MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

"In the End You Keep Silent": Help-Seeking Behavior Upon Sexual Victimization in Older Adults.

Sexual violence is considered a prominent mental health problem. Exposure to sexual victimization during lifetime has been linked to mental health problems in old age. Research in adult victims has shown that they experience many barriers for disclosure and seeking professional help upon sexual victimization. However, information on help-seeking behavior in older victims of sexual violence is non-existent. With this study we aim for a better understanding of help-seeking behavior upon sexual violence in older adults. We used a mixed methods approach with an explanatory sequential design. Data were collected through structured face-to-face interviews with a random sample of 227 sexual violence victims of 70 years and older living in Belgium. Quantitative data were triangulated with qualitative data from 15 in-depth interviews with older victims. We found that up to 60% of older sexual violence victims never disclosed their experiences and 94% never sought professional help. Help-seeking is a complex process comprising several phases, which are affected by strong feelings of shame and self-blame, ageist premises and taboos about sexuality. In the end, most victims choose to cope on their own. Occasional disclosure only happens decades after the sexual violence took place. Older victims do not spontaneously disclose to healthcare workers but expect professionals to initiate the conversation. In conclusion, few older victims disclose or seek professional help upon sexual victimization. Healthcare professionals working with older adults need capacity building through training, screening tools, and care procedures to initiate conversation on sexual violence, and to detect signs, prevent, mitigate and respond to sexual victimization in older adults.

Practices countering resident-to-resident aggression and promoting wellness care for older adults in congregate residential facilities: results from a systematic review.

Resident-to-resident aggression (RRA) is an important issue in congregate residential facilities (CRFs) for older adults and has devastating effects. This study aimed to provide an inventory and content analysis of the practices used to counter RRA and promote wellness care for older adults in CRFs. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, original, peer-reviewed research and systematic reviews published in 14 electronic databases and two gray literature sources were examined. Of the 6196 articles identified, 28 met the inclusion criteria. Practices aimed to prevent, track or intervene in RRA, mostly in long-term care centers, but few were evidence-based and ready for widespread implementation. It emerges that continuous training of staff is necessary and that it should prioritize a person-centered approach. CRFs' managers must promote a culture of wellness care and policymakers should consider the prevention practices to improve the quality of life of older adults in CRFs.

Targeting MYC-driven lymphoma: lessons learned and future directions.

MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.

Adherence to Cardiovascular Prevention Guidelines in an Academic Centre.

Background: Adherence to guidelines is associated with better patient outcomes. Although studies show suboptimal adherence to cardiovascular prevention guidelines among general practitioners, adherence among specialist physicians is understudied. The aim of this analysis was to identify practice gaps among cardiologists in a tertiary academic centre. Methods: We retrospectively audited cardiology outpatient clinic notes taken at the Cardiology Clinic at the Centre hospitalier de l'Université de Montréal (CHUM), from the period January 1, 2019 to February 28, 2019. Data were abstracted from hospital medical records. The primary outcome of interest was the rate of adherence to cardiovascular prevention guidelines. We compared the chart-documented practice at our centre to the Canadian hypertension, lipid, diabetes, antiplatelet, and heart failure guidelines in effect at the time of the audit. We also collected information regarding discussions of smoking, alcohol consumption, physical activity, and diet. Results: A total of 2503 patients were included, with a mean age of 65.6 ± 14.5 years. Dyslipidemia occurred in 63% of patients, hypertension in 55%, and coronary artery disease in 41%. Optimal low-density lipoprotein control was documented as having been achieved in just 39% of cases. Blood pressure control was adequate for 65% of patients, and glycemic control was achieved in 47% of patients with diabetes. Heart failure treatment was optimal in 34% of patients. Nearly all patients with coronary artery disease (95%) had appropriate antithrombotic therapy. The incidence of discussion of nonpharmacologic interventions varied, ranging from 91% (smoking) to 16% (diet). Conclusions: Primary and secondary prevention of cardiovascular events was found to be suboptimal in an academic tertiary-care outpatient cardiology clinic and may be representative of similar shortcomings nationwide. Strategies to ensure guideline adherence are needed.

Contexte: Le respect des lignes directrices est associé à de meilleurs résultats pour les patients. Bien que les études montrent que les omnipraticiens adhèrent de façon sous-optimale aux lignes directrices en matière de prévention des événements cardiovasculaires, l'observance chez les médecins spécialistes n'a pas été assez étudiée. Notre analyse a pour objectif de déceler les lacunes dans la pratique des cardiologues exerçant dans des centres universitaires de soins tertiaires. Méthodologie: Nous avons examiné de manière rétrospective les notes cliniques consignées au dossier des patients du Centre cardiovasculaire du Centre hospitalier de l'Université de Montréal (CHUM) et résumé les données issues des consultations ayant eu lieu du 1er janvier au 28 février 2019. Le principal résultat d'intérêt était le taux d'adhésion aux lignes directrices en matière de prévention des événements cardiovasculaires. Nous avons comparé les pratiques enregistrées dans les dossiers de notre centre aux lignes directrices canadiennes sur la prise en charge de l'hypertension, de la lipidémie, du diabète, du traitement antiplaquettaire et de l'insuffisance cardiaque en place au moment de l'évaluation. Nous avons aussi recueilli de l'information sur les discussions entourant le tabagisme, la consommation d'alcool, l'activité physique et l'alimentation. Résultats: Les données de 2 503 patients, âgés en moyenne de 65,6 ± 14,5 ans, ont été retenues. De ces patients, 63 % présentaient une dyslipidémie, 55 %, une hypertension et 41 %, une maladie coronarienne. Le taux de lipoprotéines de basse densité n'était maîtrisé de façon optimale que dans 39 % des cas. La normalisation de la pression artérielle était adéquate chez 65 % des patients, et 47 % des patients diabétiques atteignaient les cibles glycémiques. L'insuffisance cardiaque était optimalement traitée chez 34 % des patients. Presque tous les patients atteints de maladie coronarienne (95 %) recevaient un traitement antithrombotique approprié. La fréquence des discussions sur les interventions non pharmacologiques variait, allant de 91 % dans le cas du tabagisme à 16 % dans celui de l'alimentation. Conclusions: La prévention primaire et secondaire des événements cardiovasculaires s'est révélée sous-optimale dans une clinique externe de cardiologie d'un hôpital universitaire et pourrait être représentative de lacunes similaires dans l'ensemble du pays. Des stratégies visant à assurer le respect des lignes directrices sont nécessaires.

SARS-CoV-2 mRNA vaccine-induced immune responses in rheumatoid arthritis.

Our objective was to characterize T and B cell responses to vaccination with SARS-CoV-2 antigens in immunocompromised rheumatoid arthritis (RA) patients. In 22 RA patients, clinical and biological variables were analyzed before and 4 weeks after each of 3 messenger RNA (mRNA) vaccine doses and compared with unmatched healthy individuals. Sequentially sampled peripheral blood mononuclear cells and sera were collected to determine immune profiles and to analyze the T cell response to a spike peptide pool and B cell specificity to the receptor-binding domain (RBD). Anti-spike antibodies were detectable in 6 of 22 RA patients after 1 dose of vaccine with increasing titers after each booster dose, although the overall response was lower compared with that in healthy control individuals. Responding patients after the first dose were more likely to have RA antibodies and a higher baseline proportion of circulating follicular B cells. In RA patients, the mRNA vaccine elicited a robust CD4+ T response to a spike peptide pool following the first and second doses. Consistent with the serologies, RBD-specific B cells exhibited a modest increase after the first dose and the second dose resulted in marked increases only in a fraction of the RA patients to both ancestral and omicron RBD. Our results highlight the importance of multidose COVID-19 vaccination in RA patients to develop a protective humoral response. However, these patients rapidly develop specific T CD4+ responses, despite delayed B cell responses.

PROTOCOL: Psychometric properties of instruments for measuring elder abuse and neglect in community and institutional settings: A systematic review.

