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1.
Front Immunol ; 15: 1352805, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38550594

RESUMO

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.


Assuntos
Melanoma , Humanos , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral , Linfócitos T , Terapia Baseada em Transplante de Células e Tecidos , Microambiente Tumoral
2.
Sci Rep ; 14(1): 5817, 2024 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461365

RESUMO

There is an increasing need to implement neuromorphic systems that are both energetically and computationally efficient. There is also great interest in using electric elements with memory, memelements, that can implement complex neuronal functions intrinsically. A feature not widely incorporated in neuromorphic systems is history-dependent action potential time adaptation which is widely seen in real cells. Previous theoretical work shows that power-law history dependent spike time adaptation, seen in several brain areas and species, can be modeled with fractional order differential equations. Here, we show that fractional order spiking neurons can be implemented using super-capacitors. The super-capacitors have fractional order derivative and memcapacitive properties. We implemented two circuits, a leaky integrate and fire and a Hodgkin-Huxley. Both circuits show power-law spiking time adaptation and optimal coding properties. The spiking dynamics reproduced previously published computer simulations. However, the fractional order Hodgkin-Huxley circuit showed novel dynamics consistent with criticality. We compared the responses of this circuit to recordings from neurons in the weakly-electric fish that have previously been shown to perform fractional order differentiation of their sensory input. The criticality seen in the circuit was confirmed in spontaneous recordings in the live fish. Furthermore, the circuit also predicted long-lasting stimulation that was also corroborated experimentally. Our work shows that fractional order memcapacitors provide intrinsic memory dependence that could allow implementation of computationally efficient neuromorphic devices. Memcapacitors are static elements that consume less energy than the most widely studied memristors, thus allowing the realization of energetically efficient neuromorphic devices.


Assuntos
Encéfalo , Neurônios , Animais , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Simulação por Computador , Encéfalo/fisiologia
3.
Blood ; 143(22): 2314-2331, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38457357

RESUMO

ABSTRACT: For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.


Assuntos
Receptores de Activinas Tipo II , Códon sem Sentido , Endoglina , Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/patologia , Endoglina/genética , Endoglina/metabolismo , Receptores de Activinas Tipo II/genética , Proteína Smad4/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Mutação , Masculino , Feminino , Degradação do RNAm Mediada por Códon sem Sentido
4.
Cancers (Basel) ; 15(21)2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37958416

RESUMO

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.

6.
Circ Cardiovasc Qual Outcomes ; 16(10): e009905, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37702048

RESUMO

BACKGROUND: Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry. METHODS: We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative. RESULTS: A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment. CONCLUSIONS: We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.


Assuntos
Neoplasias da Mama , Cardiologistas , Cardiologia , Neoplasias , Humanos , Feminino , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapia , Oncologia , Sistema de Registros , Estudos Multicêntricos como Assunto
7.
Cancers (Basel) ; 15(8)2023 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-37190214

RESUMO

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine-kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.

9.
High Alt Med Biol ; 24(1): 37-48, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36757307

RESUMO

Laura Gochicoa-Rangel, Santiago C. Arce, Carlos Aguirre-Franco, Wilmer Madrid-Mejía, Mónica Gutiérrez-Clavería, Lorena Noriega-Aguirre, Patricia Schonffeldt-Guerrero, Agustín Acuña-Izcaray, Arturo Cortés-Telles, Luisa Martínez-Valdeavellano, Federico Isaac Hernández-Rocha, Omar Ceballos-Zúñiga, Rodrigo Del Rio Hidalgo, Sonia Sánchez, Erika Meneses-Tamayo, and Iván Chérrez-Ojeda; and on Behalf of the Respiratory Physiology Project in COVID-19 (FIRCOV). Effect of altitude on respiratory functional status in COVID-19 survivors: results from a Latin American Cohort-FIRCOV. High Alt Med Biol 24:37-48, 2023. Persistent symptoms and lung function abnormalities are common in COVID-19 survivors. Objectives: To determine the effect of altitude and other independent variables on respiratory function in COVID-19 survivors. Methods: Analytical, observational, cross-sectional cohort study done at 13 medical centers in Latin America located at different altitudes above sea level. COVID-19 survivors were invited to perform pulmonary function tests at least 3 weeks after diagnosis. Results: 1,368 participants (59% male) had mild (20%), moderate (59%), and severe (21%) disease. Restriction by spirometry was noted in 32%; diffusing capacity of the lung for carbon monoxide (DLCO) was low in 43.7%; and 22.2% walked less meters during the 6-minute walk test (6-MWT). In multiple linear regression models, higher altitude was associated with better spirometry, DLCO and 6-MWT, but lower oxygen saturation at rest and during exercise. Men were 3 times more likely to have restriction and 5.7 times more likely to have a low DLCO. Those who had required mechanical ventilation had lower DLCO and walked less during the 6-MWT. Conclusions: Men were more likely to have lower lung function than women, even after correcting for disease severity and other factors. Patients living at a higher altitude were more likely to have better spirometric patterns and walked farther but had lower DLCO and oxygen saturation.


