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Background Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Our report describes the evolution of management and characteristics associated with recurrence, disease-specific survival (DSS) and overall survival (OS) in the treatment of MCC. Methods A single institution retrospective review of MCC and SEER data to determine factors associated with RFS, DSS, and OS using a multivariable Cox regression on inverse-probability weighted cohorts. Results One hundred fifty-nine patients were identified with a median age of 75. Of these, 96% were Caucasian and 60% male. Fifty-eight out of 159 (36%) of all patients were deceased with 21/58 (36%) dead from MCC with a median follow-up of 3.1 years. Institutionally, trends over time demonstrated an increased use of immunotherapy with a concomitant decrease in chemotherapy and decreased use of radiotherapy alone. Institutionally and nationally, there has been increased surgical nodal staging. Institutionally, factors associated with shorter DSS included advanced age, active cigarette smoker (p = 0.002), cT2 disease (p = 0.007), and MCC with unknown primary (p p p p = 0.002), and cT2 disease (HR 9.59, p Conclusion Changing practice patterns in MCC management have been driven by the adoption of immunotherapy. Our study highlights that competing risks of mortality in MCC patients likely prevents OS from being an accurate surrogate outcome measure to understand factors associated with DSS.

There is evidence of the therapeutic potential of intranasal oxytocin for the treatment of pain and various psychiatric disorders, however, there is scant evidence that oxytocin reaches the brain. We quantified the concentration and distribution pattern of [125I]-radiolabeled oxytocin in the brains and peripheral tissues of rats after intranasal delivery using gamma counting and autoradiography, respectively. Radiolabel was detected in high concentrations in the trigeminal and olfactory nerves as well as in brain regions along their trajectories. Considerable concentrations were observed in the blood, however, relatively low levels of radiolabel were measured in peripheral tissues. The addition of a mucoadhesive did not enhance brain concentrations. These results provide support for intranasal OT reaching the brain via the olfactory and trigeminal neural pathways. These findings will inform the design and interpretation of clinical studies with intranasal oxytocin.

Objectives To investigate factors and complications associated with prolonged inpatient length of stay (LOS) in patients who receive total laryngectomy (TL), and to analyze its effect on short‐term and long‐term overall survival (OS). Methods The National Cancer Database (NCDB) was queried from 2004 to 2016 for patients with laryngeal cancer, who received TL within 60 days of diagnosis, and who had an inpatient LOS ≥1 night. Multivariable binary logistic regression and survival analyses on propensity score matched cohorts with Kaplan‐Meier analysis and extended Cox regression were utilized. Results Eight thousand two hundred and ninety‐eight patients from the NCDB were included. Median inpatient LOS was 8 days after TL (IQR: 7, 12). Prolonged LOS was defined as above the 75th percentile or 13 days or greater. On multivariable analysis, increasing patient age (OR 1.14 per 10 years, P = .003), female sex (OR 1.35, P

The introduction of gas warfare in World War One was impactful, as it both expanded the breadth of warfare and fueled the invention of techniques required to treat these new injuries. Gas injuries were responsible for 91,000 of 1.3 million deaths in World War One. Gassed soldiers had wounds which the world had never seen. They presented in large scale to medical tents and base hospitals across Europe. As gas casualties poured in, doctors and nurses had to treat these conditions in the best way they knew. Gas warfare changed how war was performed and how casualties of this attack were treated. The techniques learned from treating the multitudes of men with gas burns led to advances in the field of burn care, which have helped to improve mortality and reduce morbidity in hospitals across the world.

In 2014, the Radiation Therapy Oncology Group 1221 trial was initiated to analyze whether surgery with risk-based radiation therapy or chemoradiation therapy was superior to chemoradiation therapy alone in patients with clinically staged T1-2N1-2bM0 HPV-negative oropharyngeal squamous cell carcinoma. However, the study was prematurely terminated. Given the lack of a randomized controlled trial, we retrospectively approached the same question using large national cancer databases.Retrospective cohort study.The National Cancer Database and Surveillance, Epidemiology, and End Results (SEER) program from 2010 to 2016.We identified 3004 patients in the National Cancer Database and 670 patients in the SEER database. Statistical techniques included Kaplan-Meier survival analysis, binary and multinomial logistic regressions, Cox proportional hazard regressions, and inverse propensity score weighting.On weighted multivariable Cox regression, patients recommended to receive frontline surgery had improved overall survival as compared with those recommended to receive chemoradiation therapy alone (hazard ratio [HR], 0.77; 95% CI, 0.68-0.86). On post hoc multivariable analysis based on therapy actually received, frontline surgery with adjuvant chemoradiation therapy was associated with improved overall survival (HR, 0.59; 95% CI, 0.50-0.71) as compared with chemoradiation therapy without surgery. Analysis of the SEER cohort revealed improved overall survival (HR, 0.69; 95% CI, 0.54-0.87) and head and neck cancer-specific survival (HR, 0.59; 95% CI, 0.41-0.84) in patients recommended to receive frontline surgery over chemoradiation therapy alone.Our findings support the use of surgery with risk-based addition of adjuvant therapy in patients with cT1-2N1-2bM0 HPV-negative oropharyngeal cancer.

We aimed to evaluate trends and outcomes of surgical approaches to thyroid surgery. We hypothesized that there have been changes over time in the utilization of approaches to thyroidectomy, including endoscopic, robotic, and open approaches, and that patient outcomes may differ between open surgery and endoscopic or robotic approaches.Retrospective analysis.The National Cancer Database (NCDB) was queried between 2010 and 2016.National cohort of patients. Descriptive statistics were performed using χWe identified 217,938 patients within the NCDB. While endoscopic thyroid surgery increased, relatively, in use over time (0.93% to 2.34% of cases in 2010 and 2016, respectively), robotic thyroid surgery started to decline relatively to other approaches from 2013 to 2016 (0.39% to 0.25% of cases, respectively). The endoscopic approach was performed more commonly than the robotic approach within individual facilities that have reported both procedures (Endoscopic thyroid surgery has increased in utilization since 2004 but may have worse morbidity and mortality outcomes compared to open surgery.

