Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy

Genome-wide survey and expression analysis of the bHLH-PAS genes in the amphioxus Branchiostoma floridae reveal both conserved and diverged expression patterns between cephalochordates and vertebrates

BACKGROUND: The bHLH-PAS transcription factors are found in both protostomes and deuterostomes. They are involved in many developmental and physiological processes, including regional differentiation of the central nervous system, tube-formation, hypoxia signaling, aromatic hydrocarbon sensing, and circadian rhythm regulation. To understand the evolution of these genes in chordates, we analyzed the bHLH-PAS genes of the basal chordate amphioxus (Branchiostoma floridae). RESULTS: From the amphioxus draft genome database, we identified ten bHLH-PAS genes, nine of which could be assigned to known orthologous families. The tenth bHLH-PAS gene could not be assigned confidently to any known bHLH family; however, phylogenetic analysis clustered this gene with arthropod Met family genes and two spiralian bHLH-PAS-containing sequences, suggesting that they may share the same ancestry. We examined temporal and spatial expression patterns of these bHLH-PAS genes in developing amphioxus embryos. We found that BfArnt, BfNcoa, BfSim, and BfHifα were expressed in the central nervous system in patterns similar to those of their vertebrate homologs, suggesting that their functions may be conserved. By contrast, the amphioxus BfAhr and BfNpas4 had expression patterns distinct from those in vertebrates. These results imply that there were changes in gene regulation after the divergence of cephalochordates and vertebrates. CONCLUSIONS: We have identified ten bHLH-PAS genes from the amphioxus genome and determined the embryonic expression profiles for these genes. In addition to the nine currently recognized bHLH-PAS families, our survey suggests that the BfbHLHPAS-orphan gene along with arthropod Met genes and the newly identified spiralian bHLH-PAS-containing sequences represent an ancient group of genes that were lost in the vertebrate lineage. In a comparison with the expression patterns of the vertebrate bHLH-PAS paralogs, which are the result of whole-genome duplication, we found that although several members seem to retain conserved expression patterns during chordate evolution, many duplicated paralogs may have undergone subfunctionalization and neofunctionalization in the vertebrate lineage. In addition, our survey of amphioxus bHLH-PAS gene models from genome browser with experimentally verified cDNA sequences calls into question the accuracy of the current in silico gene annotation of the B. floridae genome

Electron Delocalization in Gate-Tunable Gapless Silicene

The application of a perpendicular electric field can drive silicene into a gapless state, characterized by two nearly fully spin-polarized Dirac cones owing to both relatively large spin-orbital interactions and inversion symmetry breaking. Here we argue that since inter-valley scattering from non-magnetic impurities is highly suppressed by time reversal symmetry, the physics should be effectively single-Dirac-cone like. Through numerical calculations, we demonstrate that there is no significant backscattering from a single impurity that is non-magnetic and unit-cell uniform, indicating a stable delocalized state. This conjecture is then further confirmed from a scaling of conductance for disordered systems using the same type of impurities.Comment: 6 pages, 3 figures, published versio

Bis[2-(2H-benzotriazol-2-yl)-4-methyl-6-(phenyl­imino­methyl-κN)phenolato-κO]palladium(II)

In the title complex, [Pd(C20H15N4O)2], the PdII atom is tetra­coordinated by two N atoms and two O atoms from two bidentate imine–benzotriazole phenolate ligands, forming a square-planar environment. The asymmetric unit contains two half-mol­ecules in both of which the PdII atom lies on a centre of symmetry. The average distances between the PdII atom and the coordinated O and N atoms are 1.9831 (12) and 2.012 (2) Å, respectively

