Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies

A growing body of work suggests that astrocytomas and glioblastoma multiforme will require carefully tailored, molecularly targeted therapy for successful treatment. Recent efforts to comprehensively identify mutations and gene expression changes in glioblastoma have shown that mutation of NF1 is a common alteration in human glioblastoma. We have developed and characterized a panel of 14 tumor lines from grades II through IV astrocytomas developed from our Nf1-/+;Trp53-/+cis mouse model and have used this panel to characterize signal transduction pathways and inhibitors that are candidate therapeutic targets for astrocytoma and glioblastoma. We show that these tumors express platelet-derived growth factor receptor-α, epidermal growth factor receptor, and their respective ligands to varying degrees. We find that both the MEK and PI3K signaling pathways downstream of epidermal growth factor receptor and platelet-derived growth factor receptor-α are necessary for full proliferation of astrocytoma cells; however, inhibition of the PI3K pathway is more effective than inhibition of MEK at blocking cell growth. We have examined inhibitors of the PI3K/Akt/mTOR signaling pathway and find that PI-103 and TCN show particular promise for inhibiting growth in Nf1 and Trp53 mutant astrocytoma cells.     

Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential

N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson''s and Alzheimer''s disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H⁺, Mg²⁺, Zn²⁺, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives (‘prodils’) are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity.     

Relation of body mass index (BMI) to disease free (DFS) and distant disease free survivals (DDFS) among Turkish women with operable breast carcinoma

BACKGROUND: The correlation between body mass index (BMI) and patient and tumor characteristics related to prognosis has not been well explored and may help to elucidate the mechanisms involved in the carcinogenesis. Because of the equivocal, inconsistent and uncertain research results as well as racial and ethnic differences, we aimed to evaluate the prognostic significance of high BMI in Turkish women with operable breast carcinoma. METHODS: Two hundred and sixty-six patients who had operable invasive breast carcinoma diagnosed from 2000 through 2004 in a single institution were evaluated for their demographic features, BMI, histopathological/immunohistochemical examinations and treatments. Quetelet BMI [weight (kg)/height (m)2] categories were selected according to the World Health Organization definition. Disease free survival (DSF) as well as distant disease free survival (DDSF) analyses were performed to identify independent prognostic factors. RESULTS: Post-menopausal patients were significantly in the higher quartile of BMI than pre-menopausal patients (P = 0.003). While post-menopausal obese patients had worse DSF and DDFS (P = 0.001), vascular invasion was the independent prognostic factor for both survival indices (P = 0.031). CONCLUSIONS: Post-menopausal obese Turkish women are at increased risk of developing breast tumors with aggressive phenotype and obesity is a strong predictor of poor DSF and DDFS. Preventive strategies to reduce not only the prevalence of obesity and breast cancer but also the mortality must be recognized as the cost-effective public-health policy for Turkey.     

Ponseti technique of correcting idiopathic clubfoot deformity

The efficacy of the Ponseti method of clubfoot treatment at Queen Elizabeth Central Hospital (QECH) was analysed from December 2000 to December 2001. Ninety one patients, 60 boys and 31 girls were prospectively and consecutively enrolled. 31 patients had a unilateral clubfoot and 60 had bilateral clubfeet. 77 patients had primary idiopathic clubfoot and 14 patients had clubfeet associated with other congenital anomalies such as arthrogryposis. 32 patients (35%) were lost to follow up; records were inadequate for 6 patients leaving 54 patients (59%) available for analysis. Three main groups were assessed. Group 1 (24 patients): virgin previously untreated primary idiopathic clubfeet: Ponseti method used from outset. Group 2 (19 patients): complex, primary idiopathic clubfeet: Ponseti method introduced after other manipulation techniques. Group 3 (11 patients): clubfeet associated with other congenital anomalies. In group 1, the mean age at start of treatment was 9.7 weeks and the mean time to correction of deformity was 7.4 weeks. 20 out of 24 patients (84%) had correction of deformity and remained corrected. 4 patients had recurrence of deformity mainly due to non compliance with treatment and correction was achieved once treatment restarted. In group 2, 19 patients had been on treatment for a mean period of 32 weeks prior to commencement of Ponseti treatment. In 17 of these patients the deformity was still uncorrected. Ponseti treatment was commenced at a mean age of 36 weeks and correction was achieved in all 17 patients after a mean treatment duration of 7.1 weeks. In group 3, correction of deformity was initially achieved in only 60%. The period to achieve correction was long and incidence of recurrence of deformity was high.The success of conservative treatment of clubfeet using the Ponseti method has resulted in large decrease in the number of surgical procedures performed under general anaesthaesia such as posteromedial releases in the treatment of clubfeet at QECH. This method has now been adopted as the Standard treatment of clubfoot and is being advocated nationwide.     

