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INTRODUCTION/AIMS: Myasthenia gravis (MG) is a rare, life-threatening immune-related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5-complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. METHODS: This was a retrospective review of two medical records. RESULTS: Patient 1: An 80-year-old male with recurrent, non-muscle invasive transitional cell carcinoma of the bladder developed ICI-induced AChR ab positive MG (ICI-MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58-year-old male had refractory thymoma-associated AChR ab-positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri-infusion pulse prednisone. MG remained stable and he continues eculizumab. DISCUSSION: In the first patient, eculizumab, followed by ravulizumab, improved ICI-MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI-induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation.
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Miastenia Gravis , Miositis , Humanos , Masculino , Anciano de 80 o más Años , Persona de Mediana Edad , Prednisona/uso terapéutico , Inactivadores del Complemento/uso terapéutico , Recurrencia Local de Neoplasia/complicaciones , Miastenia Gravis/inducido químicamente , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/complicaciones , Miositis/complicacionesRESUMEN
The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.
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Neurofibromatosis 1 , Neurofibromina 1 , Humanos , Neurofibromina 1/metabolismo , Neurofibromatosis 1/genética , Dimerización , Mutación , Mutación MissenseRESUMEN
The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory DNA repair pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. DNA damage response (DDR)-deficient cells are also more sensitive to DNA damaging agents like the DNA crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting the DDR pathways, which could operate through the activation of the innate immune system are less well studied. DNA accumulation in the cytosol acts as an immunogenic danger signal, inducing the expression of type-I interferon (IFN) stimulated genes (ISGs) by the activation of the cGAS-STING pathway. Here, we demonstrate that ATM -/- FaDu tumor cells have higher basal expression of ISGs when compared to WT cells and respond to ceralasertib and PBD SG-3199 by inducing higher levels of ISGs in a cGAS-STING-dependent manner. We show that sensitive tumor cells treated with ceralasertib and PBD SG-3199 activate dendritic cells (DCs) via a type-I IFN-dependent mechanism. However, STING deficiency in tumor cells does not prevent DC activation, suggesting that transactivation of the STING pathway occurs within DCs. Furthermore, depletion of the cytosolic DNA exonuclease TREX1 in tumor cells increases DC activation in response to PBD SG-3199-treated tumor cells, indicating that an increase in tumor-derived cytosolic DNA may further enhance DC activation. In summary, in this study, we show that ceralasertib and PBD SG-3199 treatment not only intrinsically target tumor cells but also extrinsically increase tumor cell immunogenicity by inducing DC activation, which is enhanced in ATM-deficient cells.
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Interferón Tipo I , Neoplasias , ADN , Daño del ADN , Células Dendríticas/metabolismo , Exodesoxirribonucleasas , Indoles , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Morfolinas , Neoplasias/genética , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Pirimidinas , SulfonamidasRESUMEN
PURPOSE: Medication samples of anti-VEGF agents can represent a good option for retina specialists to provide timely treatment for newly converted neovascular age-related macular degeneration (nvAMD) while prior-authorizations (PA) are pending. Our study examines the effect of medication sample use (ranibizumab or aflibercept) on future anti-vascular endothelial growth factor (VEGF) agent selection in nvAMD. DESIGN: Retrospective cohort study. PARTICIPANTS: nvAMD patients who underwent an initial anti-VEGF injection with a sample medication were compared to nvAMD control patients who never received a medication sample. METHODS: Charts from 2017 through 2020 were reviewed for data regarding demographics, anti-VEGF agent selection, and visual acuity outcomes for both groups. The utilization of different anti-VEGF agents in each group was compared at various time points