Genetic subgroups inform on pathobiology in adult and pediatric Burkitt lymphoma.

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified additional significantly mutated genes, including more genetic features that associate with tumor Epstein-Barr virus status, and unraveled new distinct subgroupings within BL and DLBCL with 3 predominantly comprising BLs: DGG-BL (DDX3X, GNA13, and GNAI2), IC-BL (ID3 and CCND3), and Q53-BL (quiet TP53). Each BL subgroup is characterized by combinations of common driver and noncoding mutations caused by aberrant somatic hypermutation. The largest subgroups of BL cases, IC-BL and DGG-BL, are further characterized by distinct biological and gene expression differences. IC-BL and DGG-BL and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among aBL and pBL cohorts. These findings highlight shared pathogenesis between aBL and pBL, and establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiologic, diagnostic, and therapeutic strategies.

Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

A Consumer Use Study of Over-The-Counter lovastatin (CUSTOM).

The Consumer Use Study of OTC Mevacor evaluated the ability of subjects to self-manage high levels of low-density lipoprotein (LDL) cholesterol by using a multifaceted cholesterol self-management program (the Mevacor Over-the-Counter Self-Management System; MOTC-SMS). This 26-week all-comers multicenter observational study was conducted in naturalistic storefront settings that used the fully functional MOTC-SMS to guide subjects' behavior. Of 3,316 subjects who evaluated the product (evaluators), 1,061 took >or=1 20-mg tablet of Mevacor OTC (users). Eighty-four percent of evaluators made appropriate initial use decisions. Most users demonstrated acceptable ongoing use behavior regarding treatment to goal, compliance/persistence, changes in health status, dietary patterns, and exercise habits. Throughout the study, 23 users (2%) demonstrated behavior that created the potential for suboptimal safety. After 26 weeks, median levels of LDL cholesterol were reduced by 25% among users who fasted. Of the 878 users who completed the study lipid test, 548 (62%) achieved the LDL cholesterol target goal (<130 mg/dl). Physician interactions were common. Mevacor OTC was well tolerated, with no observable adverse experiences from drug interactions or reports of myopathy. This actual use study demonstrates that the MOTC-SMS can effectively guide consumers to interact with health care professionals and to make appropriate initial and ongoing use decisions to manage their elevated levels of LDL cholesterol, with minimal potential or actual safety risk.

Antiarrhythmic effects of timolol in patientes with ventricular arrhythmais

O objetivo desse estudo foi avaliar os efeitos anti-arrítmicos do maleato de timolol, em portadores de extra-sístoles ventriculares prematuras freqüentes e multifocais (DVP), surto bigeminado e episódio de taquicardia ventricular (TV. Foi administrado maleato de timolol nas doses de 10 a 30 mg duas vezes ao dia a 31 pacientes, em estudo multiclínico duplo cego, cruzado e controlado por placebo. A avaliaçäo do grau de controle das arritmias ventriculares utilizou o eletrocardiograma dinâmico de 24 horas enquanto que o grau de beta-bloqueio foi determinado pela reduçäo da freqüência cardíaca máxima em exercício. A administraçäo do maleato de timolol causou decréscimo de: 36% na freqüência cardíaca em exercício, 39% na DVP/24 horas (de 383 ñ 80 a 232 ñ 63, p..<.05), 81% nos surtos bigeminados (de 239 ñ 84 a 44 ñ 17, p < 0,05) e 83% na incidência de mais de um episódio de taquicardia ventricular (TV) durante as 24 horas de monitorizaçäo (de 46% a 8%, p<0,01). Portanto o maleato de timolol, administrado em doses que produzam beta-bloqueio, é um agente promissor para o tratamento das DVP freqüentes e multifocais, surtos bigeminados e episódios eventuais de taquicardia ventricular

Beneficial effects of timolol in digitalized patients with atrial fibrillation and a rapid ventricular response

Quarenta e dois pacientes com fibrilaçäo atrial crônica e em uso de digitálico foram tratados com timolol. A reduçäo da freqüência ventricular foi avaliada através do teste de esforço e de monitorizaçäo contínua pelo sistema Holter. O estudo teve duraçäo de 10 semanas e foi duplamente cego, aleatório, com um grupo placebo e um grupo tratado com timolol. A administraçäo de timolol, na dose média de 10mg, duas vezes por dia, produziu uma diminuiçäo de 31% na freqüência cardíaca (de 164 + ou - 5 para 113 + ou - 4 bpm, p < 0,01) e na pressäo arterial média (de 88 + ou - 1,5 para 81 + ou - 1,9 mmHg) durante o teste na esteira rolante. O duplo-produto reduziu-se de 27,396 + ou - 1080 para 16,080 + ou - 786 (p < 0,01). A freqüência cardíaca determinada diminuiu de 90 + ou - 3 para 69 + ou - 2 bpm (p < 0,01). Sete pacientes tratados com timolol e um paciente tratado com placebo foram retirados do estudo em virtude dos efeitos colaterais (fadiga, tonteira e dispnéia). Conclui que a administraçäo de timolol é eficaz e segura em pacientes com fibrilaçäo atrial crônica e uso concomitante de digitálico