Authors' Response to a Letter to the Editor on Radial Extracorporeal Shockwave in the Management of Lateral Epicondylitis

No abstract available

http://ift.tt/2FYo14O

Physiatry Reviews for Evidence in Practice Second-Order Peer Review: Does Massage Therapy Have Value in the Treatment for Tension Type Headache?

No abstract available

http://ift.tt/2rlYsY5

Comparison Between Corticosteroid and Lidocaine Injection in the Treatment of Tennis Elbow: A Randomized, Double-Blinded, Controlled Trial

Objective The aim of the study was to compare the effects of corticosteroid injection with lidocaine injection in treating tennis elbow. Design It is a prospective, double-blinded, randomized controlled trial. Patients with tennis elbow for more than 1 mo were recruited from a hospital-based rehabilitation outpatient clinic. A total of 70 patients were recruited, and 61 patients completed the study. Patients received an injection of either 10 mg (1 ml) of triamcinolone (corticosteroid group, n = 30) or 1 ml of 1% lidocaine (lidocaine group, n = 31). All of the outcome measures were evaluated before the intervention and at 2 wks and 2 mos after treatment. Results No significant group differences were observed between the corticosteroid and lidocaine groups regarding Patient-Rated Tennis Elbow Evaluation, Disability of the Arm, Shoulder, and Hand, visual analog scale for pain, and grip strength at baseline and at 2 wks and 2 mos after treatment (P > 0.05). However, within-group comparison showed significant improvement after injection with regard to Patient-Rated Tennis Elbow Evaluation, Disability of the Arm, Shoulder, and Hand, visual analog scale for pain, and grip strength in both groups (P > 0.05). Conclusions No differences in the short-term outcomes were found between lidocaine and corticosteroid injection in a small sample of people with tennis elbow with mean duration of 3.8 mos.

http://ift.tt/2FWx1Yh

Association Between Altered Hip Extension and Kinetic Gait Variables

Kinematic and kinetic outcome measures are tightly linked in walking. Although altering motor output is a major goal of gait rehabilitation, little is understood regarding the relationship between altering a single kinematic variable and kinetic outcome changes. We designed a strategy to isolate hip extension alterations during walking on a treadmill to assess the change in kinetic outcomes. Ten healthy individuals walked on an instrumented split-belt treadmill with motion capture to calculate hip extension and kinetic outcomes at the following five different randomized cadences: self-selected cadence, self-selected ± 10%, and self-selected ± 20%. The treadmill speed was held constant at the individual's self-selected walking speed, forcing cadence changes to result in successful alterations to hip extension, varying 8.3 degrees from the self-selected −20% to +20% cadence conditions. Kinetic outcomes demonstrated similar alterations. Hip extension changes at each cadence significantly correlated with kinetic changes in propulsive impulse (r = 0.852, P

http://ift.tt/2rra6kB

Functional Balance Deterioration on Daily Activities in Patients With Migraine: A Controlled Study

Objective This study aimed to assess functional activities in different subgroups of patients with migraine. Design One-hundred forty subjects were uniformly divided into the following four groups: headache-free controls, migraine with aura, without aura, and chronic migraine. Subjects performed the tests walk across, tandem walk, sit to stand, and step up and over at the Balance Master system (Neurocom). Results All migraine groups had slower velocity and shorter step length at the walk across test (P

http://ift.tt/2FXrdxJ

Development of Systemic Inflammatory Polyarthritis After Zygapophyseal Joint Injection With Hylan G-F 20 (Synvisc-One)

Hylan G-F 20 (Synvisc-One) is a hyaluronic acid derivative used for viscosupplementation of synovial fluid in osteoarthritic joints. Injection of hylan G-F 20 is Federal Drug Administration approved for use in knee osteoarthritis and is generally well tolerated with few reported adverse effects, the most common being local pain or swelling. We present the case of a 72-year-old man with bilateral, diffuse, joint pain and swelling with elevated inflammatory markers suggestive of a systemic inflammatory polyarthropathy that developed acutely 2 days after lumbar zygapophyseal joint injection with hylan G-F 20. Systemic effects after hylan G-F 20 injection have not been well documented, and this is the first reported case of systemic inflammatory polyarthritis after injection, to our knowledge. Further research is needed to better establish the safety and efficacy of lumbar zygapophyseal joint injections with hylan G-F 20.

http://ift.tt/2rqgubB

Could Activity Modifications Indicate Physical Decline Among Adults With Symptomatic Knee Osteoarthritis?

Objectives Mobility activity modifications indicate early functional losses that act as precursors to future declines among community-dwelling older adults. However, there is scarce evidence on whether activity modifications indicate poorer physical health among adults with symptomatic osteoarthritis, a major cause of disability. Our purpose was to investigate whether patient-reported mobility activity modifications indicated poorer physical health among adults with symptomatic knee osteoarthritis. Design Secondary cross-sectional analysis of randomized trial data was performed. Preclinical Disability Questionnaire was used to group participants into the following three categories: difficulty, modified, and no difficulty walking/stair climbing. Kruskal Wallis and χ2 tests were used to compare clinical factors across groups. Results Among 121 participants (median age = 60 yrs; 73% female; 60% white), less than 10% had modified walking/stair climbing. Compared with those with no walking difficulty, participants with modified walking had significantly less balance (P = 0.01) and global health (P = 0.01) as well as greater knee pain (P = 0.05) and physical disability (P = 0.04). Those with modified stair climbing had significantly smaller walking distances (P = 0.03) compared with those with no difficulty stair climbing. Conclusions Activity modifications may signal early impairments in physical health among people with symptomatic knee osteoarthritis. If confirmed, patient-reported activity modifications may enhance symptom evaluation in osteoarthritis and enable a better understanding of the disablement process.

http://ift.tt/2FXr5OL

Alterations in the Mechanical Response of Deep Dorsal Neck Muscles in Individuals Experiencing Whiplash-Associated Disorders Compared to Healthy Controls: An Ultrasound Study

Objective The aim of this study was to investigate and compare the mechanical responses of dorsal neck muscles in individuals with whiplash-associated disorders (WAD) versus healthy individuals. Design This study included 36 individuals with WAD (26 women and 10 men) and 36 healthy controls (26 women and 10 men). Ultrasound imaging with speckle tracking was used to measure deformation and deformation rate in five dorsal neck muscles during a neck extension task. Results Compared with controls, individuals with WAD showed higher deformations of the semispinalis cervicis (P = 0.02) and multifidus (P = 0.002) muscles and higher deformation rates (P = 0.03 and 0.0001, respectively). Among individuals with WAD, multifidus deformation and deformation rate were significantly associated with pain, disability, and fatigue (r = 0.31–0.46, P = 0.0001–0.01). Conclusions These findings indicate that the mechanical responses of the deep dorsal neck muscles differ between individuals with WAD and healthy controls, possibly reflecting that these muscles use altered strategies while performing a neck extension task. This finding provides new insight into neck muscles pathology in patients with chronic WAD and may help improve rehabilitation programs. To Claim CME Credits Complete the self-assessment activity and evaluation online at http://ift.tt/1l80W45 CME Objectives Upon completion of this article, the reader should be able to: (1) Summarize the mechanical responses of dorsal neck muscles during loading of the neck muscles via an extension task in individuals with chronic whiplash associated disorders and healthy volunteers; (2) Differentiate mechanical responses between five dorsal neck muscles while loading the neck via an extension task; and (3) Describe the relationships between the mechanical responses of the dorsal neck muscles with the patients' perception of neck pain, disability, and fatigue. Level Advanced Accreditation The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Effect of Group Exercising and Adjusting the Brace at Shorter Intervals on Cobb Angle and Quality of Life of Patients With Idiopathic Scoliosis

Objective The aim of the study was to evaluate the effect of group exercise with brace adjustment at shorter intervals than used in routine practice in late-onset idiopathic scoliosis patients. Design This was a quasi-experimental study. Thirty patients with progressive scoliosis curves of 15–50 degrees and a prescription for a brace were divided into experimental and control groups, both of which participated in an 11-wk treatment program. Those in the experimental group underwent brace adjustment twice per week and performed group exercise, whereas those in the control group received a routine protocol. The quality of life and Cobb angle of patients in both groups were evaluated based on baseline and final results of the 22-item Scoliosis Research Society questionnaire and primary and secondary radiographs. Results In the experimental group, the improvement in Cobb angle and patient satisfaction was greater than that in the control group (P

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Implementation of a Multifaceted Interactive Electrodiagnostic Medicine Workshop in a Physical Medicine and Rehabilitation Residency Program

Electrodiagnostic medicine is a required component of Physical Medicine and Rehabilitation residency education, but limited resources exist to guide curriculum development. Our objective was to create a focused workshop to enhance our residency program's electrodiagnostic curriculum. We created two separate 1.5-day workshops, one basic and one advanced, for all residents. Each workshop included didactic sessions, case discussion, question and answer sessions, demonstrations, and hands-on participation with direct supervision and feedback. Presurveys and postsurveys were administered to evaluate the value of the workshops. We also assessed trends in electrodiagnostic self-assessment examination scores. Residents reported clinical electrodiagnostic rotations to be more valuable to their education than previous didactic sessions and independent learning. Self-reported knowledge of electrodiagnostic concepts, resident comfort level in planning, performing, and interpreting studies, and perceived value in independent learning of electrodiagnostic medicine improved after implementation of the workshops. There was a 7% improvement in the American Association of Neuromuscular and Electrodiagnostic Medicine electrodiagnostic self-assessment examination score compared with the previous year and a 15% improvement in the Physical Medicine and Rehabilitation self-assessment examination electrodiagnostic subscore compared with the previous 5 yrs. All participants recommended similar educational experience for other residents. This successful workshop may serve as a resource for other training programs.

http://ift.tt/2FXETIM

Effectiveness of a Group Physiotherapy Intervention in Nontraumatic, Inoperable Painful Shoulder: A Randomized Clinical Trial

Purpose The aim of the study was to assess the effectiveness of a group intervention in painful shoulder. Design This was a two-arm controlled clinical trial with a 5-wk follow-up and 1:1 allocation ratio with pretreatment and posttreatment assessments in a Spanish hospital in 2015–2016. This study comprised 74 patients with nontraumatic, inoperable painful shoulder. Patients were randomized into two groups: (1) in intervention, patients underwent group rehabilitation exercises supervised by a physical therapist and (2) in control, patients performed the same exercises as the intervention group but in their own home. The main variables were the differences preintervention and postintervention between scores on the visual analog scale, Constant-Murley scale, and Disabilities of the Arm, Shoulder and Hand scale. The mean differences in the main variables were compared between the two interventions (t test). Registration code is NCT02541279 (clinicaltrials.gov). Results Differences were found in favor of the intervention group: (1) visual analog scale = −0.1 (P = 0.723), (2) Constant-Murley = 4.1 (P = 0.085), and (3) Disabilities of the Arm, Shoulder and Hand = 14.7 (P

http://ift.tt/2roPnOi

Tibialis Posterior Tenosynovitis: A Unique Musculoskeletal Manifestation of Gout

Extra-articular manifestations of gout can present in several ways, including tenosynovitis. We present a rare case of acute tibialis posterior gouty tenosynovitis. An 82-year-old man with a history of well-controlled gout presented with acute onset of left ankle pain, occurring without inciting event. The medial ankle was slightly erythematous with moderate dorsal-medial swelling and mild dorsal-lateral swelling, with severe tenderness to palpation over the medial retro-malleolar region. Range of motion and manual muscle testing were pain limited throughout. Ultrasound examination revealed a left posterior tibialis tendon sheath tenosynovitis with effusion and overlying soft tissue edema. Tendon sheath aspirate revealed sodium urate crystals and a white blood cell count of 6400/μL. Tendon sheath injection with a mixture of 1% lidocaine and dexamethasone 4 mg resulted in symptom resolution. Repeat ultrasound examination demonstrated no evidence of tibialis posterior tendon sheath effusion. This case is unique not only because acute gouty posterior tibialis tenosynovitis is very rare, particularly in a normouricemic individual, but also because the sonographic evidence of gouty infiltration into the posterior tibialis tendon and overlying subcutaneous tissue considerably aided in arriving at the correct diagnosis in a timely manner.

http://ift.tt/2FYnVKu

Aquatic Exercises in the Treatment of Low Back Pain: A Systematic Review of the Literature and Meta-Analysis of Eight Studies

Objective Low back pain is the most common musculoskeletal condition with a high prevalence. There was no sufficient evidence to recommend that aquatic exercise was potentially beneficial to patients with low back pain. The aim of this study was to systematically analyze all evidence available in the literature about effectiveness of the aquatic exercise. Design A comprehensive search of PubMed, the Cochrane Library, Embase, and Cumulative Index to Nursing and Allied Health was conducted from their inceptions to November 2016 for randomized controlled trials, which concerned the therapeutic aquatic exercise for low back pain. The results were expressed in terms of standardized mean difference and the corresponding 95% confidence interval. Results Eight trials involving 331 patients were included in the meta-analysis, and the results showed a relief of pain (standardized mean difference = −0.65, 95% confidence interval = −1.16 to −0.14) and physical function (standardized mean difference = 0.63, 95% confidence interval = 0.17 to 1.09) after aquatic exercise. However, there was no significant effectiveness with regard to general mental health in aquatic group (standardized mean difference = 0.46; 95% confidence interval = −0.22 to 1.15). Conclusions Aquatic exercise can statistically significantly reduce pain and increase physical function in patients with low back pain. Further high-quality investigations on a larger scale are required to confirm the results.

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Regarding: Radial Extracorporeal Shockwave Therapy Is No More Effective Than Placebo in the Management of Lateral Epicondylitis A Double-Blind, Randomized, Placebo-Controlled Trial

No abstract available

http://ift.tt/2FXeaw0

Evaluation of the Effectiveness of Neuromuscular Electrical Stimulation After Total Knee Arthroplasty: A Meta-Analysis

Objective The aim of the study was to evaluate the efficacy of the use of the neuromuscular electrical stimulation after total knee arthroplasty. Design The study used a systematic review of randomized controlled trials (MEDLINE, PubMed, Cochrane Library, and PEDro) using Patient Population or Problem, Intervention, Comparison, Outcomes, Setting approach to formulate the research question, controlled terms, and Boolean operators. Inclusion and exclusion criteria were defined in advance. "Neuromuscular electrical stimulation" and "total knee arthroplasty" were used as keywords. The overall risk of bias was determined according to the following: random sequence generation, concealment, blinding mass of participants and staff, commissioning blind assessment results, incomplete data, and loans received. Results Of the 36 identified studies, six were included in the review (496 participants). In these studies, one group of patients followed a rehabilitation protocol (control group) and the other followed a rehabilitation program plus a session of neuromuscular electrical stimulation (neuromuscular electrical stimulation group). Patients of neuromuscular electrical stimulation groups got the best scores (timed up and go test, stair climbing test, and walk test). Neuromuscular electrical stimulation benefits were strong in the first postoperative weeks/months and gradually diminished. Conclusions Neuromuscular electrical stimulation allows a slightly better functional recovery after total knee arthroplasty, especially in the first period, with more evident benefits in patients with a severe lack of muscular activation. Nevertheless, there is no difference at medium-long term.

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Dynamic Change in Ultrasonographic Findings in Iliotibial Band Syndrome After Running

No abstract available

http://ift.tt/2FYP4Nw

INFLUENCE OF PHARMACOGENETIC POLYMORPHISMS AND DEMOGRAPHIC VARIABLES ON METFORMIN PHARMACOKINETICS IN AN ADMIXED BRAZILIAN COHORT

Abstract

Aim

To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort.

Methods

The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modeling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration versus time curve, between 0 and 48 h (AUC_0-48h), after single oral doses of metformin (500 or 1,000 mg).

Results

The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC_0-48h´s (ng.h.ml^-1.mg^-1) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95%CI; p = 6.10^-26, t test). Multivariate modeling revealed that metformin AUC_0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area (BSA) and individual proportions of African ancestry.

CONCLUSIONS

A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, BSA and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC_0-48h.

http://ift.tt/2FZcz8P

TGF-β family co-receptor function and signaling

Abstract

Transforming growth factor-β (TGF-β) family members, which include TGF-βs, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-β family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-β family members. While some appear to be specific to TGF-β family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-β family co-receptors, which continue to be discovered.

http://ift.tt/2DojtmB

A special issue on TGF-β signaling: regulation, crosstalk, and biology

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Feedback regulation of TGF-β signaling

Abstract

Transforming growth factor beta (TGF-β) is a multi-functional polypeptide that plays a critical role in regulating a broad range of cellular functions and physiological processes. Signaling is initiated when TGF-β ligands bind to two types of cell membrane receptors with intrinsic Ser/Thr kinase activity and transmitted by the intracellular Smad proteins, which act as transcription factors to regulate gene expression in the nucleus. Although it is relatively simple and straight-forward, this TGF-β/Smad pathway is regulated by various feedback loops at different levels, including the ligand, the receptor, Smads and transcription, and is thus fine-tuned in terms of signaling robustness, duration, specificity, and plasticity. The precise control gives rise to versatile and context-dependent pathophysiological functions. In this review, we firstly give an overview of TGF-β signaling, and then discuss how each step of TGF-β signaling is finely controlled by distinct modes of feedback mechanisms, involving both protein regulators and miRNAs.

http://ift.tt/2DlHYAS

Molecular regulation of Nodal signaling during mesendoderm formation

Abstract

One of the most important events during vertebrate embryogenesis is the formation or specification of the three germ layers, endoderm, mesoderm, and ectoderm. After a series of rapid cleavages, embryos form the mesendoderm and ectoderm during late blastulation and early gastrulation. The mesendoderm then further differentiates into the mesoderm and endoderm. Nodal, a member of the transforming growth factor β (TGF-β) superfamily, plays a pivotal role in mesendoderm formation by regulating the expression of a number of critical transcription factors, including Mix-like, GATA, Sox, and Fox. Because the Nodal signal transduction pathway is well-characterized, increasing effort has been made to delineate the spatiotemporal modulation of Nodal signaling during embryonic development. In this review, we summarize the recent progress delineating molecular regulation of Nodal signal intensity and duration during mesendoderm formation.

