Genomic testing in early stage invasive male breast cancer: An NCDB analysis from 2008 to 2014.

PURPOSE: Genomic assays, or tissue gene profiling tests, are widely used to predict recurrence of early stage invasive breast cancer and guide systemic therapy. The purpose of our study was to examine the current national trends of genomic testing in male breast cancer (MBC) and its association with systemic therapy. MATERIALS AND METHODS: The National Cancer Database (NCDB) includes 6227 cases of pathologic T1/T2 and N0/N1 MBC from 2008 to 2014 with known genomic testing status. Results of the tests were grouped as low, intermediate, and high risk of recurrence scores (RRS). Statistical analysis included multivariate logistic regression and Chi-square tests. A supplemental analysis in female breast cancer was provided as reference. RESULTS: Of the 6227 cases of MBC age 18-90, 1478 (23.74%) underwent genomic testing. Testing was significantly associated with age, race, tumor grade, year of diagnosis, receptor status, and nodal status. Distribution of RRS in MBC was 59.3% low, 27.4% intermediate, and 13.3% high. RRS in men were significantly associated with tumor grade and size, but not nodal status. Those with a low RRS were 7-times more likely to be treated with hormone therapy alone (AOR 7.18, CI 5.78-8.91, P < 0.001). Those with a high RRS were five times more likely to receive a combination of hormone and chemotherapy (AOR 5.16, CI 3.60-7.40, P < 0.001). CONCLUSION: Rates of testing and distribution of RRS in men and women with early stage invasive breast cancer are similar. Treatment patterns in MBC varied significantly based on genomic testing results, even when adjusted for other clinicopathologic features. Further investigation is required to determine the prognostic and predictive nature of genomic testing in male breast cancer.

Automated pneumothorax triaging in chest X-rays in the New Zealand population using deep-learning algorithms.

INTRODUCTION: The primary aim was to develop convolutional neural network (CNN)-based artificial intelligence (AI) models for pneumothorax classification and segmentation for automated chest X-ray (CXR) triaging. A secondary aim was to perform interpretability analysis on the best-performing candidate model to determine whether the model's predictions were susceptible to bias or confounding. METHOD: A CANDID-PTX dataset, that included 19,237 anonymized and manually labelled CXRs, was used for training and testing candidate models for pneumothorax classification and segmentation. Evaluation metrics for classification performance included Area under the receiver operating characteristic curve (AUC-ROC), sensitivity and specificity, whilst segmentation performance was measured using mean Dice and true-positive (TP)-Dice coefficients. Interpretability analysis was performed using Grad-CAM heatmaps. Finally, the best-performing model was implemented for a triage simulation. RESULTS: The best-performing model demonstrated a sensitivity of 0.93, specificity of 0.95 and AUC-ROC of 0.94 in identifying the presence of pneumothorax. A TP-Dice coefficient of 0.69 is given for segmentation performance. In triage simulation, mean reporting delay for pneumothorax-containing CXRs is reduced from 9.8 ± 2 days to 1.0 ± 0.5 days (P-value < 0.001 at 5% significance level), with sensitivity 0.95 and specificity of 0.95 given for the classification performance. Finally, interpretability analysis demonstrated models employed logic understandable to radiologists, with negligible bias or confounding in predictions. CONCLUSION: AI models can automate pneumothorax detection with clinically acceptable accuracy, and potentially reduce reporting delays for urgent findings when implemented as triaging tools.

A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has essential roles in adipogenesis and glucose homeostasis, and is a molecular target of insulin-sensitizing drugs. Although the ability of PPAR-gamma agonists to antagonize inflammatory responses by transrepression of nuclear factor kappa B (NF-kappaB) target genes is linked to antidiabetic and antiatherogenic actions, the mechanisms remain poorly understood. Here we report the identification of a molecular pathway by which PPAR-gamma represses the transcriptional activation of inflammatory response genes in mouse macrophages. The initial step of this pathway involves ligand-dependent SUMOylation of the PPAR-gamma ligand-binding domain, which targets PPAR-gamma to nuclear receptor corepressor (NCoR)-histone deacetylase-3 (HDAC3) complexes on inflammatory gene promoters. This in turn prevents recruitment of the ubiquitylation/19S proteosome machinery that normally mediates the signal-dependent removal of corepressor complexes required for gene activation. As a result, NCoR complexes are not cleared from the promoter and target genes are maintained in a repressed state. This mechanism provides an explanation for how an agonist-bound nuclear receptor can be converted from an activator of transcription to a promoter-specific repressor of NF-kappaB target genes that regulate immunity and homeostasis.

