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Several studies have examined the effect of different types of exercise on people with fibromyalgia. The aim of this study was to identify which dosage of resistance training is effective to reduce pain in women with fibromyalgia. Two authors independently selected studies included in a Cochrane Systematic Review and from an updated search up to May 2021 using the following databases: Embase, Central, Lilacs, PEDro, Current Controlled Trials, and WHO International Clinical Trials Registry Platform, Scopus and ISI Web of Science. Inclusion criteria were randomized clinical trials (RCTs) with female patients (18 years of age or older) diagnosed with fibromyalgia according to the American College of Rheumatology (ACR) criteria and the intervention, resistance exercises for pain reduction. The pain outcome value was extracted from studies for meta-analysis. Nine RCTs were included. Compared to the control groups, resistance exercise groups demonstrated a clinically and statistically significant effect on pain reduction when each exercise was performed in 1–2 sets or 3–5 sets of 4–12 or 5–20 repetitions twice a week, for 8–12 weeks, at intensities of 40–80% with one repetition maximum or perceived exertion. Resistance training exercises are effective to reduce pain in women with fibromyalgia when performed at moderate-to-high intensity in 1–2 sets of 4–20 repetitions twice a week, for 8–12 weeks. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) platform, CRD42018095205. [ABSTRACT FROM AUTHOR]

Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of l-arginine to l-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been pursued across several disease areas including immunology, oncology, nervous system dysfunction, and cardiovascular dysfunction and diseases. Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size. Here we report the cryo-electron microscopy structures of potent and inhibitory anti-hArg antibodies bound to hArg1 which form distinct macromolecular complexes that are greater than 650 kDa. With local resolutions of 3.5 Å or better we unambiguously mapped epitopes and paratopes for all five antibodies and determined that the antibodies act through orthosteric and allosteric mechanisms. These hArg1:antibody complexes present an alternative mechanism to inhibit hArg1 activity and highlight the ability to utilize antibodies as probes in the discovery and development of peptide and small molecule inhibitors for enzymes in general. Palte et al provide cryo-EM structures of five potent and inhibitory monoclonal antibodies bound to human Arginase 1, a T-cell modulating metalloenzyme and a cancer drug target. They provide structural insights that will aid in the evaluation of these antibodies as therapeutic inhibitors of arginasemediated T-cell suppression. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is highly comorbid with psychological symptoms in veterans, particularly post-traumatic stress disorder (PTSD), depression, and anxiety. Obese veterans with comorbid psychological symptoms often display suboptimal weight loss and poor physical functioning when participating in weight management programs. The MOVE! program aims to increase healthy eating and physical activity to promote weight loss in obese veterans. Adequately addressing psychological barriers is necessary to maximize outcomes in MOVE! for veterans with PTSD, depression, and anxiety. We examined the preliminary outcomes of administering the Healthy Emotions and Improving Health BehavioR Outcomes (HERO) intervention. HERO is adjunctive cognitive-behavioral therapy to MOVE! that addresses PTSD, depression, and anxiety symptom barriers to engagement in physical activity.Materials and Methods: All recruitment and study procedures were approved by the institutional review board and research and development committees of the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine in Houston, Texas. Participants gave written informed consent before enrollment. Thirty-four obese veterans with a diagnosis of PTSD, depression, and/or anxiety who were attending MOVE! were assigned to the 8-session HERO group or the usual care (UC) group. Veterans completed assessments of PTSD, depression and anxiety symptoms, physical activity, physical functioning, and weight at baseline, 8 and 16 weeks post treatment. Changes from baseline to 8- and 16-week follow-up on the self-report and clinician-rated measures were assessed, using independent samples t-tests and analyses of covariance.Results: At 8 weeks post treatment, participants in the HERO group had significantly higher step counts per day than participants in the UC group. Similarly, at 16 weeks post-treatment, participants in the HERO group continued to experience a significant increase in daily steps taken per day, as well as statistically and clinically significantly lower scores on the depression symptom and PTSD symptom severity. Participants in the HERO group also demonstrated significantly higher scores on the physical functioning inventory than participants in the UC group (44.1 ± 12.1 vs. 35.7 ± 10.7, P = 0.04) at 16 weeks post treatment.Conclusions: Findings of this small trial have important implications pending replication in a more rigorously designed large-scale study. Providing an adjunctive treatment to MOVE! that addresses psychological distress has potential benefits for psychological symptom reduction, engagement in healthy dietary habits, and greater physical activity for individuals who traditionally experience barriers to making positive weight management changes. [ABSTRACT FROM AUTHOR]

Myc, a transcription factor with oncogenic activity, is upregulated by amplification, translocation, and mutation of the cellular pathways that regulate its stability. Inhibition of the Myc oncogene by various modalities has had limited success. One Myc inhibitor, Omomyc, has limited cellular and in vivo activity. Here, we report a mini‐protein, referred to as Mad, which is derived from the cellular Myc antagonist Mxd1. Mad localizes to the nucleus in cells and is 10‐fold more potent than Omomyc in inhibiting Myc‐driven cell proliferation. Similar to Mxd1, Mad also interacts with Max, the binding partner of Myc, and with the nucleolar upstream binding factor. Mad binds to E‐Box DNA in the promoters of Myc target genes and represses Myc‐mediated transcription to a greater extent than Omomyc. Overall, Mad appears to be more potent than Omomyc both in vitro and in cells. [ABSTRACT FROM AUTHOR]