Nearly 1 in every 120 children born has a congenital heart defect. Although surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. Although primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Here, we investigate the ability of electrical stimulation (ES) to enhance the retention and therapeutic function of pediatric cardiac-derived c-kit+ progenitor cells (CPCs) in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes and increased in vitro survival and adhesion of cells. Specifically, upregulation of β1 and β5 integrins contributed to the increased retention of ES-CPCs. Lastly, we show that ES induces CPCs to release higher levels of pro-reparative factors in vitro. These findings suggest that ES can be used to increase the retention, survival, and therapeutic effect of human c-kit+ progenitor cells and can have implications on a variety of cell-based therapies. Stem Cells 2019;37:1528–1541

Background Surgical management of appendiceal carcinoid tumors is heavily debated, despite National Comprehensive Cancer Network guidelines recommending aggressive resection of tumors >2 cm. We investigated national practice patterns and the predictors and impact of guideline non-adherence. Study Design The National Cancer Database was queried for cases of appendiceal carcinoids diagnosed from 2004 to 2015 treated with either appendectomy or hemicolectomy. Multivariable logistic regression, adjusted for demographic and clinical factors, identified associations with the procedure type among patients stratified by tumor size ≤2 cm and >2 cm. Cox Proportional Hazards then identified associations with overall survival among stratified patient groups. Results Of 3,198 cases of appendiceal carcinoids, 1,893 appendectomies and 1,305 hemicolectomies were identified. Contrary to National Comprehensive Cancer Network guidelines, 32.4% of tumors ≤2 cm were treated with hemicolectomy and 31.3% of tumors >2 cm were treated with definitive appendectomy. Hemicolectomy for small tumors was associated with age 65 years and older (odds ratio [OR] 2.4; 95% CI 1.7 to 3.3; reference group age 18 to 39 years), history of malignancy (OR 2.0; 95% CI 1.6 to 2.6), tumor size 1.1 to 2 cm (OR 2.8; 95% CI 2.3 to 3.4; reference group size ≤1 cm), and lymphovascular invasion (OR 2.2; 95% CI 1.6 to 3.2); appendectomy for large tumors was associated with age 65 years and older only (OR 2.2; 95% CI 1.1 to 4.2). Procedure type was not associated with survival for small or large tumors (hazard ratio 1.0; 95% CI 0.7 to 1.4 and hazard ratio 1.1; 95% CI 0.6 to 2.0, respectively). Conclusions Despite well-known size-based treatment guidelines for appendiceal carcinoids, one-third of patients in the US undergo hemicolectomy for small tumors and appendectomy for large tumors. Guideline non-adherence, however, is not associated with overall survival. Reasons for these practice patterns should be explored, and guidelines revisited.

BackgroundSelf-paced treadmills (SPT) can provide an engaging setting for gait rehabilitation by responding directly to the user’s intent to modulate the external environment and internal effort. They also can improve gait analyses by allowing scientists and clinicians to directly measure the effect of an intervention on walking velocity. Unfortunately, many common SPT algorithms are not suitable for individuals with gait impairment because they are designed for symmetric gait patterns. When the user’s gait is asymmetric due to paresis or if it contains large accelerations, the performance is diminished. Creating and validating an SPT that is suitable for asymmetric gait will improve our ability to study rehabilitation interventions in populations with gait impairment. The objective of this study was to test and validate a novel self-paced treadmill on both symmetric and asymmetric gait patterns and evaluate differences in gait kinematics, kinetics, and muscle activity between fixed-speed and self-paced treadmill walking.MethodsWe collected motion capture, ground reaction force data, and muscle activity from 6 muscles in the dominant leg during walking from 8 unimpaired subjects. In the baseline condition, the subjects walked at 3 fixed-speeds normalized to their leg length as Froude numbers. We developed a novel kinematic method for increasing the accuracy of the user’s estimated walking velocity and compared our method against other published algorithms at each speed. Afterward, subjects walked on the SPT while matching their walking speed to a given target velocity using visual feedback of the treadmill speed. We evaluated the SPT by measuring steady-state error and the number of steps to reach the desired speed. We split the gait cycle into 7 phases and compared the kinematic, kinetic, and muscle activity between the fixed speed and self-paced mode in each phase. Then, we validated the performance of the SPT for asymmetric gait by having subjects walk on the SPT while wearing a locked-knee brace set to 0° on the non-dominant leg.ResultsOur SPT enabled controlled walking for both symmetric and asymmetric gait patterns. Starting from rest, subjects were able to control the SPT to reach the targeted speeds using visual feedback in 13–21 steps. With the locked knee brace, subjects controlled the treadmill with substantial step length and step velocity asymmetry. One subject was able to execute a step-to gait and halt the treadmill on heel-strikes with the braced leg. Our kinematic correction for step-length outperformed the competing algorithms by significantly reducing the velocity estimation error at the tested velocities. The joint kinematics, joint torques, and muscle activity were generally similar between fixed-speed and self-paced walking. Statistically significant differences were found in 5 of 63 tests for joint kinematics, 2 of 63 tests for joint torques, and 9 of 126 tests for muscle activity. The differences that were statistically significant were not found across all speeds and were generally small enough to be of limited clinical relevance.ConclusionsWe present a validated method for implementing a self-paced treadmill for asymmetric and symmetric gaits. As a result of the increased accuracy of our estimation algorithm, our SPT produced controlled walking without including a position feedback controller, thereby reducing the influence of the controller on measurements of the user’s true walking speed. Our method relies only on a kinematic correction to step length and step time which can support transfer to systems outside of the laboratory for symmetric and asymmetric gaits in clinical populations.

This chapter examines pulmonary artery catheters (PACs). PACs provide various pressure measurements and associated waveforms, including central venous pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure. They also offer the opportunity to calculate an intermittent cardiac output measurement via the thermodilution technique. However, PAC placement should be checked to ensure that the catheter is not misplaced into the right ventricle, which would lead to endocardial irritation and result in ventricular ectopy. The chapter then looks at risk factors and potential therapies for ventricular ectopy in the intensive care unit. It also considers the debate on the benefit or harm of utilizing PACs in the treatment of critically ill patients. Ultimately, understanding the risks associated with PAC use and obtaining the skill set necessary to safely interpret the data provided by these devices are the crux of optimal PAC utilization.

Merkel cell carcinoma practice guidelines recommend sentinel lymph node biopsy after wide local excision for the initial management of clinically node-negative disease without distant metastases (cN0M0). Despite guideline publication, treatment selection remains variable. We hypothesized that receipt of guideline-recommended care would be more common in patients evaluated at academic centers and institutions with high melanoma case volumes and that such therapy would be associated with improved overall survival.Retrospective cohort analysis.The National Cancer Database from 2004 to 2015.A total of 3500 patients were included. We utilized Kaplan-Meier analysis and logistic and Cox proportional hazard regressions. Survival analysis was performed on inverse probability-weighted cohorts.There has been a trend toward evaluation at academic programs at a rate of 1.58% of patients per year (95% CI, 1.06%-2.11%) since 2004. However, the percentage of patients receiving guideline-compliant primary tumor excision and lymph node evaluation has plateaued at approximately 50% since 2012. Guideline-compliant surgical management was more commonly provided to patients evaluated at academic programs than nonacademic programs but only when those institutions had a high melanoma case volume (odds ratio, 2.01; 95% CI, 1.62-2.48). Receipt of guideline-compliant primary tumor excision and lymph node evaluation was associated with improved overall survival (hazard ratio, 0.70; 95% CI, 0.64-0.76).Facility factors affect rates of receipt of guideline-compliant initial surgical management for patients with node-negative Merkel cell carcinoma. Given the survival benefit of such treatment, patients may benefit from care at hospitals with high melanoma case volumes.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Background: In the past two decades, new evidence and guidelines have emerged to refine recommendations for the use of radioactive iodine (RAI) therapy after thyroidectomy for cancer. We aim to des...

