Effects of Training Intensity on Locomotor Performance in Individuals With Chronic Spinal Cord Injury: A Randomized Crossover Study

Background. Many physical interventions can improve locomotor function in individuals with motor incomplete spinal cord injury (iSCI), although the training parameters that maximize recovery are not clear. Previous studies in individuals with other neurologic injuries suggest the intensity of locomotor training (LT) may positively influence walking outcomes. However, the effects of intensity during training of individuals with iSCI have not been tested. Objective. The purpose of this pilot, blinded-assessor randomized trial was to evaluate the effects of LT intensity on walking outcomes in individuals with iSCI. Methods. Using a crossover design, ambulatory participants with iSCI \u3e1 year duration performed either high- or low-intensity LT for ≤20 sessions over 4 to 6 weeks. Four weeks following completion, the training interventions were alternated. Targeted intensities focused on achieving specific ranges of heart rate (HR) or ratings of perceived exertion (RPE), with intensity manipulated by increasing speeds or applying loads. Results. Significantly greater increases in peak treadmill speeds (0.18 vs 0.02 m/s) and secondary measures of metabolic function and overground speed were observed following high- versus low-intensity training, with no effects of intervention order. Moderate to high correlations were observed between differences in walking speed or distances and differences in HRs or RPEs during high- versus low-intensity training. Conclusion. This pilot study provides the first evidence that the intensity of stepping practice may be an important determinant of LT outcomes in individuals with iSCI. Whether such training is feasible in larger patient populations and contributes to improved locomotor outcomes deserves further consideration

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

Poly(ADP-Ribose) Polymerase Inhibition: "Targeted" Therapy for Triple-Negative Breast Cancer

In contrast to endocrine-sensitive and HER2-positive breast cancer, novel agents capable of treating advanced triple negative breast cancer (TNBC) are lacking. PARP (Poly-(adenosine diphosphate [ADP]-ribose) polymerase) inhibitors are emerging as one of the most promising ‘targeted’ therapeutics to treat TNBC, with the intended ‘target’ being DNA repair. PARP's are a family of enzymes involved in multiple cellular processes including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized PARP inhibition, in conjunction with the loss of DNA-repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and TNBC. The focus of this review will include an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA-deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, conclude with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer

WISE/NEOWISE Preliminary Analysis and Highlights of the 67P/Churyumov-Gerasimenko Near Nucleus Environs

On January 18-19 and June 28-29 of 2010, the Wide-field Infrared Survey Explorer (WISE) spacecraft imaged the Rosetta mission target, comet 67P/Churyumov-Gerasimenko. We present a preliminary analysis of the images, which provide a characterization of the dust environment at heliocentric distances similar to those planned for the initial spacecraft encounter, but on the outbound leg of its orbit rather than the inbound. Broad-band photometry yields low levels of CO2 production at a comet heliocentric distance of 3.32 AU and no detectable production at 4.18 AU. We find that at these heliocentric distances, large dust grains with mean grain diameters on the order of a millimeter or greater dominate the coma and evolve to populate the tail. This is further supported by broad-band photometry centered on the nucleus, which yield an estimated differential dust particle size distribution with a power law relation that is considerably shallower than average. We set a 3-sigma upper limit constraint on the albedo of the large-grain dust at <= 0.12. Our best estimate of the nucleus radius (1.82 +/- 0.20 km) and albedo (0.04 +/- 0.01) are in agreement with measurements previously reported in the literature

WISE/NEOWISE observations of Active Bodies in the Main Belt

We report results based on mid-infrared photometry of 5 active main belt objects (AMBOs) detected by the Wide-field Infrared Survey Explorer (WISE) spacecraft. Four of these bodies, P/2010 R2 (La Sagra), 133P/Elst-Pizarro, (596) Scheila, and 176P/LINEAR, showed no signs of activity at the time of the observations, allowing the WISE detections to place firm constraints on their diameters and albedos. Geometric albedos were in the range of a few percent, and on the order of other measured comet nuclei. P/2010 A2 was observed on April 2-3, 2010, three months after its peak activity. Photometry of the coma at 12 and 22 {\mu}m combined with ground-based visible-wavelength measurements provides constraints on the dust particle mass distribution (PMD), dlogn/dlogm, yielding power-law slope values of {\alpha} = -0.5 +/- 0.1. This PMD is considerably more shallow than that found for other comets, in particular inbound particle fluence during the Stardust encounter of comet 81P/Wild 2. It is similar to the PMD seen for 9P/Tempel 1 in the immediate aftermath of the Deep Impact experiment. Upper limits for CO2 & CO production are also provided for each AMBO and compared with revised production numbers for WISE observations of 103P/Hartley 2.Comment: 32 Pages, including 5 Figure

Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II–III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance)

It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed

Discrete microfluidics for the isolation of circulating tumor cell subpopulations targeting fibroblast activation protein alpha and epithelial cell adhesion molecule

Circulating tumor cells consist of phenotypically distinct subpopulations that originate from the tumor microenvironment. We report a circulating tumor cell dual selection assay that uses discrete microfluidics to select circulating tumor cell subpopulations from a single blood sample; circulating tumor cells expressing the established marker epithelial cell adhesion molecule and a new marker, fibroblast activation protein alpha, were evaluated. Both circulating tumor cell subpopulations were detected in metastatic ovarian, colorectal, prostate, breast, and pancreatic cancer patients and 90% of the isolated circulating tumor cells did not co-express both antigens. Clinical sensitivities of 100% showed substantial improvement compared to epithelial cell adhesion molecule selection alone. Owing to high purity (>80%) of the selected circulating tumor cells, molecular analysis of both circulating tumor cell subpopulations was carried out in bulk, including next generation sequencing, mutation analysis, and gene expression. Results suggested fibroblast activation protein alpha and epithelial cell adhesion molecule circulating tumor cells are distinct subpopulations and the use of these in concert can provide information needed to navigate through cancer disease management challenges

New Frontiers for Organismal Biology

Understanding how complex organisms function as integrated units that constantly interact with their environment is a long-standing challenge in biology. To address this challenge, organismal biology reveals general organizing principles of physiological systems and behavior—in particular, in complex multicellular animals. Organismal biology also focuses on the role of individual variability in the evolutionary maintenance of diversity. To broadly advance these frontiers, cross-compatibility of experimental designs, methodological approaches, and data interpretation pipelines represents a key prerequisite. It is now possible to rapidly and systematically analyze complete genomes to elucidate genetic variation associated with traits and conditions that define individuals, populations, and species. However, genetic variation alone does not explain the varied individual physiology and behavior of complex organisms. We propose that such emergent properties of complex organisms can best be explained through a renewed emphasis on the context and life-history dependence of individual phenotypes to complement genetic data.Organismic and Evolutionary Biolog