Curation of the CANDID-PTX Dataset with Free-Text Reports.

Supplemental material is available for this article. Keywords: Conventional Radiography, Thorax, Trauma, Ribs, Catheters, Segmentation, Diagnosis, Classification, Supervised Learning, Machine Learning © RSNA, 2021.

Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV.

Activity-regulated transcription has been implicated in adaptive plasticity in the CNS. In many instances, this plasticity depends upon the transcription factor CREB. Precisely how neuronal activity regulates CREB remains unclear. To address this issue, we examined the phosphorylation state of components of the CREB transcriptional pathway. We show that NMDA activates transcription of CREB-responsive genes in hippocampal neurons, with ERK responsible for persistent CREB phosphorylation and CaM kinase IV (CaMKIV) responsible for phosphorylating the CREB coactivator, CBP. Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.

Host adaptation of a Wolbachia strain after long-term serial passage in mosquito cell lines.

The horizontal transfer of the bacterium Wolbachia pipientis between invertebrate hosts hinges on the ability of Wolbachia to adapt to new intracellular environments. The experimental transfer of Wolbachia between distantly related host species often results in the loss of infection, presumably due to an inability of Wolbachia to adapt quickly to the new host. To examine the process of adaptation to a novel host, we transferred a life-shortening Wolbachia strain, wMelPop, from the fruit fly Drosophila melanogaster into a cell line derived from the mosquito Aedes albopictus. After long-term serial passage in this cell line, we transferred the mosquito-adapted wMelPop into cell lines derived from two other mosquito species, Aedes aegypti and Anopheles gambiae. After a prolonged period of serial passage in mosquito cell lines, wMelPop was reintroduced into its native host, D. melanogaster, by embryonic microinjection. The cell line-adapted wMelPop strains were characterized by a loss of infectivity when reintroduced into the original host, grew to decreased densities, and had reduced abilities to cause life-shortening infection and cytoplasmic incompatibility compared to the original strain. We interpret these shifts in phenotype as evidence for genetic adaptation to the mosquito intracellular environment. The use of cell lines to preadapt Wolbachia to novel hosts is suggested as a possible strategy to improve the success of transinfection in novel target insect species.

Original Research: The Effects of Red Yeast Rice Supplementation on Cholesterol Levels in Adults.

: Purpose: Red yeast rice (RYR) supplementation has become a popular alternative to statin therapy in treating hypercholesterolemia. This state-of-the-science review seeks to explore the most recent evidence on the effectiveness and safety of RYR supplementation in treating dyslipidemic adults. METHODS: This review extends the time frame of a meta-analysis performed by Li and colleagues in 2014; specifically, we looked at the literature published between September 2013 and April 2016. We conducted a search of four electronic databases-PsycINFO, CINAHL, PubMed, and Scopus-using the terms red yeast rice and cholesterol. We excluded studies that included berberine or lovastatin. RESULTS: Fifteen articles met the inclusion criteria. Eleven articles reported on randomized controlled trials, one reported on an open-label pilot study, and one reported on an open-label clinical trial. Two articles were meta-analyses. The 13 studies involved a total of 1,246 participants, with an additional 7,467 participants reported in the two meta-analyses. Significant reductions in low-density lipoprotein cholesterol and total cholesterol levels with RYR supplementation were observed in all trials. There were no significant changes in liver and kidney function, and 10 studies noted no significant changes in creatine kinase levels. CONCLUSIONS: Although RYR appears to be a safe and effective lipid-lowering agent, there is insufficient evidence to support the recommendation of RYR supplementation to patients. Further research is needed, including long-term studies, studies that include participants with comorbidities and complex medical histories, and studies that take into account the variability of formulation and dosage of RYR in the marketplace.

Should Health Care Providers Support Electronic Cigarettes for Smoking Cessation?

Evidence on safety and effectiveness isn't yet conclusive.

Mitogen- and stress-activated protein kinase 1 mediates cAMP response element-binding protein phosphorylation and activation by neurotrophins.

Activation of the transcription factor cAMP response element-binding protein (CREB) by neurotrophins is believed to regulate the survival, differentiation, and maturation of neurons in the CNS and PNS. Although phosphorylation of Ser133 is critical for the expression of CREB-regulated genes, the identity of neurotrophin-regulated Ser133 kinases has remained controversial. We show here that neurotrophin-induced CREB phosphorylation in CNS neurons depends exclusively on the extracellular signal-regulated kinase 1/2-activated kinase mitogen- and stress-activated protein kinase 1 (MSK1). Small interfering RNA directed against ribosomal S6 kinase 1 (RSK1) and RSK2 reduced phosphorylation of a RSK substrate but did not effect CREB-dependent transcription. However, expression of a selective inhibitory MSK1 mutant markedly attenuated BDNF-stimulated CREB phosphorylation and CREB-mediated transcription. Moreover, the ability of neurotrophins to stimulate CREB phosphorylation was abolished in CNS neurons from MSK1 knock-out mice. Consistent with a role for MSK1 in Ser133 phosphorylation, neurotrophin-induced expression of CREB-regulated genes was attenuated in MSK-deficient neurons. These results indicate that MSK1 is the major neurotrophin-activated Ser133 kinase in CNS neurons.

Head and neck fascia and compartments: no space for spaces.

An accurate understanding of the arrangement of cervical fascia and its associated compartments is essential for differential diagnosis, predicting the spread of disease, and surgical management. The purpose of this detailed review is to summarize the anatomic, clinical, and radiological literature to determine what is known about the arrangement of cervical fascia and to highlight controversies and consensus. The current terminology used to describe cervical fascia and compartments is replete with confusing synonyms and inconsistencies, creating important interdisciplinary differences in understanding. The term "spaces" is inappropriate. A modified nomenclature underpinned by evidence-based anatomic and radiologic findings is proposed. This should not only enhance our understanding of cervical anatomy but also facilitate clearer interdisciplinary communication.

Micro-CT visualization of the cricothyroid joint cavity in cadavers.

OBJECTIVES/HYPOTHESIS: To directly visualize the cricothyroid joint (CTJ) cavity of the human cadaver and to correlate the appearance of the CTJ cavity to its fibrous capsule. STUDY DESIGN: Prospective. METHODS: Twenty-five cadavers (nine females and 16 males; age range, 67-95 years) were used for gross anatomy, micro-computed tomography (CT) arthrography, histology, E12 sheet plastination, and magnetic resonance imaging examinations. The cadavers were donated for the purposes of teaching and research under the Human Tissues Act. RESULTS: Using micro-CT arthrography with intra-articular filling and sheet plastination technique, this study demonstrated that the dimension of the CTJ cavity was much larger than that of the articular surfaces, particularly at the superior and anterior aspects of the joint. Connective tissue fibers were regularly orientated and significantly strengthened in the posterior and inferior aspects of the CTJ capsule. Such fibrous configuration appeared to enhance the strength of the capsule itself rather than to shorten the distance between the articular surfaces. The size of the direct contact area of the opposing articular surfaces varied significantly between the sides of the same subject and among individuals. CONCLUSIONS: This study supports the general view that the cricoid cartilage rotates in a visor-like fashion on the inferior cornu of the thyroid cartilage. However, the pivot for the CTJ rotation appears wobbly. The wobbly pivot may increase the joint mobility as the rotation allows the horizontal and vertical gliding movements of the CTJ.

Usage and recall of the Food Stamp Office Resource Kit (FSORK) by food stamp applicants in 4 California counties.

OBJECTIVE: To evaluate recall and usage of the Food Stamp Office Resource Kit (FSORK), a set of nutrition education materials designed for use in food stamp offices. DESIGN: Client intercept exit surveys, an environmental scan, and individual observations of clients in the food stamp office. SETTING: Four food stamp offices in California. PARTICIPANTS: People applying for food stamps in community social service offices: exit survey (n = 419), environmental scan (n = 308), individual observations of video (n = 111). INTERVENTION: FSORK includes a video, poster, recipe cards, and brochures for the waiting room. MAIN OUTCOME MEASURE(S): Aided and unaided recall of FSORK materials, self-efficacy, video attention (eyes on screen), and observations of materials usage. ANALYSIS: Descriptive statistics for recall, usage, and video attention. RESULTS: Nearly 70% of clients recalled, unaided, at least 1 FSORK element with the video recalled the most. In the observation study, of clients who initially engaged with the video, 40% of their viewing time was spent "watching" it. CONCLUSIONS AND IMPLICATIONS: Food stamp offices are a useful setting for nutrition education in offices that are willing and able to display the materials and show the video.

