Reducing breast cancer recurrence with weight loss,a vanguard trial: The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial

Breast cancer is the most common invasive cancer among women in developed countries. Obesity is a major risk factor for breast cancer recurrence and mortality in both pre- and postmenopausal women. Co-morbid medical conditions are common among breast cancer survivors. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is a 4-year randomized clinical trial of 693 overweight/obese women aged ≥ 21 years diagnosed with any early stage breast cancer (stages I[≥ 1 cm]-III) within the previous five years, designed to demonstrate the feasibility of achieving sustained weight loss and to examine the impact of weight loss on quality of life and co-morbidities, and to enable future exploration of biochemical mechanisms linking obesity to lower likelihood of disease-free survival. This trial is strategically designed as a vanguard for a fully-powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival. Participants were recruited between 2010 and 2012 at four sites, had completed initial therapies, and had a body mass index between 25 and 45 kg/m². The intervention featured a group-based cognitive-behavioral weight loss program with telephone counseling and tailored newsletters to support initial weight loss and subsequent maintenance, with the goal of 7% weight loss at two years. This study has high potential to have a major impact on clinical management and outcomes after a breast cancer diagnosis. This trial initiates the effort to establish weight loss support for overweight or obese breast cancer survivors as a new standard of clinical care.     

Role of prostaglandins in mediating differences in human internal mammary and radial artery relaxation elicited by hypoxia

The effects of hypoxia-reoxygenation on internal mammary (IMA) and radial (RA) arteries used for coronary artery bypass grafting (CABG) were examined to identify mechanisms regulating contractile function and differences that could contribute to vasospasm. Isolated endothelium-intact IMA and RA rings precontracted with KCl (30 mM) rapidly dilated to hypoxia (95% N(2)/5% CO(2)) with a greater relaxation in RA than IMA. Inhibitors of cyclooxygenase (10 microM indomethacin) and the thromboxane A(2) (TxA)(2) receptor [1 microM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[2-(phenylamino)carbonyl]hydrazine]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-29548)] potentiated the relaxation to hypoxia in IMA, but not RA, a response associated with increases in TxA(2). Relaxation of IMA and RA to hypoxia appears to involve a calcium-reuptake mechanism inhibited by cyclopiazonic acid (0.2 mM), and it was not attenuated by a blocker of potassium channels (10 mM TEA). The recovery of force generation of IMA, but not RA, upon reoxygenation after 30 min of hypoxia was significantly reduced in the initial phase of reoxygenation by indomethacin and SQ-29548 and by endothelin receptor blocker BQ-123 [cyclo(l-Leu-d-Trp-d-Asp-l-Pro-d-Val)]. Thus, hypoxia relaxes IMA and RA by a prostaglandin-independent mechanism potentially involving enhanced intracellular calcium reuptake. The prostaglandin-mediated alterations of responses to hypoxia-reoxygenation seen in IMA, but not in RA, may predispose IMA to vasospasm-related complications of CABG.     

体内埋植实验比较全氟丙氧基聚四氟乙烯与传统硅胶的生物相容性

目的:通过动物埋植实验评估新型生物植入材料全氟丙氧基聚四氟乙烯的生物相容性。方法:实验于2004-09/2006-04在上海交大化学化工学院和上海交大附属第一人民医院耳鼻喉头颈外科实验室完成。①实验材料:采用四氟乙烯、六氟丙烷等原料在反应瓮中以一定的温度和压力,用特定的催化剂合成全氟丙氧基聚四氟乙烯(Mr105～107),半透明状,质地与硅胶类似。用临床目前常用的隆鼻硅胶假体商品作为对照。②实验分组:取健康杂种豚鼠30只,按随机数字表法编号后将消毒后的全氟丙氧基聚四氟乙烯和硅胶模块分别置入左右后腿浅筋膜与肌肉层之间。植入全氟丙氧基聚四氟乙烯材料为新材料组,植入硅胶材料为硅胶组。为防止系统误差,编号为单数的豚鼠左后腿放置新材料,右后腿放硅胶;编号为双数的豚鼠左后腿放置硅胶,右后腿放新材料。完成手术后继续饲养豚鼠,1～10,11～20,21～30号豚鼠分别于术后15,30,60d麻醉后处死,取出埋植模块周围组织,苏木精-伊红染色。实验评估:光镜下观察埋入材料周围组织、细胞的反应和变化,判断两种材料的生物相容性差异。结果:所有豚鼠安全经受了手术,术后未出现感染,也未使用抗生素。25号豚鼠右腿出现排异反应,术后10d埋藏的硅胶排出,排出后切口自然愈合。所有豚鼠切口正常愈合。①植入后15d,两种材料周围均见大量中性粒细胞浸润,并伴有明显血管充血,材料周围无囊壁形成。②植入30d时,材料周围无明显囊壁形成,周围见大量中性粒细胞。硅胶组中发现周边组织明显渗血。③植入60d时,新材料组囊壁厚度明显薄于硅胶组[分别为(35.01±14.03),(66.63±17.96)μm],差异有显著性意义(t=6.849,P<0.01)。结论:全氟丙氧基聚四氟乙烯材料的生物相容性优于传统硅胶材料。     

Nurses using physical restraints: Are the accused also the victims? – A study using focus group interviews

Background  

To date, the literature has provided an abundance of evidence on the adverse outcomes of restraint use on patients. Reportedly, nurses are often the personnel who initiate restraint use and attribute its use to ensuring the safety of the restrained and the others. A clinical trial using staff education and administrative input as the key components of a restraint reduction program was conducted in a rehabilitation setting to examine whether there were any significant differences in the prevalence of restraint use pre- and post-intervention. Subsequent to the implementation of the intervention program, focus group interviews were conducted to determine the perspective of the nursing staff on the use of restraints and their opinions of appropriate means to reduce their use.     

Obesity and Cancer

Weight, weight gain, and obesity account for approximately 20% of all cancer cases. Evidence on the relation of each to cancer is summarized, including esophageal, thyroid, colon, renal, liver, melanoma, multiple myeloma, rectum, gallbladder, leukemia, lymphoma, and prostate in men; and postmenopausal breast and endometrium in women. Different mechanisms drive etiologic pathways for these cancers. Weight loss, particularly among postmenopausal women, reduces risk for breast cancer. Among cancer patients, data are less robust, but we note a long history of poor outcomes after breast cancer among obese women. While evidence on obesity and outcomes for other cancers is mixed, growing evidence points to benefits of physical activity for breast and colon cancers. Dosing of chemotherapy and radiation therapy among obese patients is discussed and the impact on therapy‐related toxicity is noted. Guidelines for counseling patients for weight loss and increased physical activity are presented and supported by strong evidence that increased physical activity leads to improved quality of life among cancer survivors. The “Five A's” model guides clinicians through a counseling session: assess, advise, agree, assist, arrange. The burden of obesity on society continues to increase and warrants closer attention by clinicians for both cancer prevention and improved outcomes after diagnosis.     

PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is implicated in the pathogenesis of pancreatic neuroendocrine tumors (pNETs). Activation of this pathway is driven by aberrant tyrosine kinase receptor activities. Mutations in the PI3K/Akt/mTOR pathway occur in 15% of pNETs, and expression of genes of the PI3K/Akt/mTOR pathway is altered in the majority of pNETs. The mTOR inhibitor everolimus has been approved by the FDA for the treatment of pNET, but its efficacy may be limited by its inability to prevent mTORC2-mediated activation of Akt. Specific inhibitors of PI3K, Akt, or other pathway nodes, and their concomitant use with mTOR inhibitors, or agents with dual activity, may be more effective. Preclinical studies demonstrate that inhibitors of the PI3K pathway have antitumor activity in pNET cells, either through direct inhibition of individual pathway nodes or indirect inhibition of molecular chaperones such as heat-shock protein 90. Clinical studies are underway evaluating individual node and dual node inhibitors.     

反相高效液相色谱测定丹参注射剂的三种有效成分

本文用反相高效液相色谱法,采用离子抑制技术分离了丹参注射剂中三种有效成分:丹参素、原儿茶醛、原儿茶酸。并用外标法测定了它们在丹参注射液和复方丹参注射液中的含量。考察了Waters公司分析柱(3.9×300 mm)和径向加压柱(8×100 mm),以及国产色谱柱(5×150mm)分析样品,均能获得满意的结果。比较了用多通道紫外吸收检测器和254nm固定波长紫外检测器测定样品时灵敏度的差异。     

Late Prenatal Immune Activation in Mice Leads to Behavioral and Neurochemical Abnormalities Relevant to the Negative Symptoms of Schizophrenia

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.     

Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

Background and purpose:

During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate ({"type":"entrez-nucleotide","attrs":{"text":"LY466195","term_id":"1258058612","term_text":"LY466195"}}LY466195) glutamate receptors affected dural vasodilatation induced by α-CGRP, capsaicin and periarterial electrical stimulation in rats, using intravital microscopy.

Experimental approach:

Male Sprague-Dawley rats were anaesthetized and the overlying bone was thinned to visualize the dural artery. Then, vasodilator responses to exogenous (i.v. α-CGRP) and endogenous (released by i.v. capsaicin and periarterial electrical stimulation) CGRP were elicited in the absence or presence of the above antagonists.

Key results:

α-CGRP, capsaicin and periarterial electrical stimulation increased dural artery diameter. Ketamine and MK801 inhibited the vasodilator responses to capsaicin and electrical stimulation, while only ketamine attenuated those to α-CGRP. In contrast, GYKI52466 only attenuated the vasodilatation to exogenous α-CGRP, while {"type":"entrez-nucleotide","attrs":{"text":"LY466195","term_id":"1258058612","term_text":"LY466195"}}LY466195 did not affect the vasodilator responses to endogenous or exogenous CGRP.

Conclusions and implications:

Although GYKI52466 has not been tested clinically, our data suggest that it would not inhibit migraine via vascular mechanisms. Similarly, the antimigraine efficacy of {"type":"entrez-nucleotide","attrs":{"text":"LY466195","term_id":"1258058612","term_text":"LY466195"}}LY466195 seems unrelated to vascular CGRP-mediated pathways and/or receptors. In contrast, the cranial vascular effects of ketamine and MK801 may represent a therapeutic mechanism, although the same mechanism might contribute, peripherally, to cardiovascular side effects.