Background/aim Sclerosing microcystic adenocarcinoma (SMA) is a rare oral cavity neoplasia, histologically resembling microcystic adnexal carcinoma (MAC) of the skin. Only nine SMA cases have been reported in the literature, frequently in the context of immunosuppression; SMA has not been recognized in the most recent WHO tumor classification. We sought to identify potential molecular mechanisms of tumorigenesis in a case of SMA relative to those known for MAC. Case report A 41-year-old female with psoriatic arthritis undergoing immunosuppression therapy presented with a tongue mass. Biopsy revealed a diagnosis of SMA. Partial glossectomy and neck dissection showed no residual tumor or nodal disease. Results whole exome sequencing revealed moderate mutational burden and putative loss of function mutations in CDK11B but no overlap with known MAC mutations. Conclusion We characterized the genomic profile of SMA for the first time, identifying both mutational burden and unique somatic variants associated with tumorigenesis.

Introduction Myasthenia gravis (MG) crisis has no specific reported correlation with atrial fibrillation (AF). We present a series of patients observed from a single general neurologist's outpatient and inpatient practice over a 9-year period who experienced the combination of MG crisis and AF. Case report Retrospective chart review of patients within 1 neurologist's inpatient and outpatient practice was done. Charts were selected based on the occurrence of newly diagnosed AF during MG crisis over a 9-year period. Most patients were diagnosed in the hospital and then followed as outpatients. Charts were reviewed to determine factors that may have played a role in the co-occurrence of these 2 conditions. Eight patients were identified that had co-occurring MG crisis and AF. All patients had very active MG, and were in or had recently been in MG crisis at the time their AF was discovered. Patients tended to have late-onset MG to be male, to be acetylcholinesterase receptor antibody positive, and to have improvement or remission of their AF once the MG achieved better clinical control. Conclusion New-onset AF can occur during MG crisis. The cardiac outcome improves with treatment of the underlying disease, after initial cardiac stabilization.

PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that partner with PIWI proteins to protect germline tissues from destabilizing transposon activity. While the aberrant expression of PIWI proteins has been linked with poor outcomes for many cancers, less is known about the expression or function of piRNAs in cancer. We performed array-based piRNA expression profiling in seven pairs of normal brain and glioblastoma multiforme (GBM) tissue specimens, and identified expression of ~350 piRNAs in both tissues and a subset with dysregulated expression in GBM. Over-expression of the most down-regulated piRNA in GBM tissue, piR-8041, was found to reduce glioma cell line proliferation, induce cell cycle arrest and apoptosis, and inhibit cell survival pathways. Furthermore, pre-treatment with piR-8041 significantly reduced the volume of intracranial mouse xenograft tumors. Taken together, our study reveals reduced expression in GBM of piR-8041 and other piRNAs with tumor suppressive properties, and suggests that restoration of such piRNAs may be a potential strategy for GBM therapy.

Incorporation of visible light active semiconductors without doping noble (transition) metals results in remarkably different construction principle of visible light driven photocatalysts in which light absorptions and charge transfer become more flexible and efficiencies are no longer limited in ultraviolet (UV) region. Herein, we provide a strategy to design efficient photocatalysts by introducing visible light sensitive Ce2O3 into UV active TiO2 via molten salt synthesis (MSS) of CeTiO4 for visible light CO2 reduction. By changing salt composition in the MSS process, the nanostructured CeTiO4 was prepared and exhibited distinct morphologies e.g., nanorods (NaCl NaH2PO4), polyhedrons (KCl NaCl) and cubic (KCl Na2SO4), respectively. Of the different morphologies, the nanorods of CeTiO4 showed best photoactiviy with quantum efficiencies of 0.36% and 0.065% for CO and CH4 formation, respectively. The unique morphologies well positioned band edges cause such obvious differences and co-contribute to the high performance effectiveness. This study demonstrates a strategy for the rational design and fabrication of visible light driven photocatalysts with controlled morphology, which in turn, can enhance the control and production of value-added products of CO2 reduction. This is an important step towards realizing the utilization of renewable energy sources, such as solar power, to reduce the concentration of atmospheric CO2 and form green energy sources.

Background The genomic characterization of sporadically arising gliomas has delineated molecularly and clinically distinct subclasses of disease. However, less is known about the molecular nature of gliomas that are familial in origin. We performed molecular subtyping of 163 tumor specimens from individuals with a family history of glioma and integrated germline and somatic genomic data to characterize the pathogenesis of 20 tumors in additional detail. Methods Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tumor sections to determine molecular subtypes of glioma. For 20 cases, tumor DNA was exome sequenced on an Illumina HiSeq 2000 platform and copy number profiling was performed on the Illumina HumanOmniExpress BeadChip. Genotypes at glioma risk polymorphisms were determined from germline DNA profiled on the Illumina Infinium OncoArray and deleterious germline mutations were identified from germline sequencing data. Results All 3 molecular subtypes of sporadic glioma were represented in the overall case series, including molecular glioblastoma (n = 102), oligodendroglioma (n = 21), and astrocytoma (n = 20). Detailed profiling of 20 of these cases showed characteristic subtype-specific alterations at frequencies comparable to sporadic glioma cases. All 20 cases had alterations in genes regulating telomere length. Frequencies of common glioma risk alleles were similar to those among sporadic cases, and correlations between risk alleles and same-gene somatic mutations were not observed. Conclusions This study illustrates that the molecular characteristics of familial tumors profiled largely recapitulate what is known about sporadic glioma and that both germline and somatic molecular features target common core pathways involved in gliomagenesis. Key points 1. Familial and sporadic gliomas display highly comparable molecular landscapes. 2. Germline and somatic molecular events target common core pathways involved in gliomagenesis. 3. Carriage of germline glioma risk variants is not associated with somatic events in the same gene.

Background: The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. Methods: The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Results: Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Conclusions: Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor for developing glioma-related seizures or glioma.

