Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes

<p>Abstract</p> <p>Background</p> <p>Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations.</p> <p>Methods</p> <p>GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes.</p> <p>Results</p> <p>Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg⁺⁺, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-<it>Myc </it>and <it>Trp53 </it>were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in <it>Ras </it>and genes encoding adhesion or cytoskeleton proteins such as integrin, β-catenin, α-catenin, and actin.</p> <p>Conclusion</p> <p>The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis.</p

Premature ventricular complexes : diagnostic and therapeutic considerations in clinical practice A state-of-the-art review by the American College of Cardiology Electrophysiology Council

Premature ventricular complexes (PVCs) are common arrhythmias in the clinical setting. PVCs in the structurally normal heart are usually benign, but in the presence of structural heart disease (SHD), they may indicate increased risk of sudden death. High PVC burden may induce cardiomyopathy and left ventricular (LV) dysfunction or worsen underlying cardiomyopathy. Sometimes PVCs may be a marker of underlying pathophysiologic process such as myocarditis. Identification of PVC burden is important, since cardiomyopathy and LV dysfunction can reverse after catheter ablation or pharmacological suppression. This state-of-the-art review discusses pathophysiology, clinical manifestations, how to differentiate benign and malignant PVCs, PVCs in the structurally normal heart, underlying SHD, diagnostic procedures (physical examination, electrocardiogram, ambulatory monitoring, exercise testing, echocardiography, cardiac magnetic resonance imaging, coronary angiography, electrophysiology study), and treatment (lifestyle modification, electrolyte imbalance, medical, and catheter ablation)

An international, multidisciplinary consensus set of patient-centered outcome measures for substance-related and addictive disorders

Background: In 1990, the United States’ Institute of Medicine promoted the principles of outcomes monitoring in the alcohol and other drug treatment field to improve the evidence synthesis and quality of research. While various national outcome measures have been developed and employed, no global consensus on standard measurement has been agreed for addiction: it is thus timely to build international consensus. Convened by the International Consortium for Health Outcomes Measurement (ICHOM), an international, multi-disciplinary working group reviewed the existing literature and reached consensus for a globally applicable minimum Set of outcome measures for people who seek treatment for addiction. Methods: Twenty-six addiction experts from 11 countries and five continents, including people with lived experience (n=5; 19%) convened over 16 months (December 2018-March 2020) to develop recommendations for a minimum Set of Outcome Measures,. A structured, consensus-building, modified Delphi process was employed. Evidence-based proposals for the minimum Set of measures were generated and discussed across eight videoconferences and in a subsequent structured online consultation. The resulting Set was reviewed by 123 professionals and 34 people with lived experience internationally. Results: The final consensus-based recommendation includes alcohol, substance, and tobacco use disorders, as well as gambling and gaming disorders in people aged 12 years and older. Recommended outcome domains are quantity-frequency of addictive disorders, symptom burden, health-related quality of life, global functioning, psychosocial functioning, and overall physical and mental health and wellbeing. Standard case-mix (moderator) variables and measurement time points are also recommended. Conclusions: Use of consistent and meaningful outcome measurement facilitates carer-patient relations, shared decision-making, service improvement, benchmarking, and evidence synthesis for evaluation of addiction treatment services and dissemination of best practices. The consensus Set of recommended outcomes is freely available for adoption in healthcare settings globally

An International, Multidisciplinary Consensus Set of Patient-Centered Outcome Measures for Substance-Related and Addictive Disorders.

Peer reviewed: TrueAcknowledgements: This work is in memory of Christpher Wait. We acknowledge and would like to thank all individuals involved in completing the open review feedback survey aimed at improving the set recommendation. We would also like to acknowledge individuals with lived experience expertise who were involved and participated in this research. We acknowledge and thank Umanga de Silva (ICHOM) for their administrative support.Publication status: PublishedFunder: NHS England and NHS ImprovementFunder: the NSW Agency for Clinical Innovation, AustraliaFunder: Providence Health Care, USAFunder: egion Västra Götaland, SwedenBackground: In 1990, the United States' Institute of Medicine promoted the principles of outcomes monitoring in the alcohol and other drugs treatment field to improve the evidence synthesis and quality of research. While various national outcome measures have been developed and employed, no global consensus on standard measurement has been agreed for addiction. It is thus timely to build an international consensus. Convened by the International Consortium for Health Outcomes Measurement (ICHOM), an international, multi-disciplinary working group reviewed the existing literature and reached consensus for a globally applicable minimum set of outcome measures for people who seek treatment for addiction. Methods: To this end, 26 addiction experts from 11 countries and 5 continents, including people with lived experience (n = 5; 19%), convened over 16 months (December 2018-March 2020) to develop recommendations for a minimum set of outcome measures. A structured, consensus-building, modified Delphi process was employed. Evidence-based proposals for the minimum set of measures were generated and discussed across eight videoconferences and in a subsequent structured online consultation. The resulting set was reviewed by 123 professionals and 34 people with lived experience internationally. Results: The final consensus-based recommendation includes alcohol, substance, and tobacco use disorders, as well as gambling and gaming disorders in people aged 12 years and older. Recommended outcome domains are frequency and quantity of addictive disorders, symptom burden, health-related quality of life, global functioning, psychosocial functioning, and overall physical and mental health and wellbeing. Standard case-mix (moderator) variables and measurement time points are also recommended. Conclusions: Use of consistent and meaningful outcome measurement facilitates carer-patient relations, shared decision-making, service improvement, benchmarking, and evidence synthesis for the evaluation of addiction treatment services and the dissemination of best practices. The consensus set of recommended outcomes is freely available for adoption in healthcare settings globally

Protein calorie malnutrition, nutritional intervention and personalized cancer care

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of \u3c50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of \u3e2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexiacachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients