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.     

败血症病人死亡危险性预评估方法的探讨

目的:探索可早期预测严重败血症病人死亡的临床和实验室指标或系统模型。方法:对ICU连续收治的26例严重败血症病人行前瞻性观察28天,分析其死亡的相关临床和实验室指标。结果:共有14人(54％)死亡,多死于第1周内(74％)。根据循环中的细胞间粘附分子-1水平能早期预测其脏器衰竭和死亡。一些临床指标水平在死亡病人与生存病人之间差别较大,其中包括血总胆红素、pH值、红细胞压积、氧合指数、动静脉血氧差、四项SIRS指标和一些血流动力学指标等。结论:综合上述指标可以尝试建立起了一个能够早期评估病人死亡可能性的积分系统。     

Analysis of the relationship between age and treatment response in migraine

In migraine, headache severity varies with age. As a consequence, the effectiveness of medication may also depend on a patient's age. The purpose of this study was to assess the combined effect of age and drug treatment on headache characteristics. Using data from clinical trials of sumatriptan in adolescents and adults, we show how the interaction between age and drug exposure can be parameterised as a covariate on a Markov model that describes the decline of headache severity over three clinically defined stages (no relief, relief and pain-free status). The model explains important clinical observations: (i) the rates at which the pain relief and pain-free status were attained were found to be inversely related to age; (ii) in placebo-treated patients, the mean transit time from 'no relief' to 'relief' is 3 h for young adolescents and increases to 6 h for patients aged ≥ 30 years; and (iii) sumatriptan reduces the transit time to 2 h, irrespective of age. These findings indicate that the therapeutic gain over placebo increases with age. Prospective studies of antimigraine drugs should take this relationship into account when extrapolating efficacy data from adults to adolescents.     

Symptoms of ＂Heat＂ as a Pattern of Physiopathology

Objective： The guiding criteria are considered the backbone of Chinese medicine. They have previously been described as functional features （symptoms） leading to the overall assessment of human functions on the basis of a regulatory （cybernetic） model referring to the I Ging. Methods： The Heidelberg model can explain symptoms such as created by ＂heat＂ on a rational physiological level. Results ＆ Conclusion： The overall of physiological symptoms are shown as a schematic draft. The basis of ＂heat＂ is considered to be a general increase of microcirculation in the periphery. This leads to a couple of local pathophysiological consequences and sensations like 1） red tongue （the tongue is considered an embryological somatotopic system）. 2） Sensation of warmth （by increase of capillary flow）. 3） pre-inflammatory state, leading to pain modalities like ＂worse if pressed＂, as inflammations tend to be increasingly painful under pressure; 4） reddish skin, the mechanisms by which this is induced may include the release of substance P, therefore accompanied by burning sensation. Systemic pathophysiological consequences may include. Relative lack of fluid in the larger vessels, as fluid supplies peripheral capillary flow. This may lead to water saving mechanisms like thirst, dry mucosa with do, mouth, dry nose, dry lips, dry skin, and also dry stool, yellow and sparse urine.     

Melanoma inhibitory activity (MIA) Evaluierung eines neuen tumorassoziierten Antigens als Serummarker für uveale Melanome

BACKGROUND: Currently no serological marker for the monitoring of uveal melanoma and its metastases is available. The novel tumor associated antigen Melanoma inhibitory activity (MIA) is expressed in the uveal melanoma and it's metastatic lesions. METHOD: We report about the serum samples of 38 patients with uveal melanomas. 4 of these patients had overt metastatic disease. A nonradioactive one step ELISA was used to quantify the MIA serum levels. RESULTS: In the 34 patients without overt metastatic disease the serum concentration of MIA was mean (+/- 1 SD) 3.6 +/- 1.0 ng/ml. In the 4 patients with overt metastatic disease the serum concentration of MIA was mean (+/- 1 SD) 27.7 +/- 3.0 ng/ml. The difference was statistically highly significant (student t test: p = 0.0001). CONCLUSION: MIA is expressed in primary and metastatic lesions of uveal melanomas. The elevation of MIA serum levels in patients with metastatic disease from melanomas suggests a promising role as a serum marker for monitoring patients with uveal melanoma.     

Sun-related behaviors of outdoor working men with a history of non-melanoma skin cancer

The present study describes sun exposure and sun protection behaviors of northern Australian outdoor workers with previous non-melanoma skin cancer (NMSC). In 1999 a cross-sectional study of northern Australian men with previous NMSC was conducted by self-administered questionnaire. Compared to other men, outdoor workers spent more time in the sun on average working days and days off (P < 0.0001, respectively), and outdoor workers with sun-sensitive skin reported that more skin lesions had been removed (P = 0.0461). The workplace did not reinforce sun-safe practices of 36.8% of workers who spent half their time or more outdoors. Sun-protective behaviors were not different between in- and outdoor workers. Outdoor workers experienced high levels of sun exposure, however, sun-protective behavior was similar to other workers. Workplaces should be targeted to reinforce sun-safe policies.     

Loss of p14<Superscript>ARF</Superscript> expression in melanoma

Lack of p14ARF expression or its functional inactivation has been observed in human and murine carcinomas. Although very few mutations of p14ARF have been detected in some cancer types, changes in expression seem to play an important role in the development of other human cancers such as mesotheliomas. To examine the p14ARF gene and expression of p14ARF protein in melanomas, we screened eight human melanoma cell lines and primary human melanocytes by RT-PCR, sequencing and immunoblotting. All melanoma cell lines analyzed expressed wild-type p14ARF mRNA as well as protein. P14ARF expression was investigated by immunohistochemical staining of 32 tissue samples of benign melanocytic nevi (n=14), melanomas (n=12) and melanoma metastases (n=6). In contrast to the results obtained from cell lines in vitro the immunohistochemical stainings revealed a correlation between the progression of melanoma and the lack of the p14ARF protein expression. Positive p14ARF protein staining was observed in 11 of 14 benign nevi, in 3 of 12 melanomas and in 0 of 6 melanoma metastases. In summary, we demonstrated a significant inverse correlation between p14ARF protein expression and progression of melanocytic tumors since the amount of p14ARF protein staining decreased from benign melanocytic nevi to metastatic melanoma in situ. These results suggest that p14ARF inactivation is important in the development of melanomas.