Lactate dehydrogenase type A (LDH-A) is a key metabolic enzyme catalyzing pyruvate into lactate and is excessively expressed by tumor cells. Transforming growth factor-beta2 (TGF-beta2) is a key regulator of invasion in high-grade gliomas, partially by inducing a mesenchymal phenotype and by remodeling the extracellular matrix. In this study, we tested the hypothesis that lactate metabolism regulates TGF-beta2-mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-beta2 expression, suggesting that lactate metabolism is strongly associated with TGF-beta2 in glioma cells. Here we demonstrate that TGF-beta2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin alpha(v)beta(3) receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin alpha(v)beta(3) abrogated glioma cell migration stimulated by TGF-beta2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A-induced and TGF-beta2-coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin alpha(v)beta(3). This novel interaction between lactate metabolism and TGF-beta2 might constitute a crucial mechanism for glioma migration.

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Respiratory function tests (RFTs) are commonly used as a measure of progression in ALS. This study assessed the ability of various RFTs to predict survival in ALS patients. Subjects with ALS had one or more measurements of seated and supine FVC, maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Kaplan-Meier (KM) analysis was used to determine whether patients with abnormal RFTs had shorter survival than those with normal RFTs. The sensitivity and specificity of RFTs as predictors of two-year survival were calculated from receiver operating characteristic (ROC) curves. With KM analysis, subjects with abnormal values of seated FVC, supine FVC, MIP and MEP had significantly reduced survival compared to subjects with normal values. With ROC curves, a normal supine FVC was highly predictive for two-year survival and had superior sensitivity over seated FVC. Slower rates of decline in seated or supine FVC were strong predictors of two-year survival. Our study demonstrates that respiratory function measurements are useful to predict survival in ALS patients. We show that measurements of FVC in the supine position are worth including in the assessment of respiratory function in ALS.

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Versican is a large chondroitin sulphate proteoglycan produced by several tumor cell types, including high-grade gliomas. Increased expression of distinct versican isoforms in the extracellular matrix plays a role in tumor cell growth, adhesion and migration. We have recently shown that transforming growth factor (TGF-beta)2, an important modulator of glioma invasion, interacts with versican isoforms V0/V1 during malignant progression of glioma in vitro. However, the distinct subtype of versican that modulates these effects could not be specified. Here, we show that transient down-regulation of V1 by siRNA leads to a significant reduction of proliferation and migration in glioblastoma cell lines and glioblastoma progenitor cells, whereas tumor cell attachment stays unaffected. We conclude that V1 plays a predominant role in modulating central pathophysiological mechanisms as proliferation and migration in glioblastoma. Considering that TGF-beta is a master regulator of glioma pathophysiology, and that V0/1 is induced by TGF-beta2, therapeutic regulation of V1 may induce meaningful effects on glioma cell migration not only in vitro, but also in vivo.

In previous studies the compound muscle action potential (CMAP) decrement in amyotrophic lateral sclerosis (ALS) subjects was thought to arise from degenerating neurons, from failure of conduction down axon branches, or at the neuromuscular junctions of regenerating neurons undergoing collateral sprouting. 2,3,5 To explore the significance of a decrement in ALS subjects, we gave a short train of 2 Hz stimulation in 27 subjects (mean age 54 years, 15 male) with definite ALS. 1 The CMAP amplitude was measured in response to five stimuli at supramaximal stimulus intensity from either the median, ulnar, or peroneal nerves on one to four occasions using techniques previously described. 3 CMAP decrement was defined as a greater than 10% difference between the first and fifth CMAP negative peak amplitude.A total of 106 studies were obtained from 60 ulnar, 35 median, and 11 peroneal nerves with mean CMAP amplitudes of 4.2 mV, 3.7 mV, and 2.4 mV, respectively. A decrement was observed in studies of 12/35 median (34%), 6/60 ulnar (10%), and 1/11 peroneal (9%) nerves. Using a lower limit for normal CMAP amplitude (median nerve, 4 mV; ulnar nerve, 6 mV; and peroneal nerve, 2 mV), a reduced CMAP amplitude was variably associated with a decrement (Fig. 1A,B). There was a negative correlation between the size of the CMAP decrement and the amplitude of the CMAP (r: Ϫ0.59, P-value Ͻ 0.0001). Except for one subject, a normal amplitude ulnar, median or peroneal CMAP was not associated with a decrement, i.e., the decrement was only present when there was significant loss of motor units.In a subgroup of 20 subjects, serial studies were obtained from 30 nerves. Three ALS subjects had a decrement on the initial study, and the CMAP decrement in these subjects continued to be greater than 10% on subsequent studies over 2-13 months (Fig. 1C). Of the 17 ALS subjects who lacked a decrement on the first study, six subjects showed a decrement on a subsequent study. The CMAP decrement detected in nine subjects had increased by an average of 10.8% despite a fall in CMAP amplitude by an average of 24.3% on subsequent studies. Three ALS subjects with a CMAP decrement in one nerve had studies from other nerves that did not show a decrement. No apparent clinical difference in survival was noted between the ALS subjects with and without a decrement. This is consistent with a previous report. 6 Our serial studies were performed to find evidence to distinguish between the mechanisms that may cause decrement in ALS subjects. The ALS subjects were studied over a reasonable period in which dying motor neurons would likely have disappeared, and this is supported by the observation of reduced CMAP amplitudes over time. If the decrement arose from individual dying motor neurons, then we would have similarly expected the decrement to disappear once that neuron was no longer present. Our finding that the decrement persists despite falling CMAP amplitude favors the theory that a CMAP decrement arises from regenerating neurons. It is doubtfulwhether the decreme...