Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo

Akt is a serine/threonine kinase that transduces survival signals from survival/growth factors. Deregulation and signal imbalance in cancer cells make them prone to apoptosis. Upregulation or activation of Akt to aid the survival of cancer cells is a common theme in human malignancies. We have developed small-molecule Akt inhibitors that are potent and specific. These Akt inhibitors can inhibit Akt activity and block phosphorylation by Akt on multiple downstream targets in cells. Synergy in apoptosis induction was observed when Akt inhibitors were combined with doxorubicin or camptothecin. Akt inhibitor-induced enhancement of topoisomerase inhibitor cytotoxicity was also evident in long-term cell survival assay. Synergy with paclitaxel in apoptosis induction was evident in cells pretreated with paclitaxel, and enhancement of tumor delay by paclitaxel was demonstrated through cotreatment with Akt inhibitor Compound A (A-443654). Combination with other classes of chemotherapeutic agents did not yield any enhancement of cytotoxicity. These findings provide important guidance in selecting appropriate classes of chemotherapeutic agents for combination with Akt inhibitors in cancer treatment.     

Addressing the childhood asthma crisis in Harlem: the Harlem Children's Zone Asthma Initiative

OBJECTIVES: We determined the prevalence of asthma and estimated baseline asthma symptoms and asthma management strategies among children aged 0-12 years in Central Harlem. METHODS: The Harlem Children's Zone Asthma Initiative is a longitudinal, community-based intervention designed for poor children with asthma. Children aged 0-12 years who live or go to school in the Harlem Children's Zone Project or who participate in any Harlem Children's Zone, Inc, program were screened for asthma. Children with asthma or asthma-like symptoms were invited to participate in an intensive intervention. RESULTS: Of the 1982 children currently screened, 28.5% have been told by a doctor or nurse that they have asthma, and 30.3% have asthma or asthma-like symptoms. To date, 229 children are enrolled in the Harlem Children's Zone Asthma Initiative; at baseline, 24.0% had missed school in the last 14 days because of asthma. CONCLUSION: The high prevalence of asthma among children in the Harlem Children's Zone Project is consistent with reports from other poor urban communities. Intensive efforts are under way to reduce children's asthma symptoms and improve their asthma management strategies.     

Vasoactive intestinal polypeptide induces glycogenolysis in mouse cortical slices: a possible regulatory mechanism for the local control of energy metabolism.

Mouse cerebral cortex slices will synthesize [3H]glycogen in vitro. Vasoactive intestinal polypeptide (VIP) stimulates the enzymatic breakdown of this [3H]glycogen. The concentration giving 50% of maximum effectiveness (EC50) is 26 nM. Under the same experimental conditions norepinephrine also induces a concentration-dependent [3H]glycogen hydrolysis with an EC50 of 500 nM. The effect of VIP is not mediated by the release of norepinephrine because it is not blocked by the noradrenergic antagonist d-1-propranolol and is still present in mice in which an 85% depletion of norepinephrine was induced by intracisternal 6-hydroxydopamine injections. Other cortical putative neurotransmitters such as gamma-aminobutyric acid, aspartic acid, glutamic acid, somatostatin, and acetylcholine (tested with the agonist carbamylcholine) do not induce a breakdown of [3H]glycogen. This glycogenolytic effect of VIP and norepinephrine, presumed to be mediated by cyclic AMP formation, should result, at the cellular level, in an increased glucose availability for the generation of phosphate-bound energy. Given the narrow radial pattern of arborization of the intracortical VIP neuron and the tangential intracortical trajectory of the noradrenergic fibers, these two systems may function in a complementary fashion: VIP regulating energy metabolism locally, within individual columnar modules, and norepinephrine exerting a more global effect that spans adjacent columns.     

Spiromustine: a new agent entering clinical trials

Investigational New Drugs - Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also...     

Sequential changes in cerebral blood flow and distribution of flow within the brain during hemorrhagic shock.

Sequential changes in cerebral blood flow as well as in regional blood flow to the brain (brain stem, cerebellum, hypothalamus, white matter and grey matter) were measured in unanesthetized dogs subjected to gradual prolonged hemorrhage according to a protocol which stimulates the most commonly encountered type of clinical hemorrhagic shock. Microspheres labeled with five different radioactive isotopes were injected into a left atrial catheter at five different times: control, early hypotension (immediately after hemorrhage), late hypotension (just before reinfusion of the shed blood), as well as one and eight hours after reinfusion of the shed blood. Immediately after hemorrhage, the total cerebral blood flow decreased slightly, but increased when calculated as a percent of the cardiac output. In the late hypotensive, hypovolemic stage, there was decreased flow calculated both as percentages of cardiac output and absolute flow as compared with the initial response to hemorrhage. Immediately after reinfusion of the shed blood, there were further reductions of flow. Eight hours subsequently, flow rose to values slightly above control. The patterns of each region was almost identical to that of the total cerebral flow. Since each of the major regions of the brain are approximately equally affected, changes in the level of consciousness and other cerebral functions occurring with hypovolemic shock may reflect circulation of the white matter as well as that of the whole brain.     

Peripheral pulse pressure responses to postural stress do not reflect those at the carotid artery

Objective: Interpretation of baroreflex cardiovascular control requires accurate assessment of pulse pressure (PP) in central arteries under conditions of varying systemic or hydrostatic pressure. The objective of this study was to examine whether changes in PP during postural stress were similar in the peripheral versus carotid arteries. Design: Protocol A: Pulse pressure was measured in both the left (Millar tonometer) and right (Colin Pilot) radial arteries, and in the finger (Finapres) in seated subjects (n = 7) who performed Valsalva's manoeuvre. Protocol B: PP was measured from the carotid (Millar tonometer), and from the finger and wrist kept at the level of the carotid artery, during supine and 60° head‐up postures. Results: Protocol A: Pulse pressures during Valsalva's manoeuvre were highly correlated between all devices (r = 0·6–0·8). Protocol B: compared with supine, PP was reduced in both the finger and wrist during head‐up‐tilt (HUT) (P<0·05), but not in the carotid artery. Conclusions: During Valsalva manoeuvers the Millar and Colin tonometers similarly tracked PP over a wide range of rapidly changing pressures. This observation provided confidence for the further use of the hand‐held device for central measurements during changes in posture. The results from Protocol B indicate that peripheral PP measurements are not suitable surrogates for carotid pulse pressures during HUT.     

Left ventricular dysfunction after pericardiectomy for constrictive pericarditis

A 56-year-old man was admitted to our hospital with a diagnosis of suspected constrictive pericarditis. After the diagnosis was confirmed by cardiac catheterization, an elective pericardiectomy was performed without complication. Four days after surgery dyspnea developed in the patient, and he was found to have an acute decrease in left ventricular ejection fraction (LVEF) by echocardiography. The patient's symptoms and the LVEF improved over time and returned to normal 4 weeks after surgery. Transient hemodynamic dysfunction of the left ventricle has previously been reported after pericardiectomy or pericardiocentesis; however, we know of no reports in the literature that confirm an acute reduction in LVEF by echocardiography after pericardiectomy for constrictive pericarditis.     

Angiotensin II reduces calcium uptake into bone

Children with neonatal Bartter syndrome (NBS) have hypercalciuria, nephrocalcinosis, and osteopenia. A complex of basic-fibroblast growth factor (b-FGF) and a naturally occurring glycosaminoglycan has been identified in the serum and urine of NBS patients. This complex increases bone resorption in a bone disc bioassay system. Angiotensin II (AT II), which is increased in Bartter syndrome, increases the synthesis of b-FGF by cultured endothelial cells. Addition of 10^-8 M AT II to the bioassay, a concentration reported in Bartter syndrome patients, significantly decreased calcium uptake into bone discs [E/C 0.60 (0.04), P< 0.001 compared with buffer, normal E/C >0.90]. Adding b-FGF monoclonal antibody at 10 g/ml [E/C 0.90 (0.06), P=NS] or indomethacin [E/C 1.00 (0.03), P=NS] to 10^-8 M AT II neutralized this effect. In separate experiments, newborn rats were given intraperitoneal injections of AT II. Bone discs from these animals were used in the bioassay system and calcium uptake was markedly reduced compared with discs from rats injected with phosphate-buffered saline [AT II 6.6×10^-9, E/C 0.10 (0.04), P<0.001, AT II 3.3×10^-8, E/C 0.10 (0.05), P<0.001]. AT II decreases calcium uptake in the bone disc bioassay system. This effect can be abrogated by antibody to b-FGF or prostaglandin synthetase inhibition. These results support the hypothesis that in children with NBS, elevated levels of AT II stimulate local skeletal b-FGF synthesis, with a resultant increase in bone resorption via a prostaglandin-dependent pathway.