Non-small cell lung cancer (NSCLC) collective invasion is supported by cooperativity of proliferative (follower) and invasive (leader) cells. H1299-isolated follower cells exhibit higher Yes-associated protein (YAP) expression, while leader cells were found to express elevated transcriptional coactivator with PDZ-binding motif (TAZ/WWTR1) expression. Suppressing TAZ (not YAP) in leader cells reduced invasion.
View Article and Find Full Text PDFPre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive.
View Article and Find Full Text PDFThe notion of a two-hit or multi-hit model of carcinogenesis dates to at least the 1970's and work done by Alfred Knudson. This concept was considered in the design and execution of a previous FLP/FRT screen in for conditional growth suppressors. During the course of this work, the lethal allele was identified as being of phenotypic interest.
View Article and Find Full Text PDFThe genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. To address this, rapid and genetically tractable animal models are needed that recapitulate the heterogeneity of RAS-driven cancers in vivo. Here, we generate a Drosophila melanogaster model of Ras/Lkb1 mutant carcinoma.
View Article and Find Full Text PDFThe US is facing a rise in vaccine hesitancy, delay, and refusal, though little is known about these outcomes in socio-economically disadvantaged populations. This study examines the prevalence and correlates of vaccine attitudes and behaviors in a diverse cohort of low-income mothers receiving home visiting services. Survey data were collected from 813 recipients of evidence-based home visiting services in Wisconsin from 2013 to 2018.
View Article and Find Full Text PDFLiver kinase B1 ()-inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77-1726, inhibits dihydroorotate dehydrogenase, which is essential for pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors , and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models.
View Article and Find Full Text PDFIntroduction: The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established.
Methods: We generated new RNA sequencing expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA sequencing data generated from 51 SCLC cell lines and 81 primary human SCLC samples.
Background: Research suggests that home visiting interventions can promote breastfeeding initiation, though their effects on breastfeeding continuation are unclear. No known studies have assessed the impact of home visiting on bedsharing.
Aims: To test the effects of home visiting on breastfeeding and bedsharing in a low-income, urban sample in the United States.
Treatment with fludarabine phosphate (9-β-D-arabinofuranosyl-2-F-adenine 5'-phosphate, F-araAMP) leads to regressions and cures of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (EcPNP). This occurs despite the fact that fludarabine (F-araA) is a relatively poor substrate for EcPNP, and is cleaved to liberate 2-fluoroadenine at a rate only 0.3% that of the natural E.
View Article and Find Full Text PDFMatern Child Health J
February 2020
Objectives: This study examined the prevalence and correlates of maternal and infant sleep problems among low-income families receiving home visiting services.
Methods: The study sample includes 1142 mother-infant dyads in Wisconsin, United States. Women completed a survey when their infants were between two weeks and one year old.
Introduction: Many service providers report concerns that questions about adverse events may upset clients. Studies indicate that most survey respondents answer sensitive questions without experiencing distress, although little is known about the prevalence or correlates of clients' discomfort when they are asked similar questions by direct care providers, such as home visitors.
Methods: This study used data collected between 2013 and 2018 from 1,678 clients and 161 providers in a network of home visiting programs in Wisconsin.
Clin Cancer Res
January 2018
Vimentin is an epithelial-to-mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis.
View Article and Find Full Text PDFA rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes.
View Article and Find Full Text PDFLoss of LKB1 activity is prevalent in mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype.
View Article and Find Full Text PDFIntroduction: After a failed transplant, management of a non-functional graft with pain or recurrent infections can be challenging. Transplant nephrectomy (TN) can be a morbid procedure with the potential for significant blood loss. Embolization of the renal artery alone has been proposed as a method of reducing complications from an in vivo failed kidney transplant.
View Article and Find Full Text PDFLiver kinase β1 (LKB1, also known as STK11) is a serine/threonine kinase that has multiple cellular functions including the regulation of cell polarity and motility. Murine proteomic studies show that LKB1 loss causes aberrant adhesion signaling; however, the mechanistic underpinnings of this relationship are unknown. We show that cells stably depleted of LKB1 or its co-activator STRADα have increased phosphorylation of focal adhesion kinase (FAK) at Tyr(397)/Tyr(861) and enhanced adhesion to fibronectin.
View Article and Find Full Text PDFIntroduction: Laparoscopy is a standard surgical option for live donor nephrectomy (LDN) at the majority of transplant centers. Equivalent graft survival with shorter convalescence has been reported by several large volume centers. With the arrival of an experienced laparoscopic surgeon in 2002, we began to offer laparoscopic LDN at our institution.
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