Using an opinion poll to build an obesity-prevention social marketing campaign for low-income Asian and Hispanic immigrants: report of findings.

OBJECTIVE: To gain opinions from low-income, limited-English-speaking Hispanic and Asian immigrants for formative research in a social marketing campaign. DESIGN: Nineteen questions on obesity prevention-related topics were embedded into a larger random digit-dial survey investigating the effects of language and cultural barriers on health care access. Participants were selected by ethnic encoding from consumer databases. SETTING: California's northern, southern, and Central Valley regions. PARTICIPANTS: Nine hundred and five adult Hispanic, Chinese, Vietnamese, Hmong, and Korean Californians from households < 130% of the Federal Poverty Level interviewed in 2005. VARIABLES MEASURED: Media usage, food stamp participation, health insurance, health problems, access and availability of fruits and vegetables (FVs) and physical activity, beliefs about overweight, and related regulation and policy change. ANALYSIS: Descriptive statistics and percentages for all questions. RESULTS: Latinos reported receiving most information from television; Hmong from radio. Hispanics, Koreans, and Vietnamese thought diabetes was the greatest health issue in California. Among Hmong, 83% thought FVs were too expensive, and 49% of Vietnamese thought good quality, affordable fresh FVs were too hard to find. CONCLUSIONS AND IMPLICATIONS: Identifying characteristics and opinions that distinguish these ethnic immigrant populations better enables the Network for a Healthy California to develop culturally relevant social marketing campaigns and materials.

Gender-specific modulation of immune system complement gene expression in marine medaka Oryzias melastigma following dietary exposure of BDE-47.

BDE-47 is one of the most widely found congeners of PBDEs in marine environments. The potential immunomodulatory effects of BDE-47 on fish complement system were studied using the marine medaka Oryzias melastigma as a model fish. Three-month-old O. melastigma were subjected to short-term (5 days) and long-term (21 days) exposure to two concentrations of BDE-47 (low dose at 290 ± 172 ng/day; high dose at 580 ± 344 ng/day) via dietary uptake of BDE-47 encapsulated in Artemia nauplii. Body burdens of BDE-47 and other metabolic products were analyzed in the exposed and control fish. Only a small amount of debrominated product, BDE-28, was detected, while other metabolic products were all under detection limit. Transcriptional expression of six major complement system genes involved in complement activation: C1r/s (classical pathway), MBL-2 (lectin pathway), CFP (alternative pathway), F2 (coagulation pathway), C3 (the central component of complement system), and C9 (cell lysis) were quantified in the liver of marine medaka. Endogenous expression of all six complement system genes was found to be higher in males than in females (p < 0.05). Upon dietary exposure of marine medaka to BDE-47, expression of all six complement genes were downregulated in males at day 5 (or longer), whereas in females, MBl-2, CFP, and F2 mRNAs expression were upregulated, but C3 and C9 remained stable with exposure time and dose. A significant negative relationship was found between BDE-47 body burden and mRNA expression of C1r/s, CFP, and C3 in male fish (r = -0.8576 to -0.9447). The above findings on changes in complement gene expression patterns indicate the complement system may be compromised in male O. melastigma upon dietary exposure to BDE-47. Distinct gender difference in expression of six major complement system genes was evident in marine medaka under resting condition and dietary BDE-47 challenge. The immunomodulatory effects of BDE-47 on transcriptional expression of these complement components in marine medaka were likely induced by the parent compound instead of biotransformed products. Our results clearly demonstrate that future direction for fish immunotoxicology and risk assessment of immunosuppressive chemicals must include parallel evaluation for both genders.

Dural entrance of the bridging vein in the middle cranial fossa: a novel classification of the cerebral veins for preoperative planning.

BACKGROUND AND IMPORTANCE: Understanding of the intracranial venous anatomy is essential for preoperative planning. OBJECTIVE: To identify anatomic features of the dural entrance of the bridging veins (BVs) into the dural sinuses in the middle cranial fossa on the cadaver and to correlate such features with those of digital subtraction venogram, computed tomographic venogram, and magnetic resonance venogram. CLINICAL PRESENTATION: A total of 30 adult cadavers and 86 patients were examined with anatomic dissection or neuroimages. The number, diameter, and location of the BVs entering the dural sinuses in the middle cranial fossa were recorded and compared between the cadavers and neuroimages. The dural entrances of the BVs were identifiable on neuroimages and distributed mainly at the anteromedial area of the fossa. Morphological features of the dural sinuses and meningeal veins in the fossa indicated that the techniques of lengthening the BV by dissecting it away from the dura mater or cutting a small area of the dura along the sides of the BV may not be applicable for the management of BVs in the anteromedial middle cranial fossa. CONCLUSION: Unique anatomic features of the dural entrance of BVs entering the dural sinuses in the cadaver are correlated to those on neuroimages. Identification of the dural entrance of BVs with neuroimaging modalities provides a reliable measure for preoperative planning.

