Targeting TGF-β During Epithelial-to-mesenchymal Progression as an Effective Therapy Against Colorectal Cancer

Colorectal cancer is one of the most common cancers worldwide. Understanding the mechanisms of colorectal cancer progression is crucial for the development of effective therapeutics. Epithelial-to-mesenchymal transition is a hallmark feature of cancer and is defined as the loss of epithelial cell features, such as apical-basal polarity and high expression of cell adhesion molecules, and the development of mesenchymal features, such as lack of polarity and increased cell mobility. Epithelial-to-mesenchymal is essential for cell migration, proliferation, and tumor growth. Both the TGF-β and SMAD pathway are associated with colorectal cancer progression. TGF-β is crucial to the cellular mechanism of cell differentiation and regulation. LY210976, a TGF-β inhibitor, has been proposed as a potential therapeutic for metastasis. The three studies reviewed here collectively demonstrated that LY2109761 is effective in reducing cell migration, invasion, and metastasis in mice and rabbit models. Combined with transcatheter arterial chemoembolization, inhibition of LY2109761 led to increased E-cadherin expression, indicating the maintenance of the epithelial cell phenotype, and suppressed tumor growth in rabbits. Together, these results suggest that LY2109761 is a strong candidate for inhibiting colorectal cancer spread. Future studies should continue to explore LY2109761 in preventing metastasis, especially in combination therapies in humans

Surgical vein graft preparation promotes cellular dysfunction, oxidative stress, and intimal hyperplasia in human saphenous vein

IntroductionHuman saphenous vein (HSV) is the most widely used bypass conduit for peripheral and coronary vascular reconstructions. However, outcomes are limited by a high rate of intimal hyperplasia (IH). HSV undergoes a series of ex vivo surgical manipulations prior to implantation, including hydrostatic distension, marking, and warm ischemia in solution. We investigated the impact of surgical preparation on HSV cellular function and development of IH in organ culture. We hypothesized that oxidative stress is a mediator of HSV dysfunction.MethodsHSV was collected from patients undergoing vascular bypass before and after surgical preparation. Smooth muscle and endothelial function were measured using a muscle bath. Endothelial preservation was assessed with immunohistochemical staining. An organ culture model was used to investigate the influence of surgical preparation injury on the development of IH. Superoxide levels were measured using a high-performance liquid chromatography-based assay. The influence of oxidative stress on HSV physiologic responses was investigated by exposing HSV to hydrogen peroxide (H2O2).ResultsSurgical vein graft preparation resulted in smooth muscle and endothelial dysfunction, endothelial denudation, diminished endothelial nitric oxide synthase staining, development of increased IH, and increased levels of reactive oxygen species. Experimental induction of oxidative stress in unmanipulated HSV by treatment with H2O2 promoted endothelial dysfunction. Duration of storage time in solution did not contribute to smooth muscle or endothelial dysfunction.ConclusionsSurgical vein graft preparation causes dysfunction of the smooth muscle and endothelium, endothelial denudation, reduced endothelial nitric oxide synthase expression, and promotes IH in organ culture. Moreover, increased levels of reactive oxygen species are produced and may promote further vein graft dysfunction. These results argue for less injurious means of preparing HSV prior to autologous transplantation into the arterial circulation.Clinical RelevanceApproximately 1,000,000 aortocoronary and peripheral vascular reconstructions are performed annually using human saphenous vein grafts. However, outcomes from this procedure are limited by high rates of graft failure. The leading cause of vein graft failure is intimal hyperplasia. A multifactorial process, intimal hyperplasia is thought to arise at least in part due to vein graft injury. Significant trauma occurs to the graft during surgical harvest and subsequent preparation, significantly impairing cellular function and increasing oxidative stress. Efforts to reduce early vein graft injury during harvest and preparation may have the potential to reduce subsequent vein graft failure in patients

Angiogenic mRNA and microRNA Gene Expression Signature Predicts a Novel Subtype of Serous Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death for women in the U.S. and the seventh most fatal worldwide. Although ovarian cancer is notable for its initial sensitivity to platinum-based therapies, the vast majority of patients eventually develop recurrent cancer and succumb to increasingly platinum-resistant disease. Modern, targeted cancer drugs intervene in cell signaling, and identifying key disease mechanisms and pathways would greatly advance our treatment abilities. In order to shed light on the molecular diversity of ovarian cancer, we performed comprehensive transcriptional profiling on 129 advanced stage, high grade serous ovarian cancers. We implemented a, re-sampling based version of the ISIS class discovery algorithm (rISIS: robust ISIS) and applied it to the entire set of ovarian cancer transcriptional profiles. rISIS identified a previously undescribed patient stratification, further supported by micro-RNA expression profiles, and gene set enrichment analysis found strong biological support for the stratification by extracellular matrix, cell adhesion, and angiogenesis genes. The corresponding “angiogenesis signature” was validated in ten published independent ovarian cancer gene expression datasets and is significantly associated with overall survival. The subtypes we have defined are of potential translational interest as they may be relevant for identifying patients who may benefit from the addition of anti-angiogenic therapies that are now being tested in clinical trials

Estimated Cost of Emergency Sunburn Visits—Validation of ICD-9-CM Search Criteria

To the Editor We applaud the evaluation by Guy and colleagues of costs for sunburn-associated visits to US emergency departments. Their analysis was performed using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) primary and secondary billing codes for sunburn (692.71, 692.76, and 692.77) in discharge records from the National Emergency Department Sample database

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

Personality is influenced by genetic and environmental factors1 and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci2,3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132–260,861). Of these genomewide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422–18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit– hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion–introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety)

A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts

AGING applies the Creative Commons Attribution License (CCAL) to all works we publishWe acknowledge the financial support of the University of Sheffield, The Pathological Society London, The University of Otago-Dunedin and the Development and Promotion of Science and Technology Talents Project, The Royal Thai Government. ICP is supported by a University of Malaya-MOHE High Impact Research grant (UM.C/625/1/HIR/MOHE/DENT/22)

Liquidity, term spreads and monetary policy

We propose a model with segmented markets that delivers endogenous variations in term spreads driven by banks’ portfolio decisions while facing maturity risk. Future profitability influences the term premium banks require to carry this risk. When expected profitability is relatively high (low) spreads are low (high). Spread fluctuations feed back into the macroeconomy through investment decisions. Econometric evidence corroborates this link between expected financial profitability and yield spreads. Finally, we analyse unconventional monetary policy by allowing banks to sell assets to the central bank. These interventions exploit a new channel of policy transmission through banks’ portfolio choice affecting the yield curve