The cytoskeleton in Chediak-Higashi syndrome fibroblasts

The Chediak-Higashi syndrome (CHS) trait is expressed in cultured human skin fibroblasts as an abnormal perinuclear concentration of moderately enlarged lysosomes. The cytoskeleton of CHS fibroblasts appears intact. Microtubules are normal in number and morphology, as assessed by colchicine binding studies, antitubulin immunofluorescence, and electron microscopy. Deformability by shear force is unaltered and microfilaments are abundant. However, CHS lysosomes appear to interact abnormally with the cytoskeleton, since the perinculear aggregation partially disperses after depolymerization of cell microtubules with colchicine. These results suggest that CHS is associated with a defect of either the lysosomal membrane itself or of lysosomal membrane- microtubule interaction.     

Dynamic PET/CT imaging of 18F-(2S, 4R)4-fluoroglutamine in healthy volunteers and oncological patients

European Journal of Nuclear Medicine and Molecular Imaging - The purpose of this study was to compare dynamic 18F-FGln PET/CT images of healthy subjects and cancer patients and explore the best...     

Childhood insulinoma masquerading as seizure disorder

A 9 year old girl presented with seizures, weight gain and early morning behavioural changes. She had been commenced on anticonvulsants and was subsequently diagnosed with hyperinsulinaemic hypoglycaemia. This case demonstrates the importance of blood glucose monitoring in children presenting with new‐onset seizures and/or with early morning or fasting behavioural changes, the challenges in localizing the lesion, as well as the difficulties in achieving normoglycaemia prior to, and immediately following, surgery.     

Evaluation of serum anti-mullerian hormone as a biomarker of early ovarian aging in young women undergoing IVF/ICSI cycle

Objective: To determine whether or not the level of serum anti-Müllerian hormone (AMH) is related to early ovarian aging in young women (< 35 years of age) undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Design: Retrospective cohort study. Setting: An IVF laboratory in a university hospital in Taiwan. Patient (s): 70 young women (< 35 years of age) with low level of serum AMH (< 2 ng/ml) and 104 young women with level of serum AMH (≥ 2 ng/ml) who underwent IVF/ICSI cycles between January 2011 and November 2012 were enrolled. Intervention (s): None. Main outcome measure (s): Number of oocytes, fertilization rate, embryo quality, cycle cancellation rate, clinical pregnancy/abortion rate, and perinatal/infant outcomes. Results: The clinical pregnancy rate per transfer was favorable (low AMH group vs. normal AMH group [47.2% and 47.9%]) for women < 35 years of age, including women with a low serum AMH. Similarly, the live birth rate per transfer (low AMH group vs. normal AMH group [37.7% and 35.4%]) and perinatal outcomes were also comparable between the two groups. A significantly higher cycle cancellation was noted in the low AMH group than the normal AMH group (24.2% vs. 7.6%). Conclusion: Although early ovarian aging should be taken into consideration for young and infertile women with low AMH level than expected, our results suggest that low serum AMH level may suggest early ovarian aging in accelerated oocyte loss only, but may not fully represent “early ovarian aging” based on the favorable outcomes of pregnancy.     

Short Communication New 5-HT1A receptor antagonist: [3H]p-MPPF

A new 5-HT_1A receptor antagonist ligand, [³H]p-MPPF, 4-(2′-methoxy-)-phenyl-1-[2′-(N-2′-pyridyl)-p-fluorobenzamido]ethyl-piperazine, was prepared and characterized. It demonstrated high affinity and selectivity toward 5-HT_1A receptors (K_d = 0.34 ± 0.12 nM and B_max = 145 ± 35 fmol/mg protein in rat hippocampal membrane homogenates). The binding is not sensitive to 100 μM Gpp(NH)p. Initial autoradiography studies of rat brain sections exhibit regional localization consistent with the known 5-HT_1A receptor distribution. This potential 5-HT_1A antagonist ligand may provide a powerful tool for 5-HT_1A receptor pharmacology studies in the central nervous system. © 1996 Wiley-Liss, Inc.     

Incidence and risk factors for pulmonary mycosis in kidney transplantation

IntroductionPulmonary mycosis, a severe complication following kidney transplantation, is associated with a high rate of mortality. The incidence of and independent risk factors for its development have not been well studied.MethodsWe retrospectively reviewed 2573 kidney transplant recipients. Patients were divided into case and control groups based on a diagnosis of pulmonary mycosis. The recipient baseline characteristics, posttransplant complications, immunosuppressive regimens and antibiotic usages were analyzed to identify independent risk factors.ResultsThe total incidence of pulmonary mycosis among kidney recipients was 2.1%. Upon univariate analysis, patients in the case group differed significantly from the controls based upon: older age, higher retransplantation rate, longer dialysis time, induction with ATG or anti-CD25 monoclonal antibodies, maintenance treatment with FK506 or MMF, broad-spectrum antibiotics, higher incidences of acute rejection episodes, DGF, impaired liver function, leukopenia, cytomegalovirus infection, and delayed incisional healing (P < .05). Multivariate analysis showed that older age, retransplantation, ATG induction, FK506/MMF, broad-spectrum antibiotics, leukopenia, and delayed incisional healing were independent risk factors for pulmonary mycosis.ConclusionsThe use of more potent immunosuppressive regimens seems to increase the rate of pulmonary mycosis. Patients who have five or more independent risk factors are at high risk for developing pulmonary mycosis.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.     

Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia

Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL.