Spinal muscular atrophy (SMA), a frequent neurodegenerative disease, is caused by reduced levels of functional survival of motoneuron (SMN) protein. SMN is involved in multiple pathways, including RNA metabolism and splicing as well as motoneuron development and function. Here we provide evidence for a major contribution of the Rho-kinase (ROCK) pathway in SMA pathogenesis. Using an in vivo protein interaction system based on SUMOylation of proteins, we found that SMN is directly interacting with profilin2a. Profilin2a binds to a stretch of proline residues in SMN, which is heavily impaired by a novel SMN2 missense mutation (S230L) derived from a SMA patient. In different SMA models, we identified differential phosphorylation of the ROCK-downstream targets cofilin, myosin-light chain phosphatase and profilin2a. We suggest that hyper-phosphorylation of profilin2a is the molecular link between SMN and the ROCK pathway repressing neurite outgrowth in neuronal cells. Finally, we found a neuron-specific increase in the F-/G-actin ratio that further support the role of actin dynamics in SMA pathogenesis.

Our data do not support an increased risk of LNM or recurrence after secondary surgery compared with primary surgery. Therefore, an attempt for an en-bloc resection of a possible T1 CRC without evident signs of deep invasion seems justified in order to prevent surgery of low-risk T1 CRC in a significant proportion of patients.

Spinal muscular atrophy is a neurodegenerative disease accompanied by a loss of motoneurons. Either mutations or deletions in the survival of motoneuron (SMN) gene are responsible for this defect. SMN is an assembly protein for RNA-protein complexes in the nucleus and is also found in axons of neurons. However, it is unclear which dysfunctions of SMN are important for disease progression. In this study we analyzed the contributions of different SMN regions for localization and neuronal differentiation associated with outgrowth of neurites. Suppression of endogenous SMN protein levels significantly decreased the growth of neurites. Down-regulation of the interacting protein gemin2 had the opposite effect. Surprisingly, selective overexpression of the SMN C-terminal domain promoted neurite outgrowth similar to full-length protein and could rescue the SMN knock-down effects. The knock-down led to a significant change in the G-/F-actin ratio, indicating a role for SMN in actin dynamics. Therefore, our data suggest a functional role for SMN in microfilament metabolism in axons of motoneurons.

In the absence of histological high-risk factors, a 'wait-and-see' policy with limited follow-up is justified. Piecemeal resection and non-pedunculated morphology are independent risk factors for incomplete endoscopic resection of T1 CRC.

No abstract

In a cohort-nested matched case-control study of 708 patients with pedunculated T1 colorectal carcinomas, we developed a model based on histologic features of tumors that identifies patients who require surgery (due to high risk of metastasis) with greater accuracy than previous models. Our model might be used to identify patients most likely to benefit from adjuvant surgery.

BACKGROUND & AIMS: We evaluated the incidence of interval cancers between the first and second rounds of colorectal cancer (CRC) screening with the FOB-Gold fecal immunochemical test (FIT), and the effects of different cutoff values and patient sex and age. METHODS: We collected data from participants in a population-based CRC screening program in the Netherlands who had a negative result from a first-round of FIT screening. We calculated the cumulative incidence of interval cancer after a negative result from a FIT and the sensitivity of the FIT for detection of CRC at a low (15 mg Hb/g feces) and high (47 mg Hb/g feces) cutoff value. RESULTS: Among the 485,112 participants with a negative result from a FIT, 544 interval cancers were detected; 126 were in the 111,800 participants with negative results from a FIT with the low cutoff value and 418 were in the 373,312 FIT participants with negative results from a FIT with the high cutoff value. The mean age of participants tested with the low cutoff value was 72.0 years and the mean age of participants tested the high cutoff value was 66.7 years. The age-adjusted 2-year cumulative incidence of interval cancer after a negative result from a FIT were 9.5 per 10,000 persons at the low cutoff value vs 13.8 per 10,000 persons at the high cutoff value (P < .005). The age-adjusted sensitivity of the FIT for CRC were 90.5% for the low cutoff value vs 82.9% for the high cutoff (P < .0001). The FIT identified men with CRC with 87.4% sensitivity and women with CRC with 82.6% sensitivity (P < .001). CONCLUSIONS: In an analysis of data from a FIT population-based screening program in the Netherlands, we found that incidence of interval CRC after a negative result from a FIT to be low. Although the sensitivity of detection of CRC decreased with a higher FIT cutoff value, it remained above 80%.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder of motoneurons. The disease is caused by deletions or mutations of the survival of motoneuron gene 1 (SMN1). The amount of protein expressed from the second gene, SMN2, correlated with the severity of the clinical phenotype. The histone deacetylase inhibitor valproic acid (VPA) has been shown to increase the total cellular amount of functional SMN protein and is therefore considered as a drug candidate for treatment of SMA. In this study, we analyzed the effects of VPA in PC12 cells, a model system for neuronal differentiation, with regard to neurite outgrowth and SMN expression. VPA promoted neurite outgrowth in PC12 cells. However, this effect did not correlate with upregulation of SMN protein levels, suggesting a SMN-independent mechanism for VPA regulation of neurite outgrowth. Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive degeneration of motoneurons in the spinal cord. SMA is caused by mutations and deletions of the survival of motoneuron gene SMN (1-3). The SMN1 gene is homozygously deleted in 96% of SMA patients (4). The severity of the disease is related to the amount of functional SMN protein encoded by the second gene, SMN2, which mainly expresses an exon 7 truncated form of SMN due to alternative splicing (5,6).The histone deacetylase inhibitor valproic acid (2-propylpentanoic acid, VPA; Figure 3) has recently been shown to modulate transcription of the SMN2 gene as well as to influence alternative splicing of the pre-mRNA expressed from this gene (7,8). VPA has been tested in primary fibroblasts of SMA patients and rodent hippocampal brain slice cultures for its ability to modify expression of full-length SMN (7). Additionally, the fatty acids butyrate and phenylbutyrate have been shown to increase SMN levels (9,10). In a SMA mouse model, treatment with sodium butyrate resulted in increased SMN expression in motoneurons and ameliorated SMA symptoms (10). For this reason VPA -already used as an anticonvulsant drug -is considered as a candidate substance for therapeutic treatment of SMA.Valproic acid increased neurite growth in a neuroblastoma cell line (11). However, it has not been tested yet, if the effects of VPA on neuronal differentiation are related to its modulating effects on SMN expression levels. A promoting effect on neurite outgrowth has been previously demonstrated for full-length SMN protein (12).In this study, we used PC12 cells as a model system to test the effects of VPA on neurite outgrowth, a hallmark of neuronal differentiation. PC12 cells are rat phaeochromocytoma cells of sympathoadrenal origin and represent a useful model for the analysis of neuronal differentiation (13). Treatment of undifferentiated PC12 cells with nerve growth factor (NGF) drives differentiation into a sympathetic neuronal phenotype and outgrowth of neurites. In the present study, we show that increase of neurite outgrowth by VPA is not correlated with an increase in SMN expression. The results suggest th...