Characterization of rare transforming KRAS mutations in sporadic colorectal cancer

KRAS mutational status has been shown to be a predictive biomarker of resistance to anti-EGFR monoclonal antibody (mAb) therapy in patients with metastatic colorectal cancer. We report the spectrum of KRAS mutation in 1506 patients with colorectal cancer and the identification and characterization of rare insertion mutations within the functional domain of KRAS. KRAS mutations are found in 44.5% (670/1506) of the patients. Two cases are found to harbor double mutations involving both codons 12 and 13. The frequencies of KRAS mutations at its codons 12, 13, 61, and 146 are 75.1%, 19.3%, 2.5%, and 2.7%, respectively. The most abundant mutation of codon 12 is G12D, followed by G12V and G12C while G13D is the predominant mutation in codon 13. Mutations in other codons are rare. The KRAS mutation rate is significantly higher in women (48%, 296/617) than in men (42.1%, 374/889, P = 0.023). Tumors on the right colon have a higher frequency of KRAS mutations than those on the left (57.3% vs. 40.4%, P < 0.0001). Two in-frame insertion mutations affect the phosphate-binding loop (codon 10–16) of KRAS are identified. One of them has never been reported before. Compared with wild-type protein, the insertion variants enhance the cellular accumulation of active RAS (RAS-GTP) and constitutively activate the downstream signaling pathway. NIH3T3 cells transfected with the insertion variants show enhanced anchorage-independent growth and in vivo tumorigenicity. Potentially these mutations contribute to primary resistance to anti-EGFR mAb therapy but the clinical implication requires further validation.     

Trend of colorectal cancer in Hong Kong: 1983–2006

Background and Aim: The incidence of colorectal cancer (CC) is increasing in many Asian countries, but decreasing in western countries. The present study examined the local incidence of CC in the past few decades. Methods: A population based study, using data from Hong Kong (HK) Cancer Registry, was carried out to examine the trends of CC in different age groups in HK. Comparison with other countries was made. Results: The crude rate of CC in HK increased from 29.6/100 000 in 1983 to 57.1/100 000 in 2006. Age standardized rate (ASR) increased by less than 20%. It was markedly smaller than the 190% increase in crude rate. ASR progressively increased in males. In females, ASR peaked in 1994 and declined in the last decade. In most countries, the risk of CC was higher and increasing in males, but stable or decreasing in females. With respect to age, increasing risk was noted in males above 60 years old and females above 70 years old. However, a declining rate was noted in those below 50 years old. The decrease was over 40% in the 30–34 years group over the past two decades. Conclusions: Increasing incidence of CC in HK was mostly in the older and male population, but not in the younger age group.     

High plasma concentration of factor VIII coagulant is also a risk factor for venous thromboembolism in the elderly

BACKGROUND AND OBJECTIVES: A high level of coagulant factor VIII is a well known risk factor for venous thromboembolism, but most studies have enrolled patients under 70 years old. This study aimed to test the hypothesis that an association also exists in the elderly. DESIGN AND METHODS: This hospital-based case-referent study took place at the Department of Internal Medicine and Chest Diseases, University Hospital, Brest, France. We enrolled 161 patients with a first episode of venous thrombosis and 239 subjects, referred for a clinical suspicion of venous thromboembolism which was subsequently ruled out. Factor VIII coagulant activity and plasma fibrinogen concentration were measured. RESULTS: High factor VIII coagulant activity was significantly associated with venous thromboembolism, irrespective of the age group. Patients over 70 years with factor VIII coagulant activity above 225% had a 2.4-fold increased risk of venous thromboembolism compared to those patients with levels below 130% (age- and fibrinogen-adjusted odds ratio: 2.6, 95% CI 1.1 to 6.1). INTERPRETATION AND CONCLUSIONS: Our results show that high levels of factor VIII coagulant, a determinant of venous thrombosis in adulthood, is also a risk factor in the elderly.     

Plasma fibrinogen explains much of the difference in risk of coronary heart disease between France and Northern Ireland. The PRIME study

The incidence of coronary heart disease is higher in Northern Ireland than in France. These differences have not been adequately explained. We have investigated the associations of plasma fibrinogen concentration and factor VII activity with the incidence of coronary heart disease in a prospective cohort study involving 10600 men aged 50-59 living in four regions (Lille, Strasbourg, and Toulouse in France, Belfast in Northern Ireland). Baseline fibrinogen and factor VII were measured in 9489 men free of coronary heart disease at entry (7167 in France and 2322 in Northern Ireland). Over 5 years of follow-up, 161 participants developed myocardial infarction (MI) or coronary death (100 in France and 61 in Belfast) and 151 developed angina pectoris (94 in France and 57 in Belfast). The risk of future coronary events was 1.9 times higher in Belfast than in France (95% confidence interval: 1.5-2.4). Baseline mean levels of fibrinogen were significantly higher in Belfast than in France and they were higher in participants who experienced coronary events compared with those who did not in both countries. The age-adjusted relative risk of coronary heart disease associated with a rise of one standard deviation in fibrinogen level was 1.56 (95% confidence interval: 1.29-1.95, P<0.0001) in the whole cohort. This association remained significant after adjustment for other cardiovascular risk factors (relative risk:1.36; 95% confidence interval: 1.14-1.68; P<0.0001). There was no clear geographical variation in factor VII and no significant association between factor VII levels and the risk of coronary events was observed. Classic risk factors explained 25% of the excess risk of coronary heart disease in Belfast compared with France, while fibrinogen alone accounted for 30%. These findings add to the epidemiological evidence that elevated fibrinogen is a major risk factor for coronary heart disease.     

悬吊固定法在腹腔镜阑尾切除术中的应用

0引言腹腔镜阑尾切除术(LA)因具有创伤小、恢复快,以及可探查术前诊断不明的外科急腹症等优点,已逐渐成为外科医生和阑尾炎患者首选的术式.     

Functional imaging of the auditory cortex: role of magnetoencephalography

We present the different methods for detecting cerebral activity in the auditory cortex. Positron emission tomography (PET) and functional MRI (fMRI) measure such activity indirectly by calculating the blood flow rate or the consumption of oxygen. The direct methods of detection record the electrical or magnetic activity by eletroencephalography (EEG), or magnetoencephalography (MEG), respectively. The aim of this study was to define the role of MEG amongst these different techniques using the data from recordings of evoked magnetic fields in 5 healthy subjects. The localizations demonstrated the tonotopic organization of the auditory cortex, with high-pitched sounds showing a more medial cortical projection than low-pitched sounds. These various techniques are complementary. PET allows a pharmacological study of the cortex, and could be used in patients with cochlear implants. FMRI is non-invasive, and has a high spatial resolution. EEG has an excellent temporal resolution, and EEG recordings do not require major equipment or infrastructure. MEG has a better spatial resolution, with the same temporal resolution, as EEC. MEG is particularly useful in the localization of the cortical generators of middle-latency auditory evoked responses.