High intensity variable stepping training in persons with motor incomplete spinal cord injury: a case series

Background and Purpose: Previous data suggest that large amounts of high intensity stepping training in variable contexts (tasks and environments) may improve locomotor function, aerobic capacity and treadmill gait kinematics in individuals post-stroke. Whether similar training strategies are tolerated and efficacious for patients with other acute-onset neurological diagnoses, such as motor incomplete spinal cord injury (iSCI) is unknown, particularly with potentially greater, bilateral impairments. This case series evaluated the feasibility and preliminary short and long-term efficacy of high intensity variable stepping practice in ambulatory participants >1 year post-iSCI. Case Series Description: Four participants with iSCI (neurological levels C5-T3) completed up to 40 1-hr sessions over 3–4 months. Stepping training in variable contexts was performed at up to 85% maximum predicted heart rate, with feasibility measures of patient tolerance, total steps/session, and intensity of training. Clinical measures of locomotor function, balance, peak metabolic capacity and gait kinematics during graded treadmill assessments were performed at baseline and post-training, with >1 year follow-up. Outcomes: Participants completed 24–40 sessions over 8–15 weeks, averaging 2222±653 steps/session, with primary adverse events of fatigue and muscle soreness. Modest improvements in locomotor capacity where observed at post-training, with variable changes in lower extremity kinematics during treadmill walking. Discussion: High intensity, variable stepping training was feasible and tolerated by participants with iSCI although only modest gains in gait function or quality were observed. The utility of this intervention in patients with more profound impairments may be limited

Serum microrna biomarkers for detection of non-small cell lung cancer

Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73-0.91), sensitivity of 100% (95% CI; 0.93-1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results. © 2012 Hennessey et al

Demographic and histopathologic data for serum samples.

<p>NSCLC, non-small cell lung cancer; Normal, cancer free, healthy controls.</p><p>*Only one healthy control donor was under 35 years.</p

Differential miRNA expression in sera from NSCLC patients (cancer) and healthy controls (normal) in test set.

<p>Diff, differential expression between the two miRNAs, calculated as the difference between Ct values of the two indicated miRNAs. PPV, positive predictive value; NPV, negative predictive value; SENS, sensitivity; and SPEC, specificity. The cutoff value used in training set was applied in the test set.</p

Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC.

Over a half million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide, however, 5 year overall survival is only 50% for HNSCC patients. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC. However, comprehensive pipelines with statistical algorithms that account for HNSCC biology and perform independent confirmatory and functional validation of candidates are needed to identify the most biologically relevant genes. We applied outlier statistics to high throughput gene expression data, and identified 76 top-scoring candidates with significant differential expression in tumors compared to normal tissues. We identified 15 epigenetically regulated candidates by focusing on a subset of the genes with a negative correlation between gene expression and promoter methylation. Differential expression and methylation of 3 selected candidates (BANK1, BIN2, and DTX1) were confirmed in an independent HNSCC cohorts from Johns Hopkins and TCGA (The Cancer Genome Atlas). We further performed functional evaluation of NOTCH regulator, DTX1, which was downregulated by promoter hypermethylation in tumors, and demonstrated that decreased expression of DTX1 in HNSCC tumors maybe associated with NOTCH pathway activation and increased migration potential

Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC.

Over a half million new cases of Head and Neck Squamous Cell Carcinoma (HNSCC) are diagnosed annually worldwide, however, 5 year overall survival is only 50% for HNSCC patients. Recently, high throughput technologies have accelerated the genome-wide characterization of HNSCC. However, comprehensive pipelines with statistical algorithms that account for HNSCC biology and perform independent confirmatory and functional validation of candidates are needed to identify the most biologically relevant genes. We applied outlier statistics to high throughput gene expression data, and identified 76 top-scoring candidates with significant differential expression in tumors compared to normal tissues. We identified 15 epigenetically regulated candidates by focusing on a subset of the genes with a negative correlation between gene expression and promoter methylation. Differential expression and methylation of 3 selected candidates (BANK1, BIN2, and DTX1) were confirmed in an independent HNSCC cohorts from Johns Hopkins and TCGA (The Cancer Genome Atlas). We further performed functional evaluation of NOTCH regulator, DTX1, which was downregulated by promoter hypermethylation in tumors, and demonstrated that decreased expression of DTX1 in HNSCC tumors maybe associated with NOTCH pathway activation and increased migration potential

Differential expression of miRNA diffpair miR-15b/miR27-b in sera from healthy donors (normal) and from lung cancer patients (cancer).

<p>Differential expression values were calculated as a difference of the Ct values for the two miRNAs. The threshold indicated by the horizontal line was selected to maximize the sum of sensitivity and specificity as described in data analysis. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) obtained using the differential expression of the 2 miRNA displayed as tables for the training set (on the right) and the test set (on the left).</p

Outlier Analysis Defines Zinc Finger Gene Family DNA Methylation in Tumors and Saliva of Head and Neck Cancer Patients.

Head and Neck Squamous Cell Carcinoma (HNSCC) is the fifth most common cancer, annually affecting over half a million people worldwide. Presently, there are no accepted biomarkers for clinical detection and surveillance of HNSCC. In this work, a comprehensive genome-wide analysis of epigenetic alterations in primary HNSCC tumors was employed in conjunction with cancer-specific outlier statistics to define novel biomarker genes which are differentially methylated in HNSCC. The 37 identified biomarker candidates were top-scoring outlier genes with prominent differential methylation in tumors, but with no signal in normal tissues. These putative candidates were validated in independent HNSCC cohorts from our institution and TCGA (The Cancer Genome Atlas). Using the top candidates, ZNF14, ZNF160, and ZNF420, an assay was developed for detection of HNSCC cancer in primary tissue and saliva samples with 100% specificity when compared to normal control samples. Given the high detection specificity, the analysis of ZNF DNA methylation in combination with other DNA methylation biomarkers may be useful in the clinical setting for HNSCC detection and surveillance, particularly in high-risk patients. Several additional candidates identified through this work can be further investigated toward future development of a multi-gene panel of biomarkers for the surveillance and detection of HNSCC