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1.
siGCD: a web server to explore survival interaction of genes, cells and drugs in human cancers.
Cui, X, Han, L, Liu, Y, Li, Y, Sun, W, Song, B, Zhou, W, Zhang, Y, Wang, H
Briefings in bioinformatics. 2021;(5)
Abstract
It is pivotal and remains challenge for cancer precision treatment to identify the survival outcome interactions between genes, cells and drugs. Here, we present siGCD, a web-based tool for analysis and visualization of the survival interaction of Genes, Cells and Drugs in human cancers. siGCD utilizes the cancer heterogeneity to simulate the manipulated gene expression, cell infiltration and drug treatment, which overcomes the data and experimental limitations. To illustrate the performance of siGCD, we identified the survival interaction partners of EGFR (gene level), T cells (cell level) and sorafenib (drug level), and our prediction was consistent with previous reports. Moreover, we validate the synergistic effect of regorafenib and glyburide, and found that glyburide could significantly improve the regorafenib response. These results demonstrate that siGCD could benefit cancer precision medicine in a wide range of advantageous application scenarios including gene regulatory network construction, immune cell regulatory gene identification, drug (especially multiple target drugs) response biomarker screening and combination therapeutic design.
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2.
Transcriptomic characterization reveals prognostic molecular signatures of sorafenib resistance in hepatocellular carcinoma.
Yuan, W, Tao, R, Huang, D, Yan, W, Shen, G, Ning, Q
Aging. 2021;(3):3969-3993
Abstract
Sorafenib is the first-line treatment for patients with advanced unresectable hepatocellular carcinoma (HCC); however, only a small number of patients benefit from sorafenib, and many develop sorafenib resistance (SR) and severe side effects. To identify biomarkers for SR, we systematically analyzed the molecular alterations in both sorafenib-resistant HCC specimens and cultured cells. By combining bioinformatics tools and experimental validation, four genes (C2orf27A, insulin-like growth factor 2 receptor, complement factor B, and paraoxonase 1) were identified as key genes related to SR in HCC and as independent prognostic factors significantly associated with clinical cancer stages and pathological tumor grades of liver cancer. These genes can affect the cytotoxicity of sorafenib to regulate the proliferation and invasion of Huh7 cells in vitro. Additionally, immune-cell infiltration according to tumor immune dysfunction and exclusion, a biomarker integrating the mechanisms of dysfunction and exclusion of T cells showed good predictive power for SR, with an AUC of 0.869. These findings suggest that immunotherapy may be a potential strategy for treating sorafenib-resistant HCC. Furthermore, the results enhance the understanding of the underlying molecular mechanisms of SR in HCC and will facilitate the development of precision therapy for patients with liver cancer.
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3.
Nephrotoxicity as a Complication of Chemotherapy and Immunotherapy in the Treatment of Colorectal Cancer, Melanoma and Non-Small Cell Lung Cancer.
Jagieła, J, Bartnicki, P, Rysz, J
International journal of molecular sciences. 2021;(9)
Abstract
Acute kidney injury is a common complication of many medical procedures, including those used in cancer treatment. Both chemotherapy and immunotherapy may result in deterioration of kidney function, which may lead to an increase in mortality among patients with cancer. Antineoplastic agents can affect any element of the nephron, leading to the appearance of clinical symptoms such as proteinuria, hypertension, electrolyte disorders, glomerulonephritis, acute and chronic interstitial nephritis and acute kidney injury. The medical literature describing renal complications occurring during chemotherapeutic and immunotherapeutic treatment in neoplasms, such as colorectal cancer, non-small cell lung cancer and melanoma, was analysed. The immune system plays an important role in controlling the development of neoplasms and fighting them. Oncological treatment algorithms include immunotherapy as monotherapy, combined with chemotherapy or chemotherapy as monotherapy. In the treatment of the above-mentioned neoplasms immunotherapeutics are used, such as checkpoint inhibitors (CPI) (i.e., ipilimumab, pembrolizumab, nivolumab, atezolizumab), vascular endothelial growth factor (VEGF) inhibitors (i.e., bevacizumab, ramucirumab) and a variety of chemotherapeutic agents (irinotecan, capecitabine, oxaliplatin, gefitinib, erlotinib, gemcitabine, cisplatin, paclitaxel, carboplatin, doclitaxel, vinorelbine, topotecan, etoposide). In our article, we focused on the number and type of renal complications as well as on the time of their manifestation when using specific treatment regimens. Our analysis also includes case reports. We discussed treatment of immunological complications and adjustments of the dose of chemotherapeutic agents depending on the creatinine clearance. Analysing the data from the literature, when two immunotherapeutic agents are used together, the number of recorded renal complications increases. Bevacizumab and ramucirumab are the cause of the largest number of renal complications among the immunotherapeutic agents described above. Cisplatin is the best-described substance with the greatest nephrotoxic potential among the chemotherapeutic agents. Crucial for renal complications are also cancer stage, previous chemotherapy and other risk factors of AKI such as age, comorbidities and medications used. Due to the described complications during oncological treatment, including kidney damage, it seems necessary to elaborate standards of cooperation between oncologists and nephrologists both during and after treatment of a patient with cancer. Therefore, it is necessary to conduct further research and develop algorithms for management of a cancer patient, especially during such an intensive progress in oncology.
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4.
Future Directions in Chronic Phase CML Treatment.