The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo. [ABSTRACT FROM AUTHOR]

Variovorax paradoxus is a microorganism of special interest due to its diverse metabolic capabilities, including the biodegradation of both biogenic compounds and anthropogenic contaminants. V. paradoxus also engages in mutually beneficial interactions with both bacteria and plants. The complete genome sequence of V. paradoxus S110 is composed of 6,754,997 bp with 6,279 predicted protein-coding sequences within two circular chromosomes. Genomic analysis has revealed multiple metabolic features for autotrophic and heterotrophic lifestyles. These metabolic diversities enable independent survival, as well as a symbiotic lifestyle. Consequently, Sll0 appears to have evolved into a superbly adaptable microorganism that is able to survive in ever-changing environmental conditions. Based on our findings, we suggest V. paradoxus S110 as a potential candidate for agrobiotechnological applications, such as biofertilizer and biopesticide. Because it has many associations with other biota, it is also suited to serve as an additional model system for studies of microbe-plant and microbe-microbe interactions. [ABSTRACT FROM AUTHOR]

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome. [ABSTRACT FROM AUTHOR]

The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T cell development and in the pathogenesis over 50% of human T cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward-loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by down-regulated biosynthetic pathway genes. By integrating gene expression array and ChiP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC. [ABSTRACT FROM AUTHOR]

Abstract: Previous work has demonstrated that computer functions can be controlled by eye movements recorded with the use of vertical and horizontal electrooculography (EOG). In the present study, an attempt was made to show that this newly developed task could be disrupted by dual-task demands and, therefore, would follow conventional principles of multiple-task performance. Fifteen participants performed the eye movement task under two conditions—control and divided attention. It was found that the time to process letters was significantly longer in the divided attention condition than in the control condition and that males and females showed comparable performance decrements in the divided attention condition. A task that utilizes eye movements to control computer operations for syntax construction follows the same principles of limited resource allocation of attention as more conventional perceptual-motor tasks such as reaction time and manual control of computer functions. [Copyright &y& Elsevier]

Background: Telerehabilitation (TR) has emerged as a feasible and promising approach for delivering rehabilitation services remotely, utilizing technology to bridge the gap between healthcare providers and patients. As new modalities of virtual care and health technologies continue to emerge, it is crucial to stay informed about the growing landscape of virtual care to ensure that telehealth service delivery is ethical and equitable, and improves the quality of services and patient outcomes., Objective: The primary objective of this article is to present the protocol of a rapid review to examine the equity-related aspects surrounding the implementation of TR. This includes a comprehensive analysis of the ethical dimensions and fairness concerns linked to this practice., Methods: A rapid review protocol was developed in accordance with Cochrane Rapid Reviews Methods Guidance. Medline and EMBASE databases were searched between January 2010 and March 2023. Study selection and data extraction will be conducted in two phases (Phase I) by two independent reviewers and subsequently (Phase II) by a single reviewer. Our study will utilize the PROGRESS-Plus and Equitable virtual rehabilitation in the metaverse era framework to identify dimensions where potential inequities may exist within TR interventions., Results: This rapid review is anticipated to enhance our knowledge of TR in the fields of physiotherapy and occupational therapy, with a specific focus on its influence on ethical and equitable practices and providing a foundation for informed decision-making and improved patient care., Conclusion: This rapid review will contribute to the advancement of our understanding of TR within physiotherapy and occupational therapy. Through synthesizing existing evidence, this study not only addresses current gaps in knowledge but also offers valuable insights for future research and clinical practice in TR services., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Purpose: The study aimed to examine the reporting completeness of randomized controlled trials (RCTs) of non-pharmacological interventions following concussion., Methods: We searched MEDLINE, Embase, PsycInfo, CINAHL, and Web of Science up to May 2022. Two reviewers independently screened studies and assessed reporting completeness using the Template for Intervention Description and Replication (TIDieR), Consensus on Exercise Reporting Template (CERT), and international Consensus on Therapeutic Exercise aNd Training (i-CONTENT) checklists. Additional information was sought my study authors where reporting was incomplete. Risk of bias (ROB) was assessed with the Cochrane ROB-2 Tool. RCTs examining non-pharmacological interventions following concussion., Results: We included 89 RCTs (n = 53 high ROB) examining 11 different interventions for concussion: sub-symptom threshold aerobic exercise, cervicovestibular therapy, physical/cognitive rest, vision therapy, education, psychotherapy, hyperbaric oxygen therapy, transcranial magnetic stimulation, blue light therapy, osteopathic manipulation, and head/neck cooling. Median scores were: TIDieR 9/12 (75%; interquartile range (IQR) = 5; range: 5-12), CERT 17/19 (89%; IQR = 2; range: 10-19), and i-CONTENT 6/7 (86%; IQR = 1; range: 5-7). Percentage of studies completely reporting all items was TIDieR 35% (31/89), CERT 24% (5/21), and i-CONTENT 10% (2/21). Studies were more completely reported after publication of TIDieR (t 87  = 2.08; p = 0.04) and CERT (t 19  = 2.72; p = 0.01). Reporting completeness was not strongly associated with journal impact factor (TIDieR: r s  = 0.27; p = 0.01; CERT: r s  = -0.44; p = 0.06; i-CONTENT: r s  = -0.17; p = 0.48) or ROB (TIDieR: r s  = 0.11; p = 0.31; CERT: r s  = 0.04; p = 0.86; i-CONTENT: r s  = 0.12; p = 0.60)., Conclusion: RCTs of non-pharmacological interventions following concussion demonstrate moderate to good reporting completeness, but are often missing key components, particularly modifications, motivational strategies, and qualified supervisor. Reporting completeness improved after TIDieR and CERT publication, but publication in highly cited journals and low ROB do not guarantee reporting completeness., Competing Interests: Competing interests JJvI reported being the founder of R2P Concussion Management. RM reported receiving research funds from grants from the National Institutes of Health, the Department of Defense, the National Football League and Abbott Laboratories. KOY reported receiving grant funding from the Canadian Institutes of Health Research (CIHR), book royalties (Guilford Press and Cambridge University Press), and editorial stipend from American Psychological Association, as well as funding through the Ronald and Irene Ward Chair in Pediatric Brain Injury funded by the Alberta Children's Hospital Foundation. RZ reported receiving competitively-funded research grants from CIHR, Ontario Neurotrauma Foundation, Physician Services Incorporated Foundation, Children's Hospital of Eastern Ontario Foundation, Ontario Brain Institute, Ontario SPOR Support Unit, and the National Football League Scientific Advisory Board. He holds a Clinical Research Chair in Pediatric Concussion from University of Ottawa, and is on the concussion advisory board for Parachute Canada (a non-profit injury prevention charity), and is the co-founder, Scientific Director and a minority shareholder in 360 Concussion Care. All the support had no involvement in the study design and writing of the manuscript or the decision to submit it for publication., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Introduction . A fall may impact a person's physical, emotional, and psychological well-being. Fall prevention programs are being implemented to reduce these negative outcomes. However, linguistic barriers in health services may reduce access to such prevention programs. A telehealth fall prevention program was designed to increase access to such programs in French for Francophone minority communities in Canada. This capacity-building project aimed to support community partners to deliver this telehealth program and document strategies used to reach, adopt, and implement the program within various Francophone and Acadian Minority Communities. Methods . A sequential explanatory mixed methodology was used to document reach, adoption, and implementation strategies and describe the lived experiences of program facilitators and organization representatives. Reach, adoption, and implementation were documented and analyzed descriptively, while lived experiences were analyzed using content analysis following the Consortium Framework for Implementation Research. Results . Twelve organization representatives or program facilitators from eight organizations operating in four different provinces participated in the study. Three themes emerged from the qualitative data on reach and adoption: external context, internal context, and capacity building. Four themes were identified as barriers and facilitators to implementation: level of preparation and time management, interpersonal relations and telepresence, exercise facilitation and safety, and technological problem-solving. Conclusion . Using tailored reach and adoption strategies such as prioritizing provinces with higher proportions of needs and training local community program facilitators may lead to the successful implementation of a new telehealth fall prevention program. Results from this study could potentially inform other primary prevention programs or telehealth program implementation.

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment-associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb., Methods: XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcγRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity., Results: Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system., Conclusions: These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies., Competing Interests: Competing interests: KAJ, MP-R, UE, PJ, WG, MM, DM-L, CO’T, ZL, BN, HQ, TC, RCO’H, MK, and JO’N report personal fees from Xilio Therapeutics during the conduct of the study. UR and JCW are co-founders, shareholders, and consultants to Xilio Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: According to Self-Determination Theory, the fulfillment of basic psychological needs of autonomy, competence, and relatedness plays an important role in one's motivation, engagement, and well-being. How a therapist is perceived to support or thwart these needs can impact adherence to treatment, thus influencing the effectiveness of therapeutic interventions., Objectives: This alternating single-subject design explores how the physiotherapist self-reports interpersonal behaviors, how the person living with a disability (PwD) perceives the physiotherapist's supportive/thwarting interpersonal behaviors, and how the two align in the context of telerehabilitation., Methods: Five PwD and their physiotherapist completed two telerehabilitation exercise programs. The PwD completed the Interpersonal Behavior Questionnaire (IBQ) to examine how they perceived the physiotherapist interpersonal behaviors. The physiotherapist completed the Interpersonal Behavior Questionnaire-Self (IBQ-Self) to document how they self-reported these same behaviors. Descriptive statistics were used to document self-reports and perceptions of behaviors., Results: Each PwD perceived the physiotherapist as being more supportive than thwarting. The supportive/thwarting behaviors varied across relationships. Greater alignment of the perceptions of therapist and the PwD was observed at the end of the programme when compared to baseline., Conclusion: Assessing how therapist support/thwart psychological needs and how these behaviors are perceived by PwD is recommended as it may influence the therapist's behavior and the PwD's adherence to future telerehabilitation exercise programs.