Assuntos
Altitude , COVID-19 , Humanos , Masculino , Feminino , América Latina , Estudos Transversais , Estado Funcional , Capacidade de Difusão Pulmonar , Pulmão
10.
Dent Clin North Am ; 67(1): 1-11, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36404071

RESUMO

Masticatory myofascial pain disorders (MMPD) are a common group of orofacial pain conditions affecting the muscles of mastication, with headache and cervical disorders as well as chronic widespread pain and psychosocial disorders being common comorbid conditions. As their pathophysiology is multifactorial in nature, a multimodal and interdisciplinary approach should be considered. Overall treatment goals include decreasing pain and disability, increasing mandibular range of motion, and improving quality of life. This article describes a complex case exhibiting common characteristics of MMPD while additionally reviewing the literature on classification, pathophysiology, and evidence-based treatment planning.


Assuntos
Dor Facial , Qualidade de Vida , Humanos , Dor Facial/diagnóstico , Dor Facial/etiologia , Dor Facial/terapia , Cefaleia , Mandíbula
11.
Int J Mol Sci ; 23(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36430263

RESUMO

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Sarcoma , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
12.
Biomedicines ; 10(10)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36289900

RESUMO

Peripheral blood polymorphonuclear neutrophils (PMNs) forming extracellular traps (NETs), as well as endothelial- and platelet-derived parameters, have been analyzed in patients with SARS-CoV-2 pneumonia, and their prognostic role has been evaluated. Eighty-seven consecutive patients hospitalized with SARS-CoV-2 pneumonia were prospectively selected. A sample of 30 healthy individuals served as the control group. Clinical and oxygenation (oxygen saturation to fraction of inspired oxygen ratio-SpO2/FiO2) characteristics and PMNs forming NETs, serum levels of myeloperoxidase, E-selectin, vascular cell adhesion molecule 1-VCAM1-vascular endothelial growth factor, P-selectin, platelet factor 4 and plasma concentrations of D-dimer were evaluated at hospital admission, at discharge and 14 days after discharge. Intensive care unit admission or death was the primary composite endpoint. Patients showed a higher number of PMNs forming NETs than healthy controls. The absolute number of PMNs forming NETs was inversely correlated with oxygen status (SpO2/FiO2) and positively with inflammatory (C-reactive protein, ferritin) markers and VCAM1. A decrease in, but not a normalization of NETs and endothelial-derived parameters was observed in patients who survived. In conclusion, the formation of NETs runs parallel to that of other inflammatory and endothelial activation markers, and is inverse to the oxygenation parameters, supporting a pathogenic role for PMNs in this entity.

13.
Int J Mol Sci ; 23(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36293515

RESUMO

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.


Assuntos
Antineoplásicos Imunológicos , Carcinoma de Células de Transição , Imunoconjugados , Neoplasias da Bexiga Urinária , Humanos , Anticorpos Monoclonais/farmacologia , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Carcinoma de Células de Transição/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Tirosina , Neoplasias da Bexiga Urinária/patologia
15.
Q J Exp Psychol (Hove) ; 75(5): 765-783, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34428978

RESUMO

Fear extinction is not permanent but is instead more vulnerable than the original fear memory, as traditionally shown by the return of fear phenomena. Because of this, techniques to mitigate the return of fear are needed in the clinical treatment of related psychological conditions. One promising strategy is the occasional reinforced extinction treatment, introducing a gradual and sparse number of conditioned stimulus-unconditioned stimulus (CS-US) pairings within the extinction treatment. We present the results of three experiments in which we used a threat conditioning procedure in humans. Our main aim was to evaluate whether occasional reinforced extinction could reduce two different forms of relapse: spontaneous recovery (Experiments 1 and 2) and reinstatement (Experiment 3). Contrary to our predictions and previous literature, the results indicate that an occasional reinforcement treatment did not mitigate relapse compared with standard extinction. From a theoretical standpoint, these results are more consistent with the idea that extinction entails the acquisition of new knowledge than with the idea that there are conditions in which extinction leads to a weakening of the original fear memory. These findings also question the generality of the potential benefits of using occasional reinforced extinction in clinical settings.


