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Blood Cancer Journal Feb 2024Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience... (Review)
Review
Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell-redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell-redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell-redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Antibodies, Bispecific; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Receptors, G-Protein-Coupled
PubMed: 38307865
DOI: 10.1038/s41408-023-00966-9 -
Acta Bio-medica : Atenei Parmensis Oct 2023
PubMed: 37850784
DOI: 10.23750/abm.v94i5.13541 -
Kidney360 Jul 2023Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients...
KEY POINTS
Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI.
BACKGROUND
Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood.
METHODS
We conducted a genome-wide association study in 1369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI Study; a multiethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities, and kidney function before hospitalization. We then completed functional annotation of top-performing variants for AKI using single-cell RNA sequencing data from kidney biopsies in 12 patients with AKI and 18 healthy living donors from the Kidney Precision Medicine Project.
RESULTS
No genome-wide significant associations with AKI risk were found in Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (). The top two variants with the strongest association with AKI mapped to the gene and gene locus, rs17538288 (odds ratio, 1.55; 95% confidence interval, 1.32 to 182; ) and rs7546189 (odds ratio, 1.53; 95% confidence interval, 1.30 to 1.81; ). In comparison with kidney tissue from healthy living donors, kidney biopsies in patients with AKI showed differential expression in proximal tubular epithelial cells (adjusted = 3.910) and thick ascending limb of the loop of Henle (adjusted = 8.710) and differential gene expression in thick ascending limb of the loop of Henle (adjusted = 4.910).
CONCLUSIONS
AKI is a heterogeneous clinical syndrome with various underlying risk factors, etiologies, and pathophysiology that may limit the identification of genetic variants. Although no variants reached genome-wide significance, we report two variants in the intergenic region between and , suggesting this region as a novel risk for AKI susceptibility.
Topics: Humans; Genome-Wide Association Study; Acute Kidney Injury
PubMed: 37273234
DOI: 10.34067/KID.0000000000000175 -
Cancer Immunology, Immunotherapy : CII Jul 2023CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal...
BACKGROUND
CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC).
METHODS
Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W.
RESULTS
192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%.
CONCLUSIONS
Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab's mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant.
CLINICAL TRIAL REGISTRATION
Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Antibodies, Monoclonal; Antineoplastic Agents; Fatigue
PubMed: 37016126
DOI: 10.1007/s00262-023-03430-6 -
JAMA Network Open Dec 2023It remains unclear whether pet ownership is associated with cognitive decline and to what extent pet ownership mitigates the association between living alone and...
IMPORTANCE
It remains unclear whether pet ownership is associated with cognitive decline and to what extent pet ownership mitigates the association between living alone and cognitive decline.
OBJECTIVE
To explore the association of pet ownership with cognitive decline, the interaction between pet ownership and living alone, and the extent to which pet ownership mitigates the association between living alone and cognitive decline in older adults.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used data from waves 5 (June 2010 to July 2011) to 9 (from June 2018 to July 2019) in the English Longitudinal Study of Ageing. Participants included adults 50 years and older. Data were analyzed from April 1 to June 30, 2023.
EXPOSURES
Pet ownership and living alone in wave 5.
MAIN OUTCOMES AND MEASURES
In waves 5 to 9, verbal memory and verbal fluency were assessed, and composite verbal cognition was further calculated.
RESULTS
Of the 7945 participants included, the mean (SD) age was 66.3 (8.8) years, and 4446 (56.0%) were women. Pet ownership was associated with slower rates of decline in composite verbal cognition (β = 0.008 [95% CI, 0.002-0.014] SD/y), verbal memory (β = 0.006 [95% CI, 0.001-0.012] SD/y), and verbal fluency (β = 0.007 [95% CI, 0.001-0.013] SD/y). Three-way interaction tests showed that living alone was a significant modifier in all 3 associations. Stratified analyses showed that pet ownership was associated with slower rates of decline in composite verbal cognition (β = 0.023 [95% CI, 0.011-0.035] SD/y), verbal memory (β = 0.021 [95% CI, 0.008-0.034] SD/y), and verbal fluency (β = 0.018 [95% CI, 0.005-0.030] SD/y) among individuals living alone, but not among those living with others. Joint association analyses showed no significant difference in rates of decline in composite verbal cognition, verbal memory, or verbal fluency between pet owners living alone and pet owners living with others.
CONCLUSIONS AND RELEVANCE
In this cohort study, pet ownership was associated with slower rates of decline in verbal memory and verbal fluency among older adults living alone, but not among those living with others, and pet ownership offset the associations between living alone and declining rates in verbal memory and verbal fluency. Further studies are needed to assess whether pet ownership slows the rate of cognitive decline in older adults living alone.
Topics: Female; Humans; Aged; Male; Cohort Studies; Home Environment; Longitudinal Studies; Ownership; Cognitive Dysfunction
PubMed: 38147332
DOI: 10.1001/jamanetworkopen.2023.49241 -
JAMA Network Open Oct 2023
Topics: Humans; Child; Young Adult; Adult; Ownership; Violence; Firearms
PubMed: 37851450
DOI: 10.1001/jamanetworkopen.2023.40564 -
Tidsskrift For Den Norske Laegeforening... Nov 2023
Topics: Humans; Ownership; Peer Review, Research; Publishing; Peer Group
PubMed: 37987061
DOI: 10.4045/tidsskr.23.0751 -
Frontiers in Public Health 2023Through a systematic reflection on the journey that transformed traditional state-run baby homes in Tajikistan from closed institutions into community-oriented Family... (Review)
Review
Through a systematic reflection on the journey that transformed traditional state-run baby homes in Tajikistan from closed institutions into community-oriented Family and Child Support Centres (FCSC) we reveal key moments of change. This review describes how community consultation with local participants in a development project shifted responsibility and accountability from international to local ownership and how distributed leadership contributes to the decolonisation of social services. Based on these interviews we ask, 'How do the innovations of a social development project become a fixed part of normal local social, cultural and political life; and, how do we know when a new normal is self-sustaining at a local level?' This analysis builds on a network-mapping tool previously described in this journal. Our interviews show that each participant has taken a non-linear journey, building on the networks previously described, under the influence of activities and discussions that emerged throughout the project. We consider how a monitoring, evaluation, and learning process should be responsive over time to these influences, rather than be set at the start of the project. Using the themes that emerge from participants' journeys, we apply a 'measurement for change' (M4C) approach that integrates Monitoring, Evaluation and Learning (MEL) into decision-making. The journey framework applied represents a systematic application of the M4C approach that gives us insight into where local ownership is responsible for the sustainable management of the intervention, and where continued partnership will further strengthen impact and accountability. The exercise has provided evidence of progress towards decolonisation and of the centring of local priorities in MEL and implementation processes.
Topics: Infant; Child; Humans; Leadership; Exercise; Family Support; Learning; Referral and Consultation
PubMed: 37588118
DOI: 10.3389/fpubh.2023.1155692 -
Journal of Feline Medicine and Surgery Sep 2023Unowned 'stray' domestic cats threaten wildlife, as well as create a community nuisance and contribute to high rates of euthanasia in animal shelters. These cats can...
OBJECTIVES
Unowned 'stray' domestic cats threaten wildlife, as well as create a community nuisance and contribute to high rates of euthanasia in animal shelters. These cats can experience poor welfare, contribute to the pet cat population and compromise attempts to control feral cats. However, many unowned domestic cats are cared for by semi-owners who do not consider they own these cats; therefore, semi-owners are a potentially important target population for human behaviour change interventions. The present study aimed to describe the characteristics of cat semi-owners and compare these with the general population of cat owners and non-cat owners to inform future cat management interventions.
METHODS
An online questionnaire open to all residents of New South Wales, Australia was developed and advertised. Respondents were asked 'do you care for other free-roaming or stray cats (not including the cats you own)?', whether they owned cats, about characteristics of their home and their agreement with 15 capability, social opportunity and motivation (COM) items relating to cat containment.
RESULTS
Questionnaire responses were received from 8708 people, including 588 semi-owners (7%). Semi-owners were significantly more likely to be female, live in urban areas, live in lower socioeconomic areas and rent their home. Most semi-owners also owned their own cats and owned more cats than non-semi-owners.
CONCLUSIONS AND RELEVANCE
Semi-owners of unowned 'stray' cats are a valuable potential target audience for human behaviour change interventions. Understanding that these semi-owners often have their own cats, might already be overwhelmed with cat-caring responsibilities and are disproportionately from lower socioeconomic backgrounds should guide intervention design. A nuanced approach is needed that prioritises the wellbeing of cats and semi-owners for semi-owners to 'buy in'. Any intervention should also recognise that semi-owners often face multiple, complex barriers to neutering or claiming ownership of the cats they care for, especially cost, and trust in the authorities.
Topics: Cats; Animals; Humans; Female; Male; Australia; Ownership
PubMed: 37751179
DOI: 10.1177/1098612X231194225 -
Cognition May 2024What is the relationship between experiencing individual body parts and the whole body as one's own? We theorised that body part ownership is driven primarily by the...
What is the relationship between experiencing individual body parts and the whole body as one's own? We theorised that body part ownership is driven primarily by the perceptual binding of visual and somatosensory signals from specific body parts, whereas full-body ownership depends on a more global binding process based on multisensory information from several body segments. To examine this hypothesis, we used a bodily illusion and asked participants to rate illusory changes in ownership over five different parts of a mannequin's body and the mannequin as a whole, while we manipulated the synchrony or asynchrony of visual and tactile stimuli delivered to three different body parts. We found that body part ownership was driven primarily by local visuotactile synchrony and could be experienced relatively independently of full-body ownership. Full-body ownership depended on the number of synchronously stimulated parts in a nonlinear manner, with the strongest full-body ownership illusion occurring when all parts received synchronous stimulation. Additionally, full-body ownership influenced body part ownership for nonstimulated body parts, and skin conductance responses provided physiological evidence supporting an interaction between body part and full-body ownership. We conclude that body part and full-body ownership correspond to different processes and propose a hierarchical probabilistic model to explain the relationship between part and whole in the context of multisensory awareness of one's own body.
Topics: Humans; Visual Perception; Body Image; Illusions; Human Body; Ownership; Touch Perception; Hand; Proprioception
PubMed: 38364444
DOI: 10.1016/j.cognition.2023.105697