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1.
bioRxiv ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38766122

RESUMO

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. Methods: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC 50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. Results: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t 1/2 , ∼8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. Conclusions: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

2.
CMAJ ; 196(19): E646-E656, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38772606

RESUMO

BACKGROUND: Through medicare, residents in Canada are entitled to medically necessary physician services without paying out of pocket, but still many people struggle to access primary care. We conducted a survey to explore people's experience with and priorities for primary care. METHODS: We conducted an online, bilingual survey of adults in Canada in fall 2022. We distributed an anonymous link through diverse channels and a closed link to 122 053 people via a national public opinion firm. We weighted completed responses to mirror Canada's population and adjusted for sociodemographic characteristics using regression models. RESULTS: We analyzed 9279 completed surveys (5.9% response rate via closed link). More than one-fifth of respondents (21.8%) reported having no primary care clinician, and among those who did, 34.5% reported getting a same or next-day appointment for urgent issues. Of respondents, 89.4% expressed comfort seeing another team member if their doctor recommended it, but only 35.9%, 9.5%, and 12.4% reported that their practice had a nurse, social worker, or pharmacist, respectively. The primary care attribute that mattered most was having a clinician who "knows me as a person and considers all the factors that affect my health." After we adjusted for respondent characteristics, people in Quebec, the Atlantic region, and British Columbia had lower odds of reporting a primary care clinician than people in Ontario (adjusted odds ratio 0.30, 0.33, and 0.39, respectively; p < 0.001). We also observed large provincial variations in timely access, interprofessional care, and walk-in clinic use. INTERPRETATION: More than 1 in 5 respondents did not have access to primary care, with large variation by province. Reforms should strive to expand access to relationship-based, longitudinal care in a team setting.


Assuntos
Acessibilidade aos Serviços de Saúde , Atenção Primária à Saúde , Humanos , Atenção Primária à Saúde/estatística & dados numéricos , Canadá , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Opinião Pública , Inquéritos e Questionários , Adolescente , Adulto Jovem
3.
Cell Rep ; 43(5): 114211, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38722741

RESUMO

Multiple myeloma (MM) remains an incurable hematological malignancy demanding innovative therapeutic strategies. Targeting MYC, the notorious yet traditionally undruggable oncogene, presents an appealing avenue. Here, using a genome-scale CRISPR-Cas9 screen, we identify the WNK lysine-deficient protein kinase 1 (WNK1) as a regulator of MYC expression in MM cells. Genetic and pharmacological inhibition of WNK1 reduces MYC expression and, further, disrupts the MYC-dependent transcriptional program. Mechanistically, WNK1 inhibition attenuates the activity of the immunoglobulin heavy chain (IgH) enhancer, thus reducing MYC transcription when this locus is translocated near the MYC locus. WNK1 inhibition profoundly impacts MM cell behaviors, leading to growth inhibition, cell-cycle arrest, senescence, and apoptosis. Importantly, the WNK inhibitor WNK463 inhibits MM growth in primary patient samples as well as xenograft mouse models and exhibits synergistic effects with various anti-MM compounds. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM.

4.
Artigo em Inglês | MEDLINE | ID: mdl-38722767

RESUMO

Despite low prevalence of leprosy worldwide, new cases continue to present and require swift evaluation and diagnosis to prevent complications. Here, we describe a case of lepromatous leprosy with Lucio's phenomenon initially presenting with facial and periorbital edema. A 38-year-old Brazilian woman presented to the emergency department with facial swelling and erythema, initially treated as cellulitis. Due to rapid worsening despite broad-spectrum antibiotics, she underwent soft tissue exploration and biopsy due to concern for necrotizing fasciitis. During her course, she also developed retiform purpura of bilateral upper and lower extremities. Periorbital and lower extremity pathological specimens ultimately revealed acid-fast bacilli consistent with Mycobacterium leprae, and the patient improved with multidrug therapy. This case illustrates the diagnostic difficulty of lepromatous leprosy with Lucio's phenomenon, which can initially present with periorbital edema.

5.
Clin EEG Neurosci ; : 15500594241252897, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38711326

RESUMO

Despite different etiologies, people with schizophrenia (SCZ) or with traumatic brain injury (TBI) both show aberrant neuroplasticity. One neuroplastic mechanism that may be affected is prediction error coding. We used a roving mismatch negativity (rMMN) paradigm which uses different lengths of standard tone trains and is optimized to assess predictive coding. Twenty-five SCZ, 22 TBI (mild to moderate), and 25 healthy controls were assessed. We used a frequency-deviant rMMN in which the number of standards preceding the deviant was either 2, 6, or 36. We evaluated repetition positivity to the standard tone immediately preceding a deviant tone (repetition positivity [RP], to assess formation of the memory trace), deviant negativity to the deviant stimulus (deviant negativity [DN], which reflects signaling of a prediction error), and the difference wave between the 2 (the MMN). We found that SCZ showed reduced DN and MMN compared with healthy controls and with people with mild to moderate TBI. We did not detect impairments in any index (RP, DN, or MMN) in people with TBI compared to controls. Our findings suggest that prediction error coding assessed with rMMN is aberrant in SCZ but intact in TBI, though there is a suggestion that severity of head injury results in poorer prediction error coding.

