Oxidative Stress-Induced JNK/AP-1 Signaling is a Major Pathway Involved in Selective Apoptosis of Myelodysplastic Syndrome Cells by Withaferin-A

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS

Epidural stimulation for cardiovascular function increases lower limb lean mass in individuals with chronic motor complete spinal cord injury

Chronic motor complete spinal cord injury (SCI) results in paralysis and deleterious neuromuscular and autonomic adaptations. Paralyzed muscles demonstrate atrophy, loss of force and increased fatigability. Also, SCI-induced autonomic impairment results in persistently low resting blood pressure and heart rate, among other features. We previously reported that spinal cord epidural stimulation (scES) optimized for cardiovascular (CV) function (CV-scES), which is applied in sitting position and does not activate the leg muscles, can maintain systolic blood pressure within a normotensive range during quiet sitting and during orthostatic stress. In the present study, dual-energy X-ray absorptiometry collected from six individuals with chronic clinically motor complete SCI demonstrated that 88 ± 11 sessions of CV-scES (7 days week−1; 2 h day−1 in four individuals and 5 h day−1 in two individuals) over a period of ∼6 months significantly increased lower limb lean mass (by 0.67 ± 0.39 kg or 9.4 ± 8.1%; P < 0.001). Additionally, muscle strength and fatigability data elicited by neuromuscular electrical stimulation in three of these individuals demonstrated a general increase (57 ± 117%) in maximal torque output (between 2 and 44 N m in 14 of the 17 muscle groups tested overall) and torque–time integral during intermittent, fatiguing contractions (63 ± 71%; between 7 and 230% in 16 of the 17 muscle groups tested overall). In contrast, whole-body mass and composition did not change significantly. In conclusion, long-term use of CV-scES can have a significant impact on lower limb muscle properties after chronic motor complete SCI

Effects of NMES pulse width and intensity on muscle mechanical output and oxygen extraction in able-bodied and paraplegic individuals

Purpose: Neuromuscular Electrical Stimulation (NMES) is commonly used in neuromuscular rehabilitation protocols, and its parameters selection substantially affects the characteristics of muscle activation. Here, we investigated the effects of short pulse width (200 µs) and higher intensity (short-high) NMES or long pulse width (1000 µs) and lower intensity (long-low) NMES on muscle mechanical output and fractional oxygen extraction. Muscle contractions were elicited with 100 Hz stimulation frequency, and the initial torque output was matched by adjusting stimulation intensity. Methods: Fourteen able-bodied and six spinal cord-injured (SCI) individuals participated in the study. The NMES protocol (75 isometric contractions, 1-s on–3-s off) targeting the knee extensors was performed with long-low or short-high NMES applied over the midline between anterior superior iliac spine and patella protrusion in two different days. Muscle work was estimated by torque–time integral, contractile properties by rate of torque development and half-relaxation time, and vastus lateralis fractional oxygen extraction was assessed by Near-Infrared Spectroscopy (NIRS). Results: Torque–time integral elicited by the two NMES paradigms was similar throughout the stimulation protocol, with differences ranging between 1.4% (p = 0.877; able-bodied, mid-part of the protocol) and 9.9% (p = 0.147; SCI, mid-part of the protocol). Contractile properties were also comparable in the two NMES paradigms. However, long-low NMES resulted in higher fractional oxygen extraction in able-bodied (+ 36%; p = 0.006). Conclusion: Long-low and short-high NMES recruited quadriceps femoris motor units that demonstrated similar contractile and fatigability properties. However, long-low NMES conceivably resulted in the preferential recruitment of vastus lateralis muscle fibers as detected by NIRS

Novel stochastic framework for automatic segmentation of human thigh MRI volumes and its applications in spinal cord injured individuals.

Severe spinal cord injury (SCI) leads to skeletal muscle atrophy and adipose tissue infiltration in the skeletal muscle, which can result in compromised muscle mechanical output and lead to health-related complications. In this study, we developed a novel automatic 3-D approach for volumetric segmentation and quantitative assessment of thigh Magnetic Resonance Imaging (MRI) volumes in individuals with chronic SCI as well as non-disabled individuals. In this framework, subcutaneous adipose tissue, inter-muscular adipose tissue and total muscle tissue are segmented using linear combination of discrete Gaussians algorithm. Also, three thigh muscle groups were segmented utilizing the proposed 3-D Joint Markov Gibbs Random Field model that integrates first order appearance model, spatial information, and shape model to localize the muscle groups. The accuracy of the automatic segmentation method was tested both on SCI (N = 16) and on non-disabled (N = 14) individuals, showing an overall 0.93±0.06 accuracy for adipose tissue and muscle compartments segmentation based on Dice Similarity Coefficient. The proposed framework for muscle compartment segmentation showed an overall higher accuracy compared to ANTs and STAPLE, two previously validated atlas-based segmentation methods. Also, the framework proposed in this study showed similar Dice accuracy and better Hausdorff distance measure to that obtained using DeepMedic Convolutional Neural Network structure, a well-known deep learning network for 3-D medical image segmentation. The automatic segmentation method proposed in this study can provide fast and accurate quantification of adipose and muscle tissues, which have important health and functional implications in the SCI population