Survival with total occlusion of left main coronary artery

Complete occlusion of the left main coronary artery is considered to be a terminal event in most cases. We describe two patients with this lesion who underwent successful coronary bypass surgery with complete relief of symptoms and long-term survival. The angiographic findings and clinical management of the two patients are discussed.     

ISOLATION AND PROPERTIES OF β-ENDORPHIN-(1–27), Nα-ACETYL-β-ENDORPHIN,CORTICOTROPIN, GAMMA-LIPOTROPIN AND NEUROPHYSIN FROM EQUINE PITUITARY GLANDS

Beta-endorphin-(1–27), N^α-acetyl-beta-endorphin, corticotropin, gamma-lipotropin and neurophysin have been isolated from the equine pituitary and characterized.     

Associations between trunk, leg and total body adiposity with arterial stiffness

BackgroundObesity and arterial stiffness are associated, but fat distribution patterns may be more strongly related to arterial stiffness than general obesity because of the possible increased inflammation associated with increased abdominal adiposity. The aims of this study were to examine whether fat patterning is associated with arterial stiffness, and determine whether these associations are mediated by low-grade inflammation.MethodsAdult participants from the Fels Longitudinal Study (228 males and 254 females) were assessed for brachial-ankle pulse wave velocity (BaPWV) to determine arterial stiffness. Dual energy X-ray absorptiometry was used to estimate fat percentage of the trunk and legs (e.g., TRUNKFAT% and LEGFAT%). High-sensitivity C-reactive protein (hs-CRP) levels were assayed as a general marker of inflammation. General linear regression analyses were used.ResultsBaPWV was positively associated with TRUNKFAT% (r = 0.44 in men and r = 0.38 in women), whereas it was inversely related to LEGFAT% (r = -0.40 in men and r = -0.39 in women). In multiple regression analyses, each SD increase in TRUNKFAT% was associated with an ~1.03 m/s increase in BaPWV in both men and women. Each SD increase in LEGFAT% was related to a similar magnitude of decrease (1.03 m/s) in BaPWV in both sexes. The relationships of TRUNKFAT% and LEGFAT% with BaPWV were attenuated slightly when including hs-CRP in the models, but remained significant.ConclusionsWe found that trunk and leg fat are related to BaPWV in opposite directions when total body adiposity was accounted for. However, the associations between regional fat patterning and arterial stiffness did not appear to be mediated by low-grade inflammation.American Journal of Hypertension, 2012; doi:10.1038/ajh.2012.92.     

HUMAN SOMATOTROPIN

Three analogs of the carboxyl terminal plasmin fragment of human somatotropin, [Nle¹⁷⁰, Ala^165,182,189]-human somatotropin-(145–191), [Nle¹⁷⁰, Ala^165,182,189]-human somatotropin-(140–191), and [Lys^135,136,138, Glu^137,139, Nle¹⁷⁰, Ala^165,182,189]-human somatotropin-(135–191) have been synthesized by the solid-phase method. The synthetic peptides were assayed for growth-promoting activity and their potency was found to be comparable to that of [S-carbamideomethylcysteine^165,182,189]-human somatotropin-(141–191) which was derived from the native hormone.     

Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival

Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains approximately 60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser(473) (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr(37/46) (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser(1108) (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr(389) (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.     

IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma

The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. In this study, we identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor of IGF-1R/insulin receptor (IR). We showed that treatment with an IGF-IR antibody, R1507, or an IR/IGF-IR kinase inhibitor, BMS-754807, was associated with increased activation of YES/SRC family tyrosine kinase (SFK) in rhabdomyosarcoma (RMS). Combining anti–IGF-1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition–induced activation of YES/SFK and displayed advantageous antitumor activity in vitro and in vivo. Our data provide evidence that IGF-1R blockade results in activation of the YES/SRC family kinase bypass resistance pathway in vitro and in vivo. This may be of particular clinical relevance since both Yes and IGF components are overexpressed in RMS. Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. Dual inhibition of IGF-1R and SFK may have a broader and enhanced clinical benefit for patients with RMS.     

Synthesis of a Pentekontapeptide with High Lipolytic Activity Corresponding to the Carboxyl-Terminal Fifty Amino Acids of Ovine β-Lipotropin

The synthesis of a peptide, composed of fifty amino-acid residues, corresponding to positions 42-91 in ovine beta-lipotropin has been accomplished by the solidphase method. The preformed symmetrical anhydride and active ester coupling methods were used exclusively. The synthetic product was purified by gel filtration, carboxymethylcellulose chromatography, and partition chromatography on Sephadex G-50. Its lipolytic activity in isolated rabbit fat cells was about six times that of beta-lipotropin on a weight basis.