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2.
Cell Stem Cell ; 31(7): 1038-1057.e11, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38733993

RESUMEN

Enteroendocrine cells (EECs) secrete serotonin (enterochromaffin [EC] cells) or specific peptide hormones (non-EC cells) that serve vital metabolic functions. The basis for terminal EEC diversity remains obscure. By forcing activity of the transcription factor (TF) NEUROG3 in 2D cultures of human intestinal stem cells, we replicated physiologic EEC differentiation and examined transcriptional and cis-regulatory dynamics that culminate in discrete cell types. Abundant EEC precursors expressed stage-specific genes and TFs. Before expressing pre-terminal NEUROD1, post-mitotic precursors oscillated between transcriptionally distinct ASCL1+ and HES6hi cell states. Loss of either factor accelerated EEC differentiation substantially and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and non-EC cell features. These TFs mainly bind cis-elements that are accessible in undifferentiated stem cells, and they tailor subsequent expression of TF combinations that underlie discrete EEC identities. Thus, early TF oscillations retard EEC maturation to enable accurate diversity within a medically important cell lineage.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular , Células Enteroendocrinas , Factores de Transcripción , Humanos , Células Enteroendocrinas/metabolismo , Células Enteroendocrinas/citología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Linaje de la Célula
3.
World Neurosurg ; 187: e714-e721, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38692566

RESUMEN

BACKGROUND: Acute upper airway compromise is a rare but catastrophic complication after anterior cervical discectomy and fusion. This study aims to develop a score to identify patients at risk of acute postoperative airway compromise (PAC). METHODS: Potential risk factors for acute PAC were selected by a modified Delphi process. Ten patients with acute PAC were identified of 1466 patients who underwent elective anterior cervical discectomy and fusion between July 2014 and May 2019. A comparison group was created by a randomized selection process (non-PAC group). Factors associated with PAC and a P value of < 0.10 were entered into a logistic regression model and coefficients contributed to each risk factor's overall score. Calibration of the model was evaluated using the Hosmer-Lemeshow goodness-of-fit test. Quantitative discrimination was calculated, and the final model was internally validated with bootstrap sampling. RESULTS: We identified 18 potential risk factors from our Delphi process, of which 6 factors demonstrated a significant association with airway compromise: age >65 years, current smoking status, American Society of Anesthesiologists class >2, history of a bleeding disorder, surgery of upper subaxial cervical spine (above C4), and duration of surgery >179 minutes. The final prediction model included 5 predictors with very strong performance characteristics. These 5 factors formed the PAC score, with a range from 0 to 100. A score of 20 yielded the greatest balance of sensitivity (80%) and specificity (88%). CONCLUSIONS: The acute PAC score demonstrates strong performance characteristics. The PAC score might help identify patients at risk of upper airway compromise caused by surgical site abnormalities.


Asunto(s)
Vértebras Cervicales , Discectomía , Complicaciones Posoperatorias , Fusión Vertebral , Humanos , Vértebras Cervicales/cirugía , Masculino , Femenino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Fusión Vertebral/efectos adversos , Anciano , Discectomía/efectos adversos , Factores de Riesgo , Adulto , Técnica Delphi , Obstrucción de las Vías Aéreas/etiología
5.
J Immunol ; 212(11): 1639-1646, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38629913

