Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.010
Filtrar
Más filtros

Intervalo de año de publicación
1.
Cell ; 184(5): 1232-1244.e16, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33626330

RESUMEN

Human cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind to platelet-derived growth factor receptor alpha (PDGFRα) and transforming growth factor beta receptor 3 (TGFßR3) to gain entry into multiple cell types. This complex is targeted by potent neutralizing antibodies and represents an important candidate for therapeutics against HCMV. Here, we determine three cryogenic electron microscopy (cryo-EM) structures of the trimer and the details of its interactions with four binding partners: the receptor proteins PDGFRα and TGFßR3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFRα and TGFßR3 is mutually exclusive, suggesting that they function as independent entry receptors. In addition, Trimer-PDGFRα interaction has an inhibitory effect on PDGFRα signaling. Our results provide a framework for understanding HCMV receptor engagement, neutralization, and the development of anti-viral strategies against HCMV.


Asunto(s)
Citomegalovirus/química , Glicoproteínas de Membrana/química , Proteínas del Envoltorio Viral/química , Internalización del Virus , Microscopía por Crioelectrón , Citomegalovirus/fisiología , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Proteoglicanos/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/química , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteínas del Envoltorio Viral/metabolismo
2.
Cell ; 182(2): 329-344.e19, 2020 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-32589946

RESUMEN

Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Using a high-throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 82% previously undocumented, and confirm more than 60 receptor-ligand pairs using orthogonal assays. Our study reveals a map of cell-type-specific interactions and the landscape of dysregulated receptor-ligand crosstalk in cancer, including selective loss of function for tumor-associated mutations. Furthermore, investigation of the IgSF interactome in a large cohort of cancer patients identifies interacting protein signatures associated with clinical outcome. The IgSF interactome represents an important resource to fuel biological discoveries and a framework for understanding the functional organization of the surfaceome during homeostasis and disease, ultimately informing therapeutic development.


Asunto(s)
Inmunoglobulinas/metabolismo , Neoplasias/patología , Mapas de Interacción de Proteínas , Antígeno B7-H1/metabolismo , Antígeno Carcinoembrionario/metabolismo , Comunicación Celular , Análisis por Conglomerados , Medios de Cultivo Condicionados/química , Células HEK293 , Humanos , Inmunoglobulinas/química , Inmunoglobulinas/genética , Ligandos , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Unión Proteica , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo
3.
Cell ; 174(5): 1158-1171.e19, 2018 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-30057110

RESUMEN

Characterizing cell surface receptors mediating viral infection is critical for understanding viral tropism and developing antiviral therapies. Nevertheless, due to challenges associated with detecting protein interactions on the cell surface, the host receptors of many human pathogens remain unknown. Here, we build a library consisting of most single transmembrane human receptors and implement a workflow for unbiased and high-sensitivity detection of receptor-ligand interactions. We apply this technology to elucidate the long-sought receptor of human cytomegalovirus (HCMV), the leading viral cause of congenital birth defects. We identify neuropilin-2 (Nrp2) as the receptor for HCMV-pentamer infection in epithelial/endothelial cells and uncover additional HCMV interactors. Using a combination of biochemistry, cell-based assays, and electron microscopy, we characterize the pentamer-Nrp2 interaction and determine the architecture of the pentamer-Nrp2 complex. This work represents an important approach to the study of host-pathogen interactions and provides a framework for understanding HCMV infection, neutralization, and the development of novel anti-HCMV therapies.


Asunto(s)
Infecciones por Citomegalovirus/metabolismo , Citomegalovirus/fisiología , Neuropilina-2/metabolismo , Receptores Virales/metabolismo , Anticuerpos Neutralizantes/química , Membrana Celular/metabolismo , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Mapeo Epitopo , Femenino , Células HEK293 , Humanos , Conformación Proteica , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus
4.
Cell ; 171(4): 918-933.e20, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29033132

RESUMEN

Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation-prone proteins. By revealing key roles of K11/K48-linked chains in cell-cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.


Asunto(s)
Anticuerpos Biespecíficos/análisis , Transducción de Señal , Ubiquitina/metabolismo , Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Ciclo Celular , Humanos , Mitosis , Biosíntesis de Proteínas , Ubiquitinación
5.
Genes Dev ; 37(7-8): 303-320, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-37024284

RESUMEN

MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.