Immune cells of myeloid origin, including microglia, macrophages, and myeloid-derived suppressor cells adopt immunosuppressive phenotypes that support gliomagenesis. Here, we tested an a priori hypothesis that single nucleotide polymorphisms (SNPs) in genes related to glioma-associated myeloid cell regulation and function are also associated with patient survival after glioma diagnosis. Subjects for this study were 992 glioma patients treated at The University of Texas MD Anderson Cancer Center in Houston, Texas between 1992 and 2008. Haplotype-tagging SNPs in 91 myeloid-associated genes were analyzed for association with survival by Cox regression. Individual SNP- and gene-based tests were performed separately in glioblastoma (WHO grade IV, n = 511) and lower-grade glioma (WHO grade II–III, n = 481) groups. After adjustment for multiple testing, no myeloid-associated gene variants were significantly associated with survival in glioblastoma. Two SNPs, rs147960238 in CD163 (p = 2.2 × 10−5) and rs17138945 in MET (p = 5.6 × 10−5) were significantly associated with survival of patients with lower-grade glioma. However, these associations were not confirmed in an independent analysis of 563 lower-grade glioma cases from the University of California at San Francisco Adult Glioma Study (p = 0.65 and p = 0.41, respectively). The results of this study do not support a role for inherited polymorphisms in myeloid-associated genes in affecting survival of patients diagnosed with glioblastoma or lower-grade glioma.

Nearly 1% of babies born in the US will be diagnosed with a congenital heart defect (CHD). While surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. While primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Cardiac-derived c-kit + progenitor cells (CPCs) have been widely studied as a cell-based therapy for cardiac pathologies; however, unless these cells are extracted at a very young age their therapeutic efficacy has been shown to be diminished. Finding novel ways to enhance the reparative potential of these cells is thus of critical significance. We previously reported pediatric CPCs (isolated from patients between 1-5 years of age) respond to electrical stimulation (ES) by initiating intracellular calcium oscillations. Here, we investigate the ability of ES to enhance the retention and therapeutic function of pediatric CPCs in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes, such as integrins β1 and β5, and significantly increased in vitro survival and adhesion of cells. Lastly, we show that ES induces CPCs to release higher levels of reported pro-reparative factors in vitro, including angiogenin, FGF, HGF, and VEGF. These findings suggest electrical stimulation can be utilized to increase the retention, survival, and therapeutic effect of human c- kit + progenitor cells. Furthermore, our insights into the mechanisms of increased retention and paracrine function of ES-CPCs can have implications on a variety of cell-based therapies.

Aims Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. Methods Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater. Results Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors. Conclusion Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.

Importance Merkel cell carcinoma is an aggressive, cutaneous, neuroendocrine cancer that is increasing in incidence. Understanding why the incidence of Merkel cell carcinoma is increasing through underlying factors, such as age effects, calendar period of diagnosis effects, and birth cohort effects, can help guide resource allocation and design of screening programs. Objectives To evaluate the associations of patient age, calendar period of diagnosis, and birth cohort with the increasing incidence of Merkel cell carcinoma and to provide new incidence projections to 2030. Design, Setting, and Participants A cross-sectional retrospective study with age-period-cohort analysis and incidence projection modeling using data from the Surveillance, Epidemiology, and End Results Program database of 9 registries from 1987 to 2016 was conducted among 3720 patients with Merkel cell carcinoma. Statistical analysis was conducted from October 20, 2019, to July 29, 2020. Exposures Age effects (ie, physiology), period of diagnosis effects (ie, changes in diagnostics and clinical awareness), and birth cohort effects (ie, environmental risk factors) over time were assessed. Main Outcomes and Measures Incidence rates of Merkel cell carcinoma. Results Among the 3720 patients in the study (2200 male patients [59.1%]; median age, 77 years [interquartile range, 68-84 years]), during the period from 2012 to 2016, the age-adjusted Merkel cell carcinoma incidence rate was 0.66 per 100 000 (95% CI, 0.62-0.70), which represented a 3.5-times (95% CI, 3.0-4.2) increase from 1987 to 1991. The incidence of Merkel cell carcinoma increased with patient age across calendar periods and birth cohorts; the highest incidence rate was observed for those aged 85 years or older, with an age-adjusted rate from 2012 to 2016 of 14.6 per 100 000 for men and 5.5 per 100 000 for women. Although the birth cohort effect has continued to increase over time, the calendar period of diagnosis effect has started to plateau. It is projected that there will be 3023 new cases of Merkel cell carcinoma in 2020 and 5130 new cases in 2030, increased from an estimated 1933 cases in 2010. Conclusions and Relevance The slowing down of the period effect (ie, changes in diagnostics and awareness) found in this longitudinal cohort study suggests that part of the initial increased incidence of Merkel cell carcinoma was associated with increased detection. However, the projected increase in incidence rate is likely associated with the aging population and increasing risk factor exposure in more recent birth cohorts.

Brain and other central nervous system tumors are a significant cause of morbidity and mortality, causing nearly 15,000 deaths per year in the United States alone. Epidemiologic studies have helped elucidate aspects of brain tumor etiology by tracking patterns of tumor incidence and mortality and by identifying potential risk factors for tumor development. With respect to glioma, the most common primary malignant brain tumor, incidence rates are elevated among men and individuals of Caucasian ethnicity. High-dose ionizing radiation has been established as a major risk factor for glioma development, and evidence has accumulated that a history of allergies and atopy is inversely associated with glioma risk. Recognized genetic risk factors for glioma include both rare germline mutations underlying several familial cancer syndromes and 25 single-nucleotide polymorphisms as of the most recent and largest genome-wide association study to date. Here, the current state of knowledge on brain tumor epidemiology and etiology is discussed, with an emphasis on glioma and meningioma in adults. Key challenges and open questions in the field are highlighted.

Background: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. Methods: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. Results: A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54–0.70]. There was a significant duration-response trend (P = 1.67 × 10−17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70–1.02), but no association for NSAID use. Conclusions: Our study suggests that aspirin may be associated with a reduced risk of glioma. Impact: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted.

