The role of T‐cell protein tyrosine phosphatase in epithelial carcinogenesis

T‐cell protein tyrosine phosphatase (TC‐PTP, encoded by PTPN2) is a nonreceptor PTP that is most highly expressed in hematopoietic tissues. TC‐PTP modulates a variety of physiological functions including cell cycle progression, cell survival and proliferation, and hematopoiesis through tyrosine dephosphorylation of its target substrates, such as EGFR, JAK1, JAK3, STAT1, and STAT3. Studies with whole or tissue‐specific loss of TC‐PTP function transgenic mice have shown that TC‐PTP has crucial roles in the regulation of the immune response, insulin signaling, and oncogenic signaling. More recently, the generation of epidermal‐specific TC‐PTP‐deficient mice for use in multistage skin carcinogenesis bioassays demonstrated that TC‐PTP suppresses skin tumor formation by negatively regulating STAT3 and AKT signaling. Further investigation showed that TC‐PTP also minimizes UVB‐induced epidermal cell damage by promoting apoptosis through the negative regulation of Flk‐1/JNK signaling. These findings provide major evidence for a tumor suppressive function for TC‐PTP against environment‐induced skin cancer. Here, we will discuss TC‐PTP, its substrates, and its functions with an emphasis on its role in skin carcinogenesis.     

Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development

Secretin family G protein-coupled receptors (GPCRs) are important therapeutic targets for migraine, diabetes, bone disorders, inflammatory disorders and cardiovascular disease. They possess a large N-terminal extracellular domain (ECD) known to be the primary ligand-binding determinant. Structural determination of several secretin family GPCR ECDs in complex with peptide ligands has been achieved recently, providing insight into the molecular determinants of hormone binding. Some secretin family GPCRs associate with receptor activity-modifying proteins (RAMPs), resulting in changes to receptor pharmacology. Recently, the first crystal structure of a RAMP ECD in complex with a secretin family GPCR was solved, revealing the elegant mechanism governing receptor selectivity of small molecule antagonists of the calcitonin gene-related peptide (CGRP) receptor. Here we review the structural basis of ligand binding to secretin family GPCRs, concentrating on recent progress made on the structural basis of RAMP-modified GPCR pharmacology and its implications for rational drug design.     

Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?

The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR.     

Healthy fish consumption and reduced mercury exposure: counseling women in their reproductive years

Objective

To provide family physicians with a practical, evidence-based approach to counseling women about healthy fish eating.

Sources of information

MEDLINE was searched for articles published between 1999 and 2008. Most studies described in this article provide level II or III evidence.

Main message

Fish is an important component of a healthy diet for women in their reproductive years owing to the beneficial effects of omega-3 fatty acids on the neurologic development of the fetus. However, some fish species contain considerable methylmercury, which crosses the placenta and has harmful effects on neurobehavioural development. As many jurisdictions have issued fish consumption advisories, which can be confusing, women would benefit from individualized assistance from a trusted source, their family physicians, to clarify the risks and benefits of eating fish.

Conclusion

We recommend that family physicians counsel women in their reproductive years about healthy choices regarding fish in their diet, and provide appropriate resources.     

Primary percutaneous coronary intervention for ST-elevation myocardial infarction in a patient with a single coronary artery arising from the right aortic sinus

We report the first case of primary percutaneous coronary intervention (PPCI) in a patient with a single coronary artery arising from the right aortic sinus. With the increasing availability of PPCI, more patients with coronary artery anomalies will undergo this procedure. This report highlights both the feasibility and safety of PPCI in patients with even the rarest of coronary artery anomalies.     

A prospective cohort study to investigate cost-minimisation,of Traditional open,open fAst track recovery and laParoscopic fASt track multimodal management,for surgical patients with colon carcinomas (TAPAS study)

Background

The present developments in colon surgery are characterized by two innovations: the introduction of the laparoscopic operation technique and fast recovery programs such as the Enhanced Recovery After Surgery (ERAS) recovery program. The Tapas-study was conceived to determine which of the three treatment programs: open conventional surgery, open 'ERAS' surgery or laparoscopic 'ERAS' surgery for patients with colon carcinomas is most cost minimizing?

