Implementing the exercise guidelines for cancer survivors

In 2009, the American College of Sports Medicine convened an expert roundtable to issue guidelines on exercise for cancer survivors. This multidisciplinary group evaluated the strength of the evidence for the safety and benefits of exercise as a therapeutic intervention for survivors. The panel concluded that exercise is safe and offers myriad benefits for survivors including improvements in physical function, strength, fatigue, quality of life, and possibly recurrence and survival. Recommendations for situations in which deviations from the US Physical Activity Guidelines for Americans are appropriate were provided. Here, we outline a process for implementing the guidelines in clinical practice and provide recommendations for how the oncology care provider can interface with the exercise and physical therapy community.     

Bi‐allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer

Homologous recombination (HR) DNA repair‐deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51‐based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole‐exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large‐scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi‐allelic loss‐of‐function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR‐proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi‐allelic alterations in the HR pathway to deliver a precision medicine‐based approach to select patients for therapies targeting tumour‐specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Desmin‐related myopathy

van Spaendonck‐Zwarts KY, van Hessem L, Jongbloed JDH, de Walle HEK, Capetanaki Y, van der Kooi AJ, van Langen IM, van den Berg MP, van Tintelen JP. Desmin‐related myopathy. Desmin‐related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta‐analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype–phenotype correlations. Meta‐analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype.     

Enhanced ex vivo expansion of adult mesenchymal stem cells by fetal mesenchymal stem cell ECM

Large-scale expansion of highly functional adult human mesenchymal stem cells (aMSCs) remains technologically challenging as aMSCs lose self renewal capacity and multipotency during traditional long-term culture and their quality/quantity declines with donor age and disease. Identification of culture conditions enabling prolonged expansion and rejuvenation would have dramatic impact in regenerative medicine. aMSC-derived decellularized extracellular matrix (ECM) has been shown to provide such microenvironment which promotes MSC self renewal and “stemness”. Since previous studies have demonstrated superior proliferation and osteogenic potential of human fetal MSCs (fMSCs), we hypothesize that their ECM may promote expansion of clinically relevant aMSCs. We demonstrated that aMSCs were more proliferative (∼1.6×) on fMSC-derived ECM than aMSC-derived ECMs and traditional tissue culture wares (TCPS). These aMSCs were smaller and more uniform in size (median ± interquartile range: 15.5 ± 4.1 μm versus 17.2 ± 5.0 μm and 15.5 ± 4.1 μm for aMSC ECM and TCPS respectively), exhibited the necessary biomarker signatures, and stained positive for osteogenic, adipogenic and chondrogenic expressions; indications that they maintained multipotency during culture. Furthermore, fMSC ECM improved the proliferation (∼2.2×), size (19.6 ± 11.9 μm vs 30.2 ± 14.5 μm) and differentiation potential in late-passaged aMSCs compared to TCPS. In conclusion, we have established fMSC ECM as a promising cell culture platform for ex vivo expansion of aMSCs.     

A model to control the epidemic of H5N1 influenza at the source

Background  

No country is fully prepared for a 1918-like pandemic influenza. Averting a pandemic of H5N1 influenza virus depends on the successful control of its endemicity, outbreaks in poultry and occasional spillage into human which carries a case-fatality rate of over 50%. The use of perimetric depopulation and vaccination has failed to halt the spread of the epidemic. Blanket vaccination for all poultry over a large geographical area is difficult. A combination of moratorium, segregation of water fowls from chickens and vaccination have been proved to be effective in the Hong Kong Special Administrative Region (HKSAR) since 2002 despite endemicity and outbreaks in neighbouring regions. Systematic surveillance in southern China showed that ducks and geese are the primary reservoirs which transmit the virus to chickens, minor poultry and even migratory birds.     

Roles for NAD(P)H oxidases and reactive oxygen species in vascular oxygen sensing mechanisms.

Observations that physiological levels of O2 control the rates of production of reactive O2 species by systems including NAD(P)H oxidases and that certain of these species have signalling mechanisms that regulate vascular tone has resulted in consideration of these systems in processes that mediate the sensing of changes in P(O2). Evidence exists for the participation of hydrogen peroxide-dependent regulation of prostaglandin production and soluble guanylate cyclase activity, resulting from the metabolism of peroxide by cyclooxygenase and catalase, respectively, in P(O2)-elicited signalling mechanisms that regulate vascular force generation. A microsomal NADH oxidase whose activity is controlled by the redox status of cytosolic NAD(H) appears to function as a P(O2) sensor in bovine pulmonary and coronary arteries where changes in O2 levels control the production of superoxide anion-derived hydrogen peroxide and a cGMP-mediated relaxation response. Interactions with nitric oxide and superoxide anion, and the activity of glutathione peroxidase appear to influence the function of these O2 sensing systems, and some of these interactions, along with the activation of other oxidases, may contribute to alterations in P(O2) sensing mechanisms under pathophysiological conditions that affect vascular function.     

HPLC测定九分散中麻黄碱、伪麻黄碱和士的宁的含量

本文用HPLC法对中成药九分散中麻黄碱、伪麻黄碱及士的宁进行了分离及含量测定。与药典法比较,本法的提取率较高,其中麻黄碱为药典方法的1.33倍,伪麻黄碱为1.29倍,而士的宁则与药典方法相当。在μBondapak C_(18)色谱柱上,用MeOH—KH_2PO_4溶液为流动相梯度洗脱进行了各组分的分离。各组分工作曲线线性良好,麻黄碱,伪麻黄碱在0～8μg、士的宁0～14μg范围内呈线性关系。测得回收率为麻黄碱98.94±2.2%;伪麻黄碱97.37±1.9%;士的宁100.7±1.9%。