Bistrand lesions embedded within a single helical turn of tridecameric deoxyoligonucleotide duplexes represent a model system for exploring the impact of clustered lesions that occur in vivo and pose a significant challenge to cellular repair machineries. Such investigations are essential for understanding the forces that dictate lesion‐induced mutagenesis, carcinogenesis, and cytotoxicity within a context that mimics local helical perturbations caused by an ionizing radiation event. This study characterizes the structural and energy profiles of DNA duplexes harboring synthetic abasic sites (tetrahydrofuran, F) as models of clustered bistrand abasic (AP) lesions. The standard tridecameric dGCGTACCCATGCG·dCGCATGGGTACGC duplex is employed to investigate the energetic impact of single and bistrand AP sites by strategically replacing one or two bases within the central CCC/GGG triplet. Our combined analysis of temperature‐dependent UV and circular dichroism (CD) profiles reveals that the proximity and relative orientation of AP sites within bistrand‐damaged duplexes imparts a significant thermodynamic impact. Specifically, 3′‐staggered lesions (CCF/GFG) exert a greater destabilizing effect when compared with their 5′‐counterpart (FCC/GFG). Moreover, a duplex harboring the central bistrand AP lesion (CFC/GFG) is moderately destabilized yet exhibits distinct properties relative to both the 3′ and 5′‐orientations. Collectively, our energetic data are consistent with structural studies on bistrand AP‐duplexes of similar sequence in which a 3′‐staggered lesion exerts the greatest perturbation, a finding that provides significant insight regarding the impact of orientation on lesion repair processing efficiency.

In the last years, several studies have been focused on understanding how the central nervous system controls muscles to perform a specific motor task. Although it still remains an open question, muscle synergies have come to be an appealing theory to explain the modular organization of the central nervous system. Even though the neural encoding of muscle synergies remains controversial, a large number of papers demonstrated that muscle synergies are robust across different tested conditions, which are within a day, between days, within a single subject, and between subjects that have similar demographic characteristics. Thus, muscle synergy theory has been largely used in several research fields, such as clinics, robotics, and sports. The present systematical review aims at providing an overview on the applications of muscle synergy theory in clinics, robotics, and sports; in particular, the review is focused on the papers that provide tangible information for (i) diagnosis or pathology assessment in clinics, (ii) robot-control design in robotics, and (iii) athletes’ performance assessment or training guidelines in sports.

Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society.A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another.Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial.With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively.

Background Modules of muscle recruitment can be extracted from electromyography (EMG) during motions, such as walking, running, and swimming, to identify key features of muscle coordination. These features may provide insight into gait adaptation as a result of powered assistance. The aim of this study was to investigate the changes (module size, module timing and weighting patterns) of surface EMG data during assisted and unassisted walking in an powered, myoelectric, ankle-foot orthosis (ankle exoskeleton). Methods Eight healthy subjects wore bilateral ankle exoskeletons and walked at 1.2 m/s on a treadmill. In three training sessions, subjects walked for 40 min in two conditions: unpowered (10 min) and powered (30 min). During each session, we extracted modules of muscle recruitment via nonnegative matrix factorization (NNMF) from the surface EMG signals of ten muscles in the lower limb. We evaluated reconstruction quality for each muscle individually using R2 and normalized root mean squared error (NRMSE). We hypothesized that the number of modules needed to reconstruct muscle data would be the same between conditions and that there would be greater similarity in module timings than weightings. Results Across subjects, we found that six modules were sufficient to reconstruct the muscle data for both conditions, suggesting that the number of modules was preserved. The similarity of module timings and weightings between conditions was greater then random chance, indicating that muscle coordination was also preserved. Motor adaptation during walking in the exoskeleton was dominated by changes in the module timings rather than module weightings. The segment number and the session number were significant fixed effects in a linear mixed-effect model for the increase in R2 with time. Conclusions Our results show that subjects walking in a exoskeleton preserved the number of modules and the coordination of muscles within the modules across conditions. Training (motor adaptation within the session and motor skill consolidation across sessions) led to improved consistency of the muscle patterns. Subjects adapted primarily by changing the timing of their muscle patterns rather than the weightings of muscles in the modules. The results of this study give new insight into strategies for muscle recruitment during adaptation to a powered ankle exoskeleton.

Although the evidence linking exposure to light at night (LAN) and breast cancer risk continues to accumulate, the molecular mechanisms driving this association remain to be fully elucidated. We have previously suggested that long-term exposure to LAN through shiftwork may result in dysregulated patterns of methylation genome-wide. In this study, we investigate the link between miR-34b, a miRNA suggested to be an important tumor suppressor, and shiftwork-related breast cancer. Methylation states in the miR-34b promoter region were previously compared between 10 female long-term shiftworkers and 10 folate intake- and age-matched female dayworkers participating in the Danish “Diet, Cancer and Health” prospective cohort study. In order to further explore the functional role of miR-34b in breast tumorigenesis, a genome-wide expression microarray was carried out in miR-34b-overexpressed MCF-7 breast cancer cells and the identified transcripts were further analyzed for network and functional interrelatedness using Ingenuity Pathway Analysis software. We observed a 49.1 % increase in miR-34b promoter methylation among shiftworkers at a CpG site in this region (p = 0.016). Transfection of the miR-34b mimic in an MCF-7 breast cancer cell line induced differential expression of 230 transcripts that are involved in the interferon-mediated antiviral response as well as apoptotic and antiproliferative gene networks. Together, our results suggest that long-term shiftwork may increase the risk of breast cancer via methylation-based suppression of miR-34b and a consequent reduction in immunomediated anti-tumor capacity and support our previous findings that LAN may induce epigenetic alteration of cancer-relevant microRNAs.

Despite the voluminous body of observational evidence concerning the role of miRNAs in cancer, significant knowledge gaps remain concerning the molecular circumstances that underlie the miRNA-cancer connection. In this study, we employ a multidisciplinary approach to establish an association between miR-618 and non-Hodgkin lymphoma (NHL) in a human population and attempt to explicate this association at the molecular level. A high-throughput, transcriptome-wide RIP-Chip-based method was used to identify members of the miR-618 targetome, which were analyzed for functional relevance using a gene network-based approach. Findings were confirmed by genotyping a SNP (rs2682818) in the stem-loop sequence of miR-618 in a population-based case-control study of NHL (455 cases and 527 controls). Lastly, we analyzed the functional impact of rs2682818 on miR-618 expression and its consequent implications for the lymphomagenic process. A total of 128 miR-618 targets were identified, which were enriched for genes that have functional roles in lymphoma-relevant pathways. This is consistent with our finding of a significant association between rs2682818 G > T in the miR-618 stem-loop and follicular lymphoma (FL) (OR: 1.65, 95% CI: 1.05–2.60). In vitro analysis of rs2682818's functional impact revealed that the variant T allele resulted in reduced levels of mature miR-618, which in turn may lead to deregulation of miR-618-controlled pathways relevant to follicular lymphoma. Taken together, our findings implicate miR-618 in follicular lymphomagenesis, identify miR-618 as a potential risk biomarker for follicular lymphoma, and illuminate miR-618-regulated lymphomagenic pathways that can serve as therapeutic targets for follicular lymphoma.

