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Background The Computer-Based Assessment for Sampling Personal Characteristics (CASPer) is a situational judgment test (SJT) that assesses noncognitive skills like professionalism, communication, and empathy. There are no reports of the effects of race/ethnicity and sex on CASPer scores among residency applicants. Objective We examined the effects of race/ethnicity, sex, and United States vs international medical school attendance on CASPer performance. Methods Our anesthesiology residency program required all applicants for the 2021-2022 Match cycle to complete an online video and text-based SJT (CASPer). We compared these results, reported as z-scores, with self-identified race/ethnicity, sex, United States vs international medical school attendance, and United States Medical Licensing Examination (USMLE) Step 1 scores. Results Of the 1245 applicants who completed CASPer, 783 identified as male. The racial/ethnic distribution was 512 White, 412 Asian, 106 Black, 126 Hispanic, and 89 Other/No Answer. CASPer z-scores did not differ by sex. White candidates scored higher than Black (0.18 vs -0.57, P<.001) and Hispanic (0.18 vs -0.52, P<.001) candidates. Applicants attending US medical schools scored higher than those attending international medical schools (z-scores: 0.15 vs -0.68, P<.001). There was no correlation between CASPer z-scores and USMLE Step 1 scores. Conclusions Our results suggest that CASPer scores favor White applicants over Black and Hispanic ones and applicants attending US medical schools over those attending international medical schools.

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Anestesiología , Internado y Residencia , Juicio , Humanos , Anestesiología/educación , Masculino , Femenino , Estados Unidos , Criterios de Admisión Escolar , Evaluación Educacional/métodos , Etnicidad , Adulto , Factores Sexuales

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Internado y Residencia , Humanos

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Anestesia por Inhalación , Anestesia General , Anestesia por Inhalación/métodos , Anestésicos por Inhalación/administración & dosificación , Humanos

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BACKGROUND: Central nervous system complications are reported in an increasing number of patients with Coronavirus Disease 2019 (COVID-19). COVID-19-related Guillain-Barré syndrome (GBS) is of particular importance given its association with higher mortality rates and prolonged respiratory failure. REVIEW SUMMARY: We conducted a systematic review of published cases for COVID-19-related GBS, and provide a summary of clinical management strategies for these cases. Sixty-three studies, including 86 patients, were included. Seventy-six cases with reported outcome data were eligible for the outcome analysis. Ninety-nine percent of patients were diagnosed with COVID-19 before diagnosis of GBS (median: 14 d prior, interquartile range: 7 to 20). Intravenous immunotherapy (intravenous immunoglobulin: 0.4 g/kg/d for 5 d) was the most frequently used treatment approach. The review indicated that the outcome was not favorable in 26% of cases (persistent neurological deficits). A mortality rate of 3.5% was observed in patients with COVID-19-related GBS. CONCLUSIONS: Although evidence to support specific treatments is lacking, clinicians should consider the benefits of immunotherapy and plasma exchange in addition to the standard antimicrobial and supportive therapies for patients who meet the diagnostic criteria for acute sensory and motor polyradiculoneuritis. Intravenous immunoglobulin treatment alone is not shown to result in improved outcomes or mortality. More extensive studies aimed at exploring the neurological manifestations and complications of COVID-19 and distinctive treatment options for COVID-19-related GBS are warranted.

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Tratamiento Farmacológico de COVID-19 , Síndrome de Guillain-Barré , Inmunoglobulinas Intravenosas , SARS-CoV-2 , Neoplasias de la Tiroides , Humanos , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Intercambio Plasmático/métodos , Plasmaféresis/efectos adversos , Plasmaféresis/métodos , SARS-CoV-2/efectos de los fármacos , Neoplasias de la Tiroides/tratamiento farmacológico