Background: The clinical adoption of telerehabilitation accelerated rapidly over the last few years, creating opportunities for clinicians and researchers to explore the use of digital technologies and telerehabilitation in the assessment of deficits related to neurological conditions. The objectives of this scoping review were to identify outcome measures used to remotely assess the motor function and participation in people with neurological conditions and report, when available, the psychometric data of these remote outcome measures., Methods: MEDLINE (Ovid), CINAHL, PubMed, PsychINFO, EMBASE, and Cochrane databases were searched between December 13, 2020, and January 4, 2021, for studies investigating the use of remote assessments to evaluate motor function and participation in people with neurological conditions. An updated search was completed on May 9, 2022, using the same databases and search terms. Two reviewers independently screened each title and abstract, followed by full-text screening. Data extraction was completed using a pre-piloted data extraction sheet where outcome measures were reported as per the International Classification of Functioning, Disability and Health., Results: Fifty studies were included in this review. Eighteen studies targeted outcomes related to body structures and 32 targeted those related to activity limitation and participation restriction. Seventeen studies reported psychometric data; of these, most included reliability and validity data., Conclusion: Clinical assessments of motor function of people living with neurological conditions can be completed in a telerehabilitation or remote context using validated and reliable remote assessment measures., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Many individuals who experience a moderate or severe traumatic brain injury (TBI) have long-term deficits in physical activity, balance, and mobility requiring specialized care. New delivery models are being investigated for interventions to address challenges caused by living in remote communities, difficulties with transportation, and/or physical distancing requirements. Determining the effectiveness of telerehabilitation is critical given the current movement toward remote health care delivery., Objective: We investigated the effectiveness of two teletherapy supervision schedules used to deliver a home-based, intensive exercise programme on 1) physical activity, mobility, balance, participation, and 2) concerns with falling, and satisfaction with life., Methods: A mixed methods approach with alternating single subject design (SSD) and interviews was used. Five individuals who experienced a moderate or severe TBI completed two intensive home-based telerehabilitation programmes. Programmes differed only by supervision schedule - daily or weekly. Impacts on objective and patient-reported outcomes were measured., Results: Four individuals demonstrated clinically significant improvements in physical activity level, balance, and mobility. One individual experienced less concerns with falling after both schedules, while two other individuals showed a trend in that direction after the weekly remote supervision. Important functional gains (i.e., improved balance and decreased fatigue) were also perceived and reported by family partners regardless of supervision schedule., Conclusion: Although the study has limitations, the findings indicate that exercise programmes delivered via telerehabilitation can improve balance and mobility as well as positively affect concerns with falling and physical activity levels for this population. No clear differences were seen between the two telerehabilitation supervision schedules., Competing Interests: Competing Interests: None declared., (© Canadian Physiotherapy Association, 2023.)

Purpose: Further investigation into the feasibility of using videoconferencing and activity tracking devices to provide high-intensity home-based exercise programmes for people with a moderate or severe traumatic brain injury (TBI) is needed to inform clinical implementation and patient adoption. This study aimed to (1) determine if home-based telerehabilitation exercise programmes were feasible for people with a moderate or severe TBI and (2) better understand the lived experience of people with a TBI and their family partners with this programme., Methods: A mixed-methods approach consisting of measures of feasibility and semi-structured interviews was used. Five participants with moderate to severe TBI and their family partners completed two high-intensity home-based exercise programmes delivered remotely by a physiotherapist (i.e., daily and weekly)., Results: Telerehabilitation services in home-based settings were feasible for this population. Adherence and engagement were high. Dyads were satisfied with the use of technology to deliver physiotherapy sessions., Conclusion: Telerehabilitation provides a delivery option that allows people with TBI to spend energy on therapy rather than on travelling. A pre-programme training on key components, such as the use of technology, safety precautions, and communication methods, likely improved the overall feasibility. Further research is needed to better understand the effectiveness of such a programme on balance, mobility, and physical activity levels., Competing Interests: Competing Interests: None declared., (© Canadian Physiotherapy Association, 2023.)

Objective: To examine clinician perspectives regarding the use of telehealth for concussion assessment and management., Setting: A Pan-Canadian survey., Participants: Twenty-five purposively sampled multidisciplinary clinician-researchers with concussion expertise (female, n = 21; physician, n = 11; and other health professional, n = 14)., Design: Sequential mixed-method design: (1) electronic survey and (2) semistructured interviews with focus groups via videoconference. Qualitative descriptive design., Main Outcome Measures: Survey : A 59-item questionnaire regarding the suitability of telehealth to perform recommended best practice components of concussion assessment and management. Focus groups : 10 open-ended questions explored survey results in more detail., Results: Clinicians strongly agreed that telehealth could be utilized to obtain a clinical history (96%), assess mental status (88%), and convey a diagnosis (83%) on initial assessment; to take a focused clinical history (80%); to monitor functional status (80%) on follow-up; and to manage symptoms using education on rest (92%), planning and pacing (92%), and sleep recommendations (91%); and to refer to a specialist (80%). Conversely, many clinicians believed telehealth was unsuitable to perform a complete neurologic examination (48%), cervical spine (38%) or vestibular assessment (61%), or to provide vestibular therapy (21%) or vision therapy (13%). Key benefits included convenience, provision of care, and patient-centered approach. General and concussion-specific challenges included technology, quality of care, patient and clinician characteristics, and logistics. Strategies to overcome identified challenges are presented., Conclusions: From the perspective of experienced clinicians, telehealth is suited to manage symptomatic concussion patients presenting without red flags or following an initial in-person assessment, but may have limitations in ruling out serious pathology or providing return-to-sport clearance without an in-person physical examination., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Inhaled medications are widely accepted as being the optimal route for treating pediatric respiratory diseases, a leading cause of hospitalization and death. Despite jet nebulizers being the preferred inhalation device for neonates and infants, current devices face performance issues with most of the drug never reaching the target lung location. Previous work has aimed to improve pulmonary drug deposition, yet nebulizer efficiency remains low. The development of an inhalant therapy that is efficacious and safe for pediatrics depends on a well-designed delivery system and formulation. To accomplish this, the field needs to rethink the current practice of basing pediatric treatments on adult studies. The rapidly evolving pediatric patient (i.e. neonates to eighteen) needs to be considered because they are different from adults with respect to airway anatomy, breathing patterns, and adherence. Previous research approaches to improve deposition efficiency have been limited due to the complexity of combining physics, which drives aerosol transport and deposition, and biology, especially within the area of pediatrics. To address these critical knowledge gaps, we need a better understanding of how patient age and disease state affect deposition of aerosolized drugs. The complexity of the multiscale respiratory system makes scientific investigation very challenging. The authors have simplified the complex problem into five components with these three areas as ones to address first: how the aerosol is (i) generated in a medical device, (ii) delivered to the patient, and (iii) deposited inside the lung. In this review, we discuss the technological advances and innovations made from experiments, simulations, and predictive models in each of these areas. In addition, we discuss the impact on patient treatment efficacy and recommend a clinical direction, with a focus on pediatrics. In each area, a series of research questions are posed and steps for future research to improve efficacy in aerosol drug delivery are outlined., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Produce a French-Canadian translation of AMSTAR 2, affirm its content validity, and examine interrater reliability. Methods: Based on Vallerand's methodological approach, we conducted forward and parallel inverse-translations. Subsequently, an expert panel evaluated the translations to create a preliminary experimental French-Canadian version. A second expert panel examined this version and proposed additional modifications. Twenty future health professionals then rated the second experimental version for ambiguity on a scale (from 1 to 7). The principal co-investigators then reviewed the problematic elements and proposed a pre-official version. To ascertain content validity, a final back-translation was conducted resulting in the official version. Four judges evaluated 13 systematic reviews using the official French-Canadian version of AMSTAR 2. The Kappa coefficient was used to evaluate interrater reliability. Results: This rigorous adaptation enabled the development of a Franco-Canadian version of AMSTAR 2. Its application demonstrated low ambiguity (mean 1.15; SD 0.26) as well as good overall interrater reliability (total κ > 0.64) across all items. Conclusion: The French-Canadian version of AMSTAR 2 can now support francophone clinicians, educators, and managers in Canada as they undertake evidence-based practice., (© Canadian Physiotherapy Association.)