Asunto(s)
Melanoma , Humanos , Pronóstico , Melanoma/genética , Transducción de Señal , Carcinogénesis , Transformación Celular Neoplásica , Proteínas Proto-Oncogénicas c-myc/metabolismo
6.
Immunity ; 54(7): 1511-1526.e8, 2021 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-34260887

RESUMEN

Myeloid cells encounter stromal cells and their matrix determinants on a continual basis during their residence in any given organ. Here, we examined the impact of the collagen receptor LAIR1 on myeloid cell homeostasis and function. LAIR1 was highly expressed in the myeloid lineage and enriched in non-classical monocytes. Proteomic definition of the LAIR1 interactome identified stromal factor Colec12 as a high-affinity LAIR1 ligand. Proteomic profiling of LAIR1 signaling triggered by Collagen1 and Colec12 highlighted pathways associated with survival, proliferation, and differentiation. Lair1-/- mice had reduced frequencies of Ly6C- monocytes, which were associated with altered proliferation and apoptosis of non-classical monocytes from bone marrow and altered heterogeneity of interstitial macrophages in lung. Myeloid-specific LAIR1 deficiency promoted metastatic growth in a melanoma model and LAIR1 expression associated with improved clinical outcomes in human metastatic melanoma. Thus, monocytes and macrophages rely on LAIR1 sensing of stromal determinants for fitness and function, with relevance in homeostasis and disease.


Asunto(s)
Homeostasis/fisiología , Pulmón/metabolismo , Macrófagos Alveolares/metabolismo , Monocitos/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Apoptosis/fisiología , Médula Ósea/metabolismo , Médula Ósea/patología , Células COS , Diferenciación Celular/fisiología , Línea Celular , Línea Celular Tumoral , Linaje de la Célula/fisiología , Proliferación Celular/fisiología , Chlorocebus aethiops , Femenino , Humanos , Pulmón/patología , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/patología , Células Mieloides/metabolismo , Células Mieloides/patología , Metástasis de la Neoplasia/patología , Proteómica/métodos , Transducción de Señal/fisiología
7.
Immunity ; 48(6): 1144-1159.e5, 2018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29884460

RESUMEN

PKCß-null (Prkcb-/-) mice are severely immunodeficient. Here we show that mice whose B cells lack PKCß failed to form germinal centers and plasma cells, which undermined affinity maturation and antibody production in response to immunization. Moreover, these mice failed to develop plasma cells in response to viral infection. At the cellular level, we have shown that Prkcb-/- B cells exhibited defective antigen polarization and mTORC1 signaling. While altered antigen polarization impaired antigen presentation and likely restricted the potential of GC development, defective mTORC1 signaling impaired metabolic reprogramming, mitochondrial remodeling, and heme biosynthesis in these cells, which altogether overwhelmingly opposed plasma cell differentiation. Taken together, our study reveals mechanistic insights into the function of PKCß as a key regulator of B cell polarity and metabolic reprogramming that instructs B cell fate.


Asunto(s)
Linfocitos B/inmunología , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Células Plasmáticas/inmunología , Proteína Quinasa C beta/inmunología , Animales , Hemo/biosíntesis , Ratones , Ratones Noqueados , Mitocondrias/inmunología , Mitocondrias/metabolismo , Células Plasmáticas/citología
8.
EMBO Rep ; 24(7): e56131, 2023 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-37184882

RESUMEN

In addition to triggering humoral responses, conventional B cells have been described in vitro to cross-present exogenous antigens activating naïve CD8+ T cells. Nevertheless, the way B cells capture these exogenous antigens and the physiological roles of B cell-mediated cross-presentation remain poorly explored. Here, we show that B cells capture bacteria by trans-phagocytosis from previously infected dendritic cells (DC) when they are in close contact. Bacterial encounter "instructs" the B cells to acquire antigen cross-presentation abilities, in a process that involves autophagy. Bacteria-instructed B cells, henceforth referred to as BacB cells, rapidly degrade phagocytosed bacteria, process bacterial antigens and cross-prime naïve CD8+ T cells which differentiate into specific cytotoxic cells that efficiently control bacterial infections. Moreover, a proof-of-concept experiment shows that BacB cells that have captured bacteria expressing tumor antigens could be useful as novel cellular immunotherapies against cancer.