using chi-square tests for independence of proportions. MAIN OUTCOME MEASURES: Anti-VEGF agent selection for the first four injections and at one year were examined. RESULTS: Adherence to the initial agent was high between first and subsequent injections (2nd, 3rd, 4th injection, and 1 year) in sample (96.2%, 95.9%, 91.9%, 93.4%, respectively), and control groups (98.1%, 94.2%, 94.9%, 87.8%, respectively). Bevacizumab usage was significantly lower among eyes receiving samples relative to controls at the second (1.9% vs. 38.7%, p < .001), third (3.1% vs. 41.3%, p < .001), fourth injections (4.7% vs. 40.4%, p < .001), and at 1 year (0% vs. 33.8%, p < .001). Aflibercept usage was significantly higher in sample eyes relative to controls at the second (78.3% vs. 43.4%, p < .001), third (76.3% vs. 41.5%, p < .001), and fourth injections (76.7% vs. 43.4%, p < .001), and at 1 year (77.0% vs. 52.7%, p < .001). CONCLUSIONS: Sample medications in nvAMD may be initiated for many reasons, including awaiting PA approval. Our study found that eyes receiving a sample anti-VEGF agent (ranibizumab or aflibercept) for their initial injection were less likely to receive bevacizumab at future visits relative to eyes that did not receive an anti-VEGF sample, even after one year of treatment. Given the persistent use of more expensive medications at subsequent injections for patients who were initiated on samples, insurance payors may consider waiving PA requirements for bevacizumab to avoid a paradoxical increase in health-care costs.
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Degeneración Macular , Ranibizumab , Humanos , Bevacizumab , Inhibidores de la Angiogénesis , Inyecciones Intravítreas , Estudios Retrospectivos , Factor A de Crecimiento Endotelial Vascular , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Degeneración Macular/tratamiento farmacológicoRESUMEN
Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .
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Microscopía por Crioelectrón , Péptidos y Proteínas de Señalización Intracelular , Complejos Multiproteicos , Proteína Fosfatasa 1 , Proteínas ras , Secuencias de Aminoácidos , Sitios de Unión , Guanosina Trifosfato/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Sistema de Señalización de MAP Quinasas , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Complejos Multiproteicos/ultraestructura , Mutación Missense , Fosforilación , Unión Proteica , Proteína Fosfatasa 1/química , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 1/ultraestructura , Estabilidad Proteica , Quinasas raf , Proteínas ras/química , Proteínas ras/metabolismo , Proteínas ras/ultraestructuraRESUMEN
PURPOSE: To assess clinical outcomes of patients with severe, cicatricial ocular surface disease (OSD) implanted with the currently marketed design of the Boston keratoprosthesis type II (BK2). DESIGN: Retrospective cohort study. METHODS: Records of consecutive patients undergoing BK2 implantation from June 2009 to March 2021 were assessed for postoperative visual acuity, postoperative complications, device replacement, and additional surgeries. RESULTS: Fifty-six eyes of 53 patients with a mean follow-up of 45.8 months (range, 0.2-134.7 months) were included. Stevens-Johnson syndrome/toxic epidermal necrolysis was the most common indication (49.1%), followed by mucous membrane pemphigoid (39.6%) and other OSD (11.3%). Visual acuity improved from logMAR 2.2 ± 0.5 preoperatively to 1.5 ± 1.2 at final follow-up. Of 56 eyes, 50 saw ≥20/200 at some point postoperatively. Of the eyes with a follow-up of more than 5 years, 50.0% retained a visual acuity of ≥20/200 at their final follow-up. The most common complications over the entire postoperative course (mean â¼4 years) were de novo or worsening glaucoma (41.1%), choroidal effusions (30.3%), retinal detachment (25.0%), and end-stage glaucoma (25.0%). In a univariate analysis, patients who experienced irreversible loss of ≥20/200 visual acuity were more likely to have been previously implanted with an older design of BK2, less likely to be on preoperative systemic immunosuppressive therapy, and less likely to have undergone concurrent glaucoma tube implantation, compared to patients who retained ≥20/200 acuity (P < .04 for all). CONCLUSIONS: Advances in device design and postoperative care have made implantation of BK2 a viable option for corneal blindness in the setting of severe cicatricial OSD.
