Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFß-mediated transcription.

Birt-Hogg-Dubé (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim deficiency in Bhd(-/-) cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFß-mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFß-dependent transcription and apoptosis, which has implications for the development of targeted therapies.

Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming.

As chronic myeloid leukemia (CML) progresses from the chronic phase to blast crisis, the levels of BCR-ABL increase. In addition, blast-transformed leukemic cells display enhanced resistance to imatinib in the absence of BCR-ABL-resistance mutations. In this study, we show that when BCR-ABL-transformed cell lines were selected for imatinib resistance in vitro, the cells that grew out displayed a higher BCR-ABL expression comparable to the increase seen in accelerated forms of the disease. This enhanced expression of BCR-ABL was associated with an increased rate of glycolysis but with a decreased rate of proliferation. The higher level of BCR-ABL expression in the selected cells correlated with a nonhypoxic induction of hypoxia-inducible factor-1alpha (HIF-1alpha) that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1alpha induction resulted in an enhanced rate of glycolysis but with reduced glucose flux through both the tricarboxylic acid cycle and the oxidative arm of the pentose phosphate pathway (PPP). The reduction in oxidative PPP-mediated ribose synthesis was compensated by the HIF-1alpha-dependent activation of the nonoxidative PPP enzyme, transketolase, in imatinib-resistant CML cells. In both primary cultures of cells from patients exhibiting blast transformation and in vivo xenograft tumors, use of oxythiamine, which can inhibit both the pyruvate dehydrogenase complex and transketolase, resulted in enhanced imatinib sensitivity of tumor cells. Together, these results suggest that oxythiamine can enhance imatinib efficacy in patients who present an accelerated form of the disease.

Differential effects of exercise training intensity on blood pressure and cardiovascular responses to stress in borderline hypertensive humans.

BACKGROUND: Psychologic stress has been associated with the development of hypertension. Aerobic exercise training appears to decrease cardiovascular responses to psychologic stress. OBJECTIVE: To determine the efficacy of low-intensity and moderate-intensity exercise training in reducing blood pressure and cardiovascular responses to stress. DESIGN: We sought to compare the cardiovascular responses to a psychologic stressor, the Stroop Color Word Task (Stroop), before and after 12 weeks of low-intensity (about 45% maximal oxygen uptake) and moderate-intensity (about 75% maximal oxygen uptake) aerobic exercise training. METHODS: Eighteen borderline hypertensive subjects (resting blood pressure 139 +/- 9/92 +/- 9 mmHg) were divided randomly into three groups: control (no exercise), low-intensity exercise (40-50% maximal oxygen uptake), and moderate-intensity exercise (70-80% maximal oxygen uptake). Training groups exercised three times per week at the prescribed exercise intensity. Heart rate and blood pressure were recorded during the Stroop before, and after 4 and 8 weeks of exercise training. RESULTS: In the low-intensity exercise group, exercise training attenuated mean blood pressure, systolic blood pressure, and diastolic blood pressure responses to the Stroop and decreased resting blood pressure. The moderate-intensity exercise group demonstrated a reduced diastolic blood pressure response to the Stroop. CONCLUSIONS: These results suggest that, in borderline hypertensive humans, 12 weeks of aerobic exercise training attenuates the cardiovascular responses to the Stroop. Furthermore, low-intensity exercise training appears to be a more effective stimulus than moderate-intensity exercise training in reducing resting blood pressure and blood pressure responses to stress.

Cardiovascular responses of 70- to 79-yr-old men and women to exercise training.

This study determined the effects of endurance or resistance exercise training on maximal O2 consumption (VO2max) and the cardiovascular responses to exercise of 70- to 79-yr-old men and women. Healthy untrained subjects were randomly assigned to a control group (n = 12) or to an endurance (n = 16) or resistance training group (n = 19). Training consisted of three sessions per week for 26 wk. Resistance training consisted of one set of 8-12 repetitions on 10 Nautilus machines. Endurance training consisted of 40 min at 50-70% VO2max and at 75-85% VO2max for the first and last 13 wk of training, respectively. The endurance training group increased its VO2max by 16% during the first 13 wk of training and by a total of 22% after 26 wk of training; this group also increased its maximal O2 pulse, systolic blood pressure, and ventilation, and decreased its heart rate and perceived exertion during submaximal exercise. The resistance training group did not elicit significant changes in VO2max or in other maximal or submaximal cardiovascular responses despite eliciting 9 and 18% increases in lower and upper body strength, respectively. Thus healthy men and women in their 70s can respond to prolonged endurance exercise training with adaptations similar to those of younger individuals. Resistance training in older individuals has no effect on cardiovascular responses to submaximal or maximal treadmill exercise.

Body composition in paraplegic male athletes.

The body composition and anthropometric characteristics of male paraplegic athletes (PARA, N = 22) were contrasted to an able-bodied ectomorphic (N = 22) and mesomorphic (N = 31) comparison group of moderately and highly trained male subjects. The validity of 12 body composition [density (Db)] prediction equations reported in the literature, 4 generalized, were determined (tested) on this special group of athletes (PARA). On the whole, the prediction equations over-predicted Db in PARA by 0.0039 to 0.0166 g X cm-3 (under-predicted relative fat by 1.8 to 7.4%). Five diameter, 11 circumference, and 7 skinfold measures were used in a SAS-STEPWISE multiple regression procedure with hydrostatically determined Db to develop several suitable Db prediction equations for the paraplegic athlete. Diameters were poor predictors (r = 0.60, SEE = 0.0164), while skinfolds, circumferences, or a combination of measures were acceptable, with the combined equation being best (r = 0.95, SEE = 0.0064). The findings of this study suggest that even generalized equations do not adequately predict Db in PARA and that paraplegic specific equations are presently best suited for predicting Db in paraplegic athletes. The results further indicate that although these equations meet many of the criteria of Lohman, the SEE and total error values are unusually high and make prediction of body composition using anthropometry in a heterogeneous group of PARA athletes slightly unreliable.

Nutrition Behaviors of University Majorettes.

In brief: The eating behaviors of a group of university majorettes and the effects of nutrition counseling on the majorettes were examined. At the start of the football season, 11 varsity majorettes received nutrition counseling and were interviewed to obtain 24-hour diet reports and information about their eating behaviors and weight-control practices. The interviews were repeated eight weeks later. The women all had distorted body images. Despite the counseling, the subjects ate poorly and used other unsound weight-loss practices in an effort to meet arbitrary target weights set by a faculty advisor. The health implications of these practices are discussed and remedial actions are suggested.