The Locus Ceruleus in PTSD

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Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. Lacking effective therapeutic options hinders treatment of TNBC. Here, we show that bepridil (BPD) and trifluoperazine (TFP), which are FDA-approved drugs for treatment of schizophrenia and angina respectively, inhibit Akt-pS473 phosphorylation and promote FOXO3 nuclear localization and activation in TNBC cells. BPD and TFP inhibit survival and proliferation in TNBC cells and suppress the growth of TNBC tumors, whereas silencing FOXO3 reduces the BPD- and TFP-mediated suppression of survival in TNBC cells. While BPD and TFP decrease the expression of oncogenic c-Myc, KLF5, and dopamine receptor DRD2 in TNBC cells, silencing FOXO3 diminishes BPD- and TFP-mediated repression of the expression of these proteins in TNBC cells. Since c-Myc, KLF5, and DRD2 have been suggested to increase cancer stem cell-like populations in various tumors, reducing these proteins in response to BPD and TFP suggests a novel FOXO3-dependent mechanism underlying BPD- and TFP-induced apoptosis in TNBC cells

Growing Pains: An Exploration of Etsy Policy and Seller Satisfaction

Online craft marketplaces (including apparel and accessories), where microbusinesses sell their designs and products, blossomed in 2005 with the entrance of Etsy. Today, Etsy remains the largest online marketplace with the greatest number of sellers and buyers. However, it is not known if Etsy provides the resources needed for sellers to grow their businesses or the level of seller satisfaction with services provided. A qualitative exploratory approach was used to investigate Etsy policies and seller satisfaction with Etsy services. To gain a holistic understanding of the issue under study, data sources representing differing viewpoints were content analyzed. Results indicated that although Etsy provided documentation outlining its House Rules, sellers were extremely dissatisfied with Etsy\u27s policies on store termination and communication with sellers. Recommendations for reducing seller risk on the marketplace were provided

Advance Care Planning in Faith Communities: A Quality Improvement Project

This quality improvement project examined the impact of providing an advance care planning training tool to faith community nurses in the community setting on advance care planning knowledge, self-efficacy, and implementation of advance care planning outreach and advance directive completion. The pre- and post-intervention frequencies measure and paired-t test survey design resulted in clinically significant improvements in knowledge, and self-efficacy of advance care planning among faith community nurses. A fifty-fold increase was seen in advance care planning outreach activities among the group from pre- to post-intervention. The limitations of the project included small sample size and short implementation timing. However, the role of the faith community nurse in promoting and engaging in advance care planning to help communities move toward goal concordant care is clear

Treating Lennox–Gastaut syndrome in epileptic pediatric patients with third-generation rufinamide

Lennox–Gastaut syndrome (LGS) is a rare but debilitating pediatric epileptic encephalopathy characterized by multiple intractable seizure types. Treatment of LGS is challenging because of the small number of antiepileptic drugs (AEDs) which are effective for this syndrome, as well as the need for polytherapy in the majority of patients. This review focuses on the treatment of LGS with rufinamide, a recently approved third-generation AED with reported efficacy as adjunctive therapy for LGS. All relevant papers identified through a PubMed search on the treatment of LGS with rufinamide were reviewed. To date, the literature suggests improvements in seizure frequency for pediatric patients with LGS on rufinamide. Rufinamide appears to be especially effective for atonic or drop attack seizures. Rufinamide also displays a favorable adverse event profile compared with the older anticonvulsants, as well as a minimal number of drug interactions, making it a promising option for the adjunctive treatment of seizures associated with LGS

Molecular mechanisms of amyotrophic lateral sclerosis as broad therapeutic targets for gene therapy applications utilizing adeno-associated viral vectors

Despite the devastating clinical outcome of the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), its etiology remains mysterious. Approximately 90% of ALS is characterized as sporadic, signifying that the patient has no family history of the disease. The development of an impactful disease modifying therapy across the ALS spectrum has remained out of grasp, largely due to the poorly understood mechanisms of disease onset and progression. Currently, ALS is invariably fatal and rapidly progressive. It is hypothesized that multiple factors can lead to the development of ALS, however, treatments are often focused on targeting specific familial forms of the disease (10% of total cases). There is a strong need to develop disease modifying treatments for ALS that can be effective across the full ALS spectrum of familial and sporadic cases. Although the onset of disease varies significantly between patients, there are general disease mechanisms and progressions that can be seen broadly across ALS patients. Therefore, this review explores the targeting of these widespread disease mechanisms as possible areas for therapeutic intervention to treat ALS broadly. In particular, this review will focus on targeting mechanisms of defective protein homeostasis and RNA processing, which are both increasingly recognized as design principles of ALS pathogenesis. Additionally, this review will explore the benefits of gene therapy as an approach to treating ALS, specifically focusing on the use of adeno-associated virus (AAV) as a vector for gene delivery to the CNS and recent advances in the field

Remarkable Presentation: Anaplastic Thyroid Carcinoma Arising from Chronic Hyperthyroidism

Background. Undifferentiated anaplastic carcinoma rarely develops from chronic hyperthyroidism. Although acute hyperthy- roidism can develop prior to anaplastic transformation, chronic hyperthyroidism was thought to be a protective measure against thyroid malignancy. Methods. A 79-year-old female presented acutely to the hospital with dyspnea. She had been taking methimazole for chronic hyperthyroidism due to toxic thyroid nodules, previously biopsied as benign. Upon admission, imaging showed tracheal compression, requiring a total thyroidectomy with tracheostomy for airway management. Results. Pathology demonstrated undifferentiated anaplastic thyroid carcinoma. The patient passed away shortly after hospital discharge. Despite treatment with methimazole for many years, abrupt enlargement of her toxic multinodular goiter was consistent with malignant transformation. Chronic hyperthyroidism and toxic nodules are rarely associated with thyroid malignancy, with only one previous report documenting association with anaplastic thyroid carcinoma. Conclusion. Progressive thyroid enlargement and acute worsening of previously controlled hyperthyroidism should promote concern for disease regardless of baseline thyroid function

Characterisation of Death Receptor 3 dependent aortic changes during inflammatory arthritis

Murine collagen‐induced arthritis (mCIA) is characterized by decreased vascular constriction responses and increased MMP‐9. Here, we describe additional histological alterations within the aorta and surrounding perivascular adipose tissue (PVAT), study the role of PVAT in constriction response, and investigate the potential involvement of death receptor 3 (DR3). mCIA was induced in wild‐type (WT) and DR3−/− mice with nonimmunized, age‐matched controls. Vascular function was determined in isolated aortic rings ±PVAT, using isometric tension myography, in response to cumulative serotonin concentrations. Cellular expression of F4/80 (macrophages), Ly6G (neutrophils), DR3, and MMP‐9 was determined using immunohistochemistry. In WTs, arthritis‐induced vascular dysfunction was associated with increased F4/80+ macrophages and increased DR3 expression in the aorta and PVAT. MMP‐9 was also up‐regulated in PVAT, but did not correlate with alterations of PVAT intact constriction. DR3−/− mice inherently showed increased leukocyte numbers and MMP‐9 expression in the PVAT, but retained the same nonarthritic constriction response as DR3WT mice ±PVAT. Arthritic DR3−/− mice had a worsened constriction response than DR3WT and showed an influx of neutrophils to the aorta and PVAT. Macrophage numbers were also up‐regulated in DR3−/− PVAT. Despite this influx, PVAT intact DR3−/− constriction responses were restored to the same level as DR3WT. Impaired vascular constriction in inflammatory arthritis occurs independently of total MMP‐9 levels, but correlates with macrophage and neutrophil ingress. Ablating DR3 worsens the associated vasculature dysfunction, however, DR3−/− PVAT is able to protect the aorta against aberrant vasoconstriction caused in this model

A Privileged Pedagogy for Privileged Students? A Preliminary Mixed-Methods Analysis Comparing First-Generation and Non-First-Generation College Students on Post-Evaluations of Service-Learning Courses

Service-learning is frequently described as a high-impact teaching activity that benefits students in numerous ways. However, fewer studies explore how underserved students respond to service-learning courses, and fewer still look specifically at first-generation college students. First generation college students face numerous documented obstacles to persisting and achieving in college, and a need exists for more systematic study of whether service-learning pedagogy supports or challenges first generation students as they face and overcome those obstacles. This study compared 260 undergraduate students, approximately half of whom were first-generation college students, and their self-reported gains in three student learning outcomes: academic enhancement, personal growth, and civic engagement. Through a mixed-methods analysis, findings indicate that first-generation college students responded at least as well as their peers to service-learning. In areas of difference, first-generation college students responded more strongly than their peers. Overall, results indicate surprising similarities between the first generation students and their peers, as well as important differences regarding compassion, motivation, agency, and sense of solidarity

Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy.

PurposeTo report potentially pathogenic mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes in two individuals with clinically diagnosed Meesmann corneal dystrophy (MECD).MethodsSlit-lamp examination was performed on the probands and available family members to identify characteristic features of MECD. After informed consent was obtained, saliva samples were obtained as a source of genomic DNA, and screening of KRT3 and KRT12 was performed. Potentially pathogenic variants were screened for in 200 control chromosomes. PolyPhen-2, SIFT, and PANTHER were used to predict the functional impact of identified variants. Short tandem repeat genotyping was performed to confirm paternity.ResultsSlit-lamp examination of the first proband demonstrated bilateral, diffusely distributed, clear epithelial microcysts, consistent with MECD. Screening of KRT3 revealed a heterozygous missense variant in exon 1, c.250C>T (p.(Arg84Trp)), which has a minor allele frequency of 0.0076 and was not identified in 200 control chromosomes. In silico analysis with PolyPhen-2 and PANTHER predicted the variant to be damaging to protein function; however, SIFT analysis predicted tolerance of the variant. The second proband demonstrated bilateral, diffusely distributed epithelial opacities that appeared gray-white on direct illumination and translucent on retroillumination. Neither parent demonstrated corneal opacities. Screening of KRT12 revealed a novel heterozygous insertion/deletion variant in exon 6, c.1288_1293delinsAGCCCT (p.(Arg430_Arg431delinsSerPro)). This variant was not present in either of the proband's parents or in 200 control chromosomes and was predicted to be damaging by PolyPhen-2, PANTHER, and SIFT. Haplotype analysis confirmed paternity of the second proband, indicating that the variant arose de novo.ConclusionsWe present a novel KRT12 mutation, representing the first de novo mutation and the first indel in KRT12 associated with MECD. In addition, we report a variant of uncertain significance in KRT3 in an individual with MECD. Although the potential pathogenicity of this variant is unknown, it is the first variant affecting the head domain of K3 to be reported in an individual with MECD and suggests that disease-causing variants associated with MECD may not be restricted to primary sequence alterations of either the helix-initiation or helix-termination motifs of K3 and K12