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Enfermedades de la Córnea , Glaucoma , Humanos , Córnea/cirugía , Prótesis e Implantes , Enfermedades de la Córnea/cirugía , Estudios Retrospectivos , Implantación de Prótesis , Glaucoma/cirugíaRESUMEN
DILI is a major cause of attrition in drug development with over 1000 FDA-approved drugs known to potentially cause DILI in humans. Unfortunately, DILI is often not detected until drugs have reached clinical stages, risking patients' safety and leading to substantial losses for the pharma industry. Taking into account that standard 2D models have limitations in detecting DILI it is essential to develop in vitro models that are more predictive to improve data translatability. To understand causality and mechanistic aspects of DILI in detail, a human liver MPS consisting of human primary liver parenchymal and non-parenchymal cells (NPCs) and cultured in 3D microtissues on an engineered scaffold under perfusion has been developed. Cryopreserved primary human hepatocytes (PHHs) and Kupffer cells (HKCs) were cocultured as microtissues in the MPS platform for up to two weeks, and each compound of interest was repeatably dosed onto liver microtissues at seven test concentrations for up to four days. Functional liver-specific endpoints were analyzed (including clinical biomarkers such as alanine aminotransferase, ALT) to evaluate liver function. Acute and chronic exposure to compounds of various DILI severities can be assessed by comparing responses to single and multi-dosed microtissues. The methodology has been validated with a broad set of severe and mildly hepatotoxic compounds. Here we show the data for pioglitazone and troglitazone, well-known hepatotoxic compounds withdrawn from the market for causing liver failures. Overall, it has been shown that the liver MPS model can be a useful tool to assess DILI and its association with changes in hepatic function. The model can additionally be used to assess how novel compounds behave in distinct patient subsets and how toxicity profiles may be affected by liver disease states (e.g., viral hepatitis, fatty liver disease).
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Enfermedad Hepática Inducida por Sustancias y Drogas , Alanina Transaminasa , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hepatocitos , Humanos , Macrófagos del Hígado , HígadoRESUMEN
AZD6738 (ceralasertib) is a potent and selective orally bioavailable inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. ATR is activated in response to stalled DNA replication forks to promote G2-M cell-cycle checkpoints and fork restart. Here, we found AZD6738 modulated CHK1 phosphorylation and induced ATM-dependent signaling (pRAD50) and the DNA damage marker γH2AX. AZD6738 inhibited break-induced replication and homologous recombination repair. In vitro sensitivity to AZD6738 was elevated in, but not exclusive to, cells with defects in the ATM pathway or that harbor putative drivers of replication stress such as CCNE1 amplification. This translated to in vivo antitumor activity, with tumor control requiring continuous dosing and free plasma exposures, which correlated with induction of pCHK1, pRAD50, and γH2AX. AZD6738 showed combinatorial efficacy with agents associated with replication fork stalling and collapse such as carboplatin and irinotecan and the PARP inhibitor olaparib. These combinations required optimization of dose and schedules in vivo and showed superior antitumor activity at lower doses compared with that required for monotherapy. Tumor regressions required at least 2 days of daily dosing of AZD6738 concurrent with carboplatin, while twice daily dosing was required following irinotecan. In a BRCA2-mutant patient-derived triple-negative breast cancer (TNBC) xenograft model, complete tumor regression was achieved with 3 to5 days of daily AZD6738 per week concurrent with olaparib. Increasing olaparib dosage or AZD6738 dosing to twice daily allowed complete tumor regression even in a BRCA wild-type TNBC xenograft model. These preclinical data provide rationale for clinical evaluation of AZD6738 as a monotherapy or combinatorial agent. SIGNIFICANCE: This detailed preclinical investigation, including pharmacokinetics/pharmacodynamics and dose-schedule optimizations, of AZD6738/ceralasertib alone and in combination with chemotherapy or PARP inhibitors can inform ongoing clinical efforts to treat cancer with ATR inhibitors.
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Antineoplásicos , Neoplasias de la Mama Triple Negativas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Carboplatino , Humanos , Indoles , Irinotecán , Morfolinas/farmacología , Ftalazinas , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Sulfonamidas/farmacología , Sulfóxidos/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
This study investigated the potential benefit of a pilot culturally sensitive group support intervention, named Joy Luck Academy (JLA), in fostering posttraumatic growth among Chinese American breast cancer survivors. Eighty-six Chinese American breast cancer survivors participated in an eight-week single-arm pre-/post-test trial of an intervention program, which included educational lectures and peer mentor support. The JLA participants were compared with an independent sample of 109 Chinese American breast cancer survivors who went through routine care. Both groups completed baseline and eight-week follow-up assessments of the five facets of posttraumatic growth (meaningful interpersonal relationships, finding new possibilities in life, personal strength, appreciation of life, and spirituality). From baseline to follow-up, the JLA participants displayed significant improvements in the total score of posttraumatic growth, meaningful interpersonal relationships, appreciation of life, finding new possibilities in life, and personal strength. In contrast, the routine care participants showed no significant change in any of these outcome variables. The findings suggest the potential benefit of a culturally sensitive group support intervention in facilitating posttraumatic growth for Chinese American breast cancer survivors, indicating the need for a randomized controlled trial. The educational lectures and peer mentor support may be adapted to tailor the needs of other ethnic minority cancer patients.
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Neoplasias de la Mama , Supervivientes de Cáncer , Asistencia Sanitaria Culturalmente Competente , Crecimiento Psicológico Postraumático , Intervención Psicosocial , Asiático/psicología , Neoplasias de la Mama/psicología , Supervivientes de Cáncer/psicología , China , Etnicidad/psicología , Femenino , Humanos , Grupos Minoritarios , Calidad de Vida/psicología , Determinantes Sociales de la SaludRESUMEN
BACKGROUND: Breast cancer is the most prevalent type of cancer among Asian American women. Chinese American immigrant breast cancer survivors face unique challenges because of cultural and socioecological factors. They report emotional distress and the need for social, emotional, and spiritual support. However, culturally and linguistically appropriate information for managing survivorship health care is often unavailable. OBJECTIVE: To improve the health outcomes for this underserved and understudied population, we developed, designed, and launched a randomized controlled trial to test the health benefits of a culturally sensitive social support intervention (Joy Luck Academy). In this paper, we describe the research protocol. METHODS: This randomized controlled trial will enroll Chinese-speaking, stage 0 to 3 breast cancer survivors who have completed treatment within the previous 36 months using a community-based participatory research approach. We will randomly assign 168 participants to the intervention or control group. The intervention arm will attend 7 weekly 3.5-hour peer mentor and educational sessions. The control group will receive the educational information. We will assess health outcomes at baseline, immediately after the Joy Luck Academy, and at 1- and 4-month follow-ups. The primary outcome is quality of life, as measured by the Functional Assessment of Cancer Therapy scale. Secondary outcomes include depressive symptoms, positive affect, fatigue, and perceived stress. We will also explore how the intervention influences cortisol levels. To identify how and to whom the program is effective, we will measure social and personal resources and theorized mechanisms and perform qualitative interviews with a subsample of participants to enhance the interpretation of quantitative data. RESULTS: Recruitment began in February 2015, and data collection was completed in February 2019. We expect to complete data management by August 2021 and publish results in 2022. CONCLUSIONS: If the Joy Luck Academy is demonstrated to be effective, it may be easily disseminated as an intervention for other groups of Asian American immigrant breast cancer survivors. Furthermore, similar programs could be integrated into other diverse communities. TRIAL REGISTRATION: ClinicalTrials.gov NCT02946697; http://clinicaltrials.gov/ct2/show/NCT02946697. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30950.