Method/design

The Tapas-study is a three-arm multicenter prospective cohort study.All patients with colon carcinoma, eligible for surgical treatment within the study period in four general teaching hospitals and one university hospital will be included. This design produces three cohorts: Conventional open surgery is the control exposure (cohort 1). Open surgery with ERAS recovery (cohort 2) and laparoscopic surgery with ERAS recovery (cohort 3) are the alternative exposures. Three separate time periods are used in order to prevent attrition bias.Primary outcome parameters are the two main cost factors: direct medical costs (real cost price calculation) and the indirect non medical costs (friction method). Secondary outcome parameters are mortality, complications, surgical-oncological resection margins, hospital stay, readmission rates, time back to work/recovery, health status and quality of life.Based on an estimated difference in direct medical costs (highest cost factor) of 38% between open and laparoscopic surgery (alfa = 0.01, beta = 0.05), a group size of 3×40 = 120 patients is calculated.

Discussion

The Tapas-study is three-arm multicenter cohort study that will provide a cost evaluation of three treatment programs for patients with colon carcinoma, which may serve as a guideline for choice of treatment and investment strategies in hospitals.

Trial registration

ISRCTN44649165.

     

麝香保心丸对内皮素-1诱导原代培养的人脐动脉血管平滑肌细胞增殖的影响

目的:观察麝香保心丸(SXBXW)对内皮素-1(ET-1)诱导原代培养的人脐动脉血管平滑肌细胞(VSMCs)增殖作用的影响。方法:建立ET-1刺激原代培养人脐动脉VSMCs增殖的细胞模型,设对照组、ET-1组、ET-1+SXBXW0.25g/L组、ET-1+SXBXW0.5g/L组、ET-1+SXBXW1.0g/L组和ET-1+SXBXW2.0g/L组,采用MTT法测定ET-1和SXBXW对细胞增殖的影响;用台盼蓝拒染和乳酸脱氢酶检测方法观察不同浓度的SXBXW对VSMCs的毒性作用;用流式细胞术观察ET-1和SXBXW对VSMCs增殖周期的影响。结果:与对照组相比,ET-1可显著促进VSMCs的增殖,一定剂量的SXBXW能够有效地抑制ET-1诱导的VSMCs细胞增殖,呈剂量依赖性;SXBXW抑制细胞增殖,但对活细胞数目和乳酸脱氢酶释放量均没有影响,提示对VSMCs无毒性作用。ET-1能够刺激VSMCs从G1期进入S期,从而促进细胞增殖,而SXBXW能抑制这一作用。结论:SXBXW能够有效抑制ET-1诱导的VSMCs增殖作用,其作用机制可能与其抑制细胞周期从G1期进入S期有关。     

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

Hepatitis due to hepatitis B virus(HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximabcontaining therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen(HBs Ag) and antibody to hepatitis B core antigen(antiHBc). Patients found to be positive for HBs Ag should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving highrisk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBs Ag-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.     

甲状腺术中喉返神经监测技术的标准化

目的在甲状腺手术中缺少术中神经监测(intra operative neuromonitoring,IONM)的标准化操作可导致结果变异性强,这些结果可产生错误信息并增加喉返神经损伤的危险性。因此有必要进行IONM操作的标准化。方法本研究共招募了289例进行过甲状腺切除术的患者(435根神经有危险),均由一位外科医师实施手术。每例患者均由同一位麻醉师使用EMG气管导管进行插管。每例患者均进行标准化IONM操作。该操作包括术前和术后对声带运动进行录像监测、保证电极在正确位置、喉返神经剥离前后刺激迷走神经并记录EMG信号,并摄像记录暴露的喉返神经。结果5例患者出现IONM波形异常,是由于电极错位所致,这一问题被立刻监测到。监测到1例患者在手术较早阶段出现非喉返神经损伤。甲状腺剥离时18例患者的神经失去了EMG信号,使用我们的标准化IONM操作后神经损伤的原因得以清楚阐明。结论标准化IONM操作不仅在消除错误的IONM结果方面有用且有帮助,而且有助于阐明喉返神经损伤的机制。在确定外科手术的缺陷并提高外科手术技巧后,本研究显著降低了神经麻痹的发生率。