Ischemic Stroke in Patients With Intracranial Dural Arteriovenous Fistulas

Background/PurposeIntracranial dural arteriovenous fistulas (DAVFs) can be complicated by ischemic stroke. This study investigated the frequency and determinants of ischemic stroke in patients with intracranial DAVF.MethodsWe conducted a retrospective study of consecutive patients with intracranial DAVF. Patients with pure hemorrhagic stroke or without available brain imaging for clarifying stroke type were excluded. DAVF was diagnosed by cerebral catheter angiography. Cognard classification and location of DAVFs were ascertained. The clinical characteristics, outcome, and radiographic findings were recorded. Factors associated with occurrence of ischemic stroke in the patients with DAVFs were determined.ResultsA total of 134 patients were enrolled. Six patients (4.5%) had ischemic stroke (mean age: 53.8 ± 13.4 years) and 128 patients were free from stroke (mean age: 55.4 ± 15.2 years). Men accounted for 83% in the ischemic stroke group and 34% in the non-stroke group. Chemosis, exophthalmos and tinnitus were more frequent in the non-stroke group, whereas seizure and mental decline were more frequent in the ischemic stroke group. DAVF was associated with highest risk of ischemic stroke at locations other than the cavernous sinus or large sinuses. Ischemic stroke also correlated with types of DAVF involving cortical venous drainage, including type IIb (18%), III (15%), and IV (100%). No patient with DAVF type I and IIa had ischemic stroke. The rate of ischemic stroke in patients with concomitant DAVF and cerebral sinus thrombosis was higher than in DAVF patients without cerebral sinus thrombosis. Venous infarct was the major subtype of ischemic stroke in five DAVF patients. Endovascular therapy was the most common choice in both groups, and fewer patients in the ischemic stroke group did not receive any treatment for DAVFs.ConclusionLocation and type of DAVF were two important factors related to the occurrence of ischemic stroke in DAVF patients

Sodium vanadate combined with l-ascorbic acid delays disease progression, enhances motor performance, and ameliorates muscle atrophy and weakness in mice with spinal muscular atrophy

BACKGROUND: Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. METHODS: Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. RESULTS: Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation in these organs. CONCLUSIONS: Combined treatment beginning at birth and continuing for 1 month conferred protection against neuromuscular damage in mice with milder types of SMA. Further, these mice exhibited enhanced motor performance in adulthood. Therefore, combined treatment could present a feasible treatment option for patients with late-onset SMA

Neoadjuvant Carboplatin/Paclitaxel versus 5-Fluorouracil/Cisplatin in Combination with Radiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma:A Multicenter Comparative Study

SIMPLE SUMMARY: The most beneficial neoadjuvant chemoradiotherapy for Asian patients with esophageal squamous cell carcinoma remains uncertain. Using propensity score matching by inverse probability of treatment weighting to balance the baseline variables, the neoadjuvant carboplatin/paclitaxel (CROSS) regimen versus the cisplatin/5-fluorouracil (PF) regimen in combination with 41.4–50.4 Gy of radiotherapy were compared. We found that Taiwanese patients treated with the CROSS regimen (Carboplatin + Paclitaxel + 41.4–45.0 Gy) had less treatment-related complications and more favorable survival figures. Collectively, these results suggest that CROSS is safe and effective. ABSTRACT: Background: The most beneficial neoadjuvant chemoradiotherapy (nCRT) combination for esophageal squamous cell carcinoma (ESCC) in Asia remains uncertain. Herein, we compared the neoadjuvant carboplatin/paclitaxel (CROSS) regimen versus the cisplatin/5-fluorouracil (PF) regimen in combination with 41.4–50.4 Gy of radiotherapy. Methods: Patients were stratified according to their nCRT regimen: CROSS + 41.4–45.0 Gy (CROSS), PF + 45.0 Gy (PF4500) or PF + 50.4 Gy (PF5040). Propensity score matching by inverse probability of treatment weighting (IPTW) was used to balance the baseline variables. Results: Before IPTW, a total of 334 patients were included. The lowest chemotherapy completion rate was observed in the PF5040 group (76.2% versus 89.4% and 92.0% in the remaining two groups, respectively). Compared with CROSS, both PF groups showed more severe weight loss during nCRT and a higher frequency of post-esophagectomy anastomotic leaks. The use of PF5040 was associated with the highest rate of pathological complete response (45.3%). While CROSS conferred a significant overall survival benefit over PF4500 (hazard ratio [HR] = 1.30, 95% CI = 1.05 to 1.62, p = 0.018), similar survival figures were observed when compared with PF5040 (HR = 1.17, 95% CI = 0.94 to 1.45, p = 0.166). Conclusions: The CROSS regimen conferred a significant survival benefit over PF4500, although the similar survival figures were similar to those observed with PF5040. Considering the lower incidences of severe weight loss and post-esophagectomy anastomotic leaks, CROSS represents a safe and effective neoadjuvant treatment for Taiwanese patients with ESCC