Accumulation of multiple genetic and/or epigenetic abnormalities is required for generation and progression of cancers, and the survival of cancer cells might depend on addiction to these ...abnormalities. Because disruption of such dependency on the abnormal molecules should cause the cancer cell death, so-called oncogene addiction is the rationale for molecular targeted therapy. Pancreatic cancer, especially pancreatic ductal adenocarcinoma, is one of the most lethal malignancies in humans, and remains a challenging problem in targeted therapy compared to other malignancies such as pancreatic neuroendocrine tumor. This review summarizes the molecular pathogenesis of pancreatic cancer on the basis of the recent studies of driver mutations including chromatin remodeling factors, and promising concepts “cancer stemness” and “stromal niche” for the strategy of novel targeted therapy.
Hypoxia as a key player in the AKI-to-CKD transition Tanaka, Shinji; Tanaka, Tetsuhiro; Nangaku, Masaomi
American journal of physiology. Renal physiology,
2014-Dec-01, Letnik:
307, Številka:
11
Journal Article
Recenzirano
Recent clinical and animal studies have shown that acute kidney injury (AKI), even if followed by complete recovery of renal function, can eventually result in chronic kidney disease (CKD). Renal ...hypoxia is emerging as a key player in the pathophysiology of the AKI-to-CKD transition. Capillary rarefaction after AKI episodes induces renal hypoxia, which can in turn profoundly affect tubular epithelial cells, (myo)fibroblasts, and inflammatory cells, culminating in tubulointerstitial fibrosis, i.e., progression to CKD. Damaged tubular epithelial cells that fail to redifferentiate might supply a decreased amount of vascular endothelial growth factor and contribute to capillary rarefaction, thus aggravating hypoxia and forming a vicious cycle. Mounting evidence also shows that epigenetic changes are closely related to renal hypoxia in the pathophysiology of CKD progression. Animal experiments suggest that targeting hypoxia is a promising strategy to block the transition from AKI to CKD. However, the precise mechanisms by which hypoxia induces the AKI-to-CKD transition and by which hypoxia-inducible factor activation can exert a protective effect in this context should be clarified in further studies.
It is unclear whether long-term sodium–glucose cotransporter 2 (SGLT2) inhibition such as that during the treatment of diabetes has deleterious effects on the kidney. Therefore, we first sought to ...determine whether abnormal glucose metabolism occurs in the kidneys of 22-week-old BTBR ob/ob diabetic mice. Second, the cumulative effect of chronic SGLT2 inhibition by ipragliflozin and 30% calorie restriction, either of which lowered blood glucose to a similar extent, on renal glucose metabolism was evaluated. Mass spectrometry–based metabolomics demonstrated that these diabetic mice exhibited an abnormal elevation in the renal pools of tricarboxylic acid cycle metabolites. This was almost completely nullified by SGLT2 inhibition and calorie restriction. Moreover, imaging mass spectrometry indicated an increased level of the tricarboxylic acid cycle intermediate, citrate, in the cortex of the diabetic mice. SGLT2 inhibition as well as calorie restriction almost completely eliminated citrate accumulation in the cortex. Furthermore, imaging mass spectrometry revealed that the accumulation of oxidized glutathione in the cortex of the kidneys, prominent in the glomeruli, was also canceled by SGLT2 inhibition and calorie restriction. Effects of these beneficial interventions were consistent with improvements in glomerular damage, such as albuminuria, glomerular hyperfiltration, and mesangial expansion. Tubulointerstitial macrophage infiltration and fibrosis were ameliorated only by calorie restriction, which may have been due to autophagy activation, which was observed only with calorie restriction. Thus, chronic SGLT2 inhibition is efficient in normalizing the levels of accumulated tricarboxylic acid cycle intermediates and increased oxidative stress in the kidneys of diabetic mice.
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Accumulated understanding of the molecular pathways regulating cancer progression has led to the development of novel targeted therapies. Hepatocellular carcinoma (HCC) remains a highly lethal ...disease that is resistant to conventional cytotoxic chemotherapy and radiotherapy. Unlike conventional chemotherapy, molecular‐targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. A recent clinical trial revealed an oral multikinase inhibitor, sorafenib, as the first agent that has demonstrated improved overall survival in patients with advanced HCC. The present review summarizes molecular abnormalities of HCC with a focus on clinical studies, and current status as well as problems of the targeted strategies for HCC. (Cancer Sci 2009; 100: 1–8)
The vagus nerve, the great wanderer, is involved in numerous processes throughout the body and vagus nerve stimulation (VNS) has the potential to modulate many of these functions. This wide-reaching ...capability has generated much interest across a range of disciplines resulting in several clinical trials and studies into the mechanistic basis of VNS. This review discusses current preclinical and clinical evidence supporting the efficacy of VNS in different diseases and highlights recent advancements. Studies that provide insights into the mechanism of VNS are considered.
Asymmetric hydrogenation of ketones (AHK) was revolutionized in 1987 and again in 1995 when Ru(CH3COO)2(binap)/HCl and RuCl2(binap)/diamine, respectively, were developed. Since then, the number of ...reports on Ru-catalyzed AHK has increased exponentially, and the utility of other precious metals (Os, Rh, Ir, and Pd) has also been shown. The utilization of inexpensive base metals (Fe, Co, Ni, and Cu) has been a recent trend. This digest summarizes the key advances in AHK in the past decade by categorizing the chiral ligands into six types: (i) diphosphines, (ii) diphosphines/diamines, (iii) tridentate or tetradentate phosphine amines, (iv) diamines, (v) tetradentate amines, and (vi) tetradentate thioether amines.
Suitable lesions for endoscopic treatment include not only early colorectal carcinomas but also several types of precarcinomatous adenomas. It is important to establish practical guidelines wherein ...preoperative diagnosis of colorectal neoplasia and selection of endoscopic treatment procedures are appropriately outlined and to ensure that actual endoscopic treatment is useful and safe in general hospitals when carried out in accordance with guidelines. In cooperation with the Japanese Society for Cancer of the Colon and Rectum, the Japanese Society of Coloproctology, and the Japanese Society of Gastroenterology, the Japan Gastroenterological Endoscopy Society compiled colorectal endoscopic submucosal dissection/endoscopic mucosal resection guidelines by using evidence‐based methods in 2014. The first edition of these guidelines was published 5 years ago. Accordingly, we have published the second edition of these guidelines based on recent new knowledge and evidence.
Hepatocellular carcinoma (HCC) is a complex heterogeneous disease with high morbidity and mortality. Recent progress in molecular targeted drugs including multikinase inhibitors and immune checkpoint ...inhibitors has demonstrated substantial survival improvement in patients with advanced HCC, but it remains as a challenging issue to discover surrogate markers for precisely distinguishing responders and non-responders. Genome-based medicine has changed cancer treatment from empirical use of cytotoxic agents to theoretical use of molecular targeted drugs in various types of cancer, while not in HCC due to lack of druggable targets. Integrated genomic and transcriptomic analysis reveal that HCC is divided into three major subtypes, proliferative,
CTNNB1
-mutated and metabolic disease-associated, with distinctive molecular and immunological features, and an increasing number of studies provide evidence for the close correlation between the subtype and the response to molecular targeted drugs using both of clinical data and preclinical models. Dozens of immunocompetent mouse models, such as hydrodynamic tail vain injection models and implantable syngeneic models, reflect molecular characteristics and tumor immune microenvironment of the subtypes, and help us to evaluate the efficacy of single and combination therapies and understand the molecular mechanisms underlying vulnerability and resistance to them. Thus, the consensus classification and relevant preclinical models could accelerate the establishment of predictive biomarkers and the development of subtype-specific therapies.
In vivo tumor progression requires the supply of oxygen and nutrition by neovasculature. Hepatocellular carcinoma (HCC) is one of the typical tumors with neovascularization, and the dramatic ...alteration in the arterial vascularity may lead to acquisition of the potential for vascular invasiveness and metastasis. In 2008, phase III clinical trials revealed anti-angiogenic agent "sorafenib" as the first drug that demonstrated an improved overall survival in patients with advanced HCC. A new era of HCC treatment had arrived, but there has been limited further improvement in survival benefits. This review summarizes molecular targeted therapy with a focus on angiogenesis, growth signals, and mitotic abnormalities, as well as the promising concepts of "cancer stemness" and "synthetic lethality" for the strategy of targeted therapy.
Heterogeneity is one of the essential hallmarks of malignancies. Within bulk cancer cells, a striking variability differs in biological characteristics including the proliferation rate, cell–cell ...interaction, metastatic tendency and even sensitivity to anticancer therapies. Such diversity makes the investigation and treatment of the cancers complicated. Increasing evidence suggests this plasticity of cancers is a result of self‐renewing and differentiation of a small subpopulation of cancer cells with stem‐like properties, called cancer stem cells (CSCs). More importantly, CSCs are believed to be responsible for the resistance to conventional therapies and metastatic abilities in clinical practice. This review summarizes the molecular pathogenesis of hepato‐biliary‐pancreatic CSCs on the basis of the recent studies, and promising strategy of novel therapy targeting the signal transduction pathways or potentially epigenetic addictions of CSCs.
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