RESUMEN

Recently, we reported that preexposure of B cells to IL-4 induced an alternate, signalosome-independent BCR signaling pathway leading to protein kinase C (PKC)δ phosphorylation (pTyr311), which occurs in the membrane compartment. This is considered to represent a form of receptor crosstalk and signal integration. Unlike the classical BCR signaling pathway, Lyn kinase is indispensable for BCR-induced downstream events in the alternate pathway. Our previous report that alternate BCR signaling leading to ERK phosphorylation is triggered by LPS and PAM3CSK4 (much like IL-4) raises the possibility that other signaling outcomes such as PKCδ phosphorylation might be similarly affected. To explore the range of mediators capable of producing an alternate pathway for BCR signaling, we examined PKCδ translocation and phosphorylation in LPS- and PAM3CSK4-treated B cells stimulated by anti-Ig. We found that LPS and PAM3CSK4 alter the signaling pathway used by the BCR to produce PKCδ phosphorylation. As with IL-4, elements of the signalosome are not needed for PKCδ phosphorylation when BCR triggering occurs after LPS and PAM3CSK4. However, with LPS and PAM3CSK4, anti-Ig-induced phosphorylation of PKCδ takes place in the cytosol, in contrast to the IL-4-induced alternate pathway, wherein PKCδ phosphorylation occurs in the membrane. Furthermore, the BCR signaling pathway induced by LPS and PAM3CSK4 differs from that induced by IL-4 by not requiring Lyn. Thus, an alternate, signalosome-independent BCR signaling pathway for PKCδ phosphorylation is induced by TLR agonists but differs in important ways from the alternate pathway induced by IL-4.


Asunto(s)
Interleucina-4 , Lipopéptidos , Lipopolisacáridos , Proteína Quinasa C-delta , Receptores de Antígenos de Linfocitos B , Transducción de Señal , Familia-src Quinasas , Proteína Quinasa C-delta/metabolismo , Fosforilación , Animales , Ratones , Lipopolisacáridos/farmacología , Interleucina-4/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Lipopéptidos/farmacología , Familia-src Quinasas/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Receptores Toll-Like/metabolismo , Ratones Endogámicos C57BL
6.
bioRxiv ; 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38260422

RESUMEN

Enteroendocrine cells (EECs), which secrete serotonin (enterochromaffin cells, EC) or a dominant peptide hormone, serve vital physiologic functions. As with any adult human lineage, the basis for terminal cell diversity remains obscure. We replicated human EEC differentiation in vitro , mapped transcriptional and chromatin dynamics that culminate in discrete cell types, and studied abundant EEC precursors expressing selected transcription factors (TFs) and gene programs. Before expressing the pre-terminal factor NEUROD1, non-replicating precursors oscillated between epigenetically similar but transcriptionally distinct ASCL1 + and HES6 hi cell states. Loss of either factor substantially accelerated EEC differentiation and disrupted EEC individuality; ASCL1 or NEUROD1 deficiency had opposing consequences on EC and hormone-producing cell features. Expressed late in EEC differentiation, the latter TFs mainly bind cis -elements that are accessible in undifferentiated stem cells and tailor the subsequent expression of TF combinations that specify EEC types. Thus, TF oscillations retard EEC maturation to enable accurate EEC diversification.

7.
JCO Precis Oncol ; 8: e2300349, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38237098

RESUMEN

PURPOSE: Cancer patients with advanced-stage disease have poor prognosis, typically having limited options for efficacious treatment, and genomics-based therapy guidance continues to benefit only a fraction of patients. Next-generation ex vivo approaches, such as cell mass-based response testing (MRT), offer an alternative precision medicine approach for a broader population of patients with cancer, but validation of clinical feasibility and potential impact remain necessary. MATERIALS AND METHODS: We evaluated the clinical feasibility and accuracy of using live-cell MRT to predict patient drug sensitivity. Using a unified measurement workflow with a 48-hour result turnaround time, samples were subjected to MRT after treatment with a panel of drugs in vitro. After completion of therapeutic course, clinical response data were correlated with MRT-based predictions of outcome. Specimens were collected from 104 patients with solid (n = 69) and hematologic (n = 35) malignancies, using tissue formats including needle biopsies, malignant fluids, bone marrow aspirates, and blood samples. Of the 81 (78%) specimens qualified for MRT, 41 (51%) patients receiving physician-selected therapies had treatments matched to MRT. RESULTS: MRT demonstrated high concordance with clinical responses with an odds ratio (OR) of 14.80 (P = .0003 [95% CI, 2.83 to 102.9]). This performance held for both solid and hematologic malignances with ORs of 20.67 (P = .0128 [95% CI, 1.45 to 1,375.57]) and 8.20 (P = .045 [95% CI, 0.77 to 133.56]), respectively. Overall, these results had a predictive accuracy of 80% (P = .0026 [95% CI, 65 to 91]). CONCLUSION: MRT showed highly significant correlation with clinical response to therapy. Routine clinical use is technically feasible and broadly applicable to a wide range of samples and malignancy types, supporting the need for future validation studies.