In 1999, the US Food and Drug Administration approved the alkylating agent temozolomide (TMZ) for the treatment of recurrent anaplastic astrocytoma.1 Between 1999 and 2005, off-label use of TMZ for treatment of glioblastoma multiforme (GBM) became increasingly widespread,2–6 culminating in the adoption in 2005 of maximum safe surgical resection, followed by radiotherapy with concomitant TMZ, followed by adjuvant TMZ as the new standard of care.7 This treatment advance was based on a landmark phase III trial in which patients with newly diagnosed, microscopically confirmed GBM were randomized to receive radiotherapy alone or radiotherapy plus concomitant and adjuvant TMZ.8 Median survival was 12.1 months in the group that received radiotherapy alone compared with 14.6 months in the group that received radiotherapy plus TMZ. However, efficacy in a clinical trial does not guarantee effectiveness in the general population. Using GBM cases diagnosed between 1993 and 2007 in the Surveillance, Epidemiology and End Results (SEER) Program database, we previously demonstrated a modest, but meaningful, population-based survival improvement for GBM patients in the US that began in 1999–2001 and continued through 2005–2007.9 Others have also utilized SEER to demonstrate this survival improvement.10–12 Although we showed a close ecologic association between increasing TMZ usage and improved survival,9 we were unable to directly test the hypothesis that TMZ usage explained the improved survival because SEER does not include information on chemotherapy treatment. We proposed that the rising TMZ usage in 1999–2007 was the most likely explanation for the survival improvement, but we could not rule out the possibility that other treatment advances, such as greater extent of surgical resection13–17 or more aggressive treatment of recurrent disease,18,19 also contributed. In the current study, we constructed a cohort of patients diagnosed with GBM between 1997 and 2008, including detailed treatment and follow-up information, based on national Veterans Health Administration (VHA) databases. We utilized this cohort to directly test the hypothesis that TMZ usage explained the GBM survival improvement observed during this period.

This article reviews material presented at the 2016 Scottsdale Headache Symposium. This presentation provided scientific results and rationale for the use of intranasal oxytocin for the treatment of migraine headache. Results from preclinical experiments are reviewed, including in vitro experiments demonstrating that trigeminal ganglia neurons possess oxytocin receptors and are inhibited by oxytocin. Furthermore, most of these same neurons contain CGRP, the release of which is inhibited by oxytocin. Results are also presented which demonstrate that nasal oxytocin inhibits responses of trigeminal nucleus caudalis neurons to noxious stimulation using either noxious facial shock or nitroglycerin infusion. These studies led to testing the analgesic effect of intranasal oxytocin in episodic migraineurs—studies which did not meet their primary endpoint of pain relief at 2 h, but which were highly informative and led to additional rat studies wherein inflammation was found to dramatically upregulate the number of oxytocin receptors available on trigeminal neurons. This importance of inflammation was supported by a series of in vivo rat behavioral studies, which demonstrated a clear craniofacial analgesic effect when a pre-existing inflammatory injury was present. The significance of inflammation was further solidified by a small single-dose clinical study, which showed analgesic efficacy that was substantially stronger in chronic migraine patients that had not taken an anti-inflammatory drug within 24 h of oxytocin dosing. A follow-on open label study examining effects of one month of intranasal oxytocin dosing did show a reduction in pain, but a more impressive decrease in the frequency of headaches in both chronic and high frequency episodic migraineurs. This study led to a multicountry double blind, placebo controlled study studying whether, over 2 months of dosing, “as needed” dosing of intranasal oxytocin by chronic and high frequency migraineurs would reduce the frequency of their headaches compared to a 1-month baseline period. This study failed to meet its primary endpoint, due to an extraordinarily high placebo rate in the country of most of the patients (Chile), but was also highly informative, showing strong results in other countries and strong post hoc indications of efficacy. The results provide a strong argument for further development of intranasal oxytocin for migraine prophylaxis.

Molecular epidemiologic studies of diffuse WHO grade II glioma (diffuse low-grade glioma, DLGG) have contributed greatly to our knowledge of these slow-growing but highly infiltrative tumors. Such studies have yielded valuable insights into factors that modify risk of disease development including several germline genetic variants, exposure to ionizing radiation, and history of allergy. Furthermore, new frameworks for molecular classification of low-grade gliomas have emerged that delineate tumor subtypes with distinct etiologies and outcomes; therapeutic strategies may ultimately be tailored accordingly. In this chapter, we summarize these and other recent insights into the molecular epidemiology of DLGG in adults.

One characteristic of ageing skeletal muscle is a decline in mitochondrial function. Activation of AMP-activated protein kinase (AMPK) occurs in response to an increased AMP/ATP ratio, which is one potential result of mitochondrial dysfunction. We have previously observed higher AMPK activity in old (O; 30 months) vs young adult (YA; 8 months) fast-twitch muscle in response to chronic overload. Here we tested the hypothesis that AMPK would also be hyperactivated in O vs YA fast-twitch extensor digitorum longus muscles from Fischer344× Brown Norway (FBN) rats (n= 8 per group) in response to high-frequency electrical stimulation of the sciatic nerve (HFES) or injection of AICAR, an activator of AMPK. Muscles were harvested immediately after HFES (10 sets of six 3-s contractions, 10 s rest between contractions, 1 min rest between sets) or 1 h after AICAR injection (1 mg (g body weight)−1 subcutaneously). The phosphorylations of AMPKα and acetyl-CoA carboxylase (ACC2; a downstream AMPK target) were both greatly increased (P≤ 0.05) in response to HFES in O muscles, but were either unresponsive (AMPK α) or much less responsive (ACC) in YA muscles. AMPK α2 activity was also greatly elevated in response to HFES in O muscles (but not YA muscles) despite a lower total AMPK α2 protein content in O vs YA muscles. In contrast, AMPK α2 activity was equally responsive to AICAR treatment in both age groups. Since mitochondrial content and/or efficiency could potentially underlie AMPK hyperactivation, we measured levels of mitochondrial proteins as well as citrate synthase (CS) activity. While CS activity was increased by 25% in O vs YA muscles, uncoupling protein-3 (UCP-3) protein level was upregulated with age by 353%. Thus, AMPK hyperactivation in response to contractile activity in aged fast-twitch muscle may be the result of compromised cellular energetics and not necessarily due to an inherent defect in responsiveness of the AMPK molecule per se.