http://ift.tt/2DSc9AQ

Paradoxical roles of TGF-β signaling in suppressing and promoting squamous cell carcinoma

Abstract

Transforming growth factor β (TGF-β) signaling either promotes or inhibits tumor formation and/or progression of many cancer types including squamous cell carcinoma (SCC). Canonical TGF-β signaling is mediated by a number of downstream proteins including Smad family proteins. Alterations in either TGF-β or Smad signaling can impact cancer. For instance, defects in TGF-β type I and type II receptors (TGF-βRI and TGF-βRII) and in Smad2/3/4 could promote tumor development. Conversely, increased TGF-β1 and activated TGF-βRI and Smad3 have all been shown to have tumor-promoting effects in experimental systems of human and mouse SCCs. Among TGF-β/Smad signaling, only TGF-βRII or Smad4 deletion in mouse epithelium causes spontaneous SCC in the mouse model, highlighting the critical roles of TGF-βRII and Smad4 in tumor suppression. Herein, we review the dual roles of the TGF-β/Smad signaling pathway and related mechanisms in SCC, highlighting the potential benefits and challenges of TGF-β/Smad-targeted therapies.

http://ift.tt/2DhZiXh

Quantitative single-molecule study of TGF-β/Smad signaling

Abstract

TGF-β/Smad signaling pathway triggers diverse cellular responses among different cell types and environmental conditions. Quantitative analysis of protein-protein interactions involved in TGF-β/Smad signaling is demanded for understanding the molecular mechanism of this signaling pathway. Live-cell single-molecule microcopy with high spatiotemporal resolution is a new tool to monitor key molecular events in a real-time manner. In this review, we mainly presented the recent work on the quantitative characterization of TGF-β/Smad signaling proteins by single-molecule method, and showed how it enabled us to obtain new insights about this canonical signaling process.

http://ift.tt/2DOBSd7

The role of TGF-β superfamily signaling in neurological disorders

Abstract

The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.

http://ift.tt/2DhZiGL

TGF-β signaling pathway in early mouse development and embryonic stem cells

Abstract

TGF-β superfamily signaling pathways essentially contribute to the broad spectrum of early developmental events including embryonic patterning, cell fate determination and dynamic movements. In this review, we first introduced some key developmental processes that require TGF-β signaling to show the fundamental importance of these pathways. Then we discuss how their activities are regulated, and new findings about how the TGF-β superfamily ligands bind to the chromatin to regulate transcription during embryo development.

http://ift.tt/2DR5bvC

Crosstalk between TGF-β signaling and epigenome

Abstract

The transforming growth factor beta (TGF-β) family of ligands plays major roles in embryonic development, tissue homeostasis, adult immunity, and wound repair. Dysregulation of TGF-β signaling pathway leads to severe diseases. Its key components have been revealed over the past two decades. This family of cytokines acts by activating receptor activated SMAD (R-SMAD) transcription factors, which in turn modulate the expression of specific sets of target genes. Cells of a multicellular organism have the same genetic information, yet they show structural and functional differences owing to differential expression of their genes. Studies have demonstrated that epigenetic regulation, an integral part of the TGF-β signaling, enables cells to sense and respond to TGF-β signaling in a cell context-dependent manner. R-SMAD, as the central transcription factor of TGF-β signaling, can recruit various epigenetic regulators to shape the transcriptome. In this review, we focus on epigenetic regulatory mechanisms in the TGF-β signaling during mammalian development and diseases and discuss the central role of the interaction between R-SMAD and various epigenetic regulators in this epigenetic regulation. The crosstalk between TGF-β signaling and the epigenome could serve as a versatile fine-tuning mechanism for transcriptional regulation during embryonic development and progression of diseases, particularly cancer.

http://ift.tt/2DkttgE

TGF-β signaling in cancer metastasis

Abstract

The transforming growth factor (TGF)-β signaling events are well known to control diverse processes and numerous responses, such as cell proliferation, differentiation, apoptosis, and migration. TGF-β signaling plays context-dependent roles in cancer: in pre-malignant cells TGF-β primarily functions as a tumor suppressor, while in the later stages of cancer TGF-β signaling promotes invasion and metastasis. Recent studies have also suggested that the cross-talk between TGF-β signaling and other signaling pathways, such as Hippo, Wnt, EGFR/RAS, and PI3K/AKT pathways, may substantially contribute to our current understanding of TGF-β signaling and cancer. As a result of the wide-ranging effects of TGF-β, blockade of TGF-β and its downstream signaling components provides multiple therapeutic opportunities. Therefore, the outlook for anti-TGF-β signaling therapy for numerous diseases appears bright and will provide valuable information and thinking on the drug molecular design. In this review, we focus on recent insights into the regulation of TGF-β signaling in cancer metastasis which may contribute to the development of novel cancer-targeting therapies.

http://ift.tt/2DTe3Rx

Intracellular trafficking of transforming growth factor β receptors

Abstract

Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGFβ receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin- and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGFβ signaling, localization of the activated receptor complexes on the early endosomes promotes TGFβ-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGFβ receptors, has been shown to be required for TGFβ signaling via non-Smad pathways. The importance of proper control of TGFβ receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGFβ receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGFβ signaling.

http://ift.tt/2DlHxGK

Smad3–STAT3 crosstalk in pathophysiological contexts

Abstract

Smad3 and STAT3 are intracellular molecules that transmit signals from plasma membrane receptors to the nucleus. Smad3 operates downstream of growth/differentiation factors that utilize activin receptor-like kinase (ALK)-4, 5, or 7, such as transforming growth factor-β (TGF-β), activin, and myostatin. STAT3 principally functions downstream of cytokines that exert their effects via gp130 and Janus family kinases, including interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and oncostatin M. Accumulating evidence indicates that Smad3 and STAT3 engage in crosstalk in a highly context-dependent fashion, cooperating in some conditions while acting antagonistically each other in others. Here, we review the crosstalk between Smad3 and STAT3 in various biological contexts, including early tumorigenesis, epithelial–mesenchymal transition, fibrosis, and T cell differentiation.

http://ift.tt/2DR5syD

The concomitant apoptosis and EMT underlie the fundamental functions of TGF-β

Abstract

TGF-β's multipotent cellular effects and their relations are critical for TGF-β's pathophysiological functions. However, these effects may appear to be paradoxical in understanding TGF-β's functions. Apoptosis and epithelial–mesenchymal transition (EMT) are two fundamental events that are deeply linked to various physiological and disease-related processes. These two major cellular fates are subtly regulated and can be potently stimulated by TGF-β, which profoundly contribute to the biological roles of TGF-β. Moreover, these two events are also indirectly and directly correlated with TGF-β-mediated growth inhibition and are relevant to the current understanding of the roles of TGF-β in tumorigenesis and cancer progression. Although TGF-β-induced apoptosis and EMT can be singly independent cellular events, they can also be mutually exclusive but interrelated concomitant events in various cases. Thus, the modulation of apoptosis and EMT is essential for the seemingly paradoxical functions of TGF-β. However, the concomitant effect of TGF-β on apoptosis and EMT, the balance and regulated alterations of them are still been ignored or underestimated. This review focuses on the TGF-β-induced concomitant apoptosis and EMT. We aim to provide an insight in understanding their significance, balance, and modulation in TGF-β-mediated biological functions.

http://ift.tt/2DlHtqu

From Foundation to Demolition: The Influence of Perioperative Tranexamic Acid

No abstract available

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The Impact of Prehospital Tranexamic Acid on Blood Coagulation in Trauma Patients

BACKGROUND: There is limited data on prehospital administration of tranexamic acid (TXA) in civilian trauma. The aim of this study was to evaluate changes in coagulation after severe trauma from on-scene to the hospital after TXA application in comparison to a previous study without TXA. METHODS: The study protocol was registered at ClinicalTrials.gov (NCT02354885). A prospective, multicenter, observational study investigating coagulation status in 70 trauma patients receiving TXA (1 g intravenously) on-scene versus a control group of 38 patients previously published without TXA. To account for potential differences in patient and trauma epidemiology, crystalloid and colloidal resuscitation fluid, 2 propensity score matched groups (n = 24 per group) were created. Measurements included ROTEM, standard coagulation tests and blood gas analyses on-scene and emergency department admission. Presented values are mean and [standard deviation], and difference in means and 95% confidence intervals. RESULTS: Patient epidemiology was not different between groups. Coagulation assays on-scene were comparable between the TXA and C. Prehospital hyperfibrinolysis was blunted in all 4 patients in the TXA group. Viscoelastic FIBTEM maximum clot firmness (MCF), representing functional fibrinogen levels, did not change from on-scene to the emergency department in the TXA group, whereas MCF decreased −3.7 [1.8] mm in the control group. Decrease of MCF was significantly reduced in the TXA group in EXTEM by 9.2 (7.2–11.2) mm (P

http://ift.tt/2DjHdIC

A Tale of Two Solutions: High vs Low-Chloride Intravenous Fluids

No abstract available

http://ift.tt/2DQiOLv

Low- Versus High-Chloride Content Intravenous Solutions for Critically Ill and Perioperative Adult Patients: A Systematic Review and Meta-analysis

BACKGROUND: To assess whether use of low-chloride solutions in unselected critically ill or perioperative adult patients for maintenance or resuscitation reduces mortality and renal replacement therapy (RRT) use when compared to high-chloride fluids. METHODS: Systematic review and meta-analysis with random-effects inverse variance model. PubMed, Cochrane library, EMBASE, LILACS, and Web of Science were searched from inception to October 2016. Published and unpublished randomized controlled trials in any language that enrolled critically ill and/or perioperative adult patients and compared a low- to a highchloride solution for volume maintenance or resuscitation. The primary outcomes were mortality and RRT use. We conducted trial sequential analyses and assessed risk of bias of individual trials and the overall quality of evidence. Fifteen trials with 4067 patients, most at low risk of bias, were identified. Of those, only 11 and 10 trials had data on mortality and RRT use, respectively. A total of 3710 patients were included in the mortality analysis and 3724 in the RRT analysis. RESULTS: No statistically significant impact on mortality (odds ratio, 0.90; 95% confidence interval, 0.69–1.17; P = .44; I2 = 0%) or RRT use (odds ratio, 1.12; 95% confidence interval, 0.80–1.58; P = .52; I2 = 0%) was found. Overall quality of evidence was low for both primary outcomes. Trial sequential analyses highlighted that the sample size needed was much larger than that available for properly powered outcome assessment. CONCLUSIONS: The current evidence on low- versus high-chloride solutions for unselected critically ill or perioperative adult patients demonstrates no benefit, but suffers from considerable imprecision. We noted a limited exposure volume for study fluids and a relatively low risk of the populations in each study. Together with the relatively small pooled sample size, these data leave us underpowered to detect potentially important differences. Results from well-conducted, adequately powered randomized controlled trials examining sufficiently large fluid exposure are necessary.

http://ift.tt/2DPCjnD

Brain Monitoring and the Depth of Anesthesia: Another Goldilocks Dilemma

No abstract available

http://ift.tt/2mTqzIH

Translational potential of human brain organoids

Abstract

The recent technology of 3D cultures of cellular aggregates derived from human stem cells have led to the emergence of tissue-like structures of various organs including the brain. Brain organoids bear molecular and structural resemblance with developing human brains, and have been demonstrated to recapitulate several physiological and pathological functions of the brain. Here we provide an overview of the development of brain organoids for the clinical community, focusing on the current status of the field with an critical evaluation of its translational value.

http://ift.tt/2rrwxWE

Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years

Abstract

Recent evidence indicates that measures from cerebrospinal fluid, MRI scans and cognitive testing obtained from cognitively normal individuals can be used to predict likelihood of progression to mild cognitive impairment several years later, for groups of individuals. However, it remains unclear whether these measures are useful for predicting likelihood of progression for an individual. The increasing focus on early intervention in clinical trials for Alzheimer's disease emphasizes the importance of improving the ability to identify which cognitively normal individuals are more likely to progress over time, thus allowing researchers to efficiently screen participants, as well as determine the efficacy of any treatment intervention. The goal of this study was to determine which measures, obtained when individuals were cognitively normal, predict on an individual basis, the onset of clinical symptoms associated with a diagnosis of mild cognitive impairment due to Alzheimer's disease. Cognitively normal participants (n = 224, mean baseline age = 57 years) were evaluated with a range of measures, including: cerebrospinal fluid amyloid-β and phosphorylated-tau, hippocampal and entorhinal cortex volume, cognitive tests scores and APOE genotype. They were then followed to determine which individuals developed mild cognitive impairment over time (mean follow-up = 11 years). The primary outcome was progression from normal cognition to the onset of clinical symptoms of mild cognitive impairment due to Alzheimer's disease at 5 years post-baseline. Time-dependent receiver operating characteristic analyses examined the sensitivity and specificity of individual measures, and combinations of measures, as predictors of the outcome. Six measures, in combination, were the most parsimonious predictors of transition to mild cognitive impairment 5 years after baseline (area under the curve = 0.85; sensitivity = 0.80, specificity = 0.75). The addition of variables from each domain significantly improved the accuracy of prediction. The incremental accuracy of prediction achieved by adding individual measures or sets of measures successively to one another was also examined, as might be done when enrolling individuals in a clinical trial. The results indicate that biomarkers obtained when individuals are cognitively normal can be used to predict which individuals are likely to develop clinical symptoms at 5 years post-baseline. As a number of the measures included in the study could also be used as subject selection criteria in a clinical trial, the findings also provide information about measures that would be useful for screening in a clinical trial aimed at individuals with preclinical Alzheimer's disease.

http://ift.tt/2FVSsbL

Isolated septic arthritis of hip joint: a rare presentation of melioidosis. A case report

Despite, Sri Lanka lies in the melioidosis endemic belt between 5°N and 10°N surrounded by countries known to have endemic melioidosis for many years, comparatively fewer cases of melioidosis infection have be...

http://ift.tt/2FXtYPi

Vitamin D receptor rs2228570 polymorphism is associated with LH levels in men exposed to anabolic androgenic steroids

The primary aim of this study was to investigate the association between the vitamin D receptor polymorphisms rs2228570 (Fok1) and rs731236 (TaqI) and LH and FSH levels in relation to anabolic androgenic stero...

http://ift.tt/2rmoPx7

Clinicopathologic features of colorectal carcinoma: features predicting higher T-stage and nodal metastasis

A rising frequency of colorectal carcinoma has been noted in recent years in Pakistan. In the present study, we aimed to evaluate clinicopathologic features of colorectal carcinoma in our population so that pr...

http://ift.tt/2FVSsZj

Neuroprotection by chitosan nanoparticles in oxidative stress-mediated injury

Oxidative stress is a critical component of nervous system secondary injury. Oxidative stress produces toxic chemical byproducts including reactive aldehydes that traverse intact membranes and attack neighbori...

http://ift.tt/2rnmX7r

Migraine with visual aura associated with thicker visual cortex

Abstract

Until recent years it was believed that migraine with aura was a disorder causing intermittent neurological symptoms, with no impact on brain structure. However, recent MRI studies have reported increased cortical thickness of visual and somatosensory areas in patients with migraine with aura, suggesting that such structural alterations were either due to increased neuronal density in the areas involved, or a result of multiple episodes of cortical spreading depression as part of aura attacks. Subsequent studies have yielded conflicting results, possibly due to methodological reasons, e.g. small number of subjects. In this cross-sectional study, we recruited females aged 30–60 years from the nationwide Danish Twin Registry. Brain MRI of females with migraine with aura (patients), their co-twins, and unrelated migraine-free twins (controls) were performed at a single centre and assessed for cortical thickness in predefined cortical areas (V1, V2, V3A, MT, somatosensory cortex), blinded to headache diagnoses. The difference in cortical thickness between patients and controls adjusted for age, and other potential confounders was assessed. Comparisons of twin pairs discordant for migraine with aura were also performed. Comparisons were based on 166 patients, 30 co-twins, and 137 controls. Compared with controls, patients had a thicker cortex in areas V2 [adjusted mean difference 0.032 mm (95% confidence interval 0.003 to 0.061), V3A [adjusted mean difference 0.037 mm (95% confidence interval 0.008 to 0.067)], while differences in the remaining areas examined were not statistically significant [adjusted mean difference (95% confidence interval): V1 0.022 (−0.007 to 0.052); MT: 0.018 (−0.011 to 0.047); somatosensory cortex: 0.020 (−0.009 to 0.049)]. We found no association between the regions of interest and active migraine, or number of lifetime aura attacks. Migraine with aura discordant twin pairs (n = 30) only differed in mean thickness of V2 (0.039 mm, 95% CI 0.005 to 0.074). In conclusion, females with migraine with aura have a thicker cortex corresponding to visual areas and our results indicate this may be an inherent trait rather than a result of repeated aura attacks.

http://ift.tt/2rr0Gpf

Multiple sclerosis risk variants alter expression of co-stimulatory genes in B cells

Abstract

The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells. Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene. We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10⁻⁵ in patients and ≤4.09 × 10⁻⁶ in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10⁻⁵ in controls). In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10⁻⁷). Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40. Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis.

http://ift.tt/2FZFd9Z

Spike-related haemodynamic responses overlap with high frequency oscillations in patients with focal epilepsy

Abstract

Simultaneous scalp EEG/functional MRI measures non-invasively haemodynamic responses to interictal epileptic discharges, which are related to the epileptogenic zone. High frequency oscillations are also an excellent indicator of this zone, but are primarily recorded from intracerebral EEG. We studied the spatial overlap of these two important markers in patients with drug-resistant epilepsy to assess if their combination could help better define the extent of the epileptogenic zone. We included patients who underwent EEG-functional MRI and later intracerebral EEG. Based on intracerebral EEG findings, we separated patients with unifocal seizures from patients with multifocal or unknown onset seizures. Haemodynamic t-maps were coregistered with the intracerebral electrode positions. Each EEG channel was classified as pertaining to one of the following categories: primary haemodynamic cluster (maximum t-value), secondary cluster (t-value > 90% of the primary cluster) or outside the primary and secondary clusters. We marked high frequency oscillations (ripples: 80–250 Hz; fast ripples: 250–500 Hz) during 1 h of slow wave sleep, and compared their rates in each haemodynamic category. After classifying channels as high- or low-rate, the proportion of high-rate channels within the primary or primary plus secondary clusters was compared to the proportion expected by chance. Twenty-five patients, 11 with unifocal and 14 with multifocal/unknown seizure onsets, were studied. We found a significantly higher median high frequency oscillation rate in the primary cluster compared to secondary cluster and outside these two clusters for the unifocal group (P < 0.0001), but not for the multifocal/unknown group. For the unifocal group, the number of high-rate channels within the primary or primary plus secondary clusters was significantly higher than expected by chance. This held only for the high-ripple-rate channels in the multifocal/unknown group. At the patient level, most patients (18/25, or 72%) had at least one high-rate channel within a primary cluster. In patients with unifocal epilepsy, the maximum haemodynamic response (primary cluster) related to scalp interictal discharges overlaps with the tissue generating high frequency oscillations at high rates. If intracranial EEG is warranted, this response should be explored. As a tentative clinical use of the combination of these techniques we propose that higher high frequency oscillation rates inside than outside the maximum response indicates that the patient has indeed a focal epileptogenic zone demarcated by this response, whereas similar rates inside and outside may indicate a widespread epileptogenic zone or an epileptogenic zone not covered by the implantation.

http://ift.tt/2roDI1W

Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea

Future Oncology, Ahead of Print.


http://ift.tt/2FZlPdp

Abiraterone acetate and its use in the treatment of metastatic prostate cancer: a review

Future Oncology, Ahead of Print.


http://ift.tt/2rtAsm7

False Low-Risk Single Nucleotide Polymorphism–Based Noninvasive Prenatal Screening in Pentasomy 49,XXXXY

AJP Rep 2018; 08: e4-e6
DOI: 10.1055/s-0037-1621722

Introduction Pentasomy 49,XXXXY is a sex chromosome anomaly difficult to be diagnosed prenatally. We describe a patient of pentasomy 49,XXXXY with false low-risk results using a noninvasive prenatal screening (NIPS). A 30-year-old G1P0 woman presented at 336/7 weeks, secondary to sonographic fetal anomalies. She had low-risk NIPS at 136/7 weeks. Anatomy survey showed bilateral clubfeet, clinodactyly of the left fifth digit, micropenis, and echogenic bowel. Cytogenetics analysis revealed pentasomy 49,XXXXY syndrome. We report third-trimester sonographic features of a fetus with pentasomy 49,XXXXY and the importance of thorough pre- and posttest counseling for NIPS.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

http://ift.tt/2rpY3DV

Pregnant Women's Knowledge and Beliefs about the Safety and Outcomes of Delivery at Various Gestational Ages

AJP Rep 2018; 08: e7-e12
DOI: 10.1055/s-0038-1624561

Objectives Despite the morbidity associated with late preterm and early-term births, there is limited data on pregnant women's perception of neonatal risk based on gestational age (GA). Therefore, our objective was to determine pregnant women's perception of neonatal risks at varying GAs. Method Through an anonymous 24-question survey, pregnant women were asked to designate the GA at delivery that is desirable, safe, and defined as full term. Responses were compared based on race, history of preterm birth, and medical comorbidities. Results Among the 233 survey respondents, the majority (62.9%) desired delivery at 36 to 39 weeks' gestation. Black women were more likely to desire delivery at 28 to 35 weeks compared with other racial/ethnic groups (p = 0.005). Women with a history of preterm birth or medical complications were less likely to desire delivery at 40 weeks. More than 40% of respondents thought delivery at 8 months of pregnancy was safe and 40.3% responded that 37 weeks' gestation is considered term. Conclusion Misconceptions surrounding the definition of a term pregnancy are pervasive and vary by race, obstetric history, and medical comorbidities. Our findings highlight the need for patient education about appropriate gestational length, especially in minority and high-risk populations.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

http://ift.tt/2FWQHeo

Fusion-Negative Rhabdomyosarcoma Can Arise from Endothelial Cells [Research Watch]

Aberrant myogenic activation in endothelial cells can drive fusion-negative rhabdomyosarcoma (FN-RMS).

http://ift.tt/2BgSKWZ

REV-ERB Agonists Block Autophagy in Cancer Cells [Research Watch]

Disruption of the circadian clock components reduces cancer cell viability in vitro and in vivo.

http://ift.tt/2mWKeIv

Patients with Desmoplastic Melanoma May Respond to PD-1 Blockade [Research Watch]

PD-1 blockade achieved responses in 70% of patients with desmoplastic melanoma in a retrospective analysis.

http://ift.tt/2BgSIhP

LXR Agonism Depletes MDSCs to Promote Antitumor Immunity [Research Watch]

LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells.

http://ift.tt/2mXqrIQ

Personalized chemosensitivity assays for mesothelioma- is it worth the effort?

Cell-lines formed from an individual's tumor can be used to predict response to specific therapies and determine genomic predictors. For mesothelioma, where chemotherapy remains the backbone of current therapeutic paradigms, such assays could be used to treat patients with the most effective agents specific to their "chemical profile".

http://ift.tt/2rjOBBW

Pathways impacted by genomic alterations in pulmonary carcinoid tumors

Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, typical and atypical carcinoid, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death and apoptosis and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1 and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-ĸB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.

http://ift.tt/2FVZgGi

A novel method for rapid molecular subgrouping of medulloblastoma

Purpose: The classification of medulloblastoma into WNT, SHH, Group 3 and Group 4 subgroups has become of critical importance for patient risk-stratification and subgroup-tailored clinical trials. Here, we aimed to develop a simplified, clinically applicable classification approach that can be implemented in the majority of centers treating patients with medulloblastoma. Experimental Design: We analyzed 1,577 samples comprising previously published DNA methylation microarray data (913 medulloblastomas, 457 non-medulloblastoma tumors, 85 normal tissues), and 122 frozen and formalin-fixed paraffin-embedded medulloblastoma samples. Biomarkers were identified applying stringent selection filters and Linear Discriminant Analysis (LDA) method, and validated using DNA methylation microarray data, bisulfite pyrosequencing and direct-bisulfite sequencing. Results: Using a LDA-based approach, we developed and validated a prediction method (^EpiWNT-SHH classifier) based on six epigenetic biomarkers that allowed for rapid classification of medulloblastoma into the clinically relevant subgroups WNT, SHH and non-WNT/non-SHH with excellent concordance (>99%) with current gold-standard methods, DNA methylation microarray and gene-signature profiling analysis. The ^EpiWNT-SHH classifier showed high prediction capacity using both frozen and formalin-fixed material, as well as diverse DNA methylation detection methods. Similarly, we developed a classifier specific for Group 3 and Group 4 tumors, based on five biomarkers (^EpiG3-G4) with good discriminatory capacity, allowing for correct assignment of more than 92% of tumors. ^EpiWNT-SHH and ^EpiG3-G4 methylation profiles remained stable across tumor primary, metastasis and relapse samples. Conclusions: The ^EpiWNT-SHH and ^EpiG3-G4 classifiers represent a new simplified approach for accurate, rapid and cost-effective molecular classification of single medulloblastoma DNA samples, using clinically applicable DNA methylation detection methods.

http://ift.tt/2rotkau

High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole exome sequencing on a selected cohort of children with cancer. Experimental design: To identify mutations in known and novel cancer predisposing genes, we performed trio-based whole exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Results: Four patients carried causative mutations in a known cancer predisposing gene: TP53 and DICER1 (n=3). In another four patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein-Taybi syndrome, ARID1A-based Coffin-Siris syndrome, ACTB-based Baraitser-Winter syndrome and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition. Conclusion: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in eight patients and two possible novel cancer predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition.

http://ift.tt/2FU2Wsh

Exceptional response to pembrolizumab in a metastatic, chemotherapy/radiation resistant ovarian cancer patient harboring a CD274/PD-L1-genetic rearrangement

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed. Experimental Design: We describe a heavily pretreated ovarian cancer patient with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune check-point inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (ie, automated quantitative analysis, AQUA) and whole exome sequencing (WES) techniques. Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high grade ovarian carcinoma with clear cell features.  While progressing on any standard treatment modality she demonstrated a remarkable complete response to the anti-PD1 immune check-point inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (Tumor Mutation Load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-1L gene causing aberrant PD-L1 surface expression as confirmed by immunohistochemistry (IHC) and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T cell lymphocytes (ie, CD4+/CD8+ TIL), CD68+ macrophages and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side-effects reported to date. Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression.

http://ift.tt/2rkjWVq

Adverse effects of amphotericin B in children; a retrospective comparison of conventional and liposomal formulations

Abstract

Aim

Lipid formulations of amphotericin B, rather than conventional amphotericin (c-amB), are increasingly used despite limited data comparing these preparations in children. Data on the incidence of adverse effects with amphotericin-B at standard doses are scarce. This study aimed to compare the adverse effects associated with standard doses of c-amB and liposomal amphotericin (l-amB) in children.

Methods

Children admitted to the Royal Childrenaposs Hospital Melbourne and treated with c-amB or l-amB between January 2010 and September 2013 were included. Clinical and laboratory data were retrospectively extracted from medical records to compare amphotericin-related infusion reactions, nephrotoxicity (glomerulotoxicity and tubulopathy) and hepatotoxicity.

Results

Seventy-six children received c-amB and 39 received l-amB. Standard drug administration (recommended dose and infusion time) occurred in 74% (56/76) on c-amB and 85% (33/39) on l-amB. In these 89 children, infusion-related reactions were similar with c-amB than l-amB (23% (13/56) vs. 9% (3/33); p=0.15); none occurred in children aged <90 days. There was no difference in amphotericin-associated glomerulotoxicity (c-amB 14% (8/56) vs l-amB 21% (7/33); p=0.40) or in median maximum potassium requirements (c-amB 3.1 vs l-amB 2.3 mmol/kg/d; p=0.29). Hepatotoxicity occurred more frequently with l-amB than c-amB (83% (24/29) v. 56% (20/36); p=0.032).

Conclusions

When appropriately administered, l-amB was associated with more hepatotoxicity than c-amB, with no difference in infusion-related reactions or nephrotoxicity. Differences in adverse effects between the preparations is not be as marked in children as reported in adults.

http://ift.tt/2EZ63O2

The Highly Divergent Mitochondrial Genomes Indicate That the Booklouse, Liposcelis bostrychophila (Psocoptera: Liposcelididae) Is a Cryptic Species

The booklouse, Liposcelis bostrychophila is an important storage pest worldwide. The mt genome of an asexual strain (Beibei, China) of the booklouse, L. bostrychophila, comprises two chromosomes; each chromosome contains approximate half of the 37 genes typically found in animals. The mt genomes of two sexual strains of L. bostrychophila, however, comprise five and seven chromosomes respectively; each chromosome contains one to six genes. To understand mt genome evolution in L. bostrychophila and whether L. bostrychophila is a cryptic species, we sequenced the mt genomes of six strains of asexual L. bostrychophila collected from different locations in China, Croatia and USA. The mt genomes of all of the six asexual strains of L. bostrychophila collected in China, Croatia and USA have two chromosomes. Phylogenetic analysis of mt genome sequences divided nine strains of L. bostrychophila into four groups. Each group has a distinct mt genome organization and substantial sequence divergence (48.7-87.4%) from other groups. Furthermore, the seven asexual strains of L. bostrychophila including the published Beibei strain are more closely related to two other species of booklice, L. paeta and L. sculptilis, than to the sexual strains of L. bostrychophila. Our results revealed highly divergent mt genomes in the booklouse, L. bostrychophila, and indicated that L. bostrychophila is a cryptic species.

http://ift.tt/2rn1kUu

Functional Analysis of Cancer-Associated DNA Polymerase {varepsilon} Variants in Saccharomyces cerevisiae

DNA replication fidelity relies on base selectivity of the replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). Ultramutated human cancers without MMR defects carry alterations in the exonuclease domain of DNA polymerase (Pol). They have been hypothesized to result from defective proofreading. However, modeling in yeast of the most common variant, Pol-P286R, produced an unexpectedly strong mutator effect that exceeded the effect of proofreading deficiency by two orders of magnitude and indicated the involvement of other infidelity factors. The in vivo consequences of many additional Pol mutations reported in cancers remain poorly understood. Here we genetically characterized 13 cancer-associated Pol variants in the yeast system. Only variants directly altering the DNA binding cleft in the exonuclease domain elevated mutation rate. Among these, frequently recurring variants were stronger mutators than rare variants, in agreement with the idea that mutator phenotype plays a causative role in tumorigenesis. In nearly all cases, the mutator effects exceeded those of an exonuclease-null allele, suggesting that mechanisms distinct from loss of proofreading may drive the genome instability in most ultramutated tumors. All mutator alleles were semidominant, supporting the view that heterozygosity for the polymerase mutations is sufficient for tumor development. In contrast to the DNA binding cleft alterations, peripherally located variants, including a highly recurrent V411L, did not significantly elevate mutagenesis. Finally, the analysis of Pol variants found in MMR-deficient tumors suggested that the majority cause no mutator phenotype alone but some can synergize with MMR deficiency to increase mutation rate.

http://ift.tt/2FY9GFg

Identification and Validation of a New Source of Low Grain Cadmium Accumulation in Durum Wheat

Cadmium (Cd) is a heavy metal that has no known biological function and is toxic for many living organisms. The maximum level of Cd concentration allowed in the international market for wheat grain is 0.2 mg kg-1. Because phenotyping for Cd uptake is expensive and time consuming, molecular markers associated with genes conferring low Cd uptake would expedite selection and lead to the development of durum cultivars with reduced Cd concentrations. Here, we identified single nucleotide polymorphisms (SNPs) associated with a novel low Cd uptake locus in the durum experimental line D041735, which has hexaploid common wheat in its pedigree. Genetic analysis revealed a single major QTL for Cd uptake on chromosome arm 5BL within a 0.3 cM interval flanked by SNP markers. Analysis of the intervening sequence revealed a gene with homology to an aluminum-induced protein as a candidate gene. Validation and allelism tests revealed that the low Cd uptake gene identified in this study is different from the closely linked Cdu1-B gene, which also resides on 5BL. This study therefore confirmed that the durum experimental line D041735 contains a novel low Cd uptake gene that was likely acquired from hexaploid wheat.

http://ift.tt/2rjHARI

Whole-Genome Sequencing of Suppressor DNA Mixtures Identifies Pathways That Compensate for Chromosome Segregation Defects in Schizosaccharomyces pombe

Suppressor screening is a powerful method to identify genes that when mutated, rescue the temperature sensitivity of the original mutation. Previously, however, identification of suppressor mutations has been technically difficult. Due to the small genome size of Schizosaccharomyces pombe, we developed a spontaneous suppressor screening technique, followed by a cost-effective sequencing method. Genomic DNAs of 10 revertants which survived at the restrictive temperature of the original temperature sensitive (ts) mutant were mixed together as one sample before constructing a library for sequencing. Responsible suppressor mutations were identified bioinformatically based on allele frequency. Then we isolated a large number of spontaneous extragenic suppressors for 3 ts mutants that exhibited defects in chromosome segregation at their restrictive temperature. Screening provided new insight into mechanisms of chromosome segregation: Loss of Ufd2 E4 multi-ubiquitination activity suppresses defects of an AAA ATPase, Cdc48. Loss of Wpl1, a releaser of cohesin, compensates for the Eso1 mutation, which may destabilize sister chromatid cohesion. The segregation defect of a ts histone H2B mutant is rescued if it fails to be de-ubiquitinated by the SAGA complex, because H2B is stabilized by monoubiquitination.

http://ift.tt/2FWLL9m

Natural orifice endoscopic biopsy access − a tunnel of opportunity to gastrointestinal stromal tumors

http://ift.tt/2DSxJoG

LOW CHILDHOOD HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVELS AND SUBSEQUENT RISK FOR CHRONIC INFLAMMATORY BOWEL DISEASE

and aims. Several genetic and environmental risk factors have been linked to chronic inflammatory bowel disease (IBD). The incidence of IBD has significantly increased in developed countries during last decades. The aim of the present study was to examine childhood risk factors for subsequent IBD diagnosis in a longitudinal cohort study of children and adolescents.

http://ift.tt/2DkeVOa

ER{alpha}-mediated nuclear sequestration of RSK2 is required for ER+ breast cancer tumorigenesis

Although ribosomal protein S6 kinase A3 (RSK) activation status positively correlates with patient responses to anti-estrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of ER+ breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N-terminus to activate a pro-neoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Anti-estrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to anti-estrogen therapies.

http://ift.tt/2FVCDlt

XIAP regulation by MNK links MAPK and NF{kappa}B signaling to determine an aggressive breast cancer phenotype

Hyperactivation of the NFκB pathway is a distinct feature of inflammatory breast cancer (IBC), a highly proliferative and lethal disease. Gene expression studies in IBC patient tissue have linked epidermal growth factor receptor (EGFR/HER2)-mediated MAPK signaling to NFκB hyperactivity, but the mechanism(s) by which this occurs remain unclear. Here, we report that the X-linked inhibitor of apoptosis protein (XIAP) plays a central role in linking these two pathways. XIAP overexpression correlated with poor prognoses in breast cancer patients and was frequently observed in untreated IBC patient primary tumors. XIAP drove constitutive NFκB transcriptional activity, which mediated ALDH positivity (a marker of stem-like cells), in vivo tumor growth, and an IBC expression signature in patient-derived IBC cells. Using pathway inhibitors and mathematical models, we defined a new role for the MAPK-interacting (Ser/Thr)-kinase (MNK) in enhancing XIAP expression and downstream NFκB signaling. Furthermore, targeted XIAP knockdown and treatment with a MNK inhibitor decreased tumor cell migration in a dorsal skin fold window chamber murine model that allowed for intra-vital imaging of local tumor growth and migration. Together, our results indicate a novel role for XIAP in the molecular crosstalk between MAPK and NFκB pathways in aggressive tumor growth, which has the potential to be therapeutically exploited.

http://ift.tt/2roMpct

Integrative genomic analysis predicts causative cis-regulatory mechanisms of the breast cancer-associated genetic variant rs4415084

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci (eQTL), a modified version of allele-specific expression (ASE) that systematically utilizes haplotype information, transcription factor (TF) binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding gene mitochondrial ribosomal protein S30 (MRPS30) and lncRNA RP11-53O19.1. We propose an intergenic SNP rs4321755, in linkage disequilibrium (LD) with the GWAS SNP rs4415084 (r2=0.988), to be the predicted functional SNP. The risk allele rs4321755-T, in phase with the GWAS rs4415084-T, created a GATA3 binding motif within an enhancer, resulting in differential GATA3 binding and chromatin accessibility, thereby promoting transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the role of risk SNP in modulating mitochondrial activities in breast cancer. Our computational framework provides an effective means to integrate GWAS results with high-throughput genomic and epigenomic data and can be extended to facilitate rapid functional characterization of other genetic variants modulating cancer susceptibility.

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Targeting the SphK1/S1P/S1PR1 axis that links obesity, chronic inflammation and breast cancer metastasis

Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P) which mediates cancer pathogenesis. A high fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key pro-inflammatory cytokines, macrophage infiltration and tumor progression induced by obesity. S1P produced in the lung pre-metastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL-6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL-6, macrophage infiltration and S1P-mediated signaling pathways in the lung induced by a high fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches and breast cancer metastasis, with potential implications for prevention and treatment.

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MicroRNAs and Target Genes in Pituitary Adenomas

Horm Metab Res
DOI: 10.1055/s-0043-123763

Pituitary adenomas account for the top three primary intracranial tumors in terms of total incidence rates. The clinical symptoms presented by the disease are often characterized by a series of systemic endocrine disorders, severe occupational lesions, and even some malignant features, and therefore early diagnosis and predicting recurrence would be instructive for clinical treatment of pituitary adenomas. An increasing number of specific microRNA (miRNA) expression signatures have been identified in pituitary, and miRNAs are related with the pituitary tumorigenesis, dysfunction, neurodegeneration, and metastatic non-functioning pituitary carcinoma. Here, this paper reviews the effects of aberrant miRNA expression in human pituitary adenomas and summarizes some corresponding target genes and biological significance over the last 7 years (2010–2017).
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Uncommon Cause of Abdominal Pain, Nausea and Vomiting

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Subcapsular Hepatic Hematoma Secondary to Hepatic Microaneurysms in the Setting of Systemic Amyloidosis

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An uncommon portal vein abnormality

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Combination of Pelargonium sidoides and Coptis chinensis root inhibits nuclear factor kappa B-mediated inflammatory response in vitro and in vivo

Pelargonium sidoides (PS) and Coptis chinensis root (CR) have traditionally been used to treat various diseases, including respiratory and gastrointestinal infections, dysmenorrhea, and hepatic disorders. The pre...

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A comparative study of three conservative treatments in patients with lumbar spinal stenosis: lumbar spinal stenosis with acupuncture and physical therapy study (LAP study)

Although the efficiency of conservative management for lumbar spinal stenosis (LSS) has been examined, different conservative management approaches have not been compared. We have performed the first comparati...

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Issue Information

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SCL20A2 mutation presenting with acute ischemic stroke: a case report

Primary familial brain calcification (PFBC) is a rare disorder characterized by distinctive bilateral brain calcification and variable clinical presentations. However, cerebrovascular attack was rarely reporte...

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Risk factors for Mycobacterium ulcerans infection (Buruli Ulcer) in Togo ─ a case-control study in Zio and Yoto districts of the maritime region

Buruli ulcer (BU) is a neglected mycobacterial skin infection caused by Mycobacterium ulcerans. This disease mostly affects poor rural populations, especially in areas with low hygiene standards and sanitation co...

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Characterization of Salmonella enterica from invasive bloodstream infections and water sources in rural Ghana

Non-typhoidal Salmonella (NTS) cause the majority of bloodstream infections in Ghana, however the mode of transmission and source of invasive NTS in Africa are poorly understood. This study compares NTS from wate...

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The Role of Inflammation in the Pain, Fatigue, Sleep Disturbance Symptom Cluster in Advanced Cancer

Symptom researchers have proposed a model of inflammatory cytokine activity and dysregulation in cancer to explain co-occurring symptoms including pain, fatigue, and sleep disturbance.

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Communicating Caregivers’ Challenges with Cancer Pain Management: An Analysis of Home Hospice Visits

Family caregivers of hospice cancer patients face significant challenges related to pain management. Addressing many of these challenges requires effective communication between family caregivers and hospice nurses, yet little empirical evidence exists on the nature of communication about pain management between hospice nurses and family caregivers.

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Restoration of somatosensory perception via electrical stimulation of peripheral nerves

Sensory impairment hinders a person's ability to interact with their environment, and thus reduces their quality of life. In the case of impaired somatosensory perception, visual input can only provide indirect information at non-negligible cognitive cost. Therefore, restoration of natural somatosensory perception via artificial means has led to the exploration of different biological targets (Weber et al., 2012). Stimulation of the somatosensory cortex (Bensmaia, 2015), dorsal root ganglia (Weber et al., 2011), and peripheral nerves (Pasluosta et al., 2018) can produce intuitive and near-natural tactile and proprioceptive sensations, although proprioception has been studied to a lesser extent than touch (Weber et al., 2012).

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Sensorimotor integration is problematic in amyotrophic lateral sclerosis

Pathophysiological descriptions of amyotrophic lateral sclerosis (ALS) have broadened in recent years to include recognition of widespread involvement of brain pathways in the 'connectome', including corpus callosum, with degenerative neuronal pathology in associated cortical areas, basal ganglia, brainstem, cerebellum and spinal cord. In general, these pathological changes are in the anterior brain and its connections, and thus in the classical motor and also in the emotionally expressive brain, including frontal lobes anterior to primary motor areas and temporal lobes.

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Head and Neck Tumor Control Probability: Radiation Dose-Volume Effects in SBRT for Locally-Recurrent Previously-Irradiated Head and Neck Cancer

In a systematic review of the available literature addressing the dose/volume data for tumor control probability with SBRT in patients with locally-recurrent previously-irradiated head-and-neck cancer, data from over 300 cases in 8 publications suggests that there is a dose-response relationship with superior local control and possibly improved overall survival, for doses of 35-45Gy (in 5 fractions) compared to <30 Gy. SBRT doses equivalent to 5 fraction doses of 40-50Gy are suggested for re-treatment.

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Tolerability of ADXS11-001 Lm-LLO Listeria Based Immunotherapy With Mitomycin, Fluorouracil and Radiation for Anal Cancer

ADXS11-0011 Lm-LLO is a live attenuated Listeria monocytogenes (Lm) bacterium bioengineered to secrete the HPV-16 E7 protein fused with a truncated fragment of listeriolysin O (tLLO) that preferentially infects antigen-presenting cells. Exposure to ADXS11-001 may stimulate T-cells to target HPV-transformed cells. The objective of this study was to obtain safety and preliminary efficacy data of the combination of ADXS11-001 with mitomycin, FU and intensity modulated radiation therapy (IMRT) in locally advanced anal cancer.

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Phase I Study of Accelerated Hypofractionated Radiotherapy with Concurrent Chemotherapy for Stage III Non-Small-Cell Lung Cancer: CALGB 31102 (Alliance)

Investigate the safety of accelerated hypofractionated radiotherapy (AHRT) with concurrent chemotherapy (CT) for inoperable stage III non–small-cell lung cancer (NSCLC).

http://ift.tt/2rlZwLD

Efficacy of intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B for post-neurosurgical intracranial infections due to MDR/XDR Acinectobacter baumannii: a retrospective cohort study

Post-neurosurgical intracranial infections caused by multidrug-resistant or extensively drug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality. In this study, we analyzed...

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Grantee Spotlight: Luis G. Carvajal-Carmona, PhD

Dr. Carvajal-Carmona is an Associate Professor and CRCHD R21 awardee researching cancer genetics, epidemiology, and cancer health disparities.

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iSepsis – Sepsis 3.0: Much to do about Nothing

Sepsis 3.0. Much to do about Nothing.

EMCrit Project by Paul Marik.

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Nilotinib Can Be Discontinued in Some Patients with Chronic Myelogenous Leukemia

On December 22, FDA approved an update to the label of nilotinib (Tasignia) that states that some patients with CML who are taking nilotinib and whose cancer has been in remission for an extended period can safely stop taking it.

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A Preclinical Population Pharmacokinetic Model for Anti-CD20/CD3 T-Cell-Dependent Bispecific Antibodies

Abstract

CD20 is a cell-surface receptor expressed by healthy and neoplastic B cells and is a well-established target for biologics used to treat B-cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti-CD20/CD3 T-cell-dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time-varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed-effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time-varying, linear clearance term (t_½ = 1.6 h); and iii) a slowly decaying time-varying, nonlinear clearance term (t_½ = 4.8 days). The two time-varying drug elimination terms approximately track with time scales of B-cell depletion and T-cell migration/expansion within the central blood compartment. The mixed-effects NHP model was scaled to human and prospective clinical simulations were generated.

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Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned

Abstract

Although thiopurine S-methyltransferase (TPMT) genotyping to guide thiopurine dosing is common in the pediatric cancer population, limited data exist on TPMT testing implementation in diverse, multidisciplinary settings. We established TPMT testing (genotype and enzyme) with clinical decision support, provider/patient education, and pharmacist consultations in a tertiary medical center and collected data over 3 years. During this time, 834 patients underwent 873 TPMT tests (147 (17%) genotype, 726 (83%) enzyme). TPMT tests were most commonly ordered for gastroenterology, rheumatology, dermatology, and hematology/oncology patients (661 of 834 patients (79.2%); 580 outpatient vs. 293 inpatient; P < 0.0001). Thirty-nine patients had both genotype and enzyme tests (n = 2 discordant results). We observed significant differences between TPMT test use and characteristics in a diverse, multispecialty environment vs. a pediatric cancer setting, which led to unique implementation needs. As pharmacogenetic implementations expand, disseminating lessons learned in diverse, real-world environments will be important to support routine adoption.

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Crestline’s 2018 ambulance product showcase

SASKATOON, Canada — Crestline Coach, a global leader in ambulance and specialty vehicle manufacturing, released its annual product showcase ebook. The downloadable ebook provides an inside look into how Crestline product is manufactured to be the safest and most durable product in the marketplace. Readers will also learn how Crestline is continuing advances in ambulance safety and patient care ...

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Single-cell Resolution Fluorescence Live Imaging of Drosophila Circadian Clocks in Larval Brain Culture

The goal of this protocol is to establish ex vivo Drosophila larval brain culture optimized to monitor circadian molecular rhythms with long-term fluorescence time-lapse imaging. The application of this method to pharmacological assays is also discussed.

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All-electronic Nanosecond-resolved Scanning Tunneling Microscopy: Facilitating the Investigation of Single Dopant Charge Dynamics

We demonstrate an all-electronic method to observe nanosecond-resolved charge dynamics of dopant atoms in silicon with a scanning tunneling microscope.

http://ift.tt/2BhQRK0

Cost Effectiveness of Treatments for Chronic Constipation: A Systematic Review

Abstract

Background

Chronic constipation (CC) has a significant impact on patients' quality of life and imposes an economic burden on individuals and the healthcare system. Treatment options include dietary changes, lifestyle modifications, fibre supplements, stool softeners, and laxatives.

Objective

We undertook this systematic review to comprehensively evaluate the cost effectiveness of treatments for CC.

Methods

We searched ten common databases to identify economic evaluations published to 13 June 2017. Abstract and full-text review were completed in duplicate. The quality of the included studies was assessed using the Consensus on Health Economic Criteria. Data extracted included costs and outcomes of treatments for CC and cost-effectiveness methods. A narrative synthesis was completed.

Results

From the 4338 unique citations identified, 79 proceeded to full-text review, with 10 studies forming the final dataset. Eight different definitions of CC were used to define the study populations. Study designs used were decision-tree models (4), Markov model (1), and retrospective (1) and prospective (4) studies. Quality-adjusted life-years (QALY) were reported in five studies; other outcomes included, discontinuation of laxative treatment and frequency of bowel movements. The majority of studies stated that their results were from a payer perspective; however, some of these studies only considered treatment costs, a subset of costs included in the payer perspective. Lifestyle advice, dietary treatments and abdominal massage were each compared with current care with laxatives, while polyethylene glycol (PEG) and senna–fibre combination were each compared with lactulose. Two studies compared newer treatments in patients who had not responded to laxatives: prucalopride was compared with continuing laxatives, and linaclotide was compared with lubiprostone. All of the interventions were reported by the study authors to be cost effective, with the exception of abdominal massage.

Conclusions

A consistent definition of CC is needed and the QALY should be used to capture the diverse symptoms of CC. Further analysis is needed comparing all available treatments for patients who have not responded to laxatives. Overall, results from economic evaluations appear to align with stepwise practice guidelines.

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Budget Impact Analysis of PCSK9 Inhibitors for the Management of Adult Patients with Heterozygous Familial Hypercholesterolemia or Clinical Atherosclerotic Cardiovascular Disease

Abstract

Objective

The aim of this study was to assess the budget impact of introducing the proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab to market for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular (CV) disease requiring additional lowering of low-density lipoprotein cholesterol (LDL-C).

Methods

A 3-year model estimated the costs of lipid-modifying therapy (LMT) and CV events to a hypothetical US health plan of 1 million members, comparing two scenarios—with and without the availability of PCSK9i as add-on therapy to statins. Proportions of patients with uncontrolled LDL-C despite receiving statins, and at risk of CV events, were estimated from real-world data. Total undiscounted annual LMT costs (2017 prices, including PCSK9i costs of $14,563.50), dispensing and healthcare costs, including the costs of CV events, were estimated for all prevalent patients in the target population, based on baseline risk factors. Maximum PCSK9i utilization of 1–5% over 3 years according to risk group (following the same pattern as current ezetimibe use), and 5–10% as a secondary scenario, were assumed.

Results

Total healthcare budget impacts per target patient (and per member) per month for years 1, 2 and 3 were $3.62($0.10), $7.22($0.20) and $10.79($0.30), respectively, assuming 1–5% maximum PCSK9i utilization, and $15.81($0.44), $31.52($0.88) and $47.12($1.31), respectively, assuming 5–10% utilization. Results were sensitive to changes in model timeframe, years to maximum PCSK9i utilization and PCSK9i costs.

Conclusions

The budget impact of PCSK9i as add-on therapy to statins for patients with hypercholesterolemia is relatively low compared with published estimates for other specialty biologics. Drug cost rebates and discounts are likely to further reduce budget impact.

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The Jun/miR-22/HuR regulatory axis contributes to tumourigenesis in colorectal cancer

Abstract

Background

Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood.

Methods

In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR's 3'-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun's occupancy on the C17orf91 promoter.

Results

We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3'-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22.

Conclusions

Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.

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New Research From Psychological Science

Read about the latest research published in Psychological Science:

Good Choice, Bad Judgment: How Choice Under Uncertainty Generates Overoptimism

Jordan Tong, Daniel Feiler, and Anastasia Ivantsova

Decision making often involves choosing among options without complete information, forcing us to estimate their relative favorability. We tend to choose the option with the highest estimated value, but we may fail to account for random error associated with these estimates. This blind spot, the authors hypothesized, leads us to be overoptimistic about the options we ultimately choose. Over four experiments, the authors asked participants to estimate house sale prices, job candidate scores, or the amount of money contained in jars. In general, participants did not make biased estimates when they evaluated options independently, but they significantly overestimated the most valuable option when it was part of a set. Overestimations were more dramatic when the options' true values were more clustered together and when a greater number of options were available. Participants overestimated even when they had information directly signaling the value of each option. These findings add to previous research showing how motivational and emotional factors contribute to overoptimism, revealing that contextual factors also play a role.

Evidence for Implicit–But Not Unconscious–Processing of Object-Scene Relations

Natalie Biderman and Liad Mudrik

Several studies have indicated that the relationship between an object and the surrounding scene can be perceived and can influence responding outside participants' awareness, suggesting that conscious awareness is not necessary for integration. Some research has failed to replicate the phenomenon, however, leading the authors to reexamine their own previous work using a masking paradigm. In one experiment, for example, participants were exposed to a series of images onscreen. A prime image appeared for 33 ms and was preceded and followed by mask images. A target image then appeared for 500 ms and participants reported whether the target was incongruent or congruent as quickly and accurately as possible. Contrary to the authors' previous findings, the results of these experiments showed no evidence that prime congruency affected target-classification accuracy or reaction times. Additional Bayesian analyses indicated that the results could not be explained by inconclusive or underpowered data. On the basis of these and other recent findings, the authors conclude that there is currently no compelling evidence for object-scene congruency processing outside awareness.

Dissociating Orienting Biases From Integration Effects With Eye Movements

Matthew D. Hilchey, Jason Rajsic, Greg Huffman, Raymond M. Klein, and Jay Pratt

Under what conditions is a return of attention to a prior target location facilitated or inhibited? In some paradigms, how quickly participants discriminate a stimulus feature after its location has been repeated or changed is taken as evidence of attentional bias. But these reaction times are affected by whether the stimulus feature (or response) also repeats, which requires integration of location and feature information. To separate these phenomena, the authors used eye movements to measure orienting bias independently of integration effects. In two experiments, participants saw a series of targets with randomly repeating locations and they pressed the key that corresponded to each target. As in previous work, key-press responses showed evidence of integration effects: Participants responded more quickly when both the target location and form either repeated or switched. Eye-movement data, however, revealed a consistent reorienting bias: Eye movements to the target were slower when the target location repeated than when it switched. Together, these findings show that inhibited-reorienting effects exist and can be distinguished from integration effects using an oculomotor measure.

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