A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

The pronase resistance of cholesterol-nucleating glycoproteins in human bile

BACKGROUND & AIMS: Many putative pronucleating proteins have been isolated from the biliary concanavalin A (con A)-binding fraction. The pronase resistance of the overall nucleating-promoting activity was almost never taken into consideration. The aim of this study was to identify the major pronase-resistant con A-binding glycoproteins. METHODS: Pronase-treated and -untreated con A-binding glycoproteins were separated on a Superose 12 gel permeation column (Pharmacia, Uppsala, Sweden) and tested in a crystal growth assay. Proteins were identified by amino-terminal sequencing. RESULTS: Con A-binding pronucleating activity eluted in two peaks on the Superose column. This activity was unaltered after pronase treatment. Activity peak I contained too little protein to allow amino-terminal sequencing. In activity peak II, the major pronase-resistant con A-binding glycoproteins were identified as alpha 1-antitrypsin and alpha 1- antichymotrypsin. The 130-kilodalton nucleation promoter was identified as aminopeptidase N, but the full pronase resistance of this protein, reported earlier, was not confirmed. Immunoabsorptive removal of alpha 1-antitrypsin and alpha 1-antichymotrypsin and immunopurification showed that only alpha 1-antichymotrypsin had pronucleating activity. CONCLUSIONS: The pronase resistance of the nucleating-promoting activity of the con A-binding glycoprotein fraction was confirmed. An important part of this activity could be attributed to alpha 1- antichymotrypsin. It is an acute-phase protein, as are many other pronucleating proteins, which might indicate a general mechanism of action in gallstone formation. (Gastroenterology 1996 Jun;110(6):1926-35)     

The 18- to 23-kb deletion of the Macedonian delta beta-thalassemia includes the entire delta and beta globin genes

Restriction endonuclease mapping analyses were made of DNA from a few members of a Macedonian family with hematological characteristics of delta beta-thalassemia, ie, microcytosis, normal HbA2 levels, and elevated levels of HbF (7% to 14%) with G gamma (average 40.5%) and A gamma T chains (average 59.5%). A large deletion of 18 to 23 kb was present with a 5' breakpoint within a 670-bp segment of DNA between the HpaI and NcoI restriction sites 5' to the delta globin gene, and a 3' breakpoint between the BamHI and HpaI restriction sites located some 9 to 13 kb 3' to the beta globin gene. This deletion is different from those present in other types of G gamma A gamma(delta beta)zero- thalassemia. The similarity of the hematological expression of these delta beta-thalassemic conditions which have somewhat comparable 5' breakpoints supports the idea that an important fetal hemoglobin- controlling region lies between the psi beta and delta globin genes.     

Transient leukemoid proliferation of the cytogenetically unbalanced +21 cell line of a constitutional mosaic boy

A newborn without any signs of Down's syndrome was found to have an acute proliferation that remitted without drug therapy. Chromosomal analysis of blood, bone marrow, and skin cells revealed that the child was a constitutional mosaic with normal cells and a low number of cells in which one no. 21 chromosome was replaced by a probably isochromosome for the no. 21 long arm: 46,XY/46,XY,i(21q). The abnormal cell line of the mosaic appeared to be selectively involved in this proliferation.     

Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase

Ninety-four consecutive patients with chronic myelogenous leukemia in first clinical chronic phase, median age of 34.0 years (range, 6.8 to 52.4 years), with a histocompatible sibling donor, were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation (BMT). The median time from diagnosis to BMT was 7.0 months (range, 2.3 to 72.0 months). Sixty patients were treated before BMT with hydroxyurea alone, four patients with busulfan alone, one patient with interferon alone, and the other 29 patients were treated with various combinations of these drugs. Cumulative probabilities of overall survival, event- free survival, and relapse at 5 years were 73%, 64%, and 14%, respectively. The median follow-up time for surviving patients was 38 months, ranging from 12 to 88 months. By stepwise Cox regression analysis, significant prognostic variables were age at transplant, acute graft-versus-host disease > or = grade II, cytomegalovirus- associated interstitial pneumonitis, and years from diagnosis to BMT.     

无支架异种生物瓣膜主动脉瓣替换术后左室功能变化

评价无支架异种生物瓣膜主动脉瓣替换术后２年左室功能的变化。将８０例同期施行主动脉瓣替换病人分为２组，５０例（年龄６９．３±９．３岁）应用ＴｏｒｏｎｔｏＳＰＶＴＭ瓣；３０例（年龄７１．６±７．７岁）作为对照组接受支架人工瓣膜替换。术前、术后１、６、１２及２４个月间记录Ｍ型及Ｄｏｐｐｌｅｒ超声心动图，采用计算机图像数字分析，定量测定左室功能的变化。随访期间，Ｔｏｒｏｎｔｏ组主动脉瓣跨瓣压差为０．８±０．６ｋＰａ（６．０±４．５ｍｍＨｇ），明显低于对照组２．３±０．９ｋＰａ（１７．３±６．８ｍｍＨｇ）；术后１个月，左室心肌质量下降２５％，左室＋Ｖｃｆ及－Ｖｃｆ明显增加（２．０±０．８／１．４±０．３ｓ－１，Ｐ＜０．０１；２．８±１．２／１．８±０．７ｓ－１，Ｐ＜０．０１）。术后６个月，左室功能进一步改善，心室肥厚的消退更趋完全，该变化在其后的随访期间保持稳定。结论：与支架瓣膜相比，无支架异种生物瓣膜具有较大瓣口开放面积及低跨瓣压差，这促进了术后左室功能的恢复及病理性肥厚的逆转