Background: PIWI-interacting RNAs (piRNAs), the largest class of noncoding RNAs in mammals, cooperate with PIWI proteins to safeguard the genome from insertional mutations during germline development. Although a growing number of studies have linked the PIWI–piRNA pathway to carcinogenesis, the role of piRNAs in glioma has not been explored. Methods: Utilizing directly measured and imputed genotypes from the GliomaScan genome-wide association study (1,840 cases and 2,401 controls), genetic variants in 1,428 piRNAs were analyzed for association with glioma risk. In vitro assays were performed to interrogate the functional impact of a top identified piRNA and its variant allele. Results: Variants in five piRNAs were considered to be associations of interest and four of these showed narrow clusters of enhanced association signals surrounding the index variant. Functional analyses of one of these piRNAs, piR-598, revealed that transfection of the wild-type piRNA impacted expression of genes involved in cell death/survival and reduced glioma cell viability and colony formation. However, upon delivery of piR-598 containing the variant allele at rs147061479 [OR, 1.80; 95% confidence interval (CI), 1.33–2.46; P = 1.69 × 10−4], cell proliferation was sharply increased. Conclusions: The genetic association analysis identifies several piRNAs associated with glioma risk, and follow-up functional analyses suggest that variant rs147061479 in piR-598 increases glioma risk by abolishing the tumor-suppressive function of piR-598, instead conferring growth-promoting properties. Impact: This transdisciplinary study demonstrates a role of piRNAs in gliomagenesis by evidence from both post-GWAS and in vitro functional analyses and supports expanded investigation into the link between the PIWI–piRNA pathway and cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1073–80. ©2016 AACR.

Background Robotic ankle exoskeletons can provide assistance to users and reduce metabolic power during walking. Our research group has investigated the use of proportional myoelectric control for controlling robotic ankle exoskeletons. Previously, these controllers have relied on a constant gain to map user’s muscle activity to actuation control signals. A constant gain may act as a constraint on the user, so we designed a controller that dynamically adapts the gain to the user’s myoelectric amplitude. We hypothesized that an adaptive gain proportional myoelectric controller would reduce metabolic energy expenditure compared to walking with the ankle exoskeleton unpowered because users could choose their preferred control gain. Methods We tested eight healthy subjects walking with the adaptive gain proportional myoelectric controller with bilateral ankle exoskeletons. The adaptive gain was updated each stride such that on average the user’s peak muscle activity was mapped to maximal power output of the exoskeleton. All subjects participated in three identical training sessions where they walked on a treadmill for 50 minutes (30 minutes of which the exoskeleton was powered) at 1.2 ms-1. We calculated and analyzed metabolic energy consumption, muscle recruitment, inverse kinematics, inverse dynamics, and exoskeleton mechanics. Results Using our controller, subjects achieved a metabolic reduction similar to that seen in previous work in about a third of the training time. The resulting controller gain was lower than that seen in previous work (β=1.50±0.14 versus a constant β=2). The adapted gain allowed users more total ankle joint power than that of unassisted walking, increasing ankle power in exchange for a decrease in hip power. Conclusions Our findings indicate that humans prefer to walk with greater ankle mechanical power output than their unassisted gait when provided with an ankle exoskeleton using an adaptive controller. This suggests that robotic assistance from an exoskeleton can allow humans to adopt gait patterns different from their normal choices for locomotion. In our specific experiment, subjects increased ankle power and decreased hip power to walk with a reduction in metabolic cost. Future exoskeleton devices that rely on proportional myolectric control are likely to demonstrate improved performance by including an adaptive gain. Electronic supplementary material The online version of this article (doi:10.1186/s12984-015-0086-5) contains supplementary material, which is available to authorized users.

Although PIWI-interacting RNAs (piRNAs) account for the largest class of the small non-coding RNA superfamily, virtually nothing is known of their function in human carcinogenesis. Once thought to be expressed solely in the germ line where they safeguard the genome against transposon-induced insertional mutations, piRNAs are now believed to play an active role in somatic gene regulation through sequence-specific histone modification and DNA methylation. In the current study, we investigate the role of piRNA-021285 (piR-021285) in the regulation of the breast cancer methylome. Genotypic screening of a panel of single-nucleotide polymorphism (SNP)-containing piRNAs revealed a significant association between SNP rs1326306 G>T in piR-021285 and increased likelihood for breast cancer in a Connecticut-based population (441 cases and 479 controls). Given nascent but compelling evidence of piRNA-mediated gene-specific methylation in the soma, a genome-wide methylation screen was then carried out using wild type (WT) and variant piR-021285 mimic-transfected MCF7 cells to explore whether the observed association could be attributed in part to piR-021285-induced methylation at cancer-relevant genes. We found significant methylation differences at a number of experimentally implicated breast cancer-related genes, including attenuated 5' untranslated region (UTR)/first exon methylation at the proinvasive ARHGAP11A gene in variant mimic-transfected cells. Follow-up functional analyses revealed both concurrent increased ARHGAP11A mRNA expression and enhanced invasiveness in variant versus WT piR-021285 mimic-transfected breast cancer cell lines. Taken together, our findings demonstrate the first evidence supporting a role of piRNAs, a novel group of non-coding RNA, in human tumorigenesis via a piRNA-mediated epigenetic mechanism, which warrants further confirmation and investigation.

BACKGROUND: Gliomas are highly infiltrated by immune cells including microglia, macrophages, and myeloid-derived suppressor cells (collectively, glioma-associated myeloid cells). These cells have been shown to be induced by the tumor to be immune-suppressive and tumor-supportive, and are a negative prognosticator for survival in mouse models. Here, we examine whether inherited variants in genes important to the function of glioma-associated myeloid cells are associated with survival following low-grade glioma diagnosis. METHODS: Subjects for this study were 484 patients with WHO grade II or grade III glioma treated at The University of Texas MD Anderson Cancer Center in Houston, Texas between 1992 and 2008 and followed up for survival through August, 2016. We selected 100 genes for analysis including transcription factors, cytokines and chemokines, receptors, enzymes, and other genes central to the function of glioma-associated myeloid cells. Genotyping was originally performed using the Illumina Human 610-Quad Bead Chip platform and 2,040 tagging SNPs as determined by Haploview Tagger software were selected for analysis with minor allele frequency (AF) ≥ 1%. Associations between selected SNPs and survival were evaluated by Cox regression analysis under an additive allelic model adjusting for age, sex, extent of surgery (biopsy only/partial resection/gross total resection), radiotherapy (yes/no), and chemotherapy (yes/no). Models were examined to ensure that proportional hazards assumptions were not violated. RESULTS: Median survival among low-grade glioma patients was 6.7 years. Age at diagnosis, extent of surgery, and having received radiotherapy or chemotherapy were each significantly associated with survival. Five SNPs were associated with survival at a significance level of p CONCLUSIONS: Here we provide preliminary evidence of an association between polymorphisms in two genes related to glioma-associated myeloid cell function and low-grade glioma survival. CD163 is a receptor that is highly expressed on macrophages and may play a role in macrophage-mediated anti-inflammatory responses, while MET is a receptor tyrosine kinase and well-studied proto-oncogene that is also involved in the expansion of myeloid-derived suppressor cell populations. Further investigation of these associations is warranted, and validation of these findings is planned in an independent population. Citation Format: Daniel I. Jacobs, Yanhong Liu, Konrad Gabrusiewicz, Spiridon Tsavachidis, E. Susan Amirian, Georgina N. Armstrong, Renke Zhou, Jun Wei, Cristina Ivan, George Calin, Michael Scheurer, Anna Dahlin, Terri Rice, Paige M. Bracci, Helen M. Hansen, John K. Wiencke, Margaret R. Wrensch, Beatrice Melin, Amy B. Heimberger, Melissa L. Bondy. Evaluation of polymorphisms in myeloid-associated genes and glioma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2259. doi:10.1158/1538-7445.AM2017-2259