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INTRODUCTION: Successes from anesthesiologist-led perioperative surgical homes in the adult patient population have inspired similar initiatives by pediatric hospitals. Typically the care coordination for these perioperative homes is run through hospital-funded, on-site, preanesthesia clinics. Preliminary data from pediatric perioperative homes have shown promising results in improved patient outcomes and decreased length of hospital stay. The majority of pediatric surgeries within the country are performed in nonpediatric hospitals. Such centers may not have the infrastructure or financial resources for a freestanding pediatric preanesthesia clinic. Faced with this situation at the largest safety net hospital in New England, the authors present their experience designing and implementing a "Virtual Pediatric Perioperative Home," a telemedicine-based triage and preanesthetic optimization for pediatric patients at Boston Medical Center, Boston, MA. METHODS: A retrospective chart review of all pediatric anesthesia cases at Boston Medical Center from February 1, 2019, to January 31, 2020, as well as the number of pediatric cases canceled or postponed on the day of surgery for any reason during the same time period was conducted. RESULTS: From February 1, 2019, to January 31, 2020, 1546 anesthetics were performed in children 18 years and under. Of those, 63 were designated as emergent and hence excluded from our analysis. 153 of the total 1483 (9.4%) of nonemergent bookings were canceled or postponed on the day of surgery. This represented a marked decline from our previous year's 13.7% same-day cancellation rate for pediatric patients. The most common reason for case cancellations (41.8%) was acute illness. Cancellation rates varied from month to month, with the highest cancellation rate of the year in September 2019 (18.8%). The departments of Podiatry and Gastroenterology represented the highest cancellation rates as a denominator of their case volumes, 15.4% and 15.2%, respectively. Younger children had 2.4 times the odds (95% CI: 1.720, 3.4) of cancellation compared to older children. DISCUSSION: The virtual pediatric perioperative home (VPPH) may benefit quality of care while decreasing costs to pediatric patients, families, and hospital systems. While direct financial gains may be difficult to demonstrate, the VPPH has the potential to reduce OR delays and same day cancellations related to questions of medical optimization. In the context of a socioeconomically disadvantaged patient population, our VPPH's team of subspecialists created inroads for at risk children to establish or reestablish care for their comorbidities, while collaboration with the Department of Children and Families further streamlined communication and consent for pediatric patients in foster care. CONCLUSIONS: The authors describe the design and successful implementation of a telemedicine-based pediatric preanesthesia triage and medical optimization service at a large safety net hospital. By creating a communication network of pediatric subspecialists, the anesthesiologists were able to, at minimal institutional cost, coordinate care for children with a variety of comorbidities leading up to the day of surgery. This yielded a 9.4% same day cancellation rate in a complex, socioeconomically disadvantaged pediatric patient population at a general hospital.

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Hospitales Pediátricos , Proveedores de Redes de Seguridad , Adolescente , Adulto , Boston , Niño , Humanos , Tiempo de Internación , Estudios Retrospectivos

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BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections. CONCLUSION: Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.

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ABSTRACT: Extramedullary multiple myeloma (EMM) is a subset of multiple myeloma with a poor prognosis. We report a rare case with biopsy-proven concurrent liver and mesentery primary EMM at the time of initial staging after serologic diagnosis of multiple myeloma. 18F-FDG PET/CT is valuable in detection of EMM when the patient has no osseous lesions and a negative bone marrow biopsy.

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Fluorodesoxiglucosa F18 , Neoplasias Hepáticas/diagnóstico por imagen , Mesenterio , Mieloma Múltiple/diagnóstico por imagen , Neoplasias Primarias Múltiples/diagnóstico por imagen , Neoplasias Peritoneales/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Anciano , Biopsia , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Neoplasias Primarias Múltiples/patología , Neoplasias Peritoneales/patología

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PURPOSE: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel-Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. EXPERIMENTAL DESIGN: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. RESULTS: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. CONCLUSIONS: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.

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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/mortalidad , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Renales/mortalidad , Macrófagos Asociados a Tumores/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/análisis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/terapia , Línea Celular Tumoral , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Nefrectomía , Pronóstico , RNA-Seq , Estudios Retrospectivos , Análisis de la Célula Individual , Análisis de Supervivencia , Macrófagos Asociados a Tumores/inmunología

