively, and the RR for all-grade amylase elevation under combination treatment was 6.08 (95% CI: 1.51-24.44, p = 0.011). Our meta-analysis has demonstrated that both CTLA-4 inhibitors alone and combination treatment of nivolumab and ipilimumab could increase the risk of amylase or lipase elevation, but not significantly increase the risk of pancreatitis when compared with controls.

Introduction: This pilot exploratory study aimed to compare the health-related quality of life (HRQOL) among patients diagnosed with different types of cancer receiving peripherally inserted central catheters (PICCs)., Methods: A multicenter cross-section study of cancer patients with PICCs was performed from February 1, 2013 to April 24, 2014. The primary objective of this study was to compare HRQOL in different cancer type patients with PICC. HRQOL was examined based on European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30). Multiple linear regression models were conducted for coping with potential confounding variables. We also examined PICC-related quality of daily life with a self-made questionnaire., Results: Three hundred and fifty-seven cancer patients with PICC completed the survey in nine teaching hospitals. Lung cancer patients with PICC reported the worst dyspnea. Digestive tract cancer patients reported the worst appetite loss. Patients with hematologic malignancy reported the worst emotional, social function, fatigue and financial impact. Breast cancer patients reported better HRQOL. Baseline variables were proven not significant predictors of EORTC QLQ-C30 global health status. In self-made survey, pain after PICC insertion was null or a little in 98.6% of cancer patients. Limitation of upper extremity activity was null or a little in 94.1% of patients., Conclusions: HRQOL varies in different types of cancer patients with PICC. PICC may have a low impact on cancer patients' HRQOL. Further large sample studies are needed.

Purpose: To evaluate incidence and risk factors of peripherally inserted central catheter (PICC)-related complications in cancer patients., Methods: A prospective, multicenter, cohort study of cancer patients with PICC insertion was performed from February 1, 2013 to April 24, 2014. All patients were monitored in clinic until PICCs were removed. The primary endpoint was PICC removal due to complications. Patient-, catheter- and insertion-related factors were analyzed in univariable and multivariable logistic regression analysis to identify significant independent risk factors for PICC-related complications., Results: There were 477 cancer patients included, for a total of 50,841 catheter-days. Eighty-one patients (17.0%) developed PICC-related complications, with an incidence of 1.59 per 1000 catheter days. Thirty-six (7.5%) PICCs were removed because of complications. The most common complications were skin allergy (4.6%), catheter occlusion (3.4%) and accidental withdrawal (2.3%). Nine (1.9%) patients developed symptomatic upper extremity deep venous thrombosis (UEDVT) and central line associated bloodstream infection (CLABSI) was shown in six (1.3%) PICCs with an infection rate 0.12 per 1000 catheter days. In multivariable analysis, body mass index (BMI) >25 (odds ratio, 2.09; 95% confidence interval, 1.26-3.47, p = 0.004) was shown to be a significant risk factor for PICC complications., Conclusions: Cancer patients with BMI greater than 25 were more likely to have PICC complications.

Metformin, a widely prescribed drug for treating type II diabetes, is one of the most extensively recognized metabolic modulators which has shown an important anti-cancer property. However, fairly amount of clinical trials on its single administration have not demonstrated a convincing efficiency yet. Thus, recent studies tend to combine metformin with clinical commonly used chemotherapeutic drugs to decrease their toxicity and attenuate their tumor resistance. These strategies have displayed promising clinical benefits. Interestingly, metformin experiences a diversity of molecular mechanisms when it combines different chemotherapeutic drugs. For example, AMPK/mTOR signaling pathway activation plays a major role when it combines with hormone modulating drugs. In contrast, suppression of HIF-1, p-gp and MRP1 protein expression is its main mechanism when metformin combines with anti-metabolites. Furthermore, when combining of metformin with antibiotics, inhibition of oxidative stress and inflammatory signaling pathway becomes a novel pharmaceutical mechanism for its cardio-protective effect. Induction of apoptotic mitochondria and nucleus could be the major player for the synergistic effect of its combination with cisplatin. In contrast, down-regulation of lipoprotein or cholesterol synthesis might be the undefined molecular base when metformin combines with taxane. Thus, deep exploration of molecular mechanisms of metformin with these different drugs is critical to understand its synergistic effect and help for personalized administration. In this mini-review, detailed molecular mechanisms of these combinations are discussed and summarized. This work will promote better understanding of molecular mechanisms of metformin and provide precise targets to identify specific patient groups to achieve satisfactory treatment efficacy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: To address the challenging problem of selecting distinguished genes from cancer gene expression datasets, this paper presents a gene subset selection algorithm based on the Kolmogorov-Smirnov (K-S) test and correlation-based feature selection (CFS) principles. The algorithm selects distinguished genes first using the K-S test, and then, it uses CFS to select genes from those selected by the K-S test., Results: We adopted support vector machines (SVM) as the classification tool and used the criteria of accuracy to evaluate the performance of the classifiers on the selected gene subsets. This approach compared the proposed gene subset selection algorithm with the K-S test, CFS, minimum-redundancy maximum-relevancy (mRMR), and ReliefF algorithms. The average experimental results of the aforementioned gene selection algorithms for 5 gene expression datasets demonstrate that, based on accuracy, the performance of the new K-S and CFS-based algorithm is better than those of the K-S test, CFS, mRMR, and ReliefF algorithms., Conclusions: The experimental results show that the K-S test-CFS gene selection algorithm is a very effective and promising approach compared to the K-S test, CFS, mRMR, and ReliefF algorithms.

Nanoscale drug delivery systems have been widely investigated due to their well-recognized advantages including controlled delivery of chemotherapeutic agents, enhanced therapeutic effectiveness, and reduced adverse effects compared to conventional chemotherapy with small molecules. However, further progress in the use of nanoscale delivery systems in clinical applications has been hampered by pharmacokinetic studies in biological samples which were associated with significant experimental challenges. Here, we report a rational ratiometric approach to monitor drug release kinetics by quantitatively investigating luminescence resonance energy transfer (LRET) from upconversion nanoparticles to the antitumor drug doxorubicin (DOX). Specifically, DOX molecules within the shell of mesoporous silica-coated upconversion nanoparticles selectively quenched the green emission of upconversion nanoparticles, while the intensity of red emission was essentially unaltered. Consequently, when DOX was gradually released, a steady recovery of green emission was observed. The ability to monitor the intensity ratio of green-to-red luminescence enabled a rational design for real-time investigation of drug delivery release kinetics. Importantly, the internal standard effect of red emission made this ratiometric approach suitable for complex biological microenvironments.

Diabetic patients have increased levels of advanced glycation end products (AGEs) and the role of AGEs in regulating cancer cell proliferation is unclear. Here, we found that treating colorectal and liver cancer cells with AGEs promoted cell proliferation. AGEs stimulated both the expression and activation of a key transcription factor called carbohydrate responsive element binding protein (ChREBP) which had been shown to promote glycolytic and anabolic activity as well as proliferation of colorectal and liver cancer cells. Using siRNAs or the antagonistic antibody for the receptor for advanced glycation end-products (RAGE) blocked AGEs-induced ChREBP expression or cell proliferation in cancer cells. Suppressing ChREBP expression severely impaired AGEs-induced cancer cell proliferation. Taken together, these results demonstrate that AGEs-RAGE signaling enhances cancer cell proliferation in which AGEs-mediated ChREBP induction plays an important role. These findings may provide new explanation for increased cancer progression in diabetic patients., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Objective: To demonstrate whether abnormal glucose metabolism (diabetes and prediabetes) is associated with increased risk for cancer in the Chinese population and to identify factors that modify the risk of cancer among individuals with abnormal glucose metabolism., Methods: Between 2011 and 2012, 259 657 community-dwelling adults, aged 40 years and older, were recruited from 25 centers across mainland China to participant in the baseline survey of the REACTION study, with follow-up investigations performed 3, 5, and 10 years later. Detailed questionnaires about lifestyles, physical and biochemical measurement, bio-samples including serum, urine, and whole blood for DNA extraction were collected for all the participants., Results: The mean ± standard deviation (SD) age of this cohort was 57 ± 10 years. And the prevalence of pre-existing and newly diagnosed diabetes was 10.32% and 10.57%, respectively. A total of 4511 prevalent cancer cases (988 men and 3523 women) were identified, the prevalence was 1.79. Compared to those with normal glucose metabolism, men with diabetes had a significantly lower adjusted prevalence ratio (PR) of stomach cancer (PR: 0.38, 95% CI: 0.16-0.89), and women with diabetes had significantly higher adjusted PRs of cancer of all sites (PR: 1.36, 95% CI: 1.20-1.56), and cancer of the breast (PR: 1.56, 95% CI: 1.21-2.00), the endometrium (PR: 1.58, 95% CI: 1.16-2.15), and the thyroid (PR: 1.53, 95% CI: 1.03-2.27)., Conclusion: The multi-center REACTION study has captured a broad range of data on physical, psychological and metabolic function as well as health status, biochemical and lifestyle information in 259 657 adults from the general population across the China., (© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Sensitivity and specificity of using individual tumor markers hardly meet the clinical requirement. This challenge gave rise to many efforts, e.g., combing multiple tumor markers and employing machine learning algorithms. However, results from different studies are often inconsistent, which are partially attributed to the use of different evaluation criteria. Also, the wide use of model-dependent validation leads to high possibility of data overfitting when complex models are used for diagnosis. We propose two model-independent criteria, namely, area under the curve (AUC) and Relief to evaluate the diagnostic values of individual and multiple tumor markers, respectively. For diagnostic decision support, we propose the use of logistic-tree which combines decision tree and logistic regression. Application on a colorectal cancer dataset shows that the proposed evaluation criteria produce results that are consistent with current knowledge. Furthermore, the simple and highly interpretable logistic-tree has diagnostic performance that is competitive with other complex models.

Photothermal nanomaterials have recently attracted significant research interest due to their potential applications in biological imaging and therapeutics. However, the development of small-sized photothermal nanomaterials with high thermal stability remains a formidable challenge. Here, we report the rational design and synthesis of ultrasmall (<10 nm) Fe3O4@Cu2-xS core-shell nanoparticles, which offer both high photothermal stability and superparamagnetic properties. Specifically, these core-shell nanoparticles have proven effective as probes for T2-weighted magnetic resonance imaging and infrared thermal imaging because of their strong absorption at the near-infrared region centered around 960 nm. Importantly, the photothermal effect of the nanoparticles can be precisely controlled by varying the Cu content in the core-shell structure. Furthermore, we demonstrate in vitro and in vivo photothermal ablation of cancer cells using these multifunctional nanoparticles. The results should provide improved understanding of synergistic effect resulting from the integration of magnetism with photothermal phenomenon, important for developing multimode nanoparticle probes for biomedical applications.

Large-scale cancer genome projects will soon be able to sequence many cancer genomes to comprehensively identify genetic changes in human cancer. Genome-wide association studies have also identified putative cancer associated loci. Functional validation of these genetic mutations in vivo is becoming a challenge. We describe here a DNA transposon-based platform that permits us to explore the oncogenic potential of genetic mutations in the mouse. Briefly, promoter-less human cancer gene cDNAs were first cloned into Sleeping Beauty (SB) transposons. DNA transposition in the mouse that carried both the transposons and the SB transposase made it possible for the cDNAs to be expressed from an appropriate endogenous genomic locus and in the relevant cell types for tumor development. Consequently, these mice developed a broad spectrum of tumors at very early postnatal stages. This technology thus complements the large-scale cancer genome projects.

Melanoma-associated antigen family protein-D1 (MAGE-D1) is a recently identified p75 neurotrophin receptor intracellular binding protein and functions as an adaptor that mediates multiple signaling pathways, including Dlx/Msx-mediated transcription. Here, a new regulatory function for MAGE-D1 in tumor cell motility and adhesion to endothelium is described. MAGE-D1 over-expression suppressed HeLa cell and BEL7402 cell migration, invasion, and adhesion to the monolayer of ECV304 cells. We also report that MAGE-D1 over-expression disrupted actin cytoskeleton rearrangement induced by hypoxia and down-regulated hypoxia inducible factor 1-dependent luciferase gene expression. These findings provide new insight into the ability of MAGE-D1 to suppress the motility and adhesion response of tumor cells by interfering with actin cytoskeleton reorganization and hypoxia inducible factor 1-dependent gene expression.