Although the role of core circadian gene cryptochrome 2 (CRY2) in breast tumorigenesis has been demonstrated, the correlations of CRY2 with clinical parameters in breast cancer patients and its involvement in epigenetic processes such as DNA methylation remain relatively unexplored. In the current study, we first queried the Oncomine database and the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) database to identify associations between CRY2 expression levels and clinical parameters in breast cancer patients. We then silenced CRY2 in vitro and performed a genome-wide methylation array to determine the epigenetic impact of CRY2 silencing. The Ingenuity Pathway Analysis software was used to further explore the genes exhibiting altered methylation identified using the array. We found that CRY2 was frequently down-regulated in breast cancer tissue compared to adjacent normal tissue or breast tissue from healthy controls. Lower CRY2 expression was associated with estrogen receptor (ER)-negativity (P

Background. The nasolabial flap is a versatile and effective option for the closure of nasal defects of the cheek and nasal sidewall following Mohs surgery. However, both extirpation of a tumor in the region of the base of the flap or previous use of the flap often destroy the proximal axial blood supply to the flap, excluding its immediate utilization. We describe a different use of the nasolabial flap and a technique for preserving its capacity in the case of reutilization Objective. To describe the versatility of the nasolabial flap and a delay procedure that enables its exploitation despite prior disruption of the proximal blood supply. Methods. Three different uses of the same nasolabial flap are demonstrated in one patient. The surgical techniques are discussed in detail. Results. The reconstructive results were excellent. There were no postoperative complications. Conclusion. The nasolabial flap is a versatile and effective option for the closure of nasal defects of the cheek and nasal sidewall. When the nasolabial flap has been used before, or its blood supply compromised, the delay procedure can reestablish its applicability.

Many patients with Alzheimer's disease (AD) are apraxic and the apraxia has been posited to be related to a loss of movement representations. Whereas patients with Alzheimer's disease have been reported to demonstrate normal motor learning on a rotor pursuit skill acquisition task, it is unknown whether AD subjects who are apraxic demonstrate normal skill-learning. We tested subjects with probable AD and normal controls on a rotor pursuit task. We also tested the AD subjects for ideomotor apraxia. Subjects with AD who were apraxic had normal motor learning. In addition, praxis score did not correlate with performance on the skill-acquisition task. The results suggest that ideomotor praxis and motor learning are at least partly dissociable.

Partial lateral nasal defects challenge the plastic surgeon both technically and aesthetically. Many methods for reconstruction of these defects have been described. We have used a turnover forehead flap in conjunction with composite auricular graft for the reconstruction of nasal defects. The forehead flap is turned over so that the forehead skin serves as internal lining in the nose. The composite auricular graft serves as external nasal lining and provides mechanical support to the ala. The technique was used in seven patients and is presented here with illustrations, selected cases, results, and conclusions concerning patient selection.

Adynamic aphasia is a form of transcortical motor aphasia characterized by sparse but otherwise normal spontaneous speech that may improve when concepts are introduced by external stimuli. Akinesia, impaired concept formation, inertia of concept generation, a defective semantic network, damage or impaired access to the verbal output lexicon, and defective semantic strategy formation have been proposed to account for this disorder. We studied a patient with adynamic aphasia and frontal lobe systems dysfunction due to bilateral striatocapsular infarctions. The patient was not akinetic but did demonstrate inertia of concept generation that could be overcome with prompting. However, prompting did not improve the number of concepts generated. He demonstrated a generally intact verbal lexicon and semantic network and normal lexical priming. However, his ability to sort closely related items into different classes without prior cuing regarding the nature of the classes was defective. Although his verbal memory was normal, he appeared to use a serial rather than a semantic strategy to recall items. Finally, despite normal lexical priming, he was impaired on a letter fluency task. These results most clearly demonstrate a defect in semantic strategy formation but indicate an additional and possibly related deficit in concept formation and a partial deficit in lexical strategy formation. All of these deficits appear to reflect impairment in the hierarchical organization of knowledge specific to the task at hand. This appears to be a key component of executive functions supported by frontal lobe systems.

Given the dismal prognosis faced by patients with malignant glioma, maintenance of an acceptable quality of life (QOL) is essential. Patients diagnosed with malignant glioma have been shown to experience a wide range of physical and psychosocial challenges including anxiety and depression,1–3 problems with memory and attention,4 fatigue and distress,5–7 and impaired quality of communication and relationships.6,8 However, self-reporting of such conditions by patients can be complicated by emotional and neurocognitive changes as well as by impaired language function. Accordingly, caregiver input regarding a patient's physical and mental functioning and overall QOL can be of great value to clinicians. Several studies have attempted to assess the degree to which caregiver evaluations of cancer patient QOL reflect patient self-reports.9–15 Results have suggested that caregiver assessments are comparable to patient assessments of physical functioning but are more divergent in psychosocial domains. Although the concordance of malignant glioma patient and caregiver symptom reports has been examined in a fairly large study,16 there is limited research focusing on the concordance of QOL evaluations for patients with malignant glioma. Accordingly, the primary purpose of this study was to investigate the concordance between malignant glioma patients and their caregivers on QOL assessments as measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) instrument. Further, constraints on physical, cognitive, and language functioning due the tumor or treatment place particular stresses on a patient's primary caregiver. A secondary objective of this study was to evaluate the burden experienced by caregivers of malignant glioma patients using the Caregiver Quality of Life Index-Cancer (CQOL-C) scale and to compare results with those previously reported for caregivers of non-glioma cancer patients, since little data currently exist.

Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children