Past, Present, and Future Perspectives on the Systemic Therapy for Advanced Hepatocellular Carcinoma (HCC) — A Comprehensive Review

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer, the third leading cause of cancer-related mortality, and the first leading cause of death in patients with cirrhosis. Management of primary locally advanced, inoperable, recurrent or metastatic HCC is very challenging and continues to be a topic of controversy. Herein, we shed light on the past, present, and future perspectives on the systemic therapy (hormonal therapy, cytotoxic chemotherapy, and novel molecularly targeted therapy) for management of patients with advanced HCC

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Chronic treatment with a carbon monoxide releasing molecule reverses dietary induced obesity in mice

Chronic, low level treatment with a carbon monoxide releasing molecule (CO-RM), CORM-A1, has been shown to prevent the development of obesity in response to a high fat diet. The objective of this study was to test the hypothesis that chronic, low level treatment with this CO-RM can reverse established obesity via a mechanism independent of food intake. Dietary induced obese mice were treated with CORM-A1, the inactive compound iCORM-A1, or saline every 48 hours for 30 weeks while maintained on a high fat (60%) diet. Chronic treatment with CORM-A1 resulted in a 33% decrease from initial body weight over the 30 week treatment period while treatment with iCORM and saline were associated with 18 and 25% gain in initial body weight over the same time frame. Chronic treatment with CORM-A1 did not affect food intake or activity but resulted in a significant increase in metabolism. CORM-A1 treatment also resulted in lower fasting blood glucose, improvement in insulin sensitivity and decreased heptatic steatosis. Chronic treatment with CO releasing molecules can reverse dietary induced obesity and normalize insulin resistance independent of changes in food intake or activity. These findings are likely though a mechanism which increases metabolism

Chronic Treatment With a Carbon Monoxide Releasing Molecule Reverses Dietary Induced Obesity In Mice

ABSTRACT: Chronic, low level treatment with a carbon monoxide releasing molecule (CO-RM), CORM-A1, has been shown to prevent the development of obesity in response to a high fat diet. The objective of this study was to test the hypothesis that chronic, low level treatment with this CO-RM can reverse established obesity via a mechanism independent of food intake. Dietary induced obese mice were treated with CORM-A1, the inactive compound iCORM-A1, or saline every 48 hours for 30 weeks while maintained on a high fat (60%) diet. Chronic treatment with CORM-A1 resulted in a 33% decrease from initial body weight over the 30 week treatment period while treatment with iCORM and saline were associated with 18 and 25% gain in initial body weight over the same time frame. Chronic treatment with CORM-A1 did not affect food intake or activity but resulted in a significant increase in metabolism. CORM-A1 treatment also resulted in lower fasting blood glucose, improvement in insulin sensitivity and decreased heptatic steatosis. Chronic treatment with CO releasing molecules can reverse dietary induced obesity and normalize insulin resistance independent of changes in food intake or activity. These findings are likely though a mechanism which increases metabolism

Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy

Biliverdin Reductase a Attenuates Hepatic Steatosis By Inhibition of Glycogen Synthase Kinase (GSK) 3β Phosphorylation Of Serine 73 Of Peroxisome Proliferator-Activated Receptor (PPAR) Α

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P)73 of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease

Cancer stem cell as therapeutic target for melanoma treatment

Human malignant melanoma is a highly aggressive skin tumor that is characterized by its extraordinary heterogeneity, propensity for dissemination to distant organs and resistance to cytotoxic agents. Although chemo- and immune-based therapies have been evaluated in clinical trials, most of these therapeutics do not show significant benefit for patients with advanced disease. Treatment failure in melanoma patients is attributed mainly to the development of tumor heterogeneity resulting from the formation of genetically divergent subpopulations. These subpopulations are composed of cancer stem-like cells (CSCs) as a small fraction and non-cancer stem cells that form the majority of the tumor mass. In recent years, CSCs gained more attention and suggested as valuable experimental model system for tumor study. In melanoma, intratumoral heterogeneity, progression and drug resistance result from the unique characteristics of melanoma stem cells (MSCs). These MSCs are characterized by their distinct protein signature and tumor growth-driving pathways, whose activation is mediated by driver mutation-dependent signal. The molecular features of MSCs are either in a causal or consequential relationship to melanoma progression, drug resistance and relapse. Here, we review the current scientific evidence that supports CSC hypothesis and the validity of MSCs-dependent pathways and their key molecules as potential therapeutic target for melanoma treatment