Assuntos
Extinção Psicológica , Medo , Condicionamento Clássico , Condicionamento Psicológico , Medo/psicologia , Humanos , Reforço Psicológico
16.
J Int Med Res ; 49(10): 3000605211053090, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34719990

RESUMO

OBJECTIVE: Spain's so-called Stroke Belt is an area with high prevalence of vascular disease. We aimed to determine the prevalence of undetected obstructive sleep apnea-hypopnea syndrome (OSAHS) among patients with acute ischemic stroke (AIS) in southern Spain. METHODS: We conducted a cross-sectional study at the Virgen Macarena University Hospital Stroke Unit during 2018 to 2019. We included patients <72 hours after AIS with a neuroimaging lesion and performed sleep tests. RESULTS: Seventy-two patients were included. The median participant age was 72 years. Mean body mass index was 27.07 kg/m2, and 40.28% were daily alcohol drinkers. Hypertension, atrial fibrillation, ischemic cardiomyopathy, and previous stroke were detected in 63.9%, 11.1%, 15.3%, and 17.6% of patients, respectively. Polygraphy was feasible in 91.38% of patients. The prevalence of OSAHS was 84.72% (apnea-hypopnea index ≥5). Patients with moderate and severe OSAHS were more likely to be obese and to have a larger neck circumference and facial palsy. The diagnostic criteria of central sleep apnea syndrome were met in only 1.38% of patients. CONCLUSIONS: The high prevalence of OSAHS found in the Spanish Stroke Belt justifies further investigation and development of a screening program as a strategy to identify patients with undetected OSAHS.


Assuntos
Isquemia Encefálica , Apneia Obstrutiva do Sono , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Estudos Transversais , Humanos , Prevalência , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/epidemiologia , Espanha/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia
17.
JACC CardioOncol ; 3(3): 360-380, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34604797

RESUMO

Radiation therapy is a cornerstone of cancer therapy, with >50% of patients undergoing therapeutic radiation. As a result of widespread use and improved survival, there is increasing focus on the potential long-term effects of ionizing radiation, especially cardiovascular toxicity. Radiation therapy can lead to atherosclerosis of the vasculature as well as valvular, myocardial, and pericardial dysfunction. We present a consensus statement from the International Cardio-Oncology Society based on general principles of radiotherapy delivery and cardiovascular risk assessment and risk mitigation in this population. Anatomical-based recommendations for cardiovascular management and follow-up are provided, and a priority is given to the early detection of atherosclerotic vascular disease on imaging to help guide preventive therapy. Unique management considerations in radiation-induced cardiovascular disease are also discussed. Recommendations are based on the most current literature and represent a unanimous consensus by the multidisciplinary expert panel.

18.
Disaster Med Public Health Prep ; 17: e34, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34392868

RESUMO

OBJECTIVES: This study's goal was to determine the perceived risks of infection as well as the perceived risks of hospitalization and death from COVID-19 in Ecuador and Kenya. It also assessed the factors associated with the risk-related perceptions. METHODS: Cross-sectional studies with samples from the adult populations in both countries were conducted to assess the perceived risks of contracting COVID-19. Data were collected online using the Qualtrics platform (Qualtrics, Provo, Utah, United States) from samples of 1050 heads of households, aged 18 years or older, in each country. A total of 3 statistical analyses were conducted: summary statistics, correlation, and linear regression. RESULTS: The average perceived risks of COVID-19 infection, hospitalization, and death in the Kenyan sample were 27.1%, 43.2%, and 17.2%, respectively, and the values for the Ecuadorian sample were 34%, 32.8%, and 23.3%, respectively. The Pearson's correlation coefficients between the risk measures in each country were less than 0.38. Risk measures were associated with several sociodemographic variables (e.g., income, gender, location), but not with age. CONCLUSIONS: The perceived risks of COVID-19 infection, hospitalization, and death in Kenya and Ecuador were significantly higher relative to the statistics reported; however, no strong association existed between perceived risk and age, which is a key factor in adverse health outcomes, including death, among COVID-19 infected individuals.

19.
Sci Rep ; 11(1): 13735, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215779

RESUMO

To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements. In contrast, patients with PNS involvement showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) in comparison with patients without NS. Neurosarcoidosis was identified in 5.5% of patients. CNS involvement prevails significantly over PNS involvement, and both conditions do not overlap in any patient. The systemic phenotype associated to each involvement was clearly differentiated, and can be helpful not only in the early identification of neurological involvement, but also in the systemic evaluation of patients diagnosed with neurosarcoidosis.


Assuntos
Encéfalo/patologia , Doenças do Sistema Nervoso Central/diagnóstico , Sistema Nervoso Central/patologia , Nervos Periféricos/patologia , Sarcoidose/diagnóstico , Adulto , Idoso , Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/classificação , Doenças do Sistema Nervoso Central/patologia , Estudos de Coortes , Nervos Cranianos/patologia , Feminino , Humanos , Masculino , Meninges/patologia , Pessoa de Meia-Idade , Sarcoidose/classificação , Sarcoidose/complicações , Sarcoidose/patologia , Medula Espinal/patologia
20.
Sci Rep ; 10(1): 12060, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694738

RESUMO

Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death.


Assuntos
Cardiotônicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Cálcio , Cardiotoxicidade/etiologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Doxorrubicina/farmacologia , Humanos , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo
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