Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics.

GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.

A survey of Canadian respiratory therapists working in the COVID-19 pandemic: The RRT perspective.

Introduction: Registered respiratory therapists (RRTs) are heavily involved in the care of individuals infected with COVID-19. The experiences and challenges specific to the RRT profession during the pandemic have not been qualified and the aim of this study is to bridge that gap. Methods: With institutional ethics approval, a cross-sectional survey was created through the survey software Redcap and made available online from 29 May to 6 July 2020. Any RRT working in Canada during the COVID-19 pandemic was eligible to participate. Responses to yes/no questions were calculated as frequencies and percentages, and free-text responses were summarized. Results: In total, 345 RRTs working in 11/13 of the provinces and territories, with varying years of experience completed the survey. The results reflected impacts of the pandemic that affected RRTs in a variety of ways at work, from being reassigned (30.7%) to caring for COVID-19 positive patients (57.4%) and intubated COVID-19 positive patients (50.7%). RRTs experienced communication issues around guidelines (66.7%) and some departments had run out of personal protective equipment (PPE; 19%). RRTs were personally impacted, including feeling overwhelmed by new and frequently changing guidelines (89.6%) and feeling concerned for themselves or their family members becoming infected because of their proximity to COVID-19 positive patients (89%). Discussion: RRTs reported being required to work more during the pandemic. The unpredictability and constantly changing schedules were sources of stress and anxiety. RRTs were faced with issues of overwhelming amounts of new information and had difficulty in disseminating it in a timely manner. Lack of guidance and lack of confidence in the current protocols added to the confusion, anxiety, and stress. RRTs were at the center of many high-risk moments for contracting the virus (intubation, extubation), and PPE shortages were a major challenge reported. RRTs working during the pandemic have been concerned for their own health and the health of their family members. Conclusion: The COVID-19 pandemic adds another layer of stress for RRT professionals who are working in high-risk situations and feel anxious, overwhelmed, and concerned about their personal safety.

Talk to us! Communication is a key factor in improving the comfort of MRI research participants.

CONTEXT: Magnetic resonance imaging (MRI) is an invaluable diagnostic and research tool. Having an MRI scan is not always comfortable and may deter people from taking part in MRI research. Maximizing comfort during scanning will improve participants' experiences and image quality. OBJECTIVE: To define which factors improve comfort during an MRI scan for research by asking people who have participated in MRI research. SETTING AND PARTICIPANTS: People who had participated in MRI research during the past two years were invited, as 'public advisors' to discuss their experiences together and agree on which factors are most important in ensuring comfort while participating in MRI research. RESULTS: Public advisors ranked researcher-participant communication as the most important factor. In response, an example script to guide MRI researchers in communicating with participants was developed through close consultation between research staff, public advisors and the public. This outlines the often-missing information necessary to convey to participants, including explaining the reasons behind instructions, managing expectations, providing reassurance, encouragement and progress updates during scanning. CONCLUSIONS: Drawing upon personal experiences as MRI research participants, public advisors highlighted the importance of effective and on-going researcher communication throughout. The example script may be used as a training tool for researchers to help ensure participants' comfort during scanning. PATIENT AND PUBLIC CONTRIBUTION: All contributors had previously taken part in MRI research. The project was co-designed, co-delivered and co-authored with a public research partner. Public advisors agreed key factors of importance. External public reviewers and public advisors reviewed example script drafts.

Top ten priorities for anesthesia and perioperative research: a report from the Canadian Anesthesia Research Priority Setting Partnership.

PURPOSE: The purpose of the Canadian Anesthesia Research Priority Setting Partnership (CAR PSP) was to identify a top ten list of shared priorities for research in anesthesia and perioperative care in Canada. METHODS: We used the methods of the James Lind Alliance to involve patients, caregivers, healthcare professionals, and researchers in determining the research priorities in Canada. In a first survey, participants submitted questions that they want research to answer about anesthesia and perioperative care. We summarized those responses into a longlist of questions. We reviewed the literature to see if any of those questions were already answered. In a second survey, participants chose up to ten questions from the longlist that they thought were most important to be answered with research. From that list, the highest ranking questions were discussed and assigned a final rank at an in-person workshop. RESULTS: A total of 254 participants submitted 574 research suggestions that were then summarized into 49 questions. Those questions were checked against the literature to be sure they were not already adequately addressed, and in a second survey of those 49 questions, participants chose up to 10 that they thought were most important. A total of 233 participants submitted their priorities, which were then used to choose 24 questions for discussion at the final workshop. At the final workshop, 22 participants agreed on a top ten list of priorities. CONCLUSION: The CAR PSP top ten priorities reflect a wide variety of priorities captured by a broad spectrum of Canadians who receive and provide anesthesia care. The priorities are a tool to initiate and guide patient-oriented research in anesthesia and perioperative care.

RéSUMé: OBJECTIF: L'objectif du Partenariat canadien pour l'établissement des priorités de la recherche en anesthésie (CAR-PSP) était d'établir une liste des dix principales priorités pour la recherche sur les soins anesthésiques et périopératoires au Canada. MéTHODES: Nous avons utilisé la méthodologie de la James Lind Alliance pour impliquer des patients, des aidants, des professionnels de la santé et des chercheurs afin de déterminer quelles étaient les priorités en matière de recherche au Canada. Dans une première enquête, les participants ont envoyé des questions sur les soins anesthésiques et périopératoires auxquelles ils voulaient que la recherche réponde. Nous avons résumé ces envois par une liste exhaustive de questions. Nous avons passé en revue les publications pour voir s'il existait déjà des réponses à ces questions. Dans une deuxième étude, les participants ont choisi dans la liste jusqu'à dix questions qui leur semblaient les plus importantes et pour lesquelles la recherche devrait fournir des réponses. À partir de cette liste, les questions les mieux classées ont été discutées et un classement définitif leur a été attribué au cours d'un atelier où tous les participants étaient présents en personne. RéSULTATS: Au total, 254 participants ont envoyé 574 suggestions de recherche qui ont été résumées en 49 questions. La littérature a été examinée pour s'assurer que ces questions n'avaient pas déjà reçu des réponses adéquates, et dans une seconde étude, les participants ont choisi jusqu'à 10 questions qu'ils jugeaient les plus importantes parmi ces 49 questions. Au total, 233 participants ont communiqué leurs priorités qui ont alors servi à choisir 24 questions ouvertes pour la discussion dans un atelier final. Dans cet atelier, 22 participants se sont mis d'accord sur une liste des dix principales priorités. CONCLUSION: Les dix principales priorités du CAR-PSP sont le reflet d'un grand éventail de priorités venant de Canadiens de tous horizons qui reçoivent ou fournissent des soins d'anesthésie. Ces priorités sont un outil permettant d'entamer et de guider une recherche axée sur le patient dans le domaine des soins anesthésiques et périopératoires.

Good collaborative practice: reforming capacity building governance of international health research partnerships.

In line with the policy objectives of the United Nations Sustainable Development Goals, this commentary seeks to examine the extent to which provisions of international health research guidance promote capacity building and equitable partnerships in global health research. Our evaluation finds that governance of collaborative research partnerships, and in particular capacity building, in resource-constrained settings is limited but has improved with the implementation guidance of the International Ethical Guidelines for Health-related Research Involving Humans by The Council for International Organizations of Medical Sciences (CIOMS) (2016). However, more clarity is needed in national legislation, industry and ethics guidelines, and regulatory provisions to address the structural inequities and power imbalances inherent in international health research partnerships. Most notably, ethical partnership governance is not supported by the principal industry ethics guidelines - the International Conference on Harmonization Technical Requirements for Registration of Pharmaceutical for Human Use (ICH) Good Clinical Practice (ICH-GCP). Given the strategic value of ICH-GCP guidelines in defining the role and responsibility of global health research partners, we conclude that such governance should stipulate the minimal requirements for creating an equitable environment of inclusion, mutual learning, transparency and accountability. Procedurally, this can be supported by i) shared research agenda setting with local leadership, ii) capacity assessments, and iii) construction of a memorandum of understanding (MoU). Moreover, the requirement of capacity building needs to be coordinated amongst partners to support good collaborative practice and deliver on the public health goals of the research enterprise; improving local conditions of health and reducing global health inequality. In this respect, and in order to develop consistency between sources of research governance, ICH-GCP should reference CIOMS ethical guidelines as the established standard for collaborative partnership. Moreover, greater commitment and support should be given to co-ordinate, strengthen and enforce local laws requiring equitable research partnerships and health system strengthening.

Defining Health Research for Development: The perspective of stakeholders from an international health research partnership in Ghana and Tanzania.

OBJECTIVES: The study uses a qualitative empirical method to define Health Research for Development. This project explores the perspectives of stakeholders in an international health research partnership operating in Ghana and Tanzania. METHODS: We conducted 52 key informant interviews with major stakeholders in an international multicenter partnership between GlaxoSmithKline (GSK, Vaccine Developer) and the global health nonprofit organisation PATH and its Malaria Vaccine Initiative program (PATH/MVI, Funder-Development Partner), (RTS, S) (NCT00866619). The respondents included teams from four clinical research centres (two centres in Ghana and two in Tanzania) and various collaborating partners. This paper analyses responses to the question: What is Health Research for Development? RESULTS: Based on the stakeholders' experience the respondents offered many ways of defining Health Research for Development. The responses fell into four broad themes: i) Equitable Partnerships; ii) System Sustainability; iii) Addressing Local Health Targets, and iv) Regional Commitment to Benefit Sharing. CONCLUSION: Through defining Health Research for Development six key learning points were generated from the four result themes: 1) Ensure there is local research leadership working with the collaborative partnership, and local healthcare system, to align the project agenda and activities with local research and health priorities; 2) Know the country-specific context - map the social, health, legislative and political setting; 3) Define an explicit development component and plan of action in a research project; 4) Address the barriers and opportunities to sustain system capacity. 5) Support decentralised health system decision-making to facilitate the translation pathway; 6) Govern, monitor and evaluate the development components of health research partnerships. Overall, equity and unity between partners are required to deliver health research for development.

"You cannot collect data using your own resources and put It on open access": Perspectives from Africa about public health data-sharing.

Data-sharing is a desired default in the field of public health and a source of much ethical deliberation. Sharing data potentially contributes the largest, most efficient source of scientific data, but is fraught with contextual challenges which make stakeholders, particularly those in under-resourced contexts hesitant or slow to share. Relatively little empirical research has engaged stakeholders in discussing the issue. This study sought to explore relevant experiences, contextual, and subjective explanations around the topic to provide a rich and detailed presentation of what it means to different stakeholders and contexts to share data and how that can guide practice and ethical guidance. A qualitative design involving interviews was undertaken with professionals working in public health institutions endowed with data (HDSS), ethics committees, and advisory agencies which help shape health research in Africa. A descriptive form of thematic analysis was used to summarize results into six key themes: (1) The role of HDSSs in research using public health data and data-sharing; (2) Ownership and funding are critical factors influencing data-sharing; (3) Other factors discourage data-sharing; (4) Promoting and sustaining data-sharing; (5) Ethical guidance structures; and (6) Establishing effective guidance. The themes reveal factors regarding the willingness or not to share and an intricate ethical system that current discourse could reflect. Many of the concerns resonate with the literature, but a whole other gamut of people and process issues; commitments, investments, careers, and the right ethical guidance are needed to realize a sustainable goal of reaching 'share' as a default.

A 19-SNP coronary heart disease gene score profile in subjects with type 2 diabetes: the coronary heart disease risk in type 2 diabetes (CoRDia study) study baseline characteristics.

BACKGROUND: The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits. METHODS: Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score. Genetic CHD risk was determined by genotyping 19 single nucleotide polymorphisms (SNPs) using Randox's Cardiac Risk Prediction Array and calculating a gene score (GS). Accuracy of the array was assessed by genotyping a subset of pre-genotyped samples (n = 185). RESULTS: Overall, 10-year CHD risk ranged from 2-72 % but did not differ between the randomisation groups (p = 0.13). The array results were 99.8 % concordant with the pre-determined genotypes. The GS did not differ between the Caucasian participants in the CoRDia SMI plus risk group (n = 66) (p = 0.80) and a sample of UK healthy men (n = 1360). The GS was also associated with LDL-cholesterol (p = 0.05) and family history (p = 0.03) in a sample of UK healthy men (n = 1360). CONCLUSIONS: CHD risk is high in this group of T2D subjects. The risk array is an accurate genotyping assay, and is suitable for estimating an individual's genetic CHD risk. Trial registration This study has been registered at ClinicalTrials.gov; registration identifier NCT01891786.

Characteristics of Complementary and Alternative Medicine (CAM) use among older adults with asthma.

OBJECTIVE: A growing number of asthma patients are using Complementary and Alternative Medicine (CAM). Prior studies have not examined CAM use among the older adult population. METHODS: Data from the 2011 Behavioral Risk Factor Surveillance Survey (BRFSS), a national telephone survey, and the Asthma Call-Back survey (ACBS), a survey conducted among BRFSS individuals reporting asthma, were used for the analyses. The study population consisted of 7685 individuals aged 55 years or older with current asthma. The relationship of CAM use with demographic and asthma outcomes was analyzed using logistic regression. RESULTS: CAM use was reported by 39% (3030). Breathing techniques were the most commonly reported CAM therapy. Demographic factors associated with CAM use include female gender (OR 1.36, p < 0.002), having at least a college education (OR 1.76, p < 0.001), cost barrier to healthcare (OR 1.43, p < 0.001), and living in the West (OR 1.31, p < 0.01). An inverse relationship was noted between income and CAM use. Those who had received an asthma action plan (OR 1.29, p < 0.005), current smokers (OR 1.35, p < 0.02), or impaired asthma control (as defined by symptoms affecting sleep, symptoms limiting activities, and rescue medication use) were more likely to use CAM (OR 1.37, p < 0.001; OR 1.38, p < 0.001; and OR 1.2, p < 0.046, respectively). CONCLUSIONS: A large proportion of asthmatic older adults use CAM. In addition, older adults with asthma who use CAM have decreased asthma control, and further studies are needed to determine a causal role.

Impact of neoadjuvant chemotherapy on axillary nodal involvement in patients with clinically node negative triple negative breast cancer.

BACKGROUND: We evaluated the impact of Neoadjuvant Chemotherapy (NAC) versus primary surgery (PS) on axillary disease burden/surgery in clinically node negative Triple Negative Breast Cancer (TNBC). METHODS: Two hundred forty-three Stage I-III TNBC patients have enrolled on an IRB approved multisite prospective registry. Clinical and treatment information was collected. RESULTS: One hundred fifty-five patients with clinically node negative TNBC were identified. 47%, 49%, and 4% of patients had T1, T2, and T3 disease, respectively. Patients underwent PS (103/155, 66%) or NAC (52/155, 34%) at the discretion of treating physicians. 17% of PS and 0% of NAC patients were node positive at surgery (P=0.006). For T2 disease, 32% of PS and 0% of NAC patients were node positive at surgery (P=0.001). NAC patients had a lower chance of positive SLNB (0% vs. 12%, P=0.004) and undergoing ALND (2% vs. 22%, P=0.001) than PS patients. CONCLUSION: In this clinically node negative TNBC cohort, all NAC-treated patients were node negative at surgery, whereas 17% of PS patients had involved axillary nodes. NAC should be considered for clinically node negative TNBC to reduce the extent of axillary surgery even if breast conservation is not planned.

Treatment of allergic reactions and quality of life among caregivers of food-allergic children.

BACKGROUND: Caregivers of food-allergic individuals (FAIs) have decreased quality of life (QoL). The effects of epinephrine administration on QoL are poorly understood. OBJECTIVE: To investigate the relation between QoL and epinephrine use. METHODS: A de-identified 50-question online survey was administered to caregivers of FAIs across the United States through Web site, email, and social media networks of 2 national food allergy advocacy groups. QoL was assessed using the Food Allergy Quality of Life-Parental Burden questionnaire. The effect of prior epinephrine administration on QoL was analyzed using linear regression. RESULTS: Of 3,541 respondents, 35.6% reported their FAIs received epinephrine. Mean Food Allergy Quality of Life-Parental Burden scores were higher (worse QoL) in those reporting FAIs receiving epinephrine (3.07 vs 2.84, P < .001), anaphylaxis (3.01 vs 2.75, P < .001), multiple food allergies (3.16 vs 2.67, P < .001), and multiple food allergies and epinephrine use (3.24 vs 2.57, P < .001) vs those who did not. In a regression model, reported epinephrine use; anaphylaxis; multiple FAIs; multiple food allergies; and egg or milk, wheat or soy, or seafood allergy (vs peanut or tree nut allergy) were significantly associated with an increased (worse) QoL score. Caregiver college education and increasing FAI age were associated with a decreased QoL score (improved QoL). An interaction was noted between reported epinephrine use and anaphylaxis and was associated with a decreased QoL score. CONCLUSION: The effect of epinephrine use on caregiver QoL is conditional and depends on reaction severity. Having multiple FAIs and FAIs with multiple food allergies was associated with worsening QoL. Further studies are needed to better understand the effects of treating an allergic reaction on caregiver QoL.

Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing.

NCCN guidelines recommend genetic testing for all triple-negative breast cancer (TNBC) patients aged ≤60 years. However, due to the lack of prospective information in unselected patients, these guidelines are not uniformly adopted by clinicians and insurance carriers. The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population. Stage I-IV TNBC patients were enrolled on a prospective registry at academic and community practices. All patients underwent BRCA1/2 testing. Significant family history (SFH) was defined >1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer. Mutation prevalence in the entire cohort and subgroups was calculated. 207 TNBC patients were enrolled between 2011 and 2013. Racial/ethnic distribution: Caucasian (80 %), African-American (14 %), Ashkenazi (1 %). Deleterious BRCA1/2 mutations were identified in 15.4 % (32/207) of patients (BRCA1:11.1 %, BRCA2:4.3 %). SFH reported by 36 % of patients. Mutation prevalence in patients with and without SFH was 31.6 and 6.1 %, respectively. When assessed by age at TNBC diagnosis, the mutation prevalences were 27.6 % (≤50 years), 11.4 % (51-60 years), and 4.9 % (≥61 years). Using SFH or age ≤50 as criteria, 25 and 34 % of mutations, respectively, were missed. Mutation prevalence in patients meeting NCCN guidelines was 18.3 % (32/175) and 0 % (0/32) in patients who did not meet guidelines (p = .0059). In this unselected academic and community population with negligible Ashkenazi representation, we observed an overall BRCA mutation prevalence rate of 15.4 %. BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC.

Developmental Disruption of Mef2c in Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function.

BACKGROUND: MEF2C is strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy of Mef2c, or selectively lacking both copies of Mef2c in cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. METHODS: Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. RESULTS: Loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. CONCLUSIONS: MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.

Developmental disruption of Mef2c in Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function.

MEF2C is strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy of Mef2c , or selectively lacking both copies of Mef2c in cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. We found that loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. Our findings indicate that MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response.

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment, hypoxia is known to drive malignant progression. Our study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold (DSF) chambers were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide-treated and vehicle-only-treated tumours were re-established in vitro, and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2 mg/kg/day) decreased tumour oxygenation by 45% within 24 hr, reaching a nadir of 0.09% oxygen (0.67 ± 0.06 mmHg) by Day 7; this persisted until Day 14 when it increased up to Day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at Days 7 and 14 with revascularisation occurring by Day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50 mg/kg, single dose) caused greater tumour growth delay than bicalutamide alone. Our study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit.

An In Vivo Platform for Rebuilding Functional Neocortical Tissue.

Recent progress in cortical stem cell transplantation has demonstrated its potential to repair the brain. However, current transplant models have yet to demonstrate that the circuitry of transplant-derived neurons can encode useful function to the host. This is likely due to missing cell types within the grafts, abnormal proportions of cell types, abnormal cytoarchitecture, and inefficient vascularization. Here, we devised a transplant platform for testing neocortical tissue prototypes. Dissociated mouse embryonic telencephalic cells in a liquid scaffold were transplanted into aspiration-lesioned adult mouse cortices. The donor neuronal precursors differentiated into upper and deep layer neurons that exhibited synaptic puncta, projected outside of the graft to appropriate brain areas, became electrophysiologically active within one month post-transplant, and responded to visual stimuli. Interneurons and oligodendrocytes were present at normal densities in grafts. Grafts became fully vascularized by one week post-transplant and vessels in grafts were perfused with blood. With this paradigm, we could also organize cells into layers. Overall, we have provided proof of a concept for an in vivo platform that can be used for developing and testing neocortical-like tissue prototypes.

Polymer-Induced Drag Reduction in Dilute Newtonian and Semi-Dilute Non-Newtonian Fluids: An Assessment of the Double-Gap Concentric Cylinder Method.

Polymer-induced drag reduction (DR) in fluids was studied using a rotational rheometer with double-gap concentric cylinder geometry. Although both polymers (polyacrylamide (PAM) and 2-acrylamido-2-methylpropane sulfonic acid (SPAM)) had molecular weights of several MDa, the contrasting polymer charge, nonionic and anionic, led to different polymer overlap concentrations (c*), PAM ≫ SPAM, and fluid rheology, with PAM fluids mostly Newtonian and SPAM fluids non-Newtonian (shear-thinning). Based on these differences, it was important to account for the infinite shear viscosity and normalize the polymer concentration by the intrinsic concentration (c int) so that the DR performance of the two polymer fluids could be accurately compared. Both polymers induced DR, and the maximum DR by SPAM (DR% = 28) was slightly higher than that by PAM (DR% = 22) when Re p ∼ 1700. For PAM, the loss of DR with time diminished at higher polymer concentrations (≥100 ppm, at Re p = 3149) but was found to be sensitive to high Re p, with polymer chain scission the likely cause of the reduced performance. For the semi-dilute SPAM fluids, the shear stability contrasted that of PAM, showing negligible dependence on the polymer concentration and Re p. The apparent rapid loss of DR was predominantly attributed to a time-dependent effect and not polymer degradation. In pipe flow, the maximum DR for SPAM was higher than that measured by rheometry and was attributed to differences in the flow conditions. However, changes in the normalized DR/c with polymer concentration were found to be consistent between the two flow geometries. Furthermore, the high fluid stresses in pipe flow (at high Re p) led to drag reduction losses consistent with PAM, as the time-dependent effect was not seen.

Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity.

BACKGROUND: Proteolytic enzymes have been implicated in driving tumor progression by means of their cancer cell microenvironment activity where they promote proliferation, differentiation, apoptosis, migration, and invasion. Therapeutic strategies have focused on attenuating their activity using small molecule inhibitors, but the association of proteases with the cell surface during cancer progression opens up the possibility of targeting these using antibody dependent cellular cytotoxicity (ADCC). Cathepsin S is a lysosomal cysteine protease that promotes the growth and invasion of tumour and endothelial cells during cancer progression. Our analysis of colorectal cancer patient biopsies shows that cathepsin S associates with the cell membrane indicating a potential for ADCC targeting. RESULTS: Here we report the cell surface characterization of cathepsin S and the development of a humanized antibody (Fsn0503h) with immune effector function and a stable in vivo half-life of 274 hours. Cathepsin S is expressed on the surface of tumor cells representative of colorectal and pancreatic cancer (23%-79% positive expression). Furthermore the binding of Fsn0503h to surface associated cathepsin S results in natural killer (NK) cell targeted tumor killing. In a colorectal cancer model Fsn0503h elicits a 22% cytotoxic effect. CONCLUSIONS: This data highlights the potential to target cell surface associated enzymes, such as cathepsin S, as therapeutic targets using antibodies capable of elicitingADCC in tumor cells.

The positive and the negative impacts of spasticity in patients with long-term neurological conditions: an observational study.

PURPOSE: To describe the positive and negative impacts of spasticity across different neurological disorders using the Patient Reported Impact of Spasticity Measure (PRISM), deduce any associations between severity of spasticity and its impact, and assess for differences across diagnostic subgroups. MATERIALS AND METHODS: PRISM, a spasticity-specific quality of life questionnaire validated in patients with spinal cord injuries, was given to 97 follow-up patients attending a spasticity clinic prior to symptom assessment using the REsistance to PAssive movement Scale (REPAS). RESULTS: Patients described a minor level of positive impact and a marked negative impact in the domains of "Psychological Agitation," "Daily Activities," "Need for Assistance/Positioning" and "Social Avoidance/Anxiety." Spasticity severity was, in general, a poor predictor of perceived impact, although severity and localisation of spasticity was modestly correlated with "Need for Assistance/Positioning" and "Social Embarrassment" levels. Despite comparable levels of spasticity severity, people with MS expressed a more substantial impact across some PRISM domains than did patients in other groups. CONCLUSION: PRISM can be useful to assess the impact of spasticity in various neurological conditions although further validation studies are needed.Implications for RehabilitationThe localisation of spasticity in both legs or the right arm can produce a significant impact on 'Need for Assistance/Positioning' and 'Social Embarrassment'.People with MS may experience a greater impact of spasticity than those with other neurological conditions, particularly in the domains of Social Avoidance/Anxiety and Psychological Agitation.Coexisting factors such as anxiety, depression, fatigue and pain should be investigated together with spasticity.PRISM can assist in goal setting and treatment of people with spasticity secondary to different neurological conditions.