Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to ...evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols.
Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared.
Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so.
We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.
Medicinal plant‐derived bioactive compounds modulate multiple therapeutic targets in cardiovascular diseases (CVDs), rendering herb‐derived phytochemicals effective against one of the major ...CVDs‐atherosclerosis. Danshen (Salvia milthiorriza Bunge) is a Chinese medicine that has been used in cardio‐ and cerebro‐vascular therapeutic remedies in Asian countries for many years. Emerging evidence from cellular, animal, and clinical studies suggests that major lipophilic tanshinones from Danshen can treat atherosclerotic CVDs. In this review, we highlight recent advances in understanding the molecular mechanisms of tanshinones in treating atherosclerosis, ranging from endothelial dysfunction to chronic inflammation. We also overview new molecular targets of tanshinones, including endothelial nitric oxide synthase, AMP‐activated protein kinase, ABC transporter A1, heme oxygenase 1, soluble epoxide hydrolase, 11β‐hydroxysteroid dehydrogenase, estrogen receptor, and proprotein convertase subtilisin/kexin type 9. Thus, this review provides a new perspective for advancing our understanding of the “ancient” herb Danshen from “modern” biomedical perspectives, supporting the possibility of exploiting tanshinones and derivatives as effective therapeutics against atherosclerosis‐related cardiovascular and metabolic diseases.
Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, ...acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers. During apoptosis, FOXOs are involved in mitochondria-dependent and -independent processes triggering the expression of death receptor ligands like Fas ligand, TNF apoptosis ligand and Bcl‑X
bNIP3, Bim from Bcl-2 family members. Different types of growth factors like insulin play a vital role in the regulation of FOXOs. The most important pathway interacting with FOXO in different types of cancers is the PI3K/AKT pathway. Some other important pathways such as the Ras-MEK-ERK, IKK and AMPK pathways are also associated with FOXOs in tumorigenesis. Therapeutically targeting the FOXO signaling pathway(s) could lead to the discovery and development of efficacious agents against some cancers, but this requires an enhanced understanding and knowledge of FOXO transcription factors and their regulation and functioning. This review focused on the current understanding of cell biology of FOXO transcription factors which relates to their potential role as targets for the treatment and prevention of human cancers. We also discuss drugs which are currently being used for cancer treatment along with their target pathways and also point out some potential drawbacks of those drugs, which further signifies the need for development of new drug strategies in the field of cancer treatment.
Atherosclerosis is the primary underlying cause of cardiovascular disease which preferentially develops at arterial regions exposed to disturbed flow (DF), but much less at regions of unidirectional ...laminar flow (UF). Recent studies have demonstrated that DF and UF differentially regulate important aspects of endothelial function, such as vascular inflammation, oxidative stress, vascular tone, cell proliferation, senescence, mitochondrial function, and glucose metabolism. DF and UF regulate vascular pathophysiology via differential regulation of mechanosensitive transcription factors (MSTFs) (KLF2, KLF4, NRF2, YAP/TAZ/TEAD, HIF-1α, NF-κB, AP-1, and others). Emerging studies show that MSTFs represent promising therapeutic targets for the prevention and treatment of atherosclerosis. We present here a comprehensive overview of the role of MSTFs in atherosclerosis, and highlight future directions for developing novel therapeutic agents by targeting MSTFs.
UF and DF differentially modulate several MSTFs in endothelial cells.
MSTFs regulate multiple aspects of endothelial function, including inflammation, proliferation, thrombosis, oxidative stress, and endothelial cell metabolism.
MSTFs crosstalk with each other and functionally regulate endothelial gene expression and function.
Targeting MSTFs could be a promising therapeutic strategy for atherosclerosis.
Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder ...in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic “writers”, “readers”, and “erasers”. Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics.
LOX‐1 (lectin‐like oxidized low‐density lipoprotein receptor‐1; also known as OLR1) is the dominant receptor that recognizes and internalizes oxidized low‐density lipoproteins (ox‐LDLs) in ...endothelial cells. Several genetic variants of LOX‐1 are associated with the risk and severity of coronary artery disease. The LOX‐1–ox‐LDL interaction induces endothelial dysfunction, leukocyte adhesion, macrophage‐derived foam cell formation, smooth muscle cell proliferation and migration, and platelet activation. LOX‐1 activation eventually leads to the rupture of atherosclerotic plaques and acute cardiovascular events. In addition, LOX‐1 can be cleaved to generate soluble LOX‐1 (sLOX‐1), which is a useful diagnostic and prognostic marker for atherosclerosis‐related diseases in human patients. Of therapeutic relevance, several natural products and clinically used drugs have emerged as LOX‐1 inhibitors that have antiatherosclerotic actions. We hereby provide an updated overview of role of LOX‐1 in atherosclerosis and associated vascular diseases, with an aim to highlighting the potential of LOX‐1 as a novel theranostic tool for cardiovascular disease prevention and treatment.
This article provides an updated overview of the role in atherosclerosis (and associated vascular diseases) of LOX‐1 (lectin‐like oxidized low‐density lipoprotein receptor‐1), the main receptor for the uptake of oxidized low‐density lipoproteins in endothelial cells. It also highlights the potential of LOX‐1 as a novel theranostic tool for cardiovascular disease prevention and treatment.
Cardiovascular disease is an important cause for morbidity and mortality worldwide. Flavonoids, such as naringin, and naringenin are important natural phytochemicals in the treatment or prevention of ...various disorders such as obesity, cardiac diseases, diabetes, and metabolic syndrome. Naringin and naringenin have significant therapeutic potential in several diseases through anti-oxidative, anti-inflammatory, and anti-apoptotic actions; these flavonoids play a protective role in human pathophysiology. In this review, based on the latest evidence, we present a summary of the impact of naringin, and naringenin on cardiovascular disease, and analyze and discuss the basic roles of naringin and naringenin and their mechanisms of actions in cardiovascular disease and other vascular dysfunction. The data collected in this review may serve as a comprehensive reference for the effects of naringin, and naringenin in cardiovascular disease, which may be beneficial for further research and for the design of naringin and naringenin analogs as new therapeutic options for cardiovascular diseases.
Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial ...dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.
PDF