7.
CMAJ ; 196(13): E432-E440, 2024 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-38589026

RESUMO

BACKGROUND: Variations in primary care practices may explain some differences in health outcomes during the COVID-19 pandemic. We sought to evaluate the characteristics of primary care practices by the proportion of patients unvaccinated against SARS-CoV-2. METHODS: We conducted a population-based, cross-sectional cohort study using linked administrative data sets in Ontario, Canada. We calculated the percentage of patients unvaccinated against SARS-CoV-2 enrolled with each comprehensive-care family physician, ranked physicians according to the proportion of patients unvaccinated, and identified physicians in the top 10% (v. the other 90%). We compared characteristics of family physicians and their patients in these 2 groups using standardized differences. RESULTS: We analyzed 9060 family physicians with 10 837 909 enrolled patients. Family physicians with the largest proportion (top 10%) of unvaccinated patients (n = 906) were more likely to be male, to have trained outside of Canada, to be older, and to work in an enhanced fee-for-service model than those in the remaining 90%. Vaccine coverage (≥ 2 doses of SARS-CoV-2 vaccine) was 74% among patients of physicians with the largest proportion of unvaccinated patients, compared with 87% in the remaining patient population. Patients in the top 10% group tended to be younger and live in areas with higher levels of ethnic diversity and immigration and lower incomes. INTERPRETATION: Primary care practices with the largest proportion of patients unvaccinated against SARS-CoV-2 served marginalized communities and were less likely to use team-based care models. These findings can guide resource planning and help tailor interventions to integrate public health priorities within primary care practices.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Masculino , Feminino , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Estudos Transversais , Pandemias , Médicos de Família , Ontário/epidemiologia , Estudos de Coortes , Atenção Primária à Saúde
8.
Pediatr Transplant ; 28(3): e14750, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38623880

RESUMO

BACKGROUND: Pediatric allogeneic hematopoietic cell transplant (allo-HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials. METHODS: A working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo-HCT recipients with at least one HAdV-positive PCR. RESULTS: Initial HAdV infection and disease definitions were developed and updated through an iterative process after reviewing clinical and virological details for 81 subjects with at least one positive HAdV PCR detected in a clinical specimen. Independent application of final definitions to 20 HAdV positive allo-HCT recipients by two CRCs yielded similar number of HAdV infection or disease events but with variation of degree of certainty for some events. CONCLUSIONS: Application of definitions by a CRC for a study of HAdV infection and disease is feasible and can provide consistency in the assignment of outcomes. Definitions need further refinement to improve reproducibility and to provide guidance on determining clinical improvement or worsening after initial diagnosis of HAdV infection or disease.


Assuntos
Infecções por Adenovirus Humanos , Adenovírus Humanos , Transplante de Células-Tronco Hematopoéticas , Criança , Humanos , Infecções por Adenovirus Humanos/diagnóstico , Reprodutibilidade dos Testes , Transplante Homólogo , Estudos de Coortes
9.
Cell Rep ; 43(4): 114041, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38573857

RESUMO

CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24+ ovarian cancers.


Assuntos
Aciltransferases , Antígeno CD24 , Neoplasias Ovarianas , Fagocitose , Animais , Feminino , Humanos , Camundongos , Aciltransferases/metabolismo , Amidoidrolases/metabolismo , Amidoidrolases/genética , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Glicosilfosfatidilinositóis/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia
10.
Anesthesiol Res Pract ; 2024: 8876548, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38633620

RESUMO

The adverse effects of general anesthesia on the long-term cognition of young children and senior adults have become of concern in recent years. Previously, mechanistic and pathogenic investigations focused on neurons, and little is known about the effect of commonly used intravenous anesthetics such as propofol and ketamine on astrocytes. Recently, astrocyte dysfunction has been implicated in a wide range of age-related brain diseases. In this study, we examined the survival and viability of both young and senescent astrocytes in culture after adding propofol and ketamine to the media at varying strengths. Oxidative stimulus was applied to commercially available fetal cell lines of human astrocytes in vitro to induce morphological changes in cellular senescence. Our results indicate that propofol reduces the survival of young astrocytes as compared to controls, as well as to ketamine. These effects were seen in comparisons of total cell count and at both high and low dose concentrations. High doses of propofol also significantly reduced cell viability compared to those exposed to baseline controls and ketamine. Senescent astrocytes, on the other hand, demonstrated cell count reductions as compared to baseline controls and ketamine when exposed to either DMSO or propofol. The data show differential susceptibility of young astrocytes to propofol than to ketamine. The observed cell count reduction may be related to the adverse effects of propofol on mitochondrial function and free radical production, as described in previous studies. We speculate that ketamine may have a more favorable safety profile in infants and young children.

11.
Transpl Infect Dis ; : e14270, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526183

RESUMO

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

12.
Cancer Cell ; 42(4): 605-622.e11, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38458188

RESUMO

SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.


Assuntos
Haploinsuficiência , Linfoma de Células B , Animais , Humanos , Camundongos , Cromatina , DNA Helicases/genética , Hiperplasia , Linfoma de Células B/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética
13.
Mol Cancer Ther ; 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38507740

RESUMO

The activated B cell (ABC) subset of diffuse large B cell lymphoma (DLBCL) is characterized by chronic B cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small molecule inhibitor, ABBV-MALT1, that potently shuts down B cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

14.
Can Fam Physician ; 70(3): 161-168, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38499374

RESUMO

OBJECTIVE: To understand the current landscape of artificial intelligence (AI) for family medicine (FM) research in Canada, identify how the College of Family Physicians of Canada (CFPC) could support near-term positive progress in this field, and strengthen the community working in this field. COMPOSITION OF THE COMMITTEE: Members of a scientific planning committee provided guidance alongside members of a CFPC staff advisory committee, led by the CFPC-AMS TechForward Fellow and including CFPC, FM, and AI leaders. METHODS: This initiative included 2 projects. First, an environmental scan of published and gray literature on AI for FM produced between 2018 and 2022 was completed. Second, an invitational round table held in April 2022 brought together AI and FM experts and leaders to discuss priorities and to create a strategy for the future. REPORT: The environmental scan identified research related to 5 major domains of application in FM (preventive care and risk profiling, physician decision support, operational efficiencies, patient self-management, and population health). Although there had been little testing or evaluation of AI-based tools in practice settings, progress since previous reviews has been made in engaging stakeholders to identify key considerations about AI for FM and opportunities in the field. The round-table discussions further emphasized barriers to and facilitators of high-quality research; they also indicated that while there is immense potential for AI to benefit FM practice, the current research trajectory needs to change, and greater support is needed to achieve these expected benefits and to avoid harm. CONCLUSION: Ten candidate action items that the CFPC could adopt to support near-term positive progress in the field were identified, some of which an AI working group has begun pursuing. Candidate action items are roughly divided into avenues where the CFPC is well-suited to take a leadership role in tackling priority issues in AI for FM research and specific activities or initiatives the CFPC could complete. Strong FM leadership is needed to advance AI research that will contribute to positive transformation in FM.


Assuntos
Inteligência Artificial , Medicina de Família e Comunidade , Humanos , Médicos de Família , Canadá
15.
Front Neurosci ; 18: 1348478, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38449737

RESUMO

Fragile X Syndrome (FXS) is a neurological disorder caused by epigenetic silencing of the FMR1 gene. Reactivation of FMR1 is a potential therapeutic approach for FXS that would correct the root cause of the disease. Here, using a candidate-based shRNA screen, we identify nine epigenetic repressors that promote silencing of FMR1 in FXS cells (called FMR1 Silencing Factors, or FMR1- SFs). Inhibition of FMR1-SFs with shRNAs or small molecules reactivates FMR1 in cultured undifferentiated induced pluripotent stem cells, neural progenitor cells (NPCs) and post-mitotic neurons derived from FXS patients. One of the FMR1-SFs is the histone methyltransferase EZH2, for which an FDA-approved small molecule inhibitor, EPZ6438 (also known as tazemetostat), is available. We show that EPZ6438 substantially corrects the characteristic molecular and electrophysiological abnormalities of cultured FXS neurons. Unfortunately, EZH2 inhibitors do not efficiently cross the blood-brain barrier, limiting their therapeutic use for FXS. Recently, antisense oligonucleotide (ASO)-based approaches have been developed as effective treatment options for certain central nervous system disorders. We therefore derived efficacious ASOs targeting EZH2 and demonstrate that they reactivate FMR1 expression and correct molecular and electrophysiological abnormalities in cultured FXS neurons, and reactivate FMR1 expression in human FXS NPCs engrafted within the brains of mice. Collectively, our results establish EZH2 inhibition in general, and EZH2 ASOs in particular, as a therapeutic approach for FXS.

16.
bioRxiv ; 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38464258

RESUMO

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

17.
Cancer Cell ; 42(4): 583-604.e11, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38458187

RESUMO

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.


