bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatty acid-binding protein 5 (FABP5)-related signal transduction pathway in castration-resistant prostate cancer cells: a potential therapeutic target
Authors: Naeem Abdulghani A , Abdulsamad Saud A , Rudland Philip S , Malki Mohammed I , Ke Youqiang
Published: September 2019

In this short communication, a novel fatty acid-binding protein 5 (FABP5)-related signal transduction pathway in prostate cancer is reviewed. In castration-resistant prostate cancer (CRPC) cells, the FABP5-related signal transduction pathway plays an important role during transformation of the cancer cells from androgen-dependent state to androgen-independent state. The detailed route of this signal transduction pathway can be described as follows: when FABP5 expression is increased as the increasing malignancy, excessive amounts of fatty acids from intra- and extra-cellular sources are transported into the nucleus of the cancer cells where they act as signalling molecules to stimulate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). The phosphorylated or biologically activated PPARγ then modulates the expression of its downstream target regulatory genes to trigger a series of molecular events that eventually lead to enhanced tumour expansion and aggressiveness caused by an overgrowth of the cancer cells with a reduced apoptosis and an increased angiogenesis. Suppressing the FABP5-related pathway via RNA interference against FABP5 has produced a 63-fold reduction in the average size of the tumours developed from CRPC cells in nude mice, a seven-fold reduction of tumour incidence, and a 100% reduction of metastasis rate. Experimental treatments of CRPC with novel FABP5 inhibitors have successfully inhibited the malignant progression of CRPC cells both in vitro and in nude mouse. These studies suggest that FABP5-related signal transduction pathway is a novel target for therapeutic intervention of CRPC cells.
Age and Origin of Deep Crustal Meta-igneous Xenoliths from the Scottish Midland Valley: Vestiges of an Early Palaeozoic Arc and ‘Newer Granite’ Magmatism
Authors: Badenszki Eszter , Daly J Stephen , Whitehouse Martin J , Kronz Andreas , Upton Brian G J , Horstwood Matthew S A
Published: September 2019

Deep crustal felsic xenoliths from classic Scottish Midland Valley localities, carried to the surface by Permo-Carboniferous magmatism, are shown for the first time to include metaigneous varieties with dioritic and tonalitic protoliths. Four hypotheses regarding their origin have been evaluated: (1) Precambrian basement; (2) Permo-Carboniferous underplating; (3) ‘Newer Granite’ magmatism; (4) Ordovician arc magmatism. U–Pb zircon dating results rule out the Precambrian basement and Permo-Carboniferous underplating hypotheses, but establish that the meta-igneous xenoliths represent both ‘Newer Granite’ and Ordovician (to possibly Silurian) arc magmatism. The metadiorite xenoliths are shown to have protolith ages of c. 415 Ma with εHft zircon values ranging from +0·1 to +11·1. These are interpreted to represent unexposed ‘Newer Granite’ plutons, based on age, mineralogical, isotopic and geochemical data. This shows that Devonian ‘Newer Granite’ magmatism had a greater impact on the Midland Valley and Southern Uplands crust than previously realized. Clinopyroxene–plagioclase–quartz barometry on the metadiorites from the east and west of the Midland Valley yielded a similar pressure range of c. 5–10 kbar, and a metadiorite from the east yielded a minimum two-feldspar temperature estimate of c. 793–816°C. These results indicate that the metadiorites once resided in the middle–lower crust. In contrast, two metatonalite xenoliths have a Late Ordovician protolith age (c. 453 Ma), with zircon εHft values of +7·8 to +9·0. These are interpreted as samples of a buried Late Ordovician magmatic arc situated within the Midland Valley. Inherited zircons with similar Late Ordovician ages and εHft=453 values (+1·6 to +10·8) are present in the metadiorites, suggesting that the Devonian ‘Newer Granites’ intruded within or through this Late Ordovician Midland Valley arc. A younger protolith age of c. 430 Ma from one of the metatonalites suggests that arc activity continued until Silurian times. This validates the long-standing ‘arc collision’ hypothesis for the development of the Caledonian Orogen. Based on U–Pb zircon dating, the metatonalite and metadiorite xenoliths have both experienced metamorphism between c. 400 and c. 391 Ma, probably linked to the Acadian Orogeny. An older phase of metamorphism at c. 411 Ma was possibly triggered by the combined effects of heating owing to the emplacement of the ‘Newer Granite’ plutons and the overthrusting of the Southern Uplands terrane onto the southern margin of the Midland Valley terrane.
Transition from Plume-driven to Plate-driven Magmatism in the Evolution of the Main Ethiopian Rift
Authors: Feyissa Dejene Hailemariam , Kitagawa Hiroshi , Bizuneh Tesfaye Demissie , Tanaka Ryoji , Kabeto Kurkura , Nakamura Eizo
Published: September 2019

New K–Ar ages, major and trace element concentrations, and Sr–Nd–Pb isotope data are presented for Oligocene to recent mafic volcanic rocks from the Ethiopian Plateau, the Main Ethiopian Rift (MER), and the Afar depression. Chronological and geochemical data from this study are combined with previously published datasets to reveal secular variations in magmatism throughout the entire Ethiopian volcanic region. The mafic lavas in these regions show variability in terms of silica-saturation (i.e. alkaline and sub-alkaline series) and extent of differentiation (mafic through intermediate to felsic). The P–T conditions of melting, estimated using the least differentiated basalts, reveal a secular decrease in the mantle potential temperature, from when the flood basalt magmas erupted (up to 1600 °C) to the time of the rift-related magmatism (<1500°C). Variations in the Sr–Nd–Pb isotopic compositions of the mafic lavas can account for the involvement of multiple end-member components. The relative contributions of these end-member components vary in space and time owing to changes in the thermal condition of the asthenosphere and the thickness of the lithosphere. The evolution of the Ethiopian rift is caused by a transition from plume-driven to plate-driven mantle upwelling, although the present-day mantle beneath the MER and the Afar depression is still warmer than normal asthenosphere.
Cash and the Economy: Evidence from India’s Demonetization*
Authors: Chodorow-Reich Gabriel , Gopinath Gita , Mishra Prachi , Narayanan Abhinav
Published: September 2019

We analyze a unique episode in the history of monetary economics, the 2016 Indian “demonetization.” This policy made 86% of cash in circulation illegal tender overnight, with new notes gradually introduced over the next several months. We present a model of demonetization where agents hold cash both to satisfy a cash-in-advance constraint and for tax evasion purposes. We test the predictions of the model in the cross-section of Indian districts using several novel data sets including: the geographic distribution of demonetized and new notes for causal inference; night light activity and employment surveys to measure economic activity including in the informal sector; debit/credit cards and e-wallet transactions data; and banking data on deposit and credit growth. Districts experiencing more severe demonetization had relative reductions in economic activity, faster adