137 research outputs found
Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin \u3bc-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease
Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells
BACKGROUND:
Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways.
METHODS:
Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR.
RESULTS:
IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration.
CONCLUSIONS:
IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies
Adolescent soccer is correlated with an increase of kyphosis but a reduction of low back pain: a controlled cross-sectional survey
Characterization and Optimization of a Conical Corona Reactor for Seed Treatment of Rapeseed
Plasma agriculture is a growing field that combines interdisciplinary areas with the aim of researching alternative solutions for increasing food production. In this field, plasma sources are used for the treatment of different agricultural goods in pre-and post-harvest. With the big variety of possible treatment targets, studied reactors must be carefully investigated and characterized for specific goals. Therefore, in the present study, a cone-shaped corona reactor working with argon was adapted for the treatment of small seeds, and its basic properties were investigated. The treatment of rapeseed using different voltage duty cycles led to an increase in surface wettability, possibly contributing to the accelerated germination (27% for 90% duty cycle). The discharge produced by the conical reactor was able to provide an environment abundant with reactive oxygen species that makes the process suitable for seeds treatment. However, operating in direct treatment configuration, large numbers of seeds placed in the reactor start impairing the discharge homogeneity
Synaptotagmin 13 is neuroprotective across motor neuron diseases
In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases
Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance
Multiple myeloma is still incurable due to an intrinsic aggressiveness or, more frequently, to the interactions of malignant plasma cells with bone marrow microenvironment. Myeloma cells educate bone marrow cells to support neoplastic cell growth, survival, acquisition of drug resistance resulting in disease relapse. Myeloma microenvironment is characterized by Notch signaling hyperactivation due to the increased expression of Notch1 and 2 and the ligands Jagged1 and 2 in tumor cells. Notch activation influences myeloma cell biology and promotes the reprogramming of bone marrow stromal cells. In this work we demonstrate, by in vitro, ex vivo and using a zebrafish multiple myeloma model, that Jagged inhibition causes a decrease in both myeloma-intrinsic and stromal cell-induced resistance to currently used drugs, i.e. bortezomib, lenalidomide and melphalan. The molecular mechanism of drug resistance involves the chemokine system CXCR4/SDF1\u3b1. Myeloma cell-derived Jagged ligands trigger Notch activity in bone marrow stromal cells. These, in turn, secrete higher levels of SDF1\u3b1 in the bone marrow microenvironment increasing CXCR4 activation in myeloma cells, which is further potentiated by the concomitant increased expression of this receptor induced by Notch activation. Consistently with the augmented pharmacological resistance, SDF1\u3b1 boosts the expression of BCL2, Survivin and ABCC1. These results indicate that a Jagged-tailored approach may contribute to disrupting the pharmacological resistance due to intrinsic myeloma cell features or to the pathological interplay with bone marrow stromal cells and, conceivably, improve patients' response to standard-of-care therapies
An Application of Using Support Vector Machine Based on Classification Technique for Predicting Medical Data Sets
© 2019, Springer Nature Switzerland AG. This paper illustrates the utilise of various kind of machine learning approaches based on support vector machines for classifying Sickle Cell Disease data set. It has demonstrated that support vector machines generate an essential enhancement when applied for the pre-processing of clinical time-series data set. In this aspect, the objective of this study is to present discoveries for a number of classes of approaches for therapeutically associated problems in the purpose of acquiring high accuracy and performance. The primary case in this study includes classifying the dosage necessary for each patient individually. We applied a number of support vector machines to examine sickle cell data set based on the performance evaluation metrics. The result collected from a number of models have indicated that, support vector Classifier demonstrated inferior outcomes in comparison to Radial Basis Support Vector Classifier. For our Sickle cell data sets, it was found that the Parzen Kernel Support Vector Classifier produced the highest levels of performance and accuracy during training procedure accuracy 0.89733, AUC 0.94267. Where the testing set process, accuracy 0.81778, the area under the curve with 0.86556
A compendium of long non-coding RNAs transcriptional fingerprint in multiple myeloma
Multiple myeloma (MM) is a clonal proliferation of bone marrow plasma cells characterized by highly heterogeneous genetic background and clinical course, whose pathogenesis remains largely unknown. Long ncRNAs (lncRNAs) are a large class of non-protein-coding RNA, involved in many physiological cellular and genomic processes as well as in carcinogenesis and tumor evolution. Although still in its infancy, the role of lncRNAs in MM is progressively expanding. Besides studies on selected candidates, lncRNAs expression at genome-wide transcriptome level is confined to microarray technologies, thus investigating a limited collection of transcripts. In the present study investigating a cohort of 30 MM patients, a deep RNA-sequencing analysis overwhelmed previous array studies and allowed the most accurate definition of lncRNA transcripts structure and expression, ultimately providing a comprehensive catalogue of lncRNAs specifically associated with the main MM molecular subgroups and genetic alterations. Despite the small number of analyzed samples, the high accuracy of RNA-sequencing approach for complex transcriptome processing led to the identification of 391 deregulated lncRNAs, 67% of which were also detectable and validated by whole-transcript microarrays. In addition, we identified a list of lncRNAs, with potential relevance in MM, co-expressed and in close proximity to genes that might undergo a cis-regulatory relationship
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