Asunto(s)
Linfocitos T CD8-positivos , Células Dendríticas , Presentación de Antígeno , Reactividad Cruzada , Antígenos Bacterianos
9.
Clin Infect Dis ; 79(2): 420-429, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-38769593

RESUMEN

Point-of-care ultrasound (POCUS) is a safe, noninvasive technique performed at the patient's bedside, providing immediate results to the operator. It complements physical examination and facilitates clinical decision-making. In infectious diseases, POCUS is particularly valuable, offering an initial assessment in cases of suspected infection. It often leads to an early tentative diagnosis enabling the prompt initiation of antimicrobial treatment without the delay associated with traditional radiology. POCUS provides direct visualization of affected organs, assists in evaluating fluid balance, and facilitates various interventions, all while reducing patient discomfort. For infectious disease specialists, becoming proficient in POCUS is a critical future challenge, requiring dedicated training for effective utilization.


Asunto(s)
Enfermedades Transmisibles , Sistemas de Atención de Punto , Ultrasonografía , Humanos , Ultrasonografía/métodos , Enfermedades Transmisibles/diagnóstico por imagen
10.
J Neurol Neurosurg Psychiatry ; 95(7): 630-638, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38124227

RESUMEN

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%-49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. METHODS: This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified 'QoL responders' in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. RESULTS: All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as 'QoL responders'. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. CONCLUSIONS: Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. TRIAL REGISTRATION NUMBER: GermanClinicalTrialsRegister: #6735.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Calidad de Vida , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Resultado del Tratamiento , Levodopa/uso terapéutico , Antiparkinsonianos/uso terapéutico
11.
Mov Disord ; 39(2): 235-248, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38234035

RESUMEN

BACKGROUND: Impulse-control and related behavioral disorders (ICBDs) significantly impact the lives of Parkinson's disease (PD) patients and caregivers, with lasting consequences if undiagnosed and untreated. While ICBD pathophysiology and risk factors are well-studied, a standardized severity definition and treatment evidence remain elusive. OBJECTIVE: This work aimed to establish international expert consensus on ICBD treatment strategies. To comprehensively address diverse treatment availabilities, experts from various continents were included. METHODS: From 2021 to 2023, global movement disorders specialists engaged in a Delphi process. A core expert group initiated surveys, involving a larger panel in three iterations, leading to refined severity definitions and treatment pathways. RESULTS: Experts achieved consensus on defining ICBD severity, emphasizing regular PD patient screenings for early detection. General treatment recommendations focused on continuous monitoring, collaboration with significant others, and seeking specialist advice for legal or financial challenges. For mild to severe ICBDs, gradual reduction in dopamine agonists was endorsed, followed by reductions in other PD medications. Second-line treatment strategies included diverse approaches like reversing the last medication change, cognitive behavior therapy, subthalamic nucleus deep brain stimulation, and specific medications like quetiapine, clozapine, and antidepressants. The panel reached consensus on distinct treatment pathways for punding and dopamine dysregulation syndrome, formulating therapy recommendations. Comprehensive discussions addressed management strategies for the exacerbation of either motor or non-motor symptoms following the proposed treatments. CONCLUSION: The consensus offers in-depth insights into ICBD management, presenting clear severity criteria and expert consensus treatment recommendations. The study highlights the critical need for further research to enhance ICBD management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Estimulación Encefálica Profunda , Trastornos Disruptivos, del Control de Impulso y de la Conducta , Trastornos Mentales , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/tratamiento farmacológico , Consenso , Trastornos Mentales/terapia , Dopamina/metabolismo , Agonistas de Dopamina/uso terapéutico , Trastornos Disruptivos, del Control de Impulso y de la Conducta/etiología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/terapia
12.
Eur J Clin Microbiol Infect Dis ; 43(5): 999-1002, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38376633

RESUMEN

This case report details the management of a 79-year-old male with recurrent methicillin-resistant Staphylococcus capitis bacteremia and endocarditis. The patient's clinical journey encompassed multiple hospital admissions, with challenges in managing endocarditis, pacemaker replacements, and potential cutaneous sources of infection. The treatment regimen included intravenous antibiotic therapy during hospitalization and suppressive antibiotic treatment upon discharge, alongside a decolonization strategy for his scalp lesions.


Asunto(s)
Antibacterianos , Bacteriemia , Endocarditis Bacteriana , Staphylococcus capitis , Humanos , Masculino , Anciano , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Antibacterianos/uso terapéutico , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Endocarditis Bacteriana/diagnóstico , Staphylococcus capitis/efectos de los fármacos , Staphylococcus capitis/aislamiento & purificación , Staphylococcus capitis/genética , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/diagnóstico , Recurrencia
13.
Environ Res ; 263(Pt 1): 120013, 2024 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-39284488

RESUMEN

BACKGROUND: Lead exposure reduces the cognitive development and future economic prospects of children. While previous studies in high-income settings have explored productivity losses associated with lead exposure, limited research has focused on low and middle-income countries like Mexico. OBJECTIVES: This study aims to provide a comprehensive assessment of the economic implications of lead exposure on Mexican children using, for the first time, nationally representative Blood Lead Levels (BLLs) measurements in children aged 1-4, specifically focusing on the costs of forgone lifetime income due to cognitive losses. METHODS: BLLs of children aged 1-4 were extracted from the 2018-2019 National Health and Nutrition Survey (ENSANUT). Estimations of cognitive losses were derived from a log-linear relationship between BLLs and IQ loss. Lost lifetime economic productivity per child was calculated, assuming a 2% reduction in lifetime potential productivity for each IQ point lost due to lead exposure, based on previous literature (Attina and Trasande, 2013; Larsen and Sánchez-Triana, 2023). Productivity data were obtained from representative sources for Mexico. RESULTS: The estimated economic loss amounted to US $33.02 billion, equivalent to 2.76% of Mexico's Gross Domestic Product (GDP) in 2019 (calculated for a 1-year cohort). On a national scale, the long-term loss of cognition for children 1-4 years old is 4.14 IQ points per child due to lead exposure, with significant variability across States (range: 3.26 to 5.26). Lead-poisoned children (≥5 µg/dL) suffered an average loss of 6.42 IQ points (range: 0 to 6.97). In terms of economic impact, some States like Chiapas experienced losses of 7.08% of its GDP, while others had losses as low as 0.67%. Intriguingly, states with lower Human Development Index (HDIs) exhibited relatively higher economic losses despite lower average blood lead levels. DISCUSSION: The heterogeneous impact of lead exposure across Mexican states underscores the necessity for tailored regional policies. These findings emphasize the urgency for targeted interventions and informed policy measures to mitigate the socioeconomic consequences of lead exposure on Mexican children.

14.
BMC Public Health ; 24(1): 790, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38481210

RESUMEN

BACKGROUND: Significant consequences of COVID-19 within academic/professional life are, at the psychological level, related to worry, tension, stress; coping strategies and lifestyle changes. This study describes the process of design and validation of an inventory (QPIC), which aims to assess the psychological impact that a situation of confinement can produce among university students and teachers. METHODS: Design of the instrument and psychometric tests. A sample of 862 students and 229 professors affiliated to Spanish and Colombian universities was used. Data were collected in April 2020 with the request of the favourable Bioethics Committee IR/2020. RESULTS: Six experts carried out the content validation. A confirmatory factor analysis of the theoretical dimensions proposed for the scales was performed and the internal consistency of each of the three initial scales was confirmed (0.866, 0.813 and 0.834). CONCLUSION: A rigorous and reliable instrument is achieved, consisting of two final scales: (a) Worry, tension and stress scale (b) Coping scale, which helps to measure individual psychological effects in housebound situations. It is an instrument designed, constructed ad hoc to assess the impact of confinement and subjected to validation. The factor structure and reliability of the instrument are examined and good psychometric properties are obtained. The application of this inventory will make it possible to assess the impact on people's mental health during a period of confinement.


Asunto(s)
COVID-19 , Salud Mental , Humanos , Universidades , Reproducibilidad de los Resultados , Ansiedad , COVID-19/epidemiología , Psicometría , Encuestas y Cuestionarios
15.
Am J Bioeth ; 24(2): 69-90, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37155651

RESUMEN

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants' locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant's real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas.


Asunto(s)
Trastornos Mentales , Psiquiatría , Humanos , Inteligencia Artificial , Trastornos Mentales/terapia , Comités de Ética en Investigación , Investigadores
16.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-34531301

RESUMEN

Cell surface receptors are critical for cell signaling and constitute a quarter of all human genes. Despite their importance and abundance, receptor interaction networks remain understudied because of difficulties associated with maintaining membrane proteins in their native conformation and their typically weak interactions. To overcome these challenges, we developed an extracellular vesicle-based method for membrane protein display that enables purification-free and high-throughput detection of receptor-ligand interactions in membranes. We demonstrate that this platform is broadly applicable to a variety of membrane proteins, enabling enhanced detection of extracellular interactions over a wide range of binding affinities. We were able to recapitulate and expand the interactome for prominent members of the B7 family of immunoregulatory proteins such as PD-L1/CD274 and B7-H3/CD276. Moreover, when applied to the orphan cancer-associated fibroblast protein, LRRC15, we identified a membrane-dependent interaction with the tumor stroma marker TEM1/CD248. Furthermore, this platform enabled profiling of cellular receptors for target-expressing as well as endogenous extracellular vesicles. Overall, this study presents a sensitive and easy to use screening platform that bypasses membrane protein purification and enables characterization of interactomes for any cell surface-expressed target of interest in its native state.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Proteínas de la Membrana/metabolismo , Dominios y Motivos de Interacción de Proteínas , Antígenos CD/genética , Antígenos de Neoplasias/genética , Antígenos B7/genética , Antígeno B7-H1/genética , Células HEK293 , Humanos , Proteínas de la Membrana/genética
17.
Medicina (Kaunas) ; 60(5)2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38792901

RESUMEN

Background and Objectives: This retrospective cohort study analyzes mechanical complications in hip fracture surgery using the Trochanteric Fixation Nail-Advanced (TFNA) implant. It investigates the correlation of these complications with demographic, intraoperative, and radiological factors, aiming to identify associated risk factors and suggest improvements in clinical surveillance and treatment strategies. Materials and Methods: We enrolled 253 patients diagnosed with pertrochanteric hip fractures treated between 2017 and 2021, with 126 meeting the criteria for a minimum 6-month follow-up. Data on demographics, American Anesthesia Association Classification (ASA), comorbidities, AO/OTA [AO (Arbeitsgemeinschaft für Osteosynthesefragen)/OTA (Orthopedic Trauma Association)] fracture classification, procedural details, and time to failure were collected. Radiographs were evaluated for reduction quality, the tip-apex distance (TAD), progressive varus deviation, and identification of mechanical complications. Statistical analysis was performed using SPSS software. Results: The predominant AO/OTA fracture classification was 31A2 in 67 cases (52.7%). Reduction quality was deemed good or acceptable in 123 cases (97.6%). The mean time to failure was 4.5 months (range: 2.2-6). The average TAD was 18 mm (range: 1.2-36), with a mean progressive varus deviation of 2.44° (range: 1.30-4.14). A good or acceptable reduction quality was observed in 97.6% of cases. Mechanical complications occurred in 21.4% of patients, with significant associations found with the lateral cortex fracture, use of a TFNA implant with a 130° angle, open reduction, and absence of prior osteoporosis treatment. Conclusions: The study provides insights into mechanical complications in proximal femur fractures treated with the TFNA nail, emphasizing the need for enhanced clinical and radiographic surveillance, especially in patients without osteoporosis treatment. Our findings support the necessity for further clinical studies comparing these outcomes with other implant designs and underscore the importance of personalized treatment strategies to reduce complication rates.


Asunto(s)
Fijación Intramedular de Fracturas , Complicaciones Posoperatorias , Humanos , Estudios Retrospectivos , Femenino , Masculino , Fijación Intramedular de Fracturas/métodos , Fijación Intramedular de Fracturas/efectos adversos , Fijación Intramedular de Fracturas/instrumentación , Anciano , Anciano de 80 o más Años , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Fracturas de Cadera/cirugía , Clavos Ortopédicos , Estudios de Cohortes , Fracturas del Fémur/cirugía , Factores de Riesgo , Fracturas Femorales Proximales
18.
Actas Dermosifiliogr ; 2024 Sep 11.
Artículo en Inglés, Español | MEDLINE | ID: mdl-39271008

RESUMEN

INTRODUCTION: Clinical trials have validated the use of nivolumab and pembrolizumab as adjuvant therapies regarding relapse-free survival in patients with resected stage III and IV melanoma. Evidence in real-world patients is currently limited. MATERIAL AND METHOD: The CADIM trial (Characterization of adjuvant immunotherapy in melanoma patients) recruited a total of 81 patients with resected stage III and IV melanoma on nivolumab or pembrolizumab as adjuvant therapy from February 2018 through December 2022. RESULTS: The stage distribution rate was 81.5% (n=71) for stage III, while 15 patients (18.5%) had resected stage IV. Among stage III patients, 38 were stage IIIC (46.9%). With a median follow-up of 22.8 months, the relapse-free survival in the intention-to-treat population was 84% at one year and 81.5% at 2 years. The overall survival rate was 99% at one year and 91.4% at 2 years. Grade 3-4 treatment-related adverse events were reported in 12.3% of the patients. CONCLUSIONS: This study shows the results of resected stage III and IV melanoma patients on adjuvant therapy with anti-PD-1, and eventually confirmed the safety and efficacy profile described by clinical trials. Comparing clinical trial data with real-world evidence is necessary for a more practical, reliable, and accessible use of these drugs.

19.
N Engl J Med ; 382(20): 1916-1925, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32223113

RESUMEN

BACKGROUND: Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients. METHODS: In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator's judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding. RESULTS: A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding). CONCLUSIONS: Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).


Asunto(s)
Anticoagulantes/uso terapéutico , Enoxaparina/uso terapéutico , Extremidad Inferior/cirugía , Procedimientos Ortopédicos , Complicaciones Posoperatorias/prevención & control , Rivaroxabán/uso terapéutico , Tromboembolia Venosa/prevención & control , Administración Oral , Adulto , Anticoagulantes/efectos adversos , Método Doble Ciego , Enoxaparina/efectos adversos , Femenino , Hemorragia/inducido químicamente , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Embolia Pulmonar/prevención & control , Rivaroxabán/efectos adversos , Tromboembolia Venosa/mortalidad , Trombosis de la Vena/prevención & control
20.
J Med Virol ; 95(8): e29038, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37615363

RESUMEN

We aimed to estimate self-reported vaccine coverage and SARS-CoV-2 anti-N and anti-S seroprevalence in Mexico overall and for five vaccine types. We used a nationally representative survey with 7236 dried blood spot samples for adults 18 years and older collected from August to November 2021. Anti-N and anti-S seroprevalence were estimated adjusting for the sensitivity and specificity of the immunoassay test. A multivariate Poisson regression model was used to estimate seroprevalence by vaccine type and by age group adjusting for confounders and test performance. Vaccination coverage was 74%, being higher in women compared to men, high socioeconomic status (SES) compared to low and middle SES, graduates compared to people with high school, and formal workers compared to other employment statuses. Anti-N seroprevalence was 59.2%, compared to 84.1% anti-S seroprevalence. Anti-S seroprevalence was higher for vaccinated than unvaccinated participants. All vaccines were associated with more than 70% anti-S seroprevalence, with the lowest being observed for CoronaVac and Ad5-nCoV. Fully vaccinated participants over 60 years presented a lower seroprevalence (77.6%) compared to younger adults (91.1%), with larger differences for ChAdOx1 and CoronaVac vaccines. Between August and November 2021, three out of four Mexican adults had been vaccinated. Vaccination was associated with a higher positivity to anti-S antibodies. While antibodies do not reflect immunity, our results suggest that booster doses should be offered to people over 60 years of age and to adults who received Ad5-nCoV or CoronaVac as primary vaccination schemes.


Asunto(s)
COVID-19 , Vacunas , Adulto , Masculino , Humanos , Femenino , Persona de Mediana Edad , Anciano , México/epidemiología , SARS-CoV-2 , Estudios Seroepidemiológicos , COVID-19/epidemiología , COVID-19/prevención & control
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA