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BACKGROUND: Oncology databases that integrate genomic and clinical data have become valuable resources for precision medicine. However, the generalizability of these databases has not been comprehensively assessed. OBJECTIVES: To describe the demographics, clinical characteristics, treatments, and overall survival of breast cancer cohorts in GENIE-BPC and three other databases. METHODS: This study utilized GENIE-BPC, SEER, SEER-Medicare, and Merative MarketScan Research Databases. Women with invasive breast cancer were identified through EHR, cancer registries or ICD-9/10-CM codes. The ages were 18+ years or per database requirement. Treatments were based on EHR or HCPCS/NDC codes in claims. Overall survival was estimated as time from diagnosis to death. RESULTS: Of female breast cancer patients in GENIE-BPC (n = 775), SEER (n = 548 336), SEER-Medicare (n = 68 914), and Marketscan (n = 109 499) databases, the median ages at initial diagnosis were 44, 62, 74, and 57 years, respectively. A greater proportion of patients in GENIE-BPC, compared to SEER/SEER-Medicare, had higher nuclear grades (%III-%IV: 57% vs. 26%/24%), advanced disease stage (%IV: 25.3% vs. 5%/3.6%), percent of triple negative breast cancer (19.7% vs. 10.2%/8.5%), and receipt of chemotherapy (85.0% vs. NA/22.3%). The 1-, 3-, and 5-year overall survival rates were lower in GENIE-BPC (78.5%, 60.5%, 55.5%) than in SEER (95.8%, 89.5%, 85.5%) and SEER-Medicare (91.6%, 81.4%, 75.0%). CONCLUSION: Breast cancer patients in GENIE-BPC were younger, had more advanced disease, had a higher proportion of triple negative breast cancer and recipients of chemotherapy, and had poorer overall survival. Researchers must use statistical adjustment when extrapolating results (e.g., biomarker prevalence) from GENIE-BPC to the larger breast cancer population.
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Neoplasias de la Mama , Bases de Datos Factuales , Genómica , Programa de VERF , Humanos , Femenino , Neoplasias de la Mama/terapia , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anciano , Adulto , Estados Unidos/epidemiología , Estudios de Cohortes , Medicina de Precisión/métodos , Anciano de 80 o más Años , Adulto JovenRESUMEN
A hydrophobic evaporable indano[60] fullerene ketone with low sublimation temperature (CF3-FIDO) was successfully synthesized, providing the fullerene mono-adduct derivative with the lowest sublimation temperature reported to date. The amorphous characteristic of the evaporated film was confirmed by grazing incidence X-ray diffraction (GIXRD) and atomic force microscopy (AFM). Perovskite solar cells using CF3-FIDO as the electron transport layer (ETL) achieved long-term device stability retaining 60% of their initial PCE after 500 h in air.
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Percutaneous coronary intervention (PCI) is a procedure that opens blocked arteries and restores blood flow to the heart. Timely access to hospitals offering PCI services can be a matter of life or death for patients experiencing a heart attack; however, hospitals' adoption of PCI services may vary between communities, posing potential barriers to critical care. Our cohort study of US general acute hospitals during the period 2000-20 examined PCI service adoption across communities stratified by race, ethnicity, income, and rurality and further classified as segregated or integrated. Of 5,260 hospitals, 1,621 offered PCI services in 2020 or before, 630 added PCI services between 2001 and 2010, and 225 added PCI services between 2011 and 2020. Hospitals serving Black, racially segregated communities were 48 percent less likely to adopt PCI services compared with hospitals serving non-Black, racially segregated communities, and hospitals serving Hispanic, ethnically segregated communities were 41 percent less likely to do so than those serving non-Hispanic, ethnically segregated communities. Hospitals in high-income, economically integrated communities were 1.8 times more likely to adopt PCI services than those in high-income, economically segregated communities, and rural hospitals were less likely to do so than urban hospitals. Understanding where services are expanding in relation to community need may aid in successful policy interventions.
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Disparidades en Atención de Salud , Intervención Coronaria Percutánea , Intervención Coronaria Percutánea/estadística & datos numéricos , Humanos , Estados Unidos , Disparidades en Atención de Salud/etnología , Hospitales/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Femenino , Masculino , Estudios de CohortesRESUMEN
Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a PRMT1-DDX3 axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates PINK1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer.
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Target antigens are crucial for developing chimeric antigen receptor (CAR)-T cells, but their application to ovarian cancers is limited. This study aimed to identify potential genes as CAR-T-cell antigen candidates for ovarian cancers. A differential gene expression analysis was performed on ovarian cancer samples from four datasets obtained from the GEO datasets. Functional annotation, pathway analysis, protein localization, and gene expression analysis were conducted using various datasets and tools. An oncogenicity analysis and network analysis were also performed. In total, 153 differentially expressed genes were identified in ovarian cancer samples, with 60 differentially expressed genes expressing plasma membrane proteins suitable for CAR-T-cell antigens. Among them, 21 plasma membrane proteins were predicted to be oncogenes in ovarian cancers, with nine proteins playing crucial roles in the network. Key genes identified in the oncogenic pathways of ovarian cancers included MUC1, CXCR4, EPCAM, RACGAP1, UBE2C, PRAME, SORT1, JUP, and CLDN3, suggesting them as recommended antigens for CAR-T-cell therapy for ovarian cancers. This study sheds light on potential targets for immunotherapy in ovarian cancers.
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Biología Computacional , Inmunoterapia Adoptiva , Neoplasias Ováricas , Receptores Quiméricos de Antígenos , Femenino , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/inmunología , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión GénicaRESUMEN
Importance: Stroke center certification is granted to facilities that demonstrate distinct capabilities for treating patients with stroke. A thorough understanding of structural discrimination in the provision of stroke centers is critical for identifying and implementing effective interventions to improve health inequities for socioeconomically disadvantaged populations. Objective: To determine whether (1) hospitals in socioeconomically disadvantaged communities (defined using the Area Deprivation Index) are less likely to adopt any stroke certification and (2) adoption rates differ between entry-level (acute stroke-ready hospitals) and higher-level certifications (primary, thrombectomy capable, and comprehensive) by community disadvantage status. Design, Setting, and Participants: This cohort study used newly collected stroke center data merged with data from the American Hospital Association, Healthcare Cost Report Information datasets, and the US Census. All general acute hospitals in the continental US between January 1, 2009, and December 31, 2022, were included. Data analysis was conducted from July 2023 to May 2024. Main Outcomes and Measures: The primary outcome was the likelihood of hospitals adopting stroke care certification. Cox proportional hazard and competing risk models were used to estimate the likelihood of a hospital becoming stroke certified based on the socioeconomic disadvantage status of the community. Results: Among the 5055 hospitals studied from 2009 to 2022, 2415 (47.8%) never achieved stroke certification, 602 (11.9%) were certified as acute stroke-ready hospitals, and 2038 (40.3%) were certified as primary stroke centers or higher. When compared with mixed-advantage communities, adoption of any stroke certification was most likely to occur near the most advantaged communities (hazard ratio [HR], 1.24; 95% CI, 1.07-1.44) and least likely near the most disadvantaged communities (HR, 0.43; 95% CI, 0.34-0.55). Adoption of acute stroke-ready certification was most likely in mixed-advantage communities, while adoption of higher-level certification was more likely in the most advantaged communities (HR,1.41; 95% CI, 1.22-1.62) and less likely for the most disadvantaged communities (HR, 0.31; 95% CI, 0.21-0.45). After adjusting for population size and hospital capacity, compared with mixed-advantage communities, stroke certification adoption hazard was still 20% lower for relatively disadvantaged communities (adjusted HR, 0.80; 95% CI, 0.73-0.87) and 42% lower for the most disadvantaged communities (adjusted HR, 0.58; 95% CI, 0.45-0.74). Conclusions and Relevance: In this cohort study examining hospital adoption of stroke services, when compared with mixed-advantage communities, hospitals located in the most disadvantaged communities had a 42% lower hazard of adopting any stroke certification and relatively disadvantaged communities had a 20% lower hazard of adopting any stroke certification. These findings suggest that there is a need to support hospitals in disadvantaged communities to obtain stroke certification as a way to reduce stroke disparities.
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Accidente Cerebrovascular , Poblaciones Vulnerables , Humanos , Accidente Cerebrovascular/terapia , Estados Unidos , Poblaciones Vulnerables/estadística & datos numéricos , Disparidades en Atención de Salud/estadística & datos numéricos , Masculino , Femenino , Estudios de Cohortes , Certificación/estadística & datos numéricos , Hospitales/estadística & datos numéricos , Hospitales/normas , Anciano , Factores SocioeconómicosRESUMEN
Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver ß-galactosidase and ß-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver ß-glucosidase and ß-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of ß-glucosidase or ß-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of ß-glucosidase and ß-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower ß-glucosidase and ß-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of ß-galactosidase and ß-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.
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Diseño de Fármacos , Inhibidores Enzimáticos , Simulación del Acoplamiento Molecular , beta-Galactosidasa , beta-Glucosidasa , beta-Galactosidasa/antagonistas & inhibidores , beta-Galactosidasa/metabolismo , Bovinos , Animales , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , beta-Glucosidasa/antagonistas & inhibidores , beta-Glucosidasa/metabolismo , Estructura Molecular , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/químicaRESUMEN
Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.
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Autoinmunidad , Citocinas , Lupus Eritematoso Sistémico , Transducción de Señal , Espermina , Animales , Espermina/metabolismo , Espermina/farmacología , Humanos , Transducción de Señal/efectos de los fármacos , Ratones , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Citocinas/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Janus Quinasa 1/metabolismo , Fosforilación , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Psoriasis/inmunología , Psoriasis/metabolismo , Ratones Endogámicos C57BL , Quinasas Janus/metabolismo , Femenino , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismoRESUMEN
Importance: Long-acting injectable antipsychotics (LAIs) can help decrease the rate of nonadherence to medications in patients with schizophrenia, but these drugs are underutilized in clinical practice, especially in Asian countries. One strategy for the early prescription of LAIs is to administer the drugs during patients' first admission, when they have more time to absorb medication-related knowledge. Objective: To estimate the prevalence of and risk factors for in-hospital use of LAIs among first-admission patients with schizophrenia in Taiwan and to examine the association of early discontinuation with readmission risk among patients receiving LAIs. Design, Setting, and Participants: This cohort study included data from a claims database for patients with a first admission for schizophrenia at psychiatric wards in Taiwan from 2004 to 2017. Eligible patients were diagnosed with schizophrenia or schizoaffective disorder at discharge and aged between 15 and 64 years. Data analysis was performed from April to September 2022. Exposure: In-hospital use of LAIs with or without early discontinuation. Main Outcome and Measures: Readmission for any psychotic disorder following discharge from first admission, with risk estimated via multivariable survival regression analysis, including the Cox proportional hazards (CPH) model and accelerated failure time (AFT) model. Results: Of the 56â¯211 patients with a first admission for schizophrenia (mean [SD] age, 38.1 [12.1] years; 29â¯387 men [52.3%]), 46â¯875 (83.4%) did not receive any LAIs during admission, 5665 (10.1%) received LAIs with early discontinuation, and 3671 (6.5%) received LAIs without early discontinuation. The prevalence of receiving LAIs increased by 4%, from 15.3% (3863 of 25â¯251 patients) to 19.3% (3013 of 15â¯608 patients) between 2004-2008 and 2013-2017. After controlling for sex, year, prior antipsychotic use, age at first admission, and length of stay, the CPH regression analysis revealed that the readmission risk increased among patients receiving LAIs with early discontinuation (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.21-1.30) but decreased among patients receiving LAIs without early discontinuation (aHR, 0.88; 95% CI, 0.84-0.92) compared with patients not receiving LAIs. Results remained similar for the AFT model. Conclusions and Relevance: The incidence of in-hospital use of LAIs among patients with a first admission for schizophrenia has remained low. In this study, early discontinuation of LAIs was associated with readmission risk-specifically, early discontinuation with a higher risk while the lack of early discontinuation with a lower risk compared with treatment with oral antipsychotics alone-which suggests our results have implications for improving the efficacy of LAI administration among patients with a first admission for schizophrenia.
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Antipsicóticos , Preparaciones de Acción Retardada , Readmisión del Paciente , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Readmisión del Paciente/estadística & datos numéricos , Masculino , Taiwán/epidemiología , Femenino , Adulto , Persona de Mediana Edad , Preparaciones de Acción Retardada/uso terapéutico , Factores de Riesgo , Adolescente , Adulto Joven , Estudios de Cohortes , Cumplimiento de la Medicación/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Inyecciones , Modelos de Riesgos ProporcionalesRESUMEN
In practice, individuals strive to develop highly original and valuable creative products within specific limitations. However, previous functional Magnetic Resonance Imaging (fMRI) studies focused on divergent-thinking tasks without considering the "valuableness" of an idea. Additionally, different types of creative tasks (e.g., the easier association vs. the harder association task) may engage distinct cognitive processes. This study aimed to investigate the underlying neural mechanisms associated with different types of creative thinking, specifically focusing on the generation of the most original and valuable creative product within an fMRI scanner. Twenty-one college students participated in a block design study. During each trial, participants were instructed to draw the most original and valuable product inspired by a given figure. The findings revealed that, in comparison to the harder association task, the easier association task led to broader activation across multiple brain regions. However, this broader activation resulted in inefficient thinking and poorer creative performance. Notably, the orbitofrontal cortex exhibited activation across various creativity tasks and displayed connectivity with several seed brain regions, highlighting the importance of decision-making when only one original and valuable product design is allowed. Furthermore, the complex functional connectivity observed between different brain networks reflects the intricate nature of creative thinking. To conclude, widespread activation of brain regions does not necessarily indicate superior creativity. Instead, optimal creative performance within constraints is achieved through an efficient utilization of association for generating innovative ideas, inhibition for suppressing unoriginal ideas, and decision-making to select the most creative idea.
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BACKGROUND: online environments can influence food desire and choices. We tested if online calming nature and stressful street environments can affect desire for healthy and unhealthy foods. METHOD: we asked 238 participants (40 ± 14 yrs) to rate their desire (100 mm VAS) for 7 low calorie nutrient rich foods (Healthy) and 7 high calorie nutrient poor foods (Unhealthy), and perceived stress (state anxiety in STAI), before and after imagining themselves in a control, nature park, or busy street condition. RESULTS: participants who imagined themselves being in a nature park had a significant higher desire for Healthy foods, than participants in the busy street condition (p < 0.05). Participants in the busy street condition decreased their desire for Healthy foods after they imagined themselves in a busy street (p < 0.05)). However, perceived stress did not impact the association between condition and desire for low calorie foods nor high calorie foods. CONCLUSION: this study suggests that online environments can have an impact on healthy food desires, which could be of importance for the increased number of food choices which are made in online environments.
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Conducta de Elección , Dieta Saludable , Preferencias Alimentarias , Internet , Humanos , Adulto , Preferencias Alimentarias/psicología , Femenino , Masculino , Dieta Saludable/psicología , Persona de Mediana Edad , Comportamiento del Consumidor , Adulto Joven , Estrés Psicológico/psicología , NaturalezaRESUMEN
Knee osteoarthritis (OA) involves articular cartilage degradation driven mainly by inflammation. Kaempferol (KM), known for its anti-inflammatory property, holds potential for OA treatment. This study investigated the potential of hyaluronic acid (HA)-coated gelatin nanoparticles loaded with KM (HA-KM GNP) for treating knee OA. KM was encapsulated into gelatin nanoparticles (KM GNP) and then coated with HA to form HA-KM GNPs. Physical properties were characterized, and biocompatibility and cellular uptake were assessed in rat chondrocytes. Anti-inflammatory and chondrogenic properties were evaluated using IL-1ß-stimulated rat chondrocytes, compared with HA-coated nanoparticles without KM (HA GNP) and KM alone. Preclinical efficacy was tested in an anterior cruciate ligament transection (ACLT)-induced knee OA rat model treated with intra-articular injection of HA-KM GNP. Results show spherical HA-KM GNPs (88.62 ± 3.90â¯nm) with positive surface charge. Encapsulation efficiency was 98.34â¯% with a sustained release rate of 18â¯% over 48â¯h. Non-toxic KM concentration was 2.5⯵g/mL. In IL-1ß-stimulated OA rat chondrocytes, HA-KM GNP significantly down-regulated RNA expression of IL-1ß, TNF-α, COX-2, MMP-9, and MMP-13, while up-regulating SOX9 compared to HA GNP, and KM. In vivo imaging demonstrated significantly higher fluorescence intensity within rat knee joints for 3â¯hours post HA-KM GNP injection compared with KM GNP (185.2% ± 34.1% vs. 45.0% ± 16.7%). HA-KM GNP demonstrated significant effectiveness in reducing subchondral sclerosis, attenuating inflammation, inhibiting matrix degradation, restoring cartilage thickness, and reducing the severity of OA in the ACLT rat model. In conclusion, HA-KM GNP holds promise for knee OA therapy.
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Condrocitos , Ácido Hialurónico , Quempferoles , Nanopartículas , Osteoartritis de la Rodilla , Ratas Sprague-Dawley , Animales , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoartritis de la Rodilla/patología , Quempferoles/farmacología , Quempferoles/administración & dosificación , Nanopartículas/química , Inyecciones Intraarticulares , Ratas , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Interleucina-1beta/metabolismo , Células CultivadasRESUMEN
BACKGROUND: It is unknown how changes in the percutaneous coronary intervention (PCI) "built environment" have impacted PCI volumes at the community, hospital, and patient levels. This study sought to determine how PCI hospital openings and closures effect community- and hospital-level PCI volumes as well as the likelihood of receiving PCI at a low-volume hospital. METHODS: We conducted a retrospective cohort study of 3,966,025 Medicare Fee-For-Service patients in 37,451 zip codes and 2564 U.S. hospitals who underwent PCI from 2006 to 2017. We conducted community-, hospital-, and patient-level analyses using ordinary least squares regressions with fixed effects to determine changes in PCI volumes after PCI hospital openings or closures. RESULTS: Between 2006 and 2017, a total of 17% and 7% of patients lived in communities that experienced PCI hospital openings and closures, respectively. Openings were associated with a 10% increase in community PCI volume, a 2% increase in the share of elective PCI, and a doubling in the likelihood of receiving PCI at a low-volume hospital. In communities with low baseline PCI capacity, openings were associated with a 12% increase in community PCI volume, and in high-capacity communities, an 8% increase. PCI closures were associated with a 9% decrease in community PCI volume in high-capacity communities but no measurable change in low-capacity communities. CONCLUSIONS: PCI service expansion is associated with increased PCI at low-volume hospitals and a greater number of elective procedures. Increased governmental oversight may be necessary to ensure that openings and closures of these specialized services yield the desired benefits.
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The ability to sense prey-derived cues is essential for predatory lifestyles. Under low-nutrient conditions, Arthrobotrys oligospora and other nematode-trapping fungi develop dedicated structures for nematode capture when exposed to nematode-derived cues, including a conserved family of pheromones, the ascarosides. A. oligospora senses ascarosides via conserved MAPK and cAMP-PKA pathways; however, the upstream receptors remain unknown. Here, using genomic, transcriptomic and functional analyses, we identified two families of G protein-coupled receptors (GPCRs) involved in sensing distinct nematode-derived cues. GPCRs homologous to yeast glucose receptors are required for ascaroside sensing, whereas Pth11-like GPCRs contribute to ascaroside-independent nematode sensing. Both GPCR classes activate conserved cAMP-PKA signalling to trigger trap development. This work demonstrates that predatory fungi use multiple GPCRs to sense several distinct nematode-derived cues for prey recognition and to enable a switch to a predatory lifestyle. Identification of these receptors reveals the molecular mechanisms of cross-kingdom communication via conserved pheromones also sensed by plants and animals.
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Ascomicetos , Feromonas , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ascomicetos/metabolismo , Ascomicetos/genética , Ascomicetos/fisiología , Feromonas/metabolismo , Nematodos/microbiología , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Transducción de Señal , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Caenorhabditis elegans/microbiologíaRESUMEN
Helical membrane proteins generally have a hydrophobic nature, with apolar side chains comprising the majority of the transmembrane (TM) helices. However, whenever polar side chains are present in the TM domain, they often exert a crucial role in structural interactions with other polar residues, such as TM helix associations and oligomerization. Moreover, polar residues in the TM region also often participate in protein functions, such as the Schiff base bonding between Lys residues and retinal in rhodopsin-like membrane proteins. Although many studies have focused on these functional polar residues, our understanding of stand-alone polar residues that are energetically unfavored in TM helixes is limited. Here, we adopted bacteriorhodopsin (bR) as a model system and systematically mutated 17 of its apolar Leu or Phe residues to polar Asn. Stability measurements of the resulting mutants revealed that all of these polar substitutions reduced bR stability to various extents, and the extent of destabilization of each mutant bR is also correlated to different structural factors, such as the relative accessible surface area and membrane depth of the mutation site. Structural analyses of these Asn residues revealed that they form sidechain-to-backbone hydrogen bonds that alleviate the unfavorable energetics in hydrophobic and apolar surroundings. Our results indicate that membrane proteins are able to accommodate certain stand-alone polar residues in the TM region without disrupting overall structures.
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Bacteriorodopsinas , Interacciones Hidrofóbicas e Hidrofílicas , Estabilidad Proteica , Bacteriorodopsinas/química , Bacteriorodopsinas/genética , Bacteriorodopsinas/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación , Estructura Secundaria de Proteína , Halobacterium salinarum/química , Halobacterium salinarum/genética , Halobacterium salinarum/metabolismo , Modelos MolecularesRESUMEN
Oesophageal squamous cell carcinoma (ESCC) is a common malignant tumour of the gastrointestinal tract. Early detection and access to appropriate treatment are crucial for the long-term survival of patients. However, limited diagnostic and monitoring methods are available for identifying early stage ESCC. Endoscopic screening and surgical resection are commonly used to diagnose and treat early ESCC. However, these methods have disadvantages, such as high recurrence, lethality, and mortality rates. Therefore, methods to improve early diagnosis of ESCC and reduce its mortality rate are urgently required. In 1961, Gary et al. proposed a novel liquid biopsy approach for clinical diagnosis. This involved examining exosomes, circulating tumour cells, circulating free DNA, and circulating free RNA in body fluids. The ability of liquid biopsy to obtain samples repeatedly, wide detection range, and fast detection speed make it a feasible option for non-invasive tumour detection. In clinical practice, liquid biopsy technology has gained popularity for early screening, diagnosis, treatment efficacy monitoring, and prognosis assessment. Thus, this is a highly promising examination method. However, there have been no comprehensive reviews on the four factors of liquid biopsy in the context of ESCC. This review aimed to analyse the progress of liquid biopsy research for ESCC, including its classification, components, and potential future applications.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Biopsia Líquida/métodos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago/diagnóstico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Pronóstico , Detección Precoz del Cáncer/métodos , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/sangre , ExosomasRESUMEN
BACKGROUND: Stroke centers are critical for the timely diagnosis and treatment of acute stroke and have been associated with improved treatment and outcomes; however, variability exists in the definitions and processes used to certify and designate these centers. Our study categorizes state stroke center certification and designation processes and provides examples of state processes across the United States, specifically in states with independent designation processes that do not rely on national certification. METHODS: In this cross-sectional study from September 2022 to April 2023, we used peer-reviewed literature, primary source documents from states, and communication with state officials in all 50 states to capture each state's process for stroke center certification and designation. We categorized this information and outlined examples of processes in each category. RESULTS: Our cross-sectional study of state-level stroke center certification and designation processes across states reveals significant heterogeneity in the terminology used to describe state processes and the processes themselves. We identify 3 main categories of state processes: No State Certification or Designation Process (category A; n=12), State Designation Reliant on National Certification Only (category B; n=24), and State Has Option for Self-Certification or Independent Designation (category C; n=14). Furthermore, we describe 3 subcategories of self-certification or independent state designation processes: State Relies on Self-Certification or Independent Designation for Acute Stroke Ready Hospital or Equivalent (category C1; n=3), State Has Hybrid Model for Acute Stroke Ready Hospital or Equivalent (category C2; n=5), and State Has Hybrid Model for Primary Stroke Center and Above (category C3; n=6). CONCLUSIONS: Our study found significant heterogeneity in state-level processes. A better understanding of how these differences may impact the rigor of each process and clinical performance of stroke centers is worthy of further investigation.
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Accidente Cerebrovascular , Humanos , Estados Unidos , Estudios Transversales , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Certificación , HospitalesRESUMEN
BACKGROUND: The research landscape examining social cognition (SC) impairment in patients with major depressive disorders (MDD) and bipolar disorders (BD) is notably scarce. Presently, assessments predominantly rely on static stimuli and self-reported measures, which may not capture the dynamic dimensions of social cognition. OBJECTIVES: This study aimed to validate the Chinese version of Movie Assessment of Social Cognition (MASC-CH) and to investigate whether MDD and BD exhibit distinct patterns of SC impairments, shedding light on potential differences between these two mood disorders. METHODS: The study encompassed 197 participants, aged 18-65, distributed as follows: 21 BD, 20 MDD, and 156 healthy controls (HC). We focused on examining "cognitive" and "emotional" SC scores and "undermentalizing" and "overmentalizing" error patterns, with nonsocial inference as a control. Additional assessments included the Reading Mind in the Eyes Test (RMET) and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). We also explored the association between depression severity (measured by the Hamilton Depressive Rating Scale, HDRS) and distinct SC dimensions between MDD and BD. RESULTS: The MASC-CH exhibited strong validity and reliability for SC assessment. In group comparisons, BD participants scored significantly lower on MASC-CH, while the MDD group scores were not significantly different from HC. Specifically, BD individuals had notably lower cognitive SC scores and made more undermentalizing and absence of mentalizing errors than MDD and HC. Additionally, a negative correlation between HDRS score and overmentalizing was observed in BD, not in the MDD. CONCLUSIONS: The findings indicate that depression severity scores in BD were inversely related to MASC-CH scores. In contrast, this relationship was not observed in the MDD group. These results underscore the importance of SC impairments as distinguishing characteristics of both BD and MDD. It provides valuable insights into the distinct social-cognitive profiles of both mood disorders.