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BACKGROUND: Brachiocephalic arteriovenous fistulas (BCFs) are commonly placed in outpatient settings. The impact of general anesthesia (GA), regional anesthesia (RA), or local anesthesia (LA) on perioperative recovery and fistula maturation/patency after outpatient BCF creations is unknown. We evaluated whether outcomes of outpatient BCF creations vary based on anesthesia modality. METHODS: The Vascular Quality Initiative (2011-2018) national database was queried for outpatient BCF creations. Anesthesia modalities included GA, RA, and LA. Perioperative, 3-month, and 1-year outcomes were compared between GA versus RA/LA anesthesia types. RESULTS: Among 3,527 outpatient BCF creations, anesthesia types were GA in 1,043 (29.6%), RA in 1,150 (32.6%), and LA in 1,334 (37.8%). Patients receiving GA were more often younger, obese, Medicaid recipients, without coronary artery disease, and treated in non-office-based settings (P < 0.05 for all). GA compared with RA/LA cohorts were more often admitted postoperatively (5.3% vs. 2.4%, P < 0.001) but had similar rates of thirty-day mortality (0.9 vs. 0.6%, P = 0.39). 3-month access utilization for hemodialysis was lower in GA than in RA/LA cohorts (12.6% vs. 23.6%, P < 0.001). The Kaplan-Meier analysis showed that GA and RA/LA cohorts had similar 1-year primary access occlusion-free survival (43.6% vs. 47.1%, P = 0.24) and endovascular/open reintervention-free survival (57.2% vs. 57.6%, P = 0.98). On multivariable analysis, GA compared with RA/LA use was independently associated with increased postoperative admission (odds ratio [OR]: 1.7, 95% confidence interval [CI]: 1.08-2.67, P = 0.02) and decreased 3-month access utilization (OR: 0.39, 95% CI: 0.25-0.61, P < 0.001) but had similar 1-year access occlusion (hazard ratio [HR]: 1.09, 95% CI: 0.9-1.32, P = 0.36) and reintervention (HR: 1.02, 95% CI: 0.82-1.26, P = 0.88). On subgroup analysis of the RA/LA cohort, RA compared with LA was associated with increased 3-month access utilization (OR: 1.6, 95% CI: 1.01-2.5; P = 0.04) and 1-year access reintervention (HR: 1.46, 95% CI: 1.12-1.89), but had similar 1-year access occlusion (HR: 1.2, 95% CI: 0.95-1.51, P = 0.13). CONCLUSIONS: Compared with RA/LA use, GA use in patients undergoing outpatient BCF creations was associated with increased hospital admissions, decreased access utilization at 3 months, and similar 1-year access occlusion and reintervention. RA/LA is preferable to expedite recovery and access utilization.

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Procedimientos Quirúrgicos Ambulatorios , Anestesia de Conducción , Anestesia General , Derivación Arteriovenosa Quirúrgica , Diálisis Renal , Extremidad Superior/irrigación sanguínea , Anciano , Procedimientos Quirúrgicos Ambulatorios/efectos adversos , Anestesia de Conducción/efectos adversos , Anestesia General/efectos adversos , Anestesia Local/efectos adversos , Derivación Arteriovenosa Quirúrgica/efectos adversos , Canadá , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Grado de Desobstrucción Vascular

RESUMEN

Small cell lung cancer (SCLC) is a neuroendocrine tumor treated clinically as a single disease with poor outcomes. Distinct SCLC molecular subtypes have been defined based on expression of ASCL1, NEUROD1, POU2F3, or YAP1. Here, we use mouse and human models with a time-series single-cell transcriptome analysis to reveal that MYC drives dynamic evolution of SCLC subtypes. In neuroendocrine cells, MYC activates Notch to dedifferentiate tumor cells, promoting a temporal shift in SCLC from ASCL1+ to NEUROD1+ to YAP1+ states. MYC alternatively promotes POU2F3+ tumors from a distinct cell type. Human SCLC exhibits intratumoral subtype heterogeneity, suggesting that this dynamic evolution occurs in patient tumors. These findings suggest that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.

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Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Tumores Neuroendocrinos/genética , Proteínas Proto-Oncogénicas c-myc/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Heterogeneidad Genética , Humanos , Neoplasias Pulmonares/metabolismo , Ratones Noqueados , Tumores Neuroendocrinos/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Análisis de la Célula Individual , Carcinoma Pulmonar de Células Pequeñas/metabolismo

RESUMEN

BACKGROUND: Single cell RNA sequencing (scRNAseq) has provided invaluable insights into cellular heterogeneity and functional states in health and disease. During the analysis of scRNAseq data, annotating the biological identity of cell clusters is an important step before downstream analyses and it remains technically challenging. The current solutions for annotating single cell clusters generally lack a graphical user interface, can be computationally intensive or have a limited scope. On the other hand, manually annotating single cell clusters by examining the expression of marker genes can be subjective and labor-intensive. To improve the quality and efficiency of annotating cell clusters in scRNAseq data, we present a web-based R/Shiny app and R package, Cluster Identity PRedictor (CIPR), which provides a graphical user interface to quickly score gene expression profiles of unknown cell clusters against mouse or human references, or a custom dataset provided by the user. CIPR can be easily integrated into the current pipelines to facilitate scRNAseq data analysis. RESULTS: CIPR employs multiple approaches for calculating the identity score at the cluster level and can accept inputs generated by popular scRNAseq analysis software. CIPR provides 2 mouse and 5 human reference datasets, and its pipeline allows inter-species comparisons and the ability to upload a custom reference dataset for specialized studies. The option to filter out lowly variable genes and to exclude irrelevant reference cell subsets from the analysis can improve the discriminatory power of CIPR suggesting that it can be tailored to different experimental contexts. Benchmarking CIPR against existing functionally similar software revealed that our algorithm is less computationally demanding, it performs significantly faster and provides accurate predictions for multiple cell clusters in a scRNAseq experiment involving tumor-infiltrating immune cells. CONCLUSIONS: CIPR facilitates scRNAseq data analysis by annotating unknown cell clusters in an objective and efficient manner. Platform independence owing to Shiny framework and the requirement for a minimal programming experience allows this software to be used by researchers from different backgrounds. CIPR can accurately predict the identity of a variety of cell clusters and can be used in various experimental contexts across a broad spectrum of research areas.

