Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

Incidence of Hepatitis E Virus Infection in Recipients of Blood or Blood Products Transfusion

Background

Hepatitis E, generally known to be transmitted faeco-orally, has been shown to have significant transmission by blood borne route. Paucity of data on asymptomatic viremia in blood donors and higher incidence of Hepatitis E in haemodialysis patients and thalassemics mandate a prospective study of blood recipients to elucidate the exact incidence and natural history of post transfusion Hepatitis E.

Methods

A total of 2000 recipients of blood or blood products transfusion were followed up for two months to detect development of post transfusion Hepatitis E, by clinical examination, transaminases and immunoglobulin M anti hepatitis E virus (IgM anti HEV). Estimation of hepatitis E virus ribonucleic acid (HEV RNA) was done in patients with elevated levels of transaminases.

Result

Out of 2000 patients, 5(0.25%) were positive for IgM anti HEV at the time of transfusion and were excluded from the study. Rest of 1995 patients were followed up for two months post transfusion. A total of 1303 (65.3%) patients were followed up for two months and 1636 (82.0%) patients at least once in two visits. None of the followed up patients reported development of jaundice or had clinically evident hepatitis, although 62 patients had raised transaminases detected at either one or both the visits.

Conclusion

All followed up patients were tested for IgM anti HEV at both the visits and none were found to be positive. Patients with raised transaminases were subjected to HEV RNA and all were found to be negative.Key Words: Hepatitis E, Post transfusion, Parenteral transmission     

Non-existence of caveolin-1 gene mutations in human breast cancer

Caveolin-1 is the principal constituent protein of caveolae, which are specialised plasma membrane invaginations with diverse biological roles. Caveolin-1 is suggested to have tumour suppressive functions and CAV1 gene mutations have been reported in 20% of breast cancers. The aim of the present study was to evaluate the frequency of CAV1 mutations in a large cohort of optimally accrued breast cancers. Two independent series of breast cancer samples were analysed: 82 fresh-frozen grade 3 and 158 formalin-fixed paraffin-embedded invasive ductal carcinomas of no special type were consecutively accrued and subjected to microdissection of neoplastic epithelial cells prior to DNA extraction. Thirty-nine human breast cancer cell lines were also included in this study. The trans-membrane region of CAV1 and adjacent sequences, where mutations are reported to cluster, were amplified by PCR, followed by direct sequencing and mutational analysis. None of the reported CAV1 gene mutations, including CAV1 ^P132L, were identified in either clinical samples (95% CI: 0–1.5%) or human breast cancer cell lines analysed. One novel non-synonymous germline polymorphism was detected within a reported region of high mutational frequency. This study does not corroborate the reported frequent occurrence of CAV1 gene mutations, including CAV1 ^P132L, in primary human breast carcinomas. Our findings demonstrate that if CAV1 mutations do exist, their overall mutational frequency is substantially lower than positive reports have suggested. Taken together with other studies, which have also failed to identify CAV1 mutations, our data call into question the existence and biological and clinical relevance of CAV1 gene mutations in human breast cancer.     

Statin research in critical illness: hampered by poor trial design?

Statin therapy may prevent an excessive inflammatory response after cardiopulmonary bypass for cardiac surgery. In a recent issue of Critical Care, Morgan and colleagues present data from a well-conducted systematic review and meta-analysis of randomised controlled trials using inflammatory markers as primary outcome measure. They find that pre-operative statin therapy, compared with placebo, may reduce various post-operative markers of systemic inflammation (IL-6, IL-8, C-reactive protein, tumour necrosis factor-alpha). Their ability to make definitive conclusions is limited, however, by the suboptimal methodological quality of the primary studies. Their review suggests that ICU researchers should focus on developing valid surrogate markers and use these to accurately describe the mechanisms and effectiveness of novel therapies before proceeding to large pragmatic trials using mortality as primary outcome.     

Hepatic arterial chemotherapy: role of angiography

Hepatic arterial infusion chemotherapy increases the hepatic concentration of chemotherapeutic agents without increasing systemic toxicity. Both percutaneous (most commonly left transbrachial) and surgical approaches are currently used for infusion catheter placement. Surgical catheter and pump placement has proved to be a reliable means of delivering drugs to the liver and has been commonly used for hepatic arterial chemotherapy for metastatic colorectal carcinoma. Meticulous angiographic evaluation of the hepatic vascular anatomy, its variations, and hemodynamics is necessary for correct catheter placement to achieve total liver perfusion without significant extrahepatic perfusion. Satisfactory hepatic perfusion should be documented before drug infusion. Hepatic arterial radionuclide flow imaging with technetium-99m-labeled macroaggregated serum albumin remains the most reliable means of assessing hepatic perfusion following catheter placement. Transcatheter techniques have been used to facilitate catheter placement, to prevent gastrointestinal drug toxicity, and to correct unsatisfactory perfusion following surgical catheter placement.     

2-[对-(二甲氨基)苯乙烯]碘化甲基吡啶对实验性急性心肌缺血的保护作用

于摘除心脏前1 h或4 h给予DSPM 5 mg╱kg,可预防大鼠离体心脏的缺血损伤,使缺血后恢复灌流的心脏心功能有显著恢复,尤以4h前用DSPM者更明显,DSPM 1.5～6mg╱kg可显著对抗Iso引起的小鼠心肌钙含量增加,6mg╱kg 还可减少正常心肌钙含量。提示DSPM有保护缺血心肌的作用,此作用可能与其钙拮抗作用有关。