Background: The psychometric properties of elder abuse measurement instruments have not been well-studied. Poor psychometric properties of elder abuse measurement instruments may contribute to the inconsistency of elder abuse prevalence estimates and uncertainty about the magnitude of the problem at the national, regional, and global levels. Objectives: The present review will utilise the COSMIN taxonomy on the quality of outcome measures to identify and review the instruments used in measuring elder abuse, assess the instrument's measurement properties, and identify the definitions of elder abuse and abuse subtypes measured by the instrument. Search Methods: Searches will be conducted in the following online databases: Ageline, ASSIA, CINAHL, CNKI, EMBASE, Google Scholar, LILACS, Proquest Dissertation & Theses Global, PsycINFO, PubMed, SciELO, Scopus, Sociological Abstract and WHO Index Medicus. Relevant studies will also be identified by searching the grey literature from several resources such as OpenAIRE, BASE, OISter and Age Concern NZPotential studies by searching the references of related reviews. We will contact experts who have conducted similar work or are currently conducting ongoing studies. Enquiries will also be sent to the relevant authors if any important data is missing, incomplete or unclear. Selection Criteria: All quantitative, qualitative (that address face and content validity), and mixed-method empirical studies published in peer-reviewed journals or the grey literature will be included in this review. Studies will be included if they are primary studies that (1) evaluate one or more psychometric properties; (2) contain information on instrument development, or (3) perform content validity of the instruments designed to measure elder abuse in the community or institutional settings. Studies should describe at least one of the psychometric properties, such as reliability, validity and responsiveness. Study participants represent the population of interest, including males and females aged 60 or older in community or institutional settings (i.e., nursing homes, long-term care facilities, assisted living, residential care institutions, and residential facilities). Data Collection and Analysis: Screening of titles, abstracts, and full texts of the selected studies will be evaluated based on the preset inclusion criteria by two reviewers. Two reviewers will be assessing the quality appraisal of each study using the COSMIN Risk of Bias checklist and the overall quality of evidence of each psychometric property of the instrument against the updated criteria of good measurement properties. Any dispute between the two reviewers will be resolved through discussions or consensus with a third reviewer. The overall quality of the measurement instrument will be graded using a modified GRADE approach. Data extraction will be performed using the data extraction forms adapted from the COSMIN Guideline for Systematic Reviews of Outcome Measurement Instruments. The information includes the characteristic of included instruments (name, adaptation, language used, translation and country of origin), characteristics of the tested population, psychometric properties listed in the COSMIN criteria, including details on the instrument development, content validity, structural validity, internal consistency, cross-cultural validity/measurement invariance, reliability, measurement error, criterion validity, hypotheses testing for construct validity, responsiveness and interoperability. We will perform a meta-analysis to pool psychometric properties parameters (where possible) or summarise qualitatively.

Which interventions with youths counter ageism toward older adults? Results from a realist review.

Age-related social biases - ageism - are developed at an early age. Interventions to counter ageism have been identified but little is known about their mechanisms, particularly in children. This study aimed to provide a comprehensive understanding of which interventions in youths are most effective, under which circumstances, how, and with what outcomes. Using 46 keywords in 6 databases, a realist review identified 24 studies published between 2000 and 2022 targeting youths under 18. A content analysis of these studies led to the construction of a Context-Mechanisms-Outcomes explanatory model. Contextual facilitators triggering mechanisms for changing stereotypes, prejudices and discrimination were: 1) enhancing knowledge about aging and older adults by providing nuanced information, 2) improving the quality of intergenerational contacts, 3) increasing opportunities to apply previously acquired knowledge in intergenerational interactions, and 4) promoting reflective thinking about experiences with older adults. However, stereotypes and prejudices appeared to be resistant and changes difficult to generalize. Insufficiently advanced cognitive development in children or viewing healthy and socially engaged older adults as unrepresentative of their age group were obstacles that reduced intervention effectiveness. Future studies should explore how advancing age influences interventions as well as the characteristics of older adults involved.

Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma.

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.

Pharmacokinetic Analysis of Omomyc Shows Lasting Structural Integrity and Long Terminal Half-Life in Tumor Tissue.

MYC is an oncoprotein causally involved in the majority of human cancers and a most wanted target for cancer treatment. Omomyc is the best-characterized MYC dominant negative to date. In the last years, it has been developed into a therapeutic miniprotein for solid tumor treatment and recently reached clinical stage. However, since the in vivo stability of therapeutic proteins, especially within the tumor vicinity, can be affected by proteolytic degradation, the perception of Omomyc as a valid therapeutic agent has been often questioned. In this study, we used a mass spectrometry approach to evaluate the stability of Omomyc in tumor biopsies from murine xenografts following its intravenous administration. Our data strongly support that the integrity of the functional domains of Omomyc (DNA binding and dimerization region) remains preserved in the tumor tissue for at least 72 hours following administration and that the protein shows superior pharmacokinetics in the tumor compartment compared with blood serum.