Asunto(s)
Neoplasias Hematológicas , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico
8.
Clin Chem Lab Med ; 62(5): 999-1010, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38037809

RESUMEN

OBJECTIVES: Sepsis is a life-threatening condition implicating an inadequate activation of the immune system. Platelets act as modulators and contributors to immune processes. Indeed, altered platelet turnover, thrombotic events, and changes in thrombopoietin levels in systemic inflammation have been reported, but thrombopoietin-levels in sepsis and septic-shock have not yet been systematically evaluated. We therefore performed a meta-analysis of thrombopoietin (TPO)-levels in patients with sepsis. METHODS: Two independent reviewers screened records and full-text articles for inclusion. Scientific databases were searched for studies examining thrombopoietin levels in adult sepsis and septic-shock patients until August 1st 2022. RESULTS: Of 95 items screened, six studies met the inclusion criteria, including 598 subjects. Both sepsis and severe sepsis were associated with increased levels of thrombopoietin (sepsis vs. control: standardized mean difference 3.06, 95 % CI 1.35-4.77; Z=3.50, p=0.0005) (sepsis vs. severe sepsis: standardized mean difference -1.67, 95 % CI -2.46 to -0.88; Z=4.14, p<0.0001). TPO-levels did not show significant differences between severe sepsis and septic shock patients but differed between sepsis and inflammation-associated non-septic controls. Overall, high heterogeneity and low sample size could be noted. CONCLUSIONS: Concluding, increased levels of thrombopoietin appear to be present both in sepsis and severe sepsis with high heterogeneity but thrombopoietin does not allow to differentiate between severe sepsis and septic-shock. TPO may potentially serve to differentiate sepsis from non-septic trauma and/or tissue damage related (systemic) inflammation. Usage of different assays and high heterogeneity demand standardization of methods and further large multicenter trials.


Asunto(s)
Sepsis , Choque Séptico , Adulto , Humanos , Trombopoyetina
9.
Nucleic Acids Res ; 52(D1): D61-D66, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37971305

RESUMEN

The Cistrome Data Browser is a resource of ChIP-seq, ATAC-seq and DNase-seq data from humans and mice. It provides maps of the genome-wide locations of transcription factors, cofactors, chromatin remodelers, histone post-translational modifications and regions of chromatin accessible to endonuclease activity. Cistrome DB v3.0 contains approximately 45 000 human and 44 000 mouse samples with about 32 000 newly collected datasets compared to the previous release. The Cistrome DB v3.0 user interface is implemented as a single page application that unifies menu driven and data driven search functions and provides an embedded genome browser, which allows users to find and visualize data more effectively. Users can find informative chromatin profiles through keyword, menu, and data-driven search tools. Browser search functions can predict the regulators of query genes as well as the cell type and factor dependent functionality of potential cis-regulatory elements. Cistrome DB v3.0 expands the display of quality control statistics, incorporates sequence logos into motif enrichment displays and includes more expansive sample metadata. Cistrome DB v3.0 is available at http://db3.cistrome.org/browser.


Asunto(s)
Cromatina , Bases de Datos de Proteínas , Genómica , Programas Informáticos , Animales , Humanos , Ratones , Cromatina/genética , Histonas/genética , Histonas/metabolismo , Análisis de Secuencia de ADN , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Visualización de Datos , Internet , Genómica/métodos
10.
JCI Insight ; 8(23)2023 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-37934865

RESUMEN

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and µMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.


Asunto(s)
Autoanticuerpos , Bacteriófagos , Humanos , Animales , Ratones , Proteoma , Autoinmunidad , Péptidos , Ratones Endogámicos NOD
11.
J Patient Rep Outcomes ; 7(1): 69, 2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37450086

RESUMEN

BACKGROUND: Standardized measures for evaluating patients' experiences with nonalcoholic steatohepatitis (NASH) and their perceived changes with treatment in clinical trials have been limited. To meet this need, a patient-reported outcome (PRO) measure, NASH-CHECK, was developed to evaluate symptoms and health-related quality of life for patients with NASH. The objective of this study was to conduct a quantitative evaluation of the psychometric properties of NASH-CHECK. METHODS: The study used data from a phase 2, randomized controlled trial of adult patients with NASH (NCT02855164). Analyses were conducted to determine the optimal scoring of NASH-CHECK and to evaluate reliability, construct validity, and ability to detect change in NASH-CHECK scale scores. RESULTS: Data were available for 253 patients with NASH (61% female; mean [standard deviation] age = 53 [12] years). Following initial item-level analyses, including correlations and exploratory factor analysis, three items were removed from the measure. Confirmatory factor analysis supported the formation of four multi-item scales (Cognitive Symptoms, Activity Limitations, Social Impact, and Emotional Impact) and five single-item scales (Abdominal Pain, Abdominal Bloating, Fatigue, Sleep, and Itchy Skin). Psychometric analyses of the final NASH-CHECK scales provided support for their internal reliability, test-retest reliability, construct validity, and ability to detect change. CONCLUSION: The results support NASH-CHECK as a reliable, valid, and responsive measure to assess patients' perspectives of symptoms and the health-related quality of life impact of NASH in clinical trials and in routine practice.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Calidad de Vida , Adulto , Humanos , Femenino , Persona de Mediana Edad , Masculino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Medición de Resultados Informados por el Paciente
12.
Nat Commun ; 14(1): 4126, 2023 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-37433791

RESUMEN

Cell state atlases constructed through single-cell RNA-seq and ATAC-seq analysis are powerful tools for analyzing the effects of genetic and drug treatment-induced perturbations on complex cell systems. Comparative analysis of such atlases can yield new insights into cell state and trajectory alterations. Perturbation experiments often require that single-cell assays be carried out in multiple batches, which can introduce technical distortions that confound the comparison of biological quantities between different batches. Here we propose CODAL, a variational autoencoder-based statistical model which uses a mutual information regularization technique to explicitly disentangle factors related to technical and biological effects. We demonstrate CODAL's capacity for batch-confounded cell type discovery when applied to simulated datasets and embryonic development atlases with gene knockouts. CODAL improves the representation of RNA-seq and ATAC-seq modalities, yields interpretable modules of biological variation, and enables the generalization of other count-based generative models to multi-batched data.


Asunto(s)
Ascomicetos , Aprendizaje Profundo , Bioensayo , Secuenciación de Inmunoprecipitación de Cromatina , Desarrollo Embrionario
13.
Sci Rep ; 13(1): 11095, 2023 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-37422484

RESUMEN

Scleractinian corals are primary contributors to the structural complexity of coral reef ecosystems. The structure derived from their carbonate skeletons underpins the biodiversity and myriad of ecosystem services provided by coral reefs. This study used a trait-based approach to provide new insights into the relationships between habitat complexity and coral morphology. Three-Dimensional (3D) photogrammetry techniques were used to survey 208 study plots on the island of Guam, from which structural complexity metrics were derived and physical traits of corals were quantified. Three traits at the individual colony level (e.g., morphology, size, and genera) and two site-level environmental characteristics (e.g., wave exposure and substratum-habitat type) were examined. Standard taxonomy-based metrics were also included at the reef-plot level (e.g., coral abundance, richness, and diversity). Different traits disproportionately contributed to 3D metrics of habitat complexity. Larger colonies with a columnar morphology have the highest contribution to surface complexity, slope, and vector ruggedness measure, whereas branching and encrusting columnar colonies have the highest contribution to planform and profile curvature. These results highlight the importance of considering colony morphology and size in addition to conventional taxonomic metrics for the understanding and monitoring reef structural complexity. The approach presented here provides a framework for studies in other locations to predict the trajectory of reefs under changing environmental conditions.


Asunto(s)
Antozoos , Arrecifes de Coral , Animales , Ecosistema , Guam , Biodiversidad
14.
Nat Commun ; 14(1): 2634, 2023 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-37149682

RESUMEN

Recent advances in single-cell RNA sequencing have shown heterogeneous cell types and gene expression states in the non-cancerous cells in tumors. The integration of multiple scRNA-seq datasets across tumors can indicate common cell types and states in the tumor microenvironment (TME). We develop a data driven framework, MetaTiME, to overcome the limitations in resolution and consistency that result from manual labelling using known gene markers. Using millions of TME single cells, MetaTiME learns meta-components that encode independent components of gene expression observed across cancer types. The meta-components are biologically interpretable as cell types, cell states, and signaling activities. By projecting onto the MetaTiME space, we provide a tool to annotate cell states and signature continuums for TME scRNA-seq data. Leveraging epigenetics data, MetaTiME reveals critical transcriptional regulators for the cell states. Overall, MetaTiME learns data-driven meta-components that depict cellular states and gene regulators for tumor immunity and cancer immunotherapy.


Asunto(s)
Epigénesis Genética , Microambiente Tumoral , Microambiente Tumoral/genética , Epigenómica , Inmunoterapia , Expresión Génica , Análisis de la Célula Individual
15.
bioRxiv ; 2023 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-37066405

RESUMEN

Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq), to profile mouse autoantibodies. This system and library were validated using seven genetic mouse models across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2-/- and µMT) were used to model non-specific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor (BCR)-restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate three distinct autoimmune disease models. First, serum from Lyn-/- IgD+/- mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities, lending support to the hypothesis that apoptosis is a shared origin of these antigens. Second, serum from non-obese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, enriched peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire-/- mouse sera were used to identify numerous auto-antigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 (APS1) carrying recessive mutations in AIRE. Among these were peptides derived from Perilipin-1, a validated autoimmune biomarker of generalized acquired lipodystrophy in humans. Autoreactivity to Perilipin-1 correlated with lymphocyte infiltration in adipose tissue and underscores the approach in revealing previously unknown specificities. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity.

16.
J Exp Med ; 220(7)2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37074415

RESUMEN

Autoinflammatory diseases include a number of monogenic systemic inflammatory diseases, as well as acquired autoinflammatory diseases such as gout. Here, we show that the myeloid Src-family kinases Hck, Fgr, and Lyn are critical for experimental models of gout, as well as for genetically determined systemic inflammation in the Ptpn6me-v/me-v (motheaten viable) mouse model. The Hck-/-Fgr-/-Lyn-/- mutation abrogated various monosodium urate (MSU) crystal-induced pro-inflammatory responses of neutrophils, and protected mice from the development of gouty arthritis. The Src-family inhibitor dasatinib abrogated MSU crystal-induced responses of human neutrophils and reduced experimental gouty arthritis in mice. The Hck-/-Fgr-/-Lyn-/- mutation also abrogated spontaneous inflammation and prolonged the survival of the Ptpn6me-v/me-v mice. Spontaneous adhesion and superoxide release of Ptpn6me-v/me-v neutrophils were also abolished by the Hck-/-Fgr-/-Lyn-/- mutation. Excessive activation of tyrosine phosphorylation pathways in myeloid cells may characterize a subset of autoinflammatory diseases.


Asunto(s)
Artritis Gotosa , Gota , Enfermedades Autoinflamatorias Hereditarias , Ratones , Humanos , Animales , Familia-src Quinasas/metabolismo , Neutrófilos/metabolismo , Proteínas Proto-Oncogénicas c-hck/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Artritis Gotosa/metabolismo , Gota/metabolismo , Inflamación/metabolismo , Enfermedades Autoinflamatorias Hereditarias/metabolismo
17.
Lancet Oncol ; 24(3): 273-285, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36858723

RESUMEN

BACKGROUND: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis. METHODS: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual. FINDINGS: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011). INTERPRETATION: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population. FUNDING: Genentech.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Masculino , Persona de Mediana Edad , Trastuzumab , Paclitaxel , Recurrencia Local de Neoplasia , Mama
18.
Am J Pathol ; 193(6): 702-724, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36868467

RESUMEN

HIV-1-associated nephropathy (HIVAN) is a severe complication of HIV-1 infection. To gain insight into the pathogenesis of kidney disease in the setting of HIV, a transgenic (Tg) mouse model [CD4C/HIV-negative regulator factor (Nef)] was used in which HIV-1 nef expression is under control of regulatory sequences (CD4C) of the human CD4 gene, thus allowing expression in target cells of the virus. These Tg mice develop a collapsing focal segmental glomerulosclerosis associated with microcystic dilatation, similar to human HIVAN. To identify kidney cells permissive to the CD4C promoter, CD4C reporter Tg lines were used. They showed preferential expression in glomeruli, mainly in mesangial cells. Breeding CD4C/HIV Tg mice on 10 different mouse backgrounds showed that HIVAN was modulated by host genetic factors. Studies of gene-deficient Tg mice revealed that the presence of B and T cells and that of several genes was dispensable for the development of HIVAN: those involved in apoptosis (Trp53, Tnfsf10, Tnf, Tnfrsf1b, and Bax), in immune cell recruitment (Ccl3, Ccl2, Ccr2, Ccr5, and Cx3cr1), in nitric oxide (NO) formation (Nos3 and Nos2), or in cell signaling (Fyn, Lck, and Hck/Fgr). However, deletion of Src partially and that of Hck/Lyn largely abrogated its development. These data suggest that Nef expression in mesangial cells through hematopoietic cell kinase (Hck)/Lck/Yes novel tyrosine kinase (Lyn) represents important cellular and molecular events for the development of HIVAN in these Tg mice.


Asunto(s)
Nefropatía Asociada a SIDA , Infecciones por VIH , Ratones , Humanos , Animales , Proteínas Tirosina Quinasas/metabolismo , Nefropatía Asociada a SIDA/genética , Nefropatía Asociada a SIDA/patología , Ratones Transgénicos , Infecciones por VIH/complicaciones , Tirosina , Familia-src Quinasas , Proteínas Proto-Oncogénicas c-hck
19.
Patient Relat Outcome Meas ; 14: 49-55, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36987518

RESUMEN

Introduction: Decision aids are effective tools in facilitating patient-centered care and patient involvement in the decision-making process. Given unique barriers to providing patient-centered care for Veterans, implementation of decision aids may improve overall quality of care. We aimed to assess the acceptability and feasibility of video-based and pamphlet-based decision aid use in Veterans with knee osteoarthritis. Materials and Methods: Veterans considering treatment for knee osteoarthritis received either an online video-based aid, pamphlet-based aid, or both before their surgical consult. At their visit, patients completed written pre-visit and post-visit questionnaires. The pre-visit questionnaire included questions about the patient's demographics, decision-making preferences, experiences using the assigned decision aids, and the Hip-Knee Decision Quality Instrument. The post-visit questionnaire assessed the patient's overall experience with the decision-making process and how use of the decision aid influenced their discussion with the physician. Results: All 16 patients who received the pamphlet-based aid reviewed the decision aid before their visit, compared to only five of the 12 patients who received the video-based aid. Thirteen of 20 patients indicated that they preferred to share treatment decision-making with their physician. Seventeen of 20 patients believed they would feel comfortable questioning the treatment recommendation of their surgeon after decision aid use. Most patients reported a positive experience using their decision aid, regardless of modality, and found it easily comprehensible and useful in visit preparation. A preference for a pamphlet-based aid was expressed by the majority of patients. Conclusion: Veterans considering treatment for knee osteoarthritis are well prepared to engage in a patient-centered care experience. Most patients preferred sharing the decision-making process with their physician and felt comfortable questioning them about treatment recommendations. Decision aids helped Veterans feel more informed about their treatment options and improved engagement and discussion with their physician. Pamphlet-based aids were utilized more reliably than video-based aids.

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