Purpose of Review: Studying the outcomes of congenital heart disease and their associations allows paediatric cardiologists and intensivists to improve the care and health equity of their patients. This review presents the most recent literature discussing the socioeconomic and racial disparities that pervade the outcomes of patients with congenital heart disease in every facet of treatment. The outcomes of congenital heart disease discussed are prenatal detection, maintenance of care, quality of life, neurodevelopment and mortality., Recent Findings: Historically, it has been documented that patients with congenital heart disease who are of racial and ethnic minorities disproportionately experience poor outcomes. Recently, the association between racial minorities and mortality has been traced to underlying socioeconomic disparities emphasizing that race and ethnicity are not independent determinants of health., Summary: The effect of socioeconomic status on the outcomes of congenital heart disease is profound and reaches beyond the association with racial and ethnic minorities. Changes to address these disparities in outcomes must be made at the individual, institutional, community and system levels., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The COVID-19 global pandemic pushed many rehabilitation practitioners to pivot their in-person practice to adopt telerehabilitation as their main method of delivery. In addition to documenting information on interventions used with clients, it is best practice for therapists to use reliable and validated outcome measures to inform their interventions., Objective: Through this scoping review, we aim to identify (1) which outcomes are being used remotely to assess balance, mobility, and gait in patients with neurological conditions, and (2) what psychometric data (validity, reliability, etc.) for remotely administered outcomes are available., Methods: Three main concepts will be included in our search: (1) neurological conditions; (2) administration by telerehabilitation; and (3) outcome measures for balance, mobility, and gait. Studies reporting remote assessment of neurological conditions published since 1990 will be included. The database search will be completed in MEDLINE (Ovid), CINAHL, PubMed, PsycINFO, EMBASE, and Cochrane. Gray literature including dissertations, conference papers, and protocol papers will also be sourced. Two reviewers will independently screen each title and abstract using pre-established inclusion and exclusion criteria. Manuscripts that appear to meet the criteria will be subject to further review, and full-text extraction using a pre-piloted extraction sheet if all criteria are met. The data will be categorized by assessment types describing impairments (such as balance, strength, and mobility) or activity limitations or participation restriction (such as functional mobility, ambulatory functions, and activities of daily living)., Results: This scoping review will document outcome measures currently used in the remote assessment of neurological conditions. To date, 235 titles and abstracts were screened. We are in the process of finalizing the full text screening for the inclusion of articles. We expect the full screening to be completed in November 2021 and data analysis in January 2022. Our results are expected to be published in early 2022., Conclusions: The optimal use of telerehabilitation as a mode to deliver rehabilitation intervention should be coupled with the completion of validated outcome measures. Therefore, it is crucial to further our knowledge on remote outcome measures and therapeutic assessments., International Registered Report Identifier (irrid): PRR1-10.2196/27186., (©Jennifer O'Neil, Keely Barnes, Erin Morgan Donnelly, Lisa Sheehy, Heidi Sveistrup. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 09.12.2021.)

