Inpatient teledermatology: Diagnostic and therapeutic concordance among a hospitalist, dermatologist, and teledermatologist using store-and-forward teledermatology.

BACKGROUND: Inpatient dermatology has been shown to improve patient outcomes at a reduced cost. Few hospitals have dermatologists available. Teledermatology may allow dermatologists to assess hospitalized patients remotely. OBJECTIVE: To examine the diagnostic concordance between a hospitalist, dermatologist, and teledermatologist using store-and-forward teledermatology. METHODS: For 100 consecutive patients requiring inpatient dermatology consultation, a survey was conducted by all 3 raters to convey diagnostic impressions and therapeutic recommendations. Complete and partial agreements were assessed using the Cohen kappa statistic. RESULTS: Inpatient dermatology consultation often resulted in a change in diagnosis (50.9%) and a change in systemic therapy (41.5%). Likewise, virtual teledermatology consultation would have resulted in a change in diagnosis (54.7%) and a change in systemic therapy (47.2%) at similar rates. Comparing the dermatologist and teledermatologists, diagnostic complete and partial agreement were 52.8% and 84.9%, respectively. Systemic therapy agreement was 77.4%. Teledermatologists recommended biopsy more often (68.5% vs 43.5%). LIMITATIONS: Small sample size, tertiary academic medical center, single rater for inpatient teledermatology with specific inpatient niche. CONCLUSION: Teledermatologists performed comparably to an in-person dermatologist for the diagnosis and management of hospitalized patients with skin conditions. Teledermatology may be a suitable alternative for delivery of inpatient care if no dermatologist is available.

Gene expression signature of atypical breast hyperplasia and regulation by SFRP1.

BACKGROUND: Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS: In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS: A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS: The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution.

Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.

The Role of Social Determinants of Health in Moral Injury: Implications and Future Directions.

Purpose of Review: Exposure to potentially morally injurious events (PMIEs) and the development of moral injury have yet to be conceptualized as they relate to social determinants of health (SDoH).Recent Findings.In this paper, the extant literature on moral injury and SDoH is reviewed. Specific individual-level SDoH, including gender, sex, sexual orientation, race, and ethnicity, are explored relative to PMIEs and moral injury. The relationship among environmental SDoH, including childhood environment, justice involvement, and homelessness, is described. Summary: Assessment and treatment implications are discussed, and future research directions highlighting the need for additional work addressing health inequities in moral injury are presented.

Correction: The Dkk3 gene encodes a vital intracellular regulator of cell proliferation.

[This corrects the article DOI: 10.1371/journal.pone.0181724.].

The Dkk3 gene encodes a vital intracellular regulator of cell proliferation.

Members of the Dickkopf (Dkk) family of Wnt antagonists interrupt Wnt-induced receptor assembly and participate in axial patterning and cell fate determination. One family member, DKK3, does not block Wnt receptor activation. Loss of Dkk3 expression in cancer is associated with hyperproliferation and dysregulated ß-catenin signaling, and ectopic expression of Dkk3 halts cancer growth. The molecular events mediating the DKK3-dependent arrest of ß-catenin-driven cell proliferation in cancer cells are unknown. Here we report the identification of a new intracellular gene product originating from the Dkk3 locus. This Dkk3b transcript originates from a second transcriptional start site located in intron 2 of the Dkk3 gene. It is essential for early mouse development and is a newly recognized regulator of ß-catenin signaling and cell proliferation. Dkk3b interrupts nuclear translocation ß-catenin by capturing cytoplasmic, unphosphorylated ß-catenin in an extra-nuclear complex with ß-TrCP. These data reveal a new regulator of one of the most studied signal transduction pathways in metazoans and provides a novel, completely untapped therapeutic target for silencing the aberrant ß-catenin signaling that drives hyperproliferation in many cancers.

Crucial and novel cancer drivers in a mouse model of triple-negative breast cancer.

BACKGROUND: We previously developed a mouse model of breast cancer that mimics human triple-negative breast cancer (TNBC) by inactivating the Retinoblastoma (Rb), Transformation related protein 53 (p53), and Breast cancer 1 (Brca1) pathways in the mammary gland. Despite inactivation of all three tumor suppressors throughout the epithelium, low tumor multiplicity indicated that malignant carcinoma progression requires additional oncogenic stimuli. MATERIALS AND METHODS: In order to identify collaborating genetic events, we performed integrated analysis of 18 tumors (eight tumors with inactivation of pRbf/Brca1/p53 and ten tumors with inactivation of pRbf/p53) using comparative genomic hybridization and global gene expression. We then conducted flow cytometric analysis, immunostaining, tumorsphere, and cell viability assays. RESULTS: Copy number aberrations were correlated with the transcript levels of 7.55% of genes spanned by the altered genomic regions. Recurrent genomic losses spanning large regions of chromosomes 4 and 10 included several cell death genes. Among the amplified genes were well-known drivers of tumorigenesis including Wingless-related MMTV integration site 2 (Wnt2), as well as potentially novel driver mutations including the Late cornified envelope (LCE) gene family. These tumors have a stem/luminal progenitor phenotype and active ß-catenin signaling. Tumorsphere formation and cell survival are suppressed by Wnt pathway inhibitors. CONCLUSION: Our novel mouse model mimics human TNBC and provides a platform to triage the pathways that underlie malignant tumor progression.