Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder.

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient's fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient's cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

Expression of heparanase in soft tissue sarcomas of adults.

BACKGROUND: Heparanase is an endo-ß-D-glucuronidase that cleaves heparan sulfate chains of proteoglycans, resulting in the disassembly of the extracellular matrix. Heparanase has a central role in the development of various tumors, and its expression has been associated with increased tumor growth, angiogenesis and metastasis, but there is insufficient information about the function of heparanase in sarcomas. STUDY AIMS: 1) To evaluate heparanase levels in adult soft tissue sarcomas (STS); 2) To examine the correlation between heparanase levels and pathological and clinical parameters and treatment outcome. METHODS: Pathological specimens of primary or metastatic STS were subjected to immunohistochemical analysis applying an anti-heparanase antibody. The clinical and the pathological data, together with the data of heparanase levels, were evaluated in a logistic regression model for tumor recurrence and survival. RESULTS: One hundred and one samples were examined, 55 from primary tumors and 46 from metastatic sites. A high expression of heparanase was observed in 29 (52.7%) and 22 specimens (47.8%), respectively. There was no statistically significant difference between heparanase expressions in the primary vs. metastatic sites of tumors. Moreover, no correlation was observed between heparanase staining and tumor aggressiveness, tumor recurrence or patient survival in various groups of patients. CONCLUSION: Expression of heparanase was observed in 50% of the STS, in various histological subtypes. A larger study with homogenous groups of specific sub-types of STS or stages of disease is required to validate over-expression of heparanase as a marker of disease aggressiveness.

Invasive ductal carcinoma within fibroadenoma and lung metastases.

Fibroadenomas are one of the most common benign tumors of the breast. Malignant transformation from fibroadenoma to cancer is rare. We present a case of an invasive ductal carcinoma within an otherwise benign fibroadenoma with lung metastasis in a 69-year-old woman.

Involvement of Heparanase in early pregnancy losses.

BACKGROUND: Heparanase cloned from and abundant in the placenta is implicated in cell invasion, tumor angiogenesis and metastasis. Recently, we demonstrated that heparanase is involved in the regulation of the hemostatic system. Heparanase was found to up-regulate tissue factor (TF) expression (Nadir et al., JTH, 2006) and interact with tissue factor pathway inhibitor (TFPI) on the cell surface, leading to dissociation of TFPI from the cell membrane resulting in increased cell surface coagulation activity (Nadir et al., TH, 2008). Herein, we investigated the role of heparanase in the placenta, focusing on its effect on TF, TFPI, TFPI-2, and vascular endothelial growth factor (VEGF)-A. METHODS: Twenty formalin embedded placenta samples of abortions (weeks 6-10) were studied applying real time RT-PCR and immunostaining. Ten cases were miscarriages of women with thrombophilia and recurrent fetal losses, and ten control cases were pregnancy terminations. JAR (human choriocarcinoma trophoblasts) cells were transfected with full-length heparanase cDNA or incubated with active (50+8 kDa) recombinant heparanase and the effects on TF, TFPI, TFPI-2 and VEGF-A were examined using real time RT-PCR and immunoblotting. RESULTS: Sections obtained from miscarriages revealed increased (2-3-folds) levels of heparanase, VEGF-A and TFPI-2 compared to placentas from controls in maternal as well as in fetal placenta elements. JAR cells overexpressing heparanase or incubated with exogenous recombinant heparanase exhibited a 2-3-fold increase in TFPI and TFPI-2 in cell lysates both at the protein and mRNA levels, with no detectable effect on VEGF-A and TF levels. Accumulation of TFPI and TFPI-2 in the cell culture medium was increased 4-6-folds, exceeding the observed induction of TFPI and TFPI-2 gene transcription. CONCLUSIONS: These results indicate a regulatory effect of heparanase on TFPI and TFPI-2 in trophoblasts, suggesting a potential involvement of heparanase in early miscarriages.