Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracell...Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes.展开更多
Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twe...Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confersonly a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.展开更多
Human epidermal growth factor receptor 2(HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targe...Human epidermal growth factor receptor 2(HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system.展开更多
Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of life.Despite great progressmadetowards a better unde...Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of life.Despite great progressmadetowards a better understanding of the molecular basis of diabetes,the available clinical counter-measures against insulin resistance,a defect that is central to obesity-linked type 2 diabetes,remain inadequate.Adiponectin,an abundant adipocyte-secreted factor with a wide-range of biological activities,improves insulin sensitivity in major insulin target tissues,modulates inflammatory responses,and plays a crucial role in the regulation of energy metabolism.However,adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention,and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation,and reveal therapeutic targets.Here,we discuss tissue-and cell-specific functions of adiponectin,with an emphasis on the regulation of adiponectin signaling pathways,and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation.Understanding better just why and how adiponectin and its downstream effector molecules work will be essential,together with empirical trials,to guide us to therapies that target the root cause(s)of type 2 diabetes and insulin resistance.展开更多
文摘Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes.
文摘Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confersonly a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.
文摘Human epidermal growth factor receptor 2(HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system.
基金supported by grants from the National Institutes of Health (R01 DK102965)the American Diabetes Association (#7-13-BS-043)to L.Q.D.
文摘Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of life.Despite great progressmadetowards a better understanding of the molecular basis of diabetes,the available clinical counter-measures against insulin resistance,a defect that is central to obesity-linked type 2 diabetes,remain inadequate.Adiponectin,an abundant adipocyte-secreted factor with a wide-range of biological activities,improves insulin sensitivity in major insulin target tissues,modulates inflammatory responses,and plays a crucial role in the regulation of energy metabolism.However,adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention,and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation,and reveal therapeutic targets.Here,we discuss tissue-and cell-specific functions of adiponectin,with an emphasis on the regulation of adiponectin signaling pathways,and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation.Understanding better just why and how adiponectin and its downstream effector molecules work will be essential,together with empirical trials,to guide us to therapies that target the root cause(s)of type 2 diabetes and insulin resistance.