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Non-alcoholic steatohepatitis (NASH) is a common form of chronic liver disease characterised by lipid accumulation, infiltration of immune cells, hepatocellular ballooning, collagen deposition and liver fibrosis. There is a high unmet need to develop treatments for NASH. We have investigated how liver fibrosis and features of advanced clinical disease can be modelled using an in vitro microphysiological system (MPS). The NASH MPS model comprises a co-culture of primary human liver cells, which were cultured in a variety of conditions including+/- excess sugar, fat, exogenous TGFß or LPS. The transcriptomic, inflammatory and fibrotic phenotype of the model was characterised and compared using a system biology approach to identify conditions that mimic more advanced clinical disease. The transcriptomic profile of the model was shown to closely correlate with the profile of patient samples and the model displayed a quantifiable fibrotic phenotype. The effects of Obeticholic acid and Elafibranor, were evaluated in the model, as wells as the effects of dietary intervention, with all able to significantly reduce inflammatory and fibrosis markers. Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype.
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Cirrosis Hepática/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.
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Adhesión Celular/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Neoplasias/genética , Neurofibromina 2/genética , Proteínas Supresoras de Tumor/genética , Proliferación Celular/genética , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Inhibición de Contacto/genética , Regulación de la Expresión Génica/genética , Células HEK293 , Humanos , Neoplasias/patología , Unión Proteica/genética , Mapas de Interacción de Proteínas/genética , Transducción de Señal/genéticaRESUMEN
PURPOSE: This study examined the predictors of health-related quality of life (HRQOL) and changes in HRQOL over a 1-year period among Chinese-American breast cancer survivors (BCS). METHODS: A two-wave longitudinal research design included participants from hospital-based cancer registries and community organizations in Los Angeles. Participants completed mailed questionnaires at baseline and 12-month follow-up. HRQOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G v.4). Change in HRQOL was assessed using a 7-point meaningful change score. RESULTS: Participants were 73 Chinese-American BCS, a majority of whom were middle-aged (M = 54.6, SD = 9.2), lower income (63% < 45K), and diagnosed with stage I-II (83%) breast cancer. Regression analyses showed that multilevel contextual factors including general health perception, quality of care, life stress, and improvement in general health perception significantly predicted HRQOL at baseline and follow-up. The final model explained 72% of the variance of HRQOL. The examination of meaningful change indicated that improvement was reported by 32% (n = 22) and deterioration by 25% (n = 17); the majority indicated minimal change (43%, n = 30). Improvement was associated with increases in family communication, social support, and general health perception, while deterioration was associated with declines in social support, family communication, and general health perception. CONCLUSION: Findings indicate that among Chinese-American BCS, HRQOL is influenced by socioecological factors such as family communication and life stress. Results suggest that cancer survivorship outcomes research may benefit from theoretical foundations that examine the broader contextual dimensions that seem to impact and predict HRQOL. Implications for research are discussed.
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Neoplasias de la Mama , Supervivientes de Cáncer , Neoplasias de la Mama/terapia , China , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Encuestas y Cuestionarios , Estados UnidosRESUMEN
The first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we present crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures reveal that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutations at the KRAS-CRD interface result in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.
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Proteínas Proto-Oncogénicas c-raf/química , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas ras/química , Proteínas ras/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Cisteína/metabolismo , Humanos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Dominios Proteicos/genética , Dominios y Motivos de Interacción de Proteínas , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
PURPOSE: The purpose of this study was to investigate improvements in quality of life and psychological well-being among Chinese American breast cancer survivors who participated in a pilot community education and peer-mentor support program. METHODS: One hundred and twenty-nine Chinese American breast cancer survivors who recently completed treatment participated in eight cohorts of the program, Joy Luck Academy, which included weekly education and peer-mentor support sessions. The education sessions covered topics designed to help participants adjust to new life after breast cancer treatment. The peer-mentor support component was designed to provide social support. Quality of life and psychological well-being (e.g., depressive symptoms, anxiety, and low- and high-arousal positive and negative affect) were assessed at baseline and immediately after the intervention. RESULTS: Paired samples t tests indicated improvements in quality of life, low- and high-arousal positive affect, and reductions in depressive symptoms, anxiety, and low-arousal negative affect. CONCLUSION: Our findings suggest that a psychosocial group intervention may improve quality of life and psychological well-being among Chinese American breast cancer survivors. Our intervention has the potential to be applied to other ethnic-minority cancer survivors. Future randomized controlled trials are warranted.