Purpose: To explore the experiences of adults with persistent postconcussion symptoms and clinicians to inform the development of a concussion-specific questionnaire., Methods: Using a qualitative descriptive design, we conducted 10 focus groups with persons with persistent post-concussion symptoms ( n  = 35; female 66%; age range 19.0-65.1 years) and semi-structured interviews with clinicians with concussion expertise ( n  = 16; female 81%). Thematic analysis was used to identify themes within their narratives. The International Classification of Functioning, Disability and Health (ICF) provided a standardized language for coding., Results: Three overarching themes emerged from the data: Functioning , Environmental and Personal Factors , and Capacity . Functioning mapped closely onto Activities and Participation within the ICF. Contextual factors, both Environmental and Personal , had a significant influence on functioning following concussion. Capacity was a unique finding that described how long a person is able to engage in a task before the onset or worsening of symptoms., Conclusions: Capacity is fundamental to measuring limitations in functioning based on symptom threshold and time to recovery. The impact of contextual factors on functioning needs to be considered on a continuum from barrier to facilitator. These findings provide the basis for the development of a concussion-specific questionnaire.Implications for RehabilitationClinicians should explore with their patients limitations across all areas of functioning.Clinicians should explore and address support and relationships, attitudes of others, access to affordable and high-quality healthcare, coping strategies, and a patient's own knowledge of concussion as these influence functioning.Current guidelines recommend a symptom-based approach to concussion management, whereas persons with concussion emphasize the importance of measuring functional capacity.Capacity is defined as the length of time one can perform a task before symptom onset, primarily fatigue.Currently, no concussion-specific measure of functioning exists.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a , 18 , and 27 , demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Introduction: A variety of exercise programs are recognized to be effective for the management of hand osteoarthritis (HOA). It is important to report the essential elements of these exercise programs for clinicians to replicate properly and facilitate their implementation with individuals who suffers from HOA, especially if they are found to be effective programs., Purpose of the Study: The objective of this article was to assess content reporting using three exercise reporting standardized assessment tools among exercise interventions randomized controlled trials (RCTs) involving individuals with HOA., Study Design: A descriptive study was used., Methods: Two pairs of trained assessors independently identified, selected, and scored the reporting quality of the exercise programs of RCTs on the management of HOA using three standardized assessment tools: the Consensus on Exercise Reporting Template (CERT) checklist, Consensus on Therapeutic Exercise Training (CONTENT) scale, and Template for Intervention Description and Replication (TIDieR) checklist to review the quality of reporting of 11 RCTs included in a recent Ottawa Panel guideline., Results: Based on consensus reached by two different pairs of reviewers and an arbitrator, the mean total scores for the 11 included exercise programs were reported as follows: the mean total score for the CERT, CONTENT, and TIDieR was 10.58/19 ± 4.34, 3.27/9 ± 1.90, and 5.92/12 ± 2.54, respectively. The overall Pearson's Correlation (r) between the methodological quality and intervention reporting was 0.86, 0.71, and 0.54 for moderate-to-high RCTs and 0.47, 0.79, and 0.42 for fair-to-poor methodological quality for the CERT checklist, CONTENT scale, and TIDieR checklist, respectively., Conclusions: The intervention reporting in the management of HOA is poor among low-, moderate-, and high-quality clinical trials. The least reported information was intervention parameters related to behavior change. Improving reporting is recommended to ensure replication of effective exercise programs to enhance quality of life of individuals with HOA., (Copyright © 2020 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.)

The ability to target specific proteins for degradation may open a new door toward developing therapeutics. Although effort in chemistry is essential for advancing this modality, i.e., one needs to generate proteolysis targeting chimeras (bifunctional molecules, also referred to as PROTACS) or "molecular glues" to accelerate protein degradation, we suspect that investigations could also benefit by directing attention toward physiological regulation surrounding protein homeostasis, including the methods that can be used to examine changes in protein kinetics. This perspective will first consider some metabolic scenarios that might be of importance when one aims to change protein abundance by increasing protein degradation. Specifically, could protein turnover impact the apparent outcome? We will then outline how to study protein dynamics by coupling stable isotope tracer methods with mass spectrometry-based detection; since the experimental conditions could have a dramatic effect on protein turnover, special attention is directed toward the application of methods for quantifying protein kinetics using in vitro and in vivo models. Our goal is to present key concepts that should enable mechanistically informed studies which test targeted protein degradation strategies.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3 , when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Purpose: Despite the benefits of well-child care visits, up to one-half of these visits are missed. Little is known about why children miss them, so we undertook a qualitative study to elucidate these factors., Methods: We interviewed 17 caregivers whose children had missed well-child visits and 6 clinicians, focusing on 3 areas: the value of well-child visits, barriers to attendance, and facilitators of attendance. Transcripts were analyzed with a grounded theory approach and thematic analysis., Results: Caregivers and clinicians identified similar important aspects of well-child visits: immunizations, detection of disease, and monitoring of growth and development. Both groups identified similar barriers to attendance: transportation, difficulty taking time off from work, child care, and other social stressors., Conclusions: Further work to explore how addressing social determinants of health might improve attendance of well-child visits is needed., (© 2020 Annals of Family Medicine, Inc.)