Javidi-Sharifi, N, Hobbs, G
Current hematologic malignancy reports. 2021;(6):500-508
Abstract
PURPOSE OF REVIEW This review will focus on recent and emerging treatment paradigms in chronic phase CML. The discussion of each novel treatment or drug combination will include a brief overview of scientific rational and pre-clinical data, followed by recently published or ongoing clinical trial efforts. The review will be divided into three focus areas in CML treatment: new frontline approaches and approaches to deepen remission, second treatment-free remission studies, and the treatment of refractory disease. RECENT FINDINGS The section on new frontline approaches will highlight several strategies of combination therapy. These can be grouped into immunomodulatory approaches with interferons and immune checkpoint inhibitors, targeting of leukemia stem cells with compounds such as venetoclax and pioglitazone, and BCR-ABL1-intrinsic combination therapy with asciminib. The chance at a second treatment-free remission is an important emerging clinical trial concept, and again combination approaches are under investigation. Lastly, in advanced disease, the development of novel tyrosine kinase inhibitors remains a major focus. This review will provide an overview and perspective of treatment strategies on the horizon for chronic phase CML. Despite the already excellent clinical outcomes for most patients, challenges remain with regard to deepening initial responses, prolonging treatment-free remission, and providing efficacious and tolerable options for patients with refractory disease and resistance mutations.
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5.
A comprehensive review on time-tested anticancer drug doxorubicin.
Sritharan, S, Sivalingam, N
Life sciences. 2021;:119527
Abstract
Doxorubicin or Adriamycin, is one of the most widely used chemotherapeutic drug for treating a myriad of cancers. It induces cell death through multiple intracellular targets: reactive oxygen species generation, DNA-adduct formation, topoisomerase II inhibition, histone eviction, Ca2+ and iron hemostasis regulation, and ceramide overproduction. Moreover, doxorubicin-treated dying cells undergo cellular modifications that enable neighboring dendritic cell activation and enhanced presentation of tumor antigen. In addition, doxorubicin also aids in the immune-mediated clearance of tumor cells. However, the development of chemoresistance and cardiotoxicity side effect has undermined its widespread applicability. Several formulations of doxorubicin and co-treatments with inhibitors, miRNAs, natural compounds and other chemotherapeutic drugs have been essential in reducing its dosage-dependent toxicity and combating the development of resistance. Further, more advanced research into the molecular mechanism of chemoresistance development would be vital in improving the overall survivability of clinical patients and in preventing cancer relapse.
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6.
Bioactive peptides from foods: production, function, and application.
Jia, L, Wang, L, Liu, C, Liang, Y, Lin, Q
Food & function. 2021;(16):7108-7125
Abstract
Bioactive peptides are a class of peptides with special physiological functions and have potential applications in human health and disease prevention. Bioactive peptides have gained much research attention because they affect the cardiovascular, endocrine, immune, and nervous systems. Recent research has reported that bioactive peptides are of great value for physiological function regulation, including antioxidation, anti-hypertension, antithrombosis, antibacterial properties, anti-cancer, anti-inflammation, anti-diabetic, anti-obesity, cholesterol-lowering, immunoregulation, mineral binding and opioid activities. The production of food-derived bioactive peptides is mainly through the hydrolysis of digestive enzymes and proteolytic enzymes or microbial fermentation. The purpose of this review is to introduce the production, function, application, challenges, and prospects of food-derived bioactive peptides.
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7.
Novel combinatorial strategies for boosting the efficacy of immune checkpoint inhibitors in advanced breast cancers.
Tolba, MF, Elghazaly, H, Bousoik, E, Elmazar, MMA, Tolaney, SM
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2021;(10):1979-1994
Abstract
The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-βɣ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers.
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8.
Antitumor Effects of Selenium.
Kim, SJ, Choi, MC, Park, JM, Chung, AS
International journal of molecular sciences. 2021;(21)
Abstract
Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. Hydrogen selenide from selenite, and methylselenol (MSeH) from Se-methylselenocyteine (MSeC) and methylseleninicacid (MSeA) are the most reactive metabolites produced reactive oxygen species (ROS); furthermore, these metabolites may involve in oxidizing sulfhydryl groups, including glutathione. Selenite also reacted with glutathione and produces hydrogen selenide via selenodiglutathione (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus. However, a more pronounced effect was shown in the subsequent treatment of sodium selenite with chemotherapy and radiation therapy. High doses of sodium selenite were effective to increase radiation therapy and chemotherapy, and further to reduce radiation side effects and drug resistance. In our study, advanced cancer patients can tolerate until 5000 μg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short, and, further, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells. Further clinical studies of high amount sodium selenite are required to treat advanced cancer patients.
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9.
The Cancer Chemopreventive and Therapeutic Potential of Tetrahydrocurcumin.
Lai, CS, Ho, CT, Pan, MH
Biomolecules. 2020;(6)
Abstract
In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.
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10.
Mitochondria-targeted compounds in the treatment of cancer.
Kafkova, A, Trnka, J
Neoplasma. 2020;(3):450-460
Abstract
Mitochondria are highly dynamic organelles involved in many cellular functions. Beyond their central role in metabolism, they also take a part in maintaining calcium homeostasis, cell death, immunity, and ROS production. Changes in these functions have been shown to be crucial for the adaptation and survival of cancer cells. Mitochondria, therefore, constitute a promising target for the development of novel anticancer agents. The triphenylphosphonium (TPP+) moiety has been widely used to target molecules into mitochondria. TPP+ derivatives of a variety of conventional cytostatic drugs, natural substances, metformin, antioxidants or a range of newly synthesized molecules have shown promising results against cancer cells. In this review, we discuss biochemical differences between cancer cells and normal cells with a specific focus on mitochondria, and how mitochondrially targeted molecules can be used to selectively affect mitochondrial function in normal and cancer cells. We summarize the published data on mitochondrially targeted anticancer agents and propose future research avenues.