Aven‐mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma

Conventional high‐grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis‐free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti‐apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G₂ cell‐cycle arrest; Chk1 protein levels were attenuated and ATR–Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven‐depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven‐controlled ATR–Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix‐embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR–Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

小鼠皮肤超氧化物歧化酶活性与枸杞多糖的干预

目的:观察枸杞多糖对皮肤胶原代谢和自由基产生的影响,探讨其抗皮肤衰老的作用。方法:实验于2005-06/2006-05在广东医学院整形外科研究所完成。①实验材料:清洁级昆明小鼠60只,月龄2个月,体质量16～24g,雌雄各半。②实验分组:将小鼠随机分为正常对照组、衰老模型组和抗衰老模型组,每组20只。③实验干预:模型组每日用D-半乳糖溶液皮下注射制造衰老模型,用量和时间为80mg/(kg·d)7d,120mg/(kg·d)14d,140mg/(kg·d)14d,180mg/(kg·d)7d。正常对照组每日注射同体积的生理盐水。抗衰老模型组在注射D-半乳糖期间以枸杞多糖灌胃,剂量为20mg/(kg·d),正常对照组和衰老组则以同体积的生理盐水代之灌胃。④实验评估:42d后切取小鼠颈背部皮肤,测定超氧化物歧化酶活力、羟脯氨酸和丙二醛含量。结果:56只小鼠进入结果分析(4只死亡)。①小鼠皮肤超氧化物歧化酶活力:与正常对照组相比,衰老组和抗衰老组小鼠皮肤超氧化物歧化酶活力降低,差异有显著性意义(P<0.01);抗衰老组与衰老模型组比较,超氧化物歧化酶活力增加,差异有显著性意义(P<0.01)。②与正常对照组相比,衰老组和抗衰老组小鼠皮肤羟脯氨酸和丙二醛含量增加,差异有显著性意义(P<0.01);抗衰老组与衰老组比较,羟脯氨酸和丙二醛含量均降低,差异有显著性意义(P<0.01)。结论:枸杞多糖改善皮肤老化的作用与提高小鼠皮肤超氧化物歧化酶活力,降低羟脯氨酸、丙二醛含量,影响胶原代谢有关。     

三七总皂甙对人肝癌细胞缝隙连接细胞间通讯的调节机制

目的：观察三七总皂甙对人肝癌细胞SMMC-7721缝隙连接细胞间通讯、以及缝隙连接蛋白32mRNA和磷酸化细胞外信号调节激酶1，2表达的影响。方法：实验于2005—08／2006—03在江西省分子医学重点实验室完成。①实验操作：SMMC-7721细胞用含100mg／L，200mg／L，400mg／L三七总皂甙的培养液预处理，对照组SMMC-7721细胞不加三七总皂甙。②实验评估：采用划痕标记，染料示踪技术检测缝隙连接细胞间通讯的变化；采用反转录-聚合酶链反应检测缝隙连接蛋白32mRNA水平；采用流式细胞仪检测磷酸化细胞外信号调节激酶1／2的表达。结果：①对照组染料局限于划痕两侧的细胞内，无明显的荧光染料传输，GJIC阴性；三七总皂甙可上调染料传输范围，且随三七总皂甙剂量增高，染料传输范围逐渐增大，最远可达三四层细胞。②反转录-聚合酶链反应结果显示，各组细胞缝隙连接蛋白32mRNA水平差异无显著性意义（P〉0．05）。③流式细胞仪结果显示，对照组SMMC-7721细胞磷酸化细胞外信号调节激酶1／2表达的阳性率较高，伴随三七总皂甙剂量增加磷酸化细胞外信号调节激酶1／2表达的阳性率逐渐下降，呈一定的剂量依赖效应。结论：三七总皂甙可能通过抑制SMMC-7721细胞磷酸化细胞外信号调节激酶1／2的活化减少缝隙连接蛋白32的磷酸化，进而上调SMMC-7721细胞的缝隙连接细胞间通讯功能。     

Four cancer cases after esophageal atresia repair: Time to start screening the upper gastrointestinal tract

Esophageal atresia(EA) is one of the most common congenital digestive malformations and requires surgical correction early in life. Dedicated centers have reported survival rates up to 95%. The most frequent comorbidities after EA repair are dysphagia(72%) and gastroesophageal reflux(GER)(67%). Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma. Several long-term follow-up studies found an increased risk of Barrett's esophagus and esophageal carcinoma in EA patients, both at a relatively young age. Given these findings, the recent ESPGHAN-NASPGHAN guideline recommends routine endoscopy in adults born with EA. We report a series of four EA patients who developed a carcinoma of the gastrointestinal tract: three esophageal carcinoma and one colorectal carcinoma in a colonic interposition. These cases emphasize the importance of lifelong screening of the upper gastrointestinal tract in EA patients.     

Effects of Erxian decoction, a Chinese medicinal formulation, on serum lipid profile in a rat model of menopause

Background

Infantile colic is a common painful clinical condition associated with signs of distended intestines and an increase in colon peristalsis. However, clinical documentation of observed gastrointestinal functions in the condition is still lacking. Even though the ailment is common, no clear treatment guidelines exist. While acupuncture with minimal stimulation has been shown to be effective in reducing crying behaviour of infants suffering from colic, the documented effect of acupuncture on gastrointestinal function in children with infantile colic is scarce. This case series study aims to document the symptoms of routinely rated gastrointestinal function and the changes in these symptoms after minimal acupuncture in a larger group of children with infantile colic.

Methods

This study included 913 infants with normal weights, and lengths at birth. The infants' mean age was 5.4 weeks when the observations started, and had colic symptoms since two weeks after birth. Light needling stimulation of the acupuncture point LI4 was performed for 10-20 seconds bilaterally on a daily basis for a mean of 6.2 consecutive days. A questionnaire with verbal rating scales for the parents' evaluation was used before and after the treatment period.

Results

Before treatment the infants were assessed by the parents in terms of 'often have inflated stomachs' (99%) and 'seldom drool' (76%), 'regurgitate' (53%) and 'belch' (62%). Moreover, the reported frequency of defecation was 5-8 times per day (64%), with a yellowish-green colour (61%) and with a water-thin consistency (74%). After treatment, the variables of inflated stomachs, drooling and regurgitating were systematically changed, and rated by the parents as occurring 'sometimes' while belching was rated as occurring 'often' and the frequency of defecation was reduced to 1-4 times/day with a mustard yellow colour and a gruel-like consistency. The parents also rated their impression of the infants' general colic symptoms including crying behaviour as much ameliorated in 76% of the cases.

Conclusion

The results of the present study show that minimal acupuncture at LI4 in infantile colic is an effective and easy treatment procedure that, furthermore, is reported to be without serious side effects.     

Genetics of cardiovascular and renal complications in diabetes

The development of debilitating complications represents a major heathcare burden associated with the treatment of diabetes. Despite advances in new therapies for controlling hyperglycemia, the burden associated with diabetic complications remains high, especially in relation to cardiovascular and renal complications. Furthermore, an increasing proportion of patients develop type 2 diabetes at a younger age, putting them at higher risk of developing complications as a result of the increased exposure to hyperglycemia. Diabetes has become the main contributing cause to end‐stage renal disease in most countries. Although there has been important breakthroughs in our understanding of the genetics of type 1 and type 2 diabetes, bringing important insights towards the pathogenesis of diabetes, there has been comparatively less progress in our understanding of the genetic basis of diabetic complications. Genome‐wide association studies are beginning to expand our understanding of the genetic architecture relating to diabetic complications. Improved understanding of the genetic basis of diabetic cardiorenal complications might provide an opportunity for improved risk prediction, as well as the development of new therapies.     

Treatment of refractory adult lymphoblastic leukemia (ALL) with 4'(9- acridinylamino) methanesulfon-M-anisidide (AMSA)

Twenty-four adults with ALL were treated with AMSA alone or in combination. Twenty-two were treated at time of relapse and two patients after failing primary induction therapy. All had been treated with anthracyclines prior to receiving AMSA. Of the 22 patients with ALL in relapse, 4 achieved a complete remission. Two of these patients have relapsed while receiving maintenance chemotherapy; one died 1 mo after achieving remission due to the occurrence of cholycystitis in the setting of pancytopenia and one patient underwent bone marrow transplantation and is in remission at 8 mo after the second remission. Both patients who failed primary induction therapy remain in remission at 11 and 36 mo, respectively. The use of AMSA should be considered for patients with ALL who fail primary induction as well as those whose leukemia becomes resistant to conventional agents.     

Morphological assessment of pancreatic islet hormone content following aerobic exercise training in rats with poorly controlled Type 1 diabetes mellitus

Regular exercise has been shown to improve many complications of Type 1 diabetes mellitus (T1DM) including enhanced glucose tolerance and increased cardiac function. While exercise training has been shown to increase insulin content in pancreatic islets of rats with T1DM, experimental models were severely hyperglycemic and not undergoing insulin treatment. Further, research to date has yet to determine how exercise training alters glucagon content in pancreatic islets. The purpose of the present investigation was to determine the impact of a 10-week aerobic training program on pancreatic islet composition in insulin-treated rats with T1DM. Second, it was determined whether the acute, exercise-mediated reduction in blood glucose experienced in rats with T1DM would become larger in magnitude following aerobic exercise training. Diabetes was induced in male Sprague-Dawley rats by multiple low dose injections of streptozotocin (20mg/kg i.p.) and moderate intensity aerobic exercise training was performed on a motorized treadmill for one hour per day for a total of 10 weeks. Rats with T1DM demonstrated significantly less islet insulin, and significantly more islet glucagon hormone content compared with non-T1DM rats, which did not significantly change following aerobic training. The reduction in blood glucose in response to a single exercise bout was similar across 10 weeks of training. Results also support the view that different subpopulations of islets exist, as small islets (<50 μm diameter) had significantly more insulin and glucagon in rats with and without T1DM.