[Mapping the research activities on social accountability in health of an emerging international community]. / Cartographier les activités de recherche en responsabilité sociale en santé d'une communauté internationale en émergence.

We used environmental analysis to document the nature and characteristics of research on social accountability (SA) in health conducted by members of an emerging international Francophone network on SA. We developed a questionnaire focusing on research inputs, activities, and outputs, which could serve as a reference in other institutions and networks. The results provide a better understanding of SA research within the international Francophone community. Networks that aim to promote research among their members should carry out such mapping to leverage the strengths of the community and act as catalysts and stepping stones for future research.

Mindfulness-based stress reduction to improve depression, pain and high patient global assessment in controlled rheumatoid arthritis.

Objective: The aim was to improve distressing patient-reported outcomes (PROs) that persisted in RA patients with clinically controlled inflammation (controlled RA). Methods: In a pragmatic pilot study, we offered mindfulness-based stress reduction (MBSR), a group intervention, to controlled RA patients who had high (≥16) Centre for Evaluation Studies depression (CES-D) scores and/or patient general assessment of disease activity (PGA) at least 2/10 larger than evaluator general assessment (EGA) (PGA-EGA: Delta). Evaluations before, 6 and 12 months after MBSR included CES-D, PGA, modified HAQ, simple disease activity index (SDAI), anxiety (general anxiety disorder 7; GAD-7), coping strategies (coping with health injuries and problems; CHIP), sleep disturbance and pain. Facilitators and obstacles to recruitment and participation were identified. A subset of patients was interviewed for qualitative analysis of their experience. Results: Out of 306 screened patients, 65 were referred, 39 (60%) agreed and 28 (43%) completed MBSR. Anticipated burden, timing and frequency of group meetings, commuting issues, age extremes and co-morbidities were barriers to participation. Up to 12 months after MBSR, anxiety, depression, emotion-oriented coping, sleep and function significantly improved. Nonetheless, no significant impact was observed on pain, PGA, Delta or SDAI. The interviews revealed that benefits, including integration of effective coping strategies, were maintained. Conclusion: We addressed MBSR feasibility issues and selection of outcomes in controlled RA patients with distressing PROs. For patients who chose to participate in MBSR, lasting benefits were evident for anxiety, depression, sleep and function. Larger studies are required to evaluate the weaker impact of MBSR on RA-related pain and PGA.

Smoking status impacts treatment efficacy in smoke-induced lung inflammation: A pre-clinical study.

Rationale: Smoking status and smoking history remain poorly accounted for as variables that could affect the efficacy of new drugs being tested in chronic obstructive pulmonary disease (COPD) patients. As a proof of concept, we used a pre-clinical model of cigarette smoke (CS) exposure to compare the impact of treatment during active CS exposure or during the cessation period on the anti-inflammatory effects IL-1α signaling blockade. Methods: Mice were exposed to CS for 2 weeks, followed by a 1-week cessation, then acutely re-exposed for 2 days. Mice were treated with an anti-IL-1α antibody either during CS exposure or during cessation and inflammatory outcomes were assessed. Results: We found that mice re-exposed to CS displayed reduced neutrophil counts and cytokine levels in the bronchoalveolar lavage (BAL) compared to mice exposed only acutely. Moreover, we found that treatment with an anti-IL-1α antibody during the initial CS exposure delayed inflammatory processes and interfered with pulmonary adaptation, leading to rebound pulmonary neutrophilia, increased BAL cytokine secretion (CCL2) and upregulated Mmp12 expression. Conversely, administration of anti-IL-1α during cessation had the opposite effect, improving BAL neutrophilia, decreasing CCL2 levels and reducing Mmp12 expression. Discussion: These results suggest that pulmonary adaptation to CS exposure dampens inflammation and blocking IL-1α signaling during CS exposure delays the inflammatory response. More importantly, the same treatment administered during cessation hastens the return to pulmonary inflammatory homeostasis, strongly suggesting that smoking status and treatment timing should be considered when testing new biologics in COPD.

Malat1 deficiency prevents hypoxia-induced lung dysfunction by protecting the access to alveoli.

Hypoxia is common in lung diseases and a potent stimulator of the long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1). Herein, we investigated the impact of Malat1 on hypoxia-induced lung dysfunction in mice. Malat1-deficient mice and their wild-type littermates were tested after 8 days of normoxia or hypoxia (10% oxygen). Hypoxia decreased elastance of the lung by increasing lung volume and caused in vivo hyperresponsiveness to methacholine without altering the contraction of airway smooth muscle. Malat1 deficiency also modestly decreased lung elastance but only when tested at low lung volumes and without altering lung volume and airway smooth muscle contraction. The in vivo responsiveness to methacholine was also attenuated by Malat1 deficiency, at least when elastance, a readout sensitive to small airway closure, was used to assess the response. More impressively, in vivo hyperresponsiveness to methacholine caused by hypoxia was virtually absent in Malat1-deficient mice, especially when hysteresivity, a readout sensitive to small airway narrowing heterogeneity, was used to assess the response. Malat1 deficiency also increased the coefficient of oxygen extraction and decreased ventilation in conscious mice, suggesting improvements in gas exchange and in clinical signs of respiratory distress during natural breathing. Combined with a lower elastance at low lung volumes at baseline, as well as a decreased propensity for small airway closure and narrowing heterogeneity during a methacholine challenge, these findings represent compelling evidence suggesting that the lack of Malat1 protects the access to alveoli for air entering the lung.

Factors shaping the global political priority of addressing elder abuse: a qualitative policy analysis.

Background: Globally, 1 in 6 people aged 60 years and older experience elder abuse in the community annually, with potentially severe physical and mental health, financial, and social consequences. Yet, elder abuse remains a low global priority. We aimed to identify the factors accounting for the low global political priority of elder abuse. Methods: We systematically searched relevant peer-reviewed literature and organisational reports in multiple databases and interviewed 26 key informants in the field of elder abuse. We used policy frameworks developed by previous research into the determinants of the priority of global health issues, and a qualitative methodology to thematically analyse the literature and interviews through triangulation of the data. Findings: The main factors identified were related to the nature of the issue (the inherent complexity of elder abuse, pervasive ageism, insufficient awareness and doubts about prevalence estimates, and the intractability of the issue), the policy environment (the restricted ability in the field of elder abuse to capitalise on policy windows and processes), and the capabilities of the proponents of prevention of elder abuse (disagreements over the nature of the problem and solutions, challenges in individual and organisational leadership, and an absence of alliances with other issues). Interpretation: Around 25 years ago, elder abuse started to register on the global agenda. Since then, the global priority for prevention of elder abuse has barely increased. This study identifies several inter-related factors that account for the issue's low priority and opportunities for overcoming these challenges. Chief among these opportunities is the UN Decade of Healthy Ageing 2021-2030, a unique 10-year-long policy window to increase the political priority of the prevention of elder abuse. Funding: World Health Organization.

Recombinant human ß-defensin 2 delivery improves smoking-induced lung neutrophilia and bacterial exacerbation.

Treatment of the cigarette smoke-associated lung diseases, such as chronic obstructive pulmonary disease (COPD), has largely focused on broad-spectrum anti-inflammatory therapies. However, these therapies, such as high-dose inhaled corticosteroids, enhance patient susceptibility to lung infection and exacerbation. Our objective was to assess whether the cationic host defense peptide, human ß-defensin 2 (hBD-2), can simultaneously reduce pulmonary inflammation in cigarette smoke-exposed mice while maintaining immune competence during bacterial exacerbation. Mice were exposed to cigarette smoke acutely (4 days) or chronically (5 days/wk for 7 wk) and administered hBD-2 intranasally or by gavage. In a separate model of acute exacerbation, chronically exposed mice treated with hBD-2 were infected with nontypeable Haemophilus influenzae before euthanasia. In the acute exposure model, cigarette smoke-associated pulmonary neutrophilia was significantly blunted by both local and systemic hBD-2 administration. Similarly, chronically exposed mice administered hBD-2 therapeutically exhibited reduced pulmonary neutrophil infiltration and downregulated proinflammatory signaling in the lungs compared with vehicle-treated mice. Finally, in a model of acute bacterial exacerbation, hBD-2 administration effectively limited neutrophil infiltration in the lungs while markedly reducing pulmonary bacterial load. This study shows that hBD-2 treatment can significantly attenuate lung neutrophilia induced by cigarette smoke exposure while preserving immune competence and promoting an appropriate host-defense response to bacterial stimuli.