Gene Probe Analysis in an Informative Family with Multiple Endocrine Neoplasia Syndrome Type 2A (MEN 2A). Improvement in Carrier Risk Estimation

Gene probe analysis of the MEN 2A locus on chromosome 10 hasbeen undertaken using the markers TB10.163, RBP 3 and TB14.34in a large kindred with familial medullary thyroid carcinomas,with or without phaeochromocytomas or primary hyperparathyroidism.A maximum LOD score of 2.97 gave strong evidence of close linkagewith zero recombination. For 12 members of the family so far not known to be affectedby any form of the disease the estimated risk of carrying thegene has been considerably decreased in all but one, whose riskhas been greatly increased.     

Risk factors for infection in Malaysian patients with systemic lupus erythematosus

To determine the incidence, types and risk factors for infection in systemic lupus erythematosus (SLE) patients in Kuala Lumpur, Malaysia, we retrospectively reviewed the medical records of 102 patients with definite SLE attending a specialist clinic. Details of major infections (pneumonia or severe infection requiring intravenous therapy) and minor infections, and their time of onset in relation to immunosuppressive therapy and disease flares were recorded. There were 77 major and 163 minor infections during 564 patient-years of follow-up. In the month following a course of pulse methylprednisolone, the incidence of major infection was 20 times higher and the incidence of minor infection was 10 times higher than at other periods (p<0.0001). In the month after disease flare, the incidence of major infection was 10 times higher and the incidence of minor infection six times higher than at other times (p<0.0001). After allowing for methylprednisolone therapy and disease flares, there was no increase in the rate of infections during treatment with azathioprine, oral or intravenous cyclophosphamide. There was no effect of renal involvement on infection rate.      

Current practice of autologous hematopoietic progenitor cell mobilization in adult patients with multiple myeloma and lymphoma: The results of a survey from Turkish hematology research and education group (ThREG)

Autologous hematopoietic cell transplantation (AHCT) is an established treatment option for adult patients presenting with multiple myeloma (MM), Hodgkin lymphoma (HL) and various subtypes of non-Hodgkin lymphoma (NHL) in upfront and/or relapsed/refractory disease settings. Although there are recently published consensus guidelines addressing critical issues regarding autologous hematopoietic progenitor cell mobilization (HPCM), mobilization strategies of transplant centers show high variability in terms of routine practice. In order to understand the current institutional policies regarding HPCM in Turkey and to obtain the required basic data for preparation of a national positional statement on this issue, Turkish Hematology Research and Education Group (ThREG) conducted a web-based HPCM survey. The survey was designed to include multiple-choice questions regarding institutional practice of HPCM in adults presenting MM, HL, and NHL. The representatives of 27 adult HCT centers participated to the study. Here we report the results of this survey shedding light on the real-world experience in Turkey in terms of autologous HPCM mobilization strategies in patients presenting with MM and lymphoma.     

Detection of fetal red cells in fetomaternal hemorrhage using a fetal hemoglobin monoclonal antibody by flow cytometry

BACKGROUND: The laboratory determination of the level of fetal cells in maternal circulation remains an important support in the obstetrical management of women with suspected uterine trauma and in the proper dose administration of anti-D for prevention of Rh hemolytic disease of the newborn. Limitations in the sensitivity and precision of the widely used manual Kleihauer-Betke test have prompted an increased utilization of flow cytometric methods for fetal cell detection in maternal blood samples. STUDY DESIGN AND METHODS: Murine monoclonal antibodies directed against fetal hemoglobin (HbF) were developed, conjugated to fluorescein isothiocyanate, and used in a multiparametric flow cytometric assay developed for the quantitation of fetal red cells. A rapid intracellular staining method using brief glutaraldehyde fixation and Triton X-100 permeabilization prior to monoclonal antibody incubation was developed, along with optimization of the flow cytometric analysis protocol for the analysis of 50,000 cells. The performance of the assay was assessed for linearity and precision and correlated with the Kleihauer-Betke acid elution method. RESULTS: The anti-HbF flow cytometric method showed good correlation with the Kleihauer-Betke method (r2 = 0.86) and superior precision with a CV < 15 percent for blood samples with > 0.1 percent fetal cells. Analysis of 150 blood samples from nonpregnant adults, including individuals with elevated HbF due to hemoglobinopathies and hereditary persistence of HbF, gave a mean value of 0.02 percent fetal cells, and all results were less than 0.1 percent. CONCLUSIONS: The anti-HbF flow cytometric method for detection of fetal cells offers a simple, reliable, and more precise alternative to the Kleihauer-Betke manual technique for the assessment of fetomaternal hemorrhage. The method has additional potential applications for the study of HbF levels or frequency of adult red cells with low levels of HbF (F cells) in individuals with hemoglobinopathies.     

Polymyositis complicated with complete atrioventricular block--a case report and review of the literature

A 35-year-old woman, diagnosed with polymyositis about 5 years before was admitted to the authors' clinics with syncope attack due to complete atrioventricular (AV) block. Progression of left bundle branch block to complete AV block despite all immune-suppressive treatment, and rarity of this complication in patients with polymyositis prompted the authors to report this case.