Background: Traumatic brain injury (TBI) may impact an individual physically, cognitively, socially, and emotionally. Poor balance, reduced mobility, and low daily physical activity often will require ongoing physical rehabilitation intervention. However, face-to-face specialized physiotherapy is not always accessible for individuals living in rural settings., Objective: We will answer four questions: (1) What is the feasibility of a remotely supervised, home-based, intensive exercise intervention with survivors of moderate and severe TBI? (2) Does the frequency of remote supervision have an impact on the feasibility of completing a home-based intensive exercise program? (3) Does the frequency of remote supervision impact balance, functional mobility, and physical activity? (4) What is the lived experience of remote supervision for both survivors and caregivers?, Methods: Four participants will complete two intensive, 4-week (five days per week) home-based exercise interventions remotely supervised via synchronous videoconference. Each exercise intervention will have a goal of 160 to 300 repetitions or 60 minutes of tailored exercises to promote neuroplasticity and be defined as an intensive home-based exercise intervention. An alternating single-subject design will allow for the comparison between two frequencies of remote supervision, once weekly and five times weekly. Daily repeated outcome measures, pre- and postintervention outcome measures, and 1-month follow-up outcome measures will be collected to explore the effect on feasibility and physical variables. Daily outcome measures include step count and Five Times Sit-to-Stand test. Pre-post measures include assessment of quiet stance and the Community Balance and Mobility Scale. A semistructured interview will be completed at the end of each intervention segment to document the lived experience of both survivors and their study partners. Finally, five questionnaires will be used to understand the overall experience: the Mayo-Portland Adaptability Inventory-4 Participation Index, Satisfaction With Life Scale, Fall Efficacy Scale-International, Interpersonal Behavior Questionnaire, and System Usability Scale. Data will be analyzed following traditional single-subject methods of analysis., Results: Ethics approval was received from both the Bruyère Research Institute and University of Ottawa review boards in March 2019. Recruitment is underway., Conclusions: The proposed intervention is complex in nature due to the involvement of multiple technology sources and the inclusion of a complex dyad (survivors and caregivers) in a community setting. This type of research is timely given that alternative methods of physical intervention delivery are needed to facilitate gains in balance, mobility, physical activity among TBI survivors with limited access to clinical care, and the quality of the patients' experience., International Registered Report Identifier (irrid): PRR1-10.2196/14867., (©Jennifer O'Neil, Mary Egan, Shawn Marshall, Martin Bilodeau, Luc Pelletier, Heidi Sveistrup. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 09.10.2019.)

Purpose: The main purpose of this article is to produce a French-Canadian translation of the Consolidated criteria for reporting qualitative studies (COREQ) scale under the proposed name "échelle COREQ" and to assess the transcultural validity of its content. The secondary purpose is to examine the inter-rater reliability of the French-Canadian version of the COREQ scale. Method: A modified approach to Vallerand's methodology (1989) for cross-cultural validation was used. First, a parallel back-translation of the COREQ scale was performed, by both professionals and clinicians. Next, a first committee of experts(P1) examined the translations to create a first draft of the French-Canadian version of the COREQ scale. This draft was then evaluated and modified by a second committee of experts (P2). Finally, 28future professionals (master's students in physiotherapy) rated this second draft of the tool for clarity using a seven-point scale (1:very clear; 7:very ambiguous). The principal co-investigators then reviewed the problematic elements and proposed final changes. Two independent raters used this French-Canadian version of the COREQ scale to assess 13qualitative studies that were published in French after the year2007. The kappa coefficient was used to examine inter-rate reliability. Results: The different elements of the final version of the COREQ scale received an average ambiguity rating between 1.04 and 2.56. These low values show a high level of clarity for the French-Canadian version of the COREQ scale. In relation to the total score of the COREQ scale, inter-rater reliability ( n  = 2) is considered to be average to excellent for 62.5% of individual elements, according to the kappa values obtained. Conclusions: A valid French-Canadian version of the COREQ scale was created using this rigorous five-step process., (© Canadian Physiotherapy Association.)

Background: Therapeutic exercise in the form of group circuit-class training can improve mobility and gait while being cost-effective among patients who survived a stroke. Accurate clinical replication of interventions, especially when they are effective, is needed to advance research and treatment. However, replication is difficult when reporting is not detailed., Objective: The objective of this study was to assess the quality of reporting of interventions within the selected studies using three different scales and to assess the criterion validity between the scales., Methods: Two independent assessors used the CERT, the CONTENT scale, and TIDieR checklist to review the quality of reporting of 16 randomized controlled trials (RCTs) from a recent Cochrane Review. Assessments were done independently before a consensus was reached with an experienced third reviewer mediating any disagreements. Criterion validity between the three quality reporting tools was measured using weighted Cohen's kappa coefficients., Results: The mean (±SD) for the CERT was 9.31 (±1.66) out of 19 points; the TIDieR checklist was 8.81 (±1.33) out of 12 points; and the CONTENT was 4.82 (±1.22) out of 9 points for the 16 included RCTs. The CERT and CONTENT scale had a fair agreement (k = 0.455, p = 0.064), while both CERT and CONTENT had only slight agreement with TIDieR (k = 0.143, p = 0.267; k = 0.200, p = 0.182, respectively)., Conclusions: The results of this study indicate a lack of reporting from the 16 RCTs on post-stroke therapeutic circuit-class exercise programs. This presents a major barrier to knowledge translation and clinical implementation of effective exercise programs for stroke rehabilitation.

The Myc oncogene is overexpressed in many cancers, yet targeting it for cancer therapy has remained elusive. One strategy for inhibition of Myc expression is through stabilization of the G-quadruplex (G4), a G-rich DNA secondary structure found within the Myc promoter; stabilization of G4s has been shown to halt transcription of downstream gene products. Here we used the Automated Ligand Identification System (ALIS), an affinity selection-mass spectrometry method, to identify compounds that bind to the Myc G4 out of a pool of compounds that had previously been shown to inhibit Myc expression in a reporter screen. Using an ALIS-based screen, we identified hits that bound to the Myc G4, a small subset of which bound preferentially relative to G4s from the promoters of five other genes. To determine functionality and specificity of the Myc G4-binding compounds in cell-based assays, we compared inhibition of Myc expression in cells with and without Myc G4 regulation. Several compounds inhibited Myc expression only in the Myc G4-containing line, and one compound was verified to function through Myc G4 binding. Our study demonstrates that ALIS can be used to identify selective nucleic acid-binding compounds from phenotypic screen hits, increasing the pool of drug targets beyond proteins.

