PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers.

Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110ß inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110α or p110ß. Ablation of p110α, but not p110ß, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110ß conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110ß inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/ß may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.

The effect of normally consumed amounts of sucrose or high fructose corn syrup on lipid profiles, body composition and related parameters in overweight/obese subjects.

The American Heart Association (AHA) has advocated that women and men not consume more than 100 and 150 kcal/day, respectively, from added sugars. These levels are currently exceeded by over 90% of the adult population in the United States. Few data exist on longer-term metabolic effects when sucrose and High Fructose Corn Syrup (HFCS), the principal sources of added dietary sugars, are consumed at levels typical of the general population. Sixty five overweight and obese individuals were placed on a eucaloric (weight stable) diet for 10-weeks, which incorporated sucrose- or HFCS-sweetened, low-fat milk at 10% or 20% of calories in a randomized, double-blinded study. All groups responded similarly (interaction p > 0.05). There was no change in body weight in any of the groups over the 10-week study, or in systolic or diastolic blood pressure. Likewise, there were no changes in total cholesterol, triglycerides, low-density lipoprotein (LDL), or apolipoprotein B (Apo B). We conclude that (1) when consumed as part of a eucaloric diet fructose--when given with glucose (as normally consumed) does not promote weight gain or an atherogenic lipid profile even when consumed at two to four times the level recently recommended by the AHA. (2) There were no differences between HFCS and sucrose on these parameters.

Consumption of whole-grain cereals during weight loss: effects on dietary quality, dietary fiber, magnesium, vitamin B-6, and obesity.

OBJECTIVE: While various weight-management approaches produce weight loss, they may differ in dietary quality. We monitored changes in nutrient intakes in overweight and obese subjects on three different weight-management programs. DESIGN: Randomized clinical trial (pilot study) with two 12-week phases: phase 1, weekly counseling; phase 2, monitoring only. SUBJECTS/SETTING: One hundred eighty nonsmoking, sedentary overweight and obese adults began this outpatient study; 134 (body mass index [calculated as kg/m(2)]=30.9+/-2.4; age=42.3+/-1.2 years) were used in analyses. INTERVENTION: Twenty-four weeks of exercise only (control group), hypocaloric diet plus exercise, or hypocaloric diet with fiber-rich whole-grain cereals plus exercise. MAIN OUTCOME MEASURES: At weeks 0, 12, and 24, diet quality was assessed by 3-day food records and body weight was measured. STATISTICAL ANALYSES PERFORMED: Three-way analysis of variance with repeated measures. RESULTS: The hypocaloric diet with fiber-rich whole-grain cereals plus exercise decreased energy intake more than exercise only (P=0.032). By week 12, the hypocaloric diet with fiber-rich whole-grain cereals plus exercise and the hypocaloric diet plus exercise decreased total fat more than exercise only, which was sustained in the hypocaloric diet with fiber-rich whole-grain cereals plus exercise at 24 weeks (P<0.001). At weeks 12 and 24, the hypocaloric diet with fiber-rich whole-grain cereals plus exercise reduced saturated fat intake more than exercise only. The hypocaloric diet with fiber-rich whole-grain cereals plus exercise increased total fiber, insoluble fiber (both P<0.001), magnesium (P=0.004), and vitamin B-6 (P=0.002) intakes more than the hypocaloric diet plus exercise and exercise only. Calcium and vitamin E intakes were inadequate in all groups. Weight loss was similar in the hypocaloric diet with fiber-rich whole-grain cereals plus exercise and the hypocaloric diet plus exercise. CONCLUSIONS: Weight-reduction strategies may be associated with reduced intake of micronutrients, such as calcium and vitamin E. However, a hypocaloric diet with fiber-rich whole-grain cereal is effective for improving or maintaining other aspects of dietary quality during weight loss.

The use of CD38 expression by monoclonal B lymphocytes as a prognostic factor in B-cell chronic lymphocytic leukemia.

In B-cell chronic lymphocytic leukemia (B-CLL) the Rai and Binet staging criteria are not always able to accurately predict the prognosis of each patient. Rapidly evolving, violent disease is often seen in the so-called "good-prognosis" group, which highlights the need of additional and more refined prognostic markers. Several of these markers are described in the literature, with varying abilities to predict patient survival. Among the promising prognostic markers is flowcytometric analysis of CD38 on the monoclonal B cells in CLL. Several studies have shown that expression of CD38 is associated with a decreased overall-, or progression free survival. CD38 expression may be analyzed as percentage positive cells or as antibodies bound per cell. Addition of CD38 to the flow cytometry antibody panel for B-CLL analysis is a relatively easy way to obtain important prognostic information.

Estenose aórtica: diagnóstico e exercício / Aortic stenosis: diagnosis and physical activity

A estenose aórtica é uma das cardiopatias associadas à morte súbita relacionada ao esporte. Quando da suspeita clínica, a investigação diagnóstica visa à confirmação e à estratificação de sua gravidade, com atenção especial a seus riscos na atividade esportiva. O exame clínico habitual consta de anamnese e exame físico detalhados, eletrocardiografia, radiografia de tórax e ecocardiografia com Doppler colorido, e, obrigatoriamente, teste ergométrico procurando chegar até sintoma-sinal limitante ou freqüência cardíaca máxima prevista. O estudo hemodinâmico é necessário conforme a abordagem individual. O fato de ser atleta nos obriga, em várias ocasiões, a ser mais invasivos na conduta escolhida. A etiologia é fator de grande importância para a continuidade no esporte, porque as causas congênita e reumática, em sua história natural, podem ter evolução desfavorável ainda com o atleta no auge da atividade esportiva profissional; assim sendo, entendemos recomendável desencorajar o início ou o prosseguimento da carreira esportiva competitiva, mesmo que naquele momento o indivíduo ainda esteja assintomático, isto é, sem repercussão clínica e hemodinâmica. Neste artigo são revisadas as recomendações para a orientação de atividades físicas competitivas e recreativas em indivíduos com estenose aórtica em seus diversos graus de evolução e após procedimento intervencionista. Também são abordados aspectos peculiares ao atleta...

The effects of chronic otitis media on motor performance in 5- and 6-year-old children.

Two 16-member groups of 5- and 6-year-old children, one group with a history of chronic otitis media and one without such a history, were tested on three measures of motor performance. These were the Motor Accuracy Test-Revised, the Stott Test of Motor Impairment, and measures of duration of standing balance. These instruments assess, respectively, fine motor coordination, overall motor skills, and balance. On each of these measures, children with a history of chronic otitis media scored lower than children without such a history. However, when these scores were compared statistically, no significant differences were found between the two groups. Because the results of this study were inconclusive, routine motor performance evaluation of children with a history of chronic otitis media is not advocated at this time.

The effects of introducing the Klein-Bell ADL Scale in a rehabilitation service.

This study investigated the impact of introducing the Klein-Bell ADL Scale into a rehabilitation medicine service. A pretest and a posttest questionnaire of rehabilitation team members and a pretest and a posttest audit of occupational therapy documentation were completed. Results of the questionnaire suggested that the ADL scale influenced rehabilitation team members' observations in the combined area of occupational therapy involvement in self-care, improvement in the identification of treatment goals and plans, and communication between team members. Results of the audit suggested that the thoroughness and quantification of occupational therapy documentation improved. The clinical implications of these findings recommend the use of the Klein-Bell ADL Scale in rehabilitation services for improving occupational therapy documentation and for enhancing rehabilitation team effectiveness.