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Asiático/psicología , Neoplasias de la Mama/psicología , Supervivientes de Cáncer/psicología , Intervención Psicosocial/métodos , Calidad de Vida/psicología , Adulto , Neoplasias de la Mama/etnología , China/etnología , Asistencia Sanitaria Culturalmente Competente/métodos , Femenino , Humanos , Persona de Mediana Edad , Grupo Paritario , Apoyo SocialRESUMEN
BACKGROUND: People living with dementia often experience crisis. Home treatment of crisis is an alternative to hospital admission that can have better outcomes. This systematic review is about people with dementia living at home and in crisis. It identifies modifiable factors in the crisis process that may facilitate crisis resolution. METHODS: The protocol is registered on PROSPERO. A systematic search of MEDLINE, EMBASE, CINAHL, AHMED, PsycINFO, Cochrane Library and references of retrieved publications, identified empirical research in English language and date range January 2000 to February 2019. Two researchers independently screened abstracts, selected publications and extracted data using a framework based on published guidelines. This is a report of the analysis and narrative synthesis. RESULTS: The search identified 2755 titles and abstracts, 76 were selected for full-text examination and 13 agreed for inclusion. The included studies evidence that: for a person with dementia, crisis is a process that begins with a problem judged to put them or others at risk of harm. It leads to decision and action to treat this risk, thus resolve the crisis. Such crisis can be predicted or unpredicted and progress quickly or slowly. Medical treatment, community resources and psychosocial support of personal resources, decision making, relationships and social networks, are all modifiable factors that can treat the risk of harm during crisis. Carers' and professionals' knowledge and skills in dementia care are likely to play a key role in crisis resolution in the home. CONCLUSION: There has been limited investigation of the process and management of crisis at home for people living with dementia. The results of this review provide a foundation for future research. There is no consensus on critical components of home treatment to facilitate crisis resolution. However, education in dementia care for carers and professionals is likely to prove essential to successful home treatment.
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Demencia , Cuidadores , Atención a la Salud , Servicios de Atención de Salud a Domicilio , Hospitalización , HumanosRESUMEN
Best practice in dementia care is support in the home. Yet, crisis is common and can often result in hospital admission with adverse consequences. The objective of this mixed-methods case study research was to identify the critical factors for resolving crisis for a person with dementia living at home. The research was an in-depth investigation of what happens during crisis for people with dementia and how it is managed by a Home Treatment Crisis Team to resolution and outcome at 6 weeks and 6 months. The methods were; observation of crisis management for 15 patients with dementia (max three observations per patient, total 41), interviews with patients with dementia (n = 5), carers (n = 13) and professionals (n = 14, range one to six interviews per person, total 29), focus group (nine professionals), and extraction of demographics and medical history from medical records. Analysis focused on the identification of factors important for crisis resolution and avoidance of hospital admission. Critical factors for the Home Treatment Crisis Team to enable successful crisis resolution were: immediate action to reduce risk of harm, expertise in dementia care and carer education, communication skills to establish trust and promote benefits of home treatment, shared decision-making, medication management, addressing the needs of carers independently of the person with dementia and, local availability of respite and other community services. The Home Treatment Crisis Team integrated the seven factors to deploy a biopsychosocial systems approach with embedded respect for personhood. This approach enabled crisis resolution for a person with dementia by creating a system of services, treatments, resources and relationships, 'Safe Dementia Space', in the community with avoidance of hospital admission in more than 80% of referrals. The identified critical factors for crisis resolution are important considerations in the design and delivery of home treatment services for people with dementia.