Purpose/Rationale: Physical exercise interventions for the management of knee osteoarthritis are well known to be effective and accessible forms of rehabilitation and symptom management. However, without adequate reporting of these interventions, accurate replication and clinical use is negatively impacted., Objectives: The main objective of this article was to assess content reporting using The Consensus on Exercise Reporting Template list and 2016 American College of Sports Medicine guidelines among moderate- to high-quality exercise interventions randomized controlled trials (total score of ≥6/10 on the PEDro scale) involving individuals with knee osteoarthritis., Results: The Consensus on Exercise Reporting Template mean total score for all 47 included randomized controlled trials was 4.42 out of 19, demonstrating generally low quality of reporting. The Consensus on Exercise Reporting Template list and the 2016 American College of Sports Medicine guidelines scores were moderately correlated (based on 95% confidence interval, intraclass correlation coefficient = 0.508) for aerobic interventions only., Conclusion: The content analysis of exercise interventions in knee osteoarthritis demonstrated low scores for moderate- to high-quality trials. Improved standardized reporting is recommended to ensure knowledge transfer and replication of effective exercise programs for individuals with knee osteoarthritis.

Studies on the long-term consequences of traumatization found different diagnostic trajectories: chronic, recovered, delayed and resilient. This distinction, however, was never studied in victims of torture or severe political persecution. We aimed to verify the trajectory classes of PTSD empirically and to analyze potential predictors of such trajectories. Former political prisoners from East Germany, first interviewed in 1995, were re-assessed fourteen years later. In 1995, retrospective symptom reports dating back to shortly after the prisoners' release dates were assessed. Predictors of the four different trajectories were divided into pre-trauma, peri-trauma, and post-trauma factors. As a result, the four long-term trajectories were validated in the current sample with the following percentages: chronic (36%), resilient (27%), recovered (26%) and delayed (11%) trajectories. Trajectories were mainly distinguished by pre- and post-traumatic factors, e.g. pre-trauma education or post-trauma disclosure opportunities. We conclude that the four long-term trajectories of trauma sequelae deserve more attention to adequately deal with survivors of severe persecution. Furthermore, the specific predictors of long-term trajectory deserve more attention for re-integration or in rehabilitation.

To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappaB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.

We examined the relationship between parental efficacy and depressive symptoms in a diverse sample of low income mothers. The sample consisted of 607 European American, African American, and Hispanic mothers who participated in The Early Steps Project, a multi-site, longitudinal, preventative intervention study. Parental efficacy was found to be significantly associated with depressive symptoms in the entire sample of low income mothers. Ethnicity moderated results, however, such that parental efficacy was significantly associated with depressive symptoms for European American mothers but was not for the African American and Hispanic mothers. Ethnic differences in the various categories of depressive symptoms (i.e., total, somatic, and psychological) were also explored, with the results showing that African American mothers reported higher levels of depressive symptoms than both European American and Hispanic mothers in each of the categories. The theoretical and clinical implications of these results are discussed.

gamma-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.

Activation of beta-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated beta-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. beta-Catenin-induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized beta-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in beta-catenin-induced lymphomas. Thus, beta-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

Activation of the basic-helix-loop-helix (bHLH) gene TAL1 (or SCL) is a frequent gain-of-function mutation in T cell acute lymphoblastic leukemia (T-ALL). To provide genetic evidence that tal1/scl induces leukemia by interfering with E47 and HEB, we expressed tal1/scl in an E2A or HEB heterozygous background. These mice exhibit disease acceleration and perturbed thymocyte development due to repression of E47/HEB target genes. In tal1/scl thymocytes, we find the corepressor mSin3A bound to the CD4 enhancer, whereas an E47/HEB/p300 complex is detected in wild-type thymocytes. Furthermore, tal1/scl tumors are sensitive to pharmacologic inhibition of HDAC and undergo apoptosis. These data demonstrate that tal1/scl induces leukemia by repressing E47/HEB and suggest that HDAC inhibitors may prove efficacious in T-ALL patients who express TAL1/SCL.

TAL-1/SCL activation is a common genetic event in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Expression of tal-1/scl or a DNA binding mutant of tal-1/scl induces arrest of thymocyte development, resulting in decreases in double-positive and single-positive CD4 thymocytes. Moreover, nuclear p65/p50 heterodimers are detected in premalignant tal-1/scl and mut tal-1/scl thymocytes, suggesting that E2A depletion may induce developmental arrest and stimulate NF-kappaB activation. Increased NF-kappaB activity is also observed in tal-1/scl tumors and bcl-2 is overexpressed. To examine the contribution of NF-kappaB to tal-1/scl tumor growth in vivo, we expressed a mutant form of IkappaBalpha in tal-1/scl tumor cells. Although expression of mutant IkappaBalpha inhibited the tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB response, it had no effect on tumor growth in mice. These data suggest that NF-kappaB activation is an early event in tal-1/scl-induced leukemogenesis, associated with arrest of thymocyte development, and does not appear to contribute to tal-1/scl-induced tumor growth.