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Internet , Anotación de Secuencia Molecular , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Programas Informáticos , Algoritmos , Animales , Secuencia de Bases , Agregación Celular , Análisis por Conglomerados , Bases de Datos Genéticas , Humanos , Ratones

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Challenges with distinguishing circulating tumor DNA (ctDNA) from next-generation sequencing (NGS) artifacts limits variant searches to established solid tumor mutations. Here we show early and random PCR errors are a principal source of NGS noise that persist despite duplex molecular barcoding, removal of artifacts due to clonal hematopoiesis of indeterminate potential, and suppression of patterned errors. We also demonstrate sample duplicates are necessary to eliminate the stochastic noise associated with NGS. Integration of sample duplicates into NGS analytics may broaden ctDNA applications by removing NGS-related errors that confound identification of true very low frequency variants during searches for ctDNA without a priori knowledge of specific mutations to target.

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ADN Tumoral Circulante/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Adulto , Código de Barras del ADN Taxonómico , Femenino , Hematopoyesis/genética , Humanos , Masculino , Persona de Mediana Edad

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Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding ß-catenin. HCC-associated CTNNB1 mutations stabilize the ß-catenin protein, leading to nuclear and/or cytoplasmic localization of ß-catenin and downstream activation of Wnt target genes. In patient HCC samples, ß-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in ß-catenin activation are not well understood. To define mechanisms of ß-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated ß-catenin in (1) a small number of hepatocytes in early development; or (2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated ß-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/ß-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish ß-catenin-driven HCC. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish ß-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous ß-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.

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PURPOSE: We previously reported an interaction with warfarin anticoagulation when initiating treatment with direct-acting antiviral agents for hepatitis C infection. A decreased warfarin sensitivity led to subtherapeutic anticoagulation. To study this interaction further, we expanded our research to include patients treated with the combination of elbasvir and grazoprevir concurrent with warfarin anticoagulation and investigated changes in warfarin sensitivity during and after treatment. METHODS: Using electronic health records of the Veterans Health Administration, patients starting treatment with elbasvir-grazoprevir for hepatitis C infection concurrent with warfarin anticoagulation were identified. Inclusion required stable warfarin anticoagulation prior to 12 weeks of treatment with elbasvir-grazoprevir. A warfarin sensitivity index (WSI) was calculated at the start of treatment, after 12 weeks after treatment, and at the end of treatment. The primary endpoint was the difference in WSI from pre- to end-treatment. The secondary endpoint was the WSI difference from before treatment to Changes in International Normalized Ratio, warfarin doses, and time in therapeutic range were measured. RESULTS: In the final sample of 43 patients, the mean WSI decreased during treatment from 0.53 to 0.40, or 25.2%. After treatment, the mean WSI rose to 0.51. Although the mean weekly warfarin dose increased from 40.3 to 44.6 mg during treatment, the mean International Normalized Ratio decreased from 2.40 to 1.96, recovering to 2.59 after treatment. The time spent in therapeutic range decreased from 74.1% before treatment to 39.8% during treatment and back to 64.9% 12 weeks posttreatment. CONCLUSION: When elbasvir-grazoprevir was added to stable warfarin anticoagulation, warfarin sensitivity decreased significantly during treatment and returned to baseline after treatment.

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Antivirales/administración & dosificación , Benzofuranos/administración & dosificación , Hepatitis C/tratamiento farmacológico , Imidazoles/administración & dosificación , Quinoxalinas/administración & dosificación , Warfarina/farmacología , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacología , Antivirales/farmacología , Benzofuranos/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Interacciones Farmacológicas , Humanos , Imidazoles/farmacología , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Quinoxalinas/farmacología , Estudios Retrospectivos , Warfarina/administración & dosificación

