BRAF inactivation drives aneuploidy by deregulating CRAF

Aspartate-594 is the third most common BRAF residue mutated in human cancer. Mutants of this residue are kinase inactive, and the mechanism(s) by which they contribute to cancer has remained perplexing. Using a conditional knock-in mouse model, we show that the (D594A)Braf mutant does not drive tumor development per se but is able to induce aneuploidy in murine splenocytes and mouse embryonic fibroblasts and contributes to immortalization through the propagation of aneuploid cells. (D594A)Braf lacks kinase activity but induces the related gene product Craf as well as the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway. Here, we show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells. These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf.     

Ten‐year follow‐up of a phase 2 study of dose‐intense paclitaxel with cisplatin and cyclophosphamide as initial therapy for poor‐prognosis,advanced‐stage epithelial ovarian cancer

BACKGROUND:

The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced‐stage epithelial ovarian cancer (EOC) who were receiving dose‐intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule.

METHODS:

Patients with stage III/IV EOC received cyclophosphamide 750 mg/m², followed by a 24‐hour infusion of paclitaxel 250 mg/m² and cisplatin 75 mg/m² on Day 2. Filgrastim began on Day 3 at 10 μg/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel.

RESULTS:

Sixty‐two patients were enrolled. Thirty‐two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent‐to‐treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow‐up of 11.4 years, the median progression‐free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel.

CONCLUSIONS:

The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose‐dense or dose‐intense paclitaxel regimens in women with newly diagnosed, advanced‐stage EOC. Cancer 2010. © 2010 American Cancer Society.     

Risk factors for musculoskeletal symptoms among crawfish farmers in Louisiana--a pilot study

The prevalence of musculoskeletal symptoms (MSS) among crawfish farmers is unknown. The purpose of this study was to assess the prevalence of MSS in nine body regions among crawfish farmers, and to examine associations between MSS and crawfish farm work activities. Questionnaires were mailed to randomly selected crawfish farmers in the State of Louisiana, USA. Site-specific MSS, demographics, and crawfish farm work information was obtained from the previous six months. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression adjusting for potential confounders. Among the participants (N = 184), shoulder MSS were reported most frequently (62%). Wrist/hand and low back MSS were significantly associated with tractor use (OR(adj) = 2.89; 95% CI = 1.28-6.56) and (OR(adj) = 2.41; 95% CI = 1.03-5.67), respectively. Also, upper back MSS were associated with the number of years working on a crawfish farm (OR(adj) = 3.07; 95% CI = 1.17-8.04). Shoulder and low back MSS were common. Tractor use may increase the risk of wrist/hand and low back MSS. Future studies need accurately assess exposures to physical risk factors for MSS so ergonomic interventions can be developed.     

Vitamin D Deficiency and Tuberculosis Progression

To assess the association between vitamin D deficiency and tuberculosis disease progression, we studied vitamin D levels in a cohort of tuberculosis patients and their contacts (N = 129) in Pakistan. Most (79%) persons showed deficiency. Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis.     

The changing epidemiology pattern and frequency distribution of hepatitis C virus in Pakistan

Information regarding the changing pattern in hepatitis C virus (HCV) genotypes/subtypes and resulting disease outcome is not well known. The specific objective of this study was to find out the frequency distribution of HCV genotypes and changing pattern of various HCV genotypes overtime in well-characterized Pakistani HCV isolates. The genotype distribution of HCV from all the four provinces of Pakistan was tracked for a period of 10 years (2000–2009) on total 20,552 consecutive anti-HCV and HCV RNA positive patients sample using type-specific genotyping assay. Of these, 16,891 (82.2%) samples were successfully genotyped. Of these 11,189 (54.4%) were males and 9363 (45.55%) were females. Of the successfully genotyped samples, 12,537 (74.2%) were with 3a, 1834 (10.9%) with 3b, 50 (0.24%) with 3c, 678 (3.3%) with 1a, 170 (0.83%) with 1b, 49 (0.24%) with 1c, 431 (2.1%) with 2a, 48 (0.23%) with 2b, 3 (0.01%) with 2c, 13 (0.06%) with 5a, 12 (0.06%) with 6a, 101 (0.49%) with 4, and 965 (4.7%) were with mixed-genotype infection. A changing pattern of HCV genotypes prevalence was observed in Pakistan overtime, with an increase in the relative proportion of genotype 3a and mixed genotypes and a decrease of genotypes 3b, 2b, 4, 5a and 2a. This changed HCV genotype pattern might have direct impact on HCV disease outcome and new therapeutic strategies may be needed.     

Clinical disease registries in acute myocardial infarction

Disease registries,containing systematic records of cases,have for nearly 100 years been valuable in exploring and understanding various aspects of cardiology. This is particularly true for myocardial infarction,where such registries have provided both epidemiological and clinical information that was not readily available from randomised controlled trials in highlyselected populations. Registries,whether mandated or voluntary,prospective or retrospective in their analysis,have at their core a common study population and common data definitions. In this review we highlight how registries have diversified to offer information on epidemiology,risk modelling,quality assurance/improvement and original research-through data mining,transnational comparisons and the facilitation of enrolment in,and follow-up during registry-based randomised clinical trials.     

Effect of intra-abdominal pressure on respiratory function in patients undergoing ventral hernia repair

AIM: To determine the influence of intra-abdominal pressure (IAP) on respiratory function after surgical repair of ventral hernia and to compare two different methods of IAP measurement during the perioperative period.METHODS: Thirty adult patients after elective repair of ventral hernia were enrolled into this prospective study. IAP monitoring was performed via both a balloon-tipped nasogastric probe [intragastric pressure (IGP), CiMON, Pulsion Medical Systems, Munich, Germany] and a urinary catheter [intrabladder pressure (IBP), UnoMeterAbdo-Pressure Kit, UnoMedical, Denmark] on five consecutive stages: (1) after tracheal intubation (AI); (2) after ventral hernia repair; (3) at the end of surgery; (4) during spontaneous breathing trial through the endotracheal tube; and (5) at 1 h after tracheal extubation. The patients were in the complete supine position during all study stages.RESULTS: The IAP (measured via both techniques) increased on average by 12% during surgery compared to AI (P < 0.02) and by 43% during spontaneous breathing through the endotracheal tube (P < 0.01). In parallel, the gradient between РаСО₂ and EtCO₂ [Р(а-et)CO₂] rose significantly, reaching a maximum during the spontaneous breathing trial. The PаO₂/FiO₂ decreased by 30% one hour after tracheal extubation (P = 0.02). The dynamic compliance of respiratory system reduced intraoperatively by 15%-20% (P < 0.025). At all stages, we observed a significant correlation between IGP and IBP (r = 0.65-0.81, P < 0.01) with a mean bias varying from -0.19 mmHg (2SD 7.25 mmHg) to -1.06 mm Hg (2SD 8.04 mmHg) depending on the study stage. Taking all paired measurements together (n = 133), the median IGP was 8.0 (5.5-11.0) mmHg and the median IBP was 8.8 (5.8-13.1) mmHg. The overall r² value (n = 30) was 0.76 (P < 0.0001). Bland and Altman analysis showed an overall bias for the mean values per patient of 0.6 mmHg (2SD 4.2 mmHg) with percentage error of 45.6%. Looking at changes in IAP between the different study stages, we found an excellent concordance coefficient of 94.9% comparing ΔIBP and ΔIGP (n = 117).CONCLUSION: During ventral hernia repair, the IAP rise is accompanied by changes in Р(а-et)CO₂ and PаO₂/FiO₂-ratio. Estimation of IAP via IGP or IBP demonstrated excellent concordance.     

Migration of a biliary stent causing duodenal perforation and biliary peritonitis

Migration of endoscopically placed biliary stents is a well-recognized complication of endoscopic retrograde cholangiopancreatography. Less than 1% of migrated stents however cause intestinal perforation. We present a case of a migrated biliary stent that resulted in duodenal perforation and biliary peritonitis.     

The importance of qualitative and quantitative regional wall motion abnormality assessment at rest in pediatric coronary allograft vasculopathy

CAV remains one of the main limiting factors for survival in children after heart transplantation. In this study, we explored the incremental value of routine CMR for evaluation and detection of CAV using qualitative and quantitative analysis of regional and global myocardial function and strain. This was a prospective imaging biomarker validation trial. Twenty‐two patients (11 male), aged between 10 and 17 years (median 14 years) post‐heart transplantation, were prospectively enrolled and underwent CMR in addition to their biennial review workup with Echo, angiography, and IVUS. Nine healthy control patients were enrolled to undergo CMR alone. Echo was used to analyze WMAs and systolic function. CMR images were analyzed qualitatively for RWMA and quantitatively for volumetric analysis, S and SR. All results were compared to IVUS and angiography assessments. Qualitatively, CMR detected RWMA corresponding to angiographic disease in 3 patients that were not detected on Echo. However, quantitative strain analysis suggested RWMA in an extra 9 patients. Detection of regional wall motion abnormality using quantitative strain analysis was associated with a higher mean stenosis grade (P=.04) and reduced graft survival (P=.04) compared to those with no quantitative wall motion abnormality. Overall, only longitudinal stain was abnormal in patients compared with controls, but there was no correlation between any of the global indices of S or SR and IVUS measurements. CMR is more sensitive than Echo for the visual detection of significant WMAs. Quantitative CMR strain analysis at rest may give additional information to discriminate those at greatest risk.