Assuntos
Linfoma , Células B de Memória , Animais , Humanos , Camundongos , Proteínas de Ligação a DNA/genética , Linfoma/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Int J Pharm Pract ; 32(3): 216-222, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38484181

RESUMO

OBJECTIVES: Community pharmacists play an important role in primary care access and delivery for all patients, including patients with a family physician or nurse practitioner ("attached") and patients without a family physician or nurse practitioner ("unattached"). During the COVID-19 pandemic, community pharmacists were accessible care providers for unattached patients and patients who had difficulty accessing their usual primary care providers ("semi-attached"). Before and during the pandemic, pharmacist services expanded in several Canadian provinces. The aim of this qualitative study was to explore patient experiences receiving care from community pharmacists, and their perspectives on the scope of practice of community pharmacists. METHODS: Fifteen patients in Nova Scotia, Canada, were interviewed. Participant narratives pertaining to pharmacist care were analyzed thematically. KEY FINDINGS: Attached, "semi-attached," and unattached patients valued community pharmacists as a cornerstone of care and sought pharmacists for a variety of health services, including triaging and system navigation. Patients spoke positively about expanding the scope of practice for community pharmacists, and better optimization of pharmacists in primary care. CONCLUSIONS: System decision-makers should consider the positive role community pharmacists can play in achieving primary care across the Quintuple Aim (population health, patient and provider experiences, reducing costs, and supporting equity in health).


Assuntos
Serviços Comunitários de Farmácia , Farmacêuticos , Atenção Primária à Saúde , Papel Profissional , Pesquisa Qualitativa , Humanos , Nova Escócia , Atenção Primária à Saúde/organização & administração , Farmacêuticos/organização & administração , Masculino , Feminino , Serviços Comunitários de Farmácia/organização & administração , Pessoa de Meia-Idade , Idoso , Adulto , COVID-19/epidemiologia , Acessibilidade aos Serviços de Saúde
19.
Clin EEG Neurosci ; : 15500594231222979, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38298008

RESUMO

People with schizophrenia (SCZ) and bipolar disorder (BD) have impairments in processing social information, including faces. The neural correlates of face processing are widely studied with the N170 ERP component. However, it is unclear whether N170 deficits reflect neural abnormalities associated with these clinical conditions or differences in social environments. The goal of this study was to determine whether N170 deficits would still be present in SCZ and BD when compared with socially isolated community members. Participants included 66 people with SCZ, 37 with BD, and 125 community members (76 "Community-Isolated"; 49 "Community-Connected"). Electroencephalography was recorded during a face processing task in which participants identified the gender of a face, the emotion of a face (angry, happy, neutral), or the number of stories in a building. We examined group differences in the N170 face effect (greater amplitudes for faces vs buildings) and the N170 emotion effect (greater amplitudes for emotional vs neutral expressions). Groups significantly differed in levels of social isolation (Community-Isolated > SCZ > BD = Community-Connected). SCZ participants had significantly reduced N170 amplitudes to faces compared with both community groups, which did not differ from each other. The BD group was intermediate and did not differ from any group. There were no significant group differences in the processing of specific emotional facial expressions. The N170 is abnormal in SCZ even when compared to socially isolated community members. Hence, the N170 seems to reflect a social processing impairment in SCZ that is separate from level of social isolation.

20.
Schizophr Res ; 266: 92-99, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387253

RESUMO

BACKGROUND: Social cognition training (SCT) can improve social cognition deficits in schizophrenia. However, little is known about patterns of response to SCT or individual characteristics that predict response. METHODS: 76 adults with schizophrenia randomized to receive 8-12 weeks of remotely-delivered SCT were included in this analysis. Social cognition was measured with a composite of six assessments. Latent class growth analyses identified trajectories of social cognitive response to SCT. Random forest and logistic regression models were trained to predict membership in the trajectory group that showed improvement from baseline measures including symptoms, functioning, motivation, and cognition. RESULTS: Five trajectory groups were identified: Group 1 (29 %) began with slightly above average social cognition, and this ability significantly improved with SCT. Group 2 (9 %) had baseline social cognition approximately one standard deviation above the sample mean and did not improve with training. Groups 3 (18 %) and 4 (36 %) began with average to slightly below-average social cognition and showed non-significant trends toward improvement. Group 5 (8 %) began with social cognition approximately one standard deviation below the sample mean, and experienced significant deterioration in social cognition. The random forest model had the best performance, predicting Group 1 membership with an area under the curve of 0.73 (SD 0.24; 95 % CI [0.51-0.87]). CONCLUSIONS: Findings suggest that there are distinct patterns of response to SCT in schizophrenia and that those with slightly above average social cognition at baseline may be most likely to experience gains. Results may inform future research seeking to individualize SCT treatment for schizophrenia.


Assuntos
Esquizofrenia , Adulto , Humanos , Esquizofrenia/complicações , Esquizofrenia/terapia , Cognição Social , Resultado do Tratamento , Cognição , Motivação
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