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BACKGROUND: The authors' purpose was to evaluate the histopathology of flexor tenosynovium in true, idiopathic recurrent carpal tunnel syndrome for the presence of abnormal inflammatory or pathologic findings that might explain causation or that differ from those previously described for primary, idiopathic carpal tunnel syndrome. METHODS: Thirty-five patients (19 women and 16 men; mean age, 72 years) underwent open revision carpal tunnel release a mean 13 years (range, 0.5 to 30 years) after primary carpal tunnel release. Recurrence was confirmed by recurrent symptoms, positive provocative tests, and electrodiagnostic testing. All patients underwent tenosynovial biopsy, including Congo red staining for amyloid. RESULTS: Histopathologic findings demonstrated noninflammatory, fibrous connective tissue in 31 of 35 patients (89 percent); and mild, chronic inflammation (without granulomas) in four of 35 patients (11 percent). Nine of 35 patients (26 percent) had positive results for amyloid, with a statistically higher incidence in men (p = 0.03) and advanced age (p = 0.02). Subtyping performed in eight of nine amyloid-positive specimens confirmed seven cases of transthyretin-type amyloid typically seen in localized (senile) amyloidosis and one case of light-chain amyloid in a patient who was subsequently diagnosed with myeloma. CONCLUSIONS: Flexor tenosynovium in patients with recurrent carpal tunnel syndrome does not appear to be substantially different histologically from that previously described in primary idiopathic carpal tunnel syndrome, although a slightly higher prevalence of amyloid was seen in this group (especially older men). No patients have developed systemic amyloidosis. Routine biopsy of tenosynovium in idiopathic, recurrent carpal tunnel syndrome is unnecessary.

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Síndrome del Túnel Carpiano/patología , Síndrome del Túnel Carpiano/cirugía , Sinovectomía/métodos , Membrana Sinovial/patología , Tendones/patología , Adulto , Factores de Edad , Anciano , Biopsia con Aguja , Estudios de Cohortes , Bases de Datos Factuales , Descompresión Quirúrgica/métodos , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Resultado del Tratamiento

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The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.

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Diferenciación Celular/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Factores de Transcripción SOXB1/inmunología , Microambiente Tumoral/inmunología , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Diferenciación Celular/genética , Línea Celular Tumoral , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Factor Nuclear Tiroideo 1/genética , Factor Nuclear Tiroideo 1/metabolismo , Microambiente Tumoral/genética

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We propose a novel conditional graphical model - spaceMap - to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation of DNA copy number alterations (CNAs) on downstream protein levels in tumors. Through a penalized multivariate regression framework, spaceMap jointly models high dimensional protein levels as responses and high dimensional CNAs as predictors. In this setup, spaceMap infers an undirected network among proteins together with a directed network encoding how CNAs perturb the protein network. spaceMap can be applied to learn other types of regulatory relationships from high dimensional molecular profiles, especially those exhibiting hub structures. Simulation studies show spaceMap has greater power in detecting regulatory relationships over competing methods. Additionally, spaceMap includes a network analysis toolkit for biological interpretation of inferred networks. We applies spaceMap to the CNAs, gene expression and proteomics data sets from CPTAC-TCGA breast (n=77) and ovarian (n=174) cancer studies. Each cancer exhibits disruption of 'ion transmembrane transport' and 'regulation from RNA polymerase II promoter' by CNA events unique to each cancer. Moreover, using protein levels as a response yields a more functionally-enriched network than using RNA expressions in both cancer types. The network results also help to pinpoint crucial cancer genes and provide insights on the functional consequences of important CNA in breast and ovarian cancers. The R package spaceMap - including vignettes and documentation - is hosted on https://topherconley.github.io/spacemap.

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Neoplasias de la Mama/genética , Biología Computacional/métodos , Variaciones en el Número de Copia de ADN , Neoplasias Ováricas/genética , Femenino , Humanos

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The life expectancy of patients with chronic phase chronic myeloid leukemia on tyrosine kinase inhibitor therapy now approaches that of the general population. Approximately 60% of patients treated with second generation tyrosine kinase inhibitors achieve a deep molecular response, the prerequisite for a trial of treatment-free remission. Those patients unlikely to achieve deep molecular response may benefit from more intensive therapy up front. To identify biomarkers predicting deep molecular response we performed transcriptional profiling on CD34+ progenitor cells from newly diagnosed chronic phase chronic myeloid leukemia patients treated with nilotinib on a prospective clinical trial. Using unsupervised and targeted analytical strategies, we show that gene expression profiles are similar in patients with and without subsequent deep molecular response. This result is in contrast to the distinct expression signature of CD34+ chronic phase chronic myeloid leukemia patients failing to achieve a cytogenetic response on imatinib and suggests that deep molecular response to second-generation tyrosine kinase inhibitors is governed by the biology of more primitive chronic myeloid leukemia cells or extrinsic factors.