Stable introduction of a life-shortening Wolbachia infection into the mosquito Aedes aegypti.

Most pathogens require a relatively long period of development in their mosquito vector before they can be transmitted to a new human host; hence, only older insects are of epidemiological importance. The successful transfer of a life-shortening strain of the inherited bacterial symbiont, Wolbachia, into the major mosquito vector of dengue, Aedes aegypti, halved adult life span under laboratory conditions. The association is stable, and the Wolbachia strain is maternally inherited at high frequency. It is capable of inducing complete cytoplasmic incompatibility, which should facilitate its invasion into natural field populations and its persistence over time. Our data suggest that targeting mosquito age with inherited Wolbachia infections may be a viable strategy to reduce the transmission of pathogens such as dengue viruses.

Dural entrance of the bridging vein into the transverse sinus provides a reliable measure for preoperative planning: an anatomic comparison between cadavers and neuroimages.

OBJECTIVE: Understanding the anatomy of the transverse sinus and its associated bridging veins (BVs) is essential to approaching the posterior and middle incisural space. The venous phase of neuroimages has received increasing attention in preoperative planning. The aims of this study are to identify anatomic features of the dural entrance of the BVs into the transverse sinus on the cadaver and to correlate such features with those of digital subtraction angiography (DSA), computed tomographic venography (CTV), and magnetic resonance venography (MRV). METHODS: A total of 30 adult cadavers and 76 patients were examined through anatomic dissection and DSA, CTV, and MRV, respectively. The number, diameter, and location of the BVs entering the sinus were measured, and comparisons were made between the cadavers and neuroimages. RESULTS: We found that the way BVs entered the transverse sinus varied but was identifiable in DSA, CTV, and MRV images. Compared with the cadavers, DSA, CTV, and MRV revealed less than 50% of the BV entering the sinus because the smaller BVs were not seen on the neuroimages. However, the distribution pattern of the dural entrance of the BVs into the transverse sinus was relatively consistent between cadavers and neuroimages. CONCLUSION: Unique anatomic features of the dural entrance of a BV into the transverse sinus in the cadaver correspond to those evident in neuroimages; thus, identification of the dural entrance of the BVs with neuroimaging modalities provides a reliable measure for preoperative planning.

Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.

PE-1/METS, an antiproliferative Ets repressor factor, is induced by CREB-1/CREM-1 during macrophage differentiation.

The molecular mechanisms involved in regulating the balance between cellular proliferation and differentiation remain poorly understood. Members of the Ets-domain family of transcription factors are candidates for proteins that might differentially regulate cell cycle control and cell type-specific genes during the differentiation of myeloid progenitor cells. The Ets repressor PE-1/METS has been suggested to contribute to growth arrest during terminal macrophage differentiation by repressing Ets target genes involved in Ras-dependent proliferation. An important feature of this regulatory model is that PE-1/METS is itself induced by the program of macrophage differentiation elicited by M-CSF. Here, we present evidence that the PE-1/METS gene is a transcriptional target of the cyclic AMP response element-binding protein-1 (CREB-1). CREB-1 expression is dramatically up-regulated during macrophage differentiation and phosphorylation of CREB-1 and the related factor CREM-1 are stimulated by M-CSF in a SAPK2/p38-dependent manner. Chromatin immunoprecipitation experiments demonstrate that CREB-1/CREM-1 are recruited to the PE-1/METS promoter as well as to the promoters of other genes that are up-regulated during terminal macrophage differentiation. Overexpression of CREB-1 stimulates the activities of the PE-1/METS, and macrosialin promoters, while expression of a dominant negative form of CREB-1 during macrophage differentiation inhibits expression of the PE-1/METS and macrosialin genes. Inhibition of CREB function also results in reduced expression of CD54 and impaired cell adhesion. Taken together, these findings reveal new roles of CREB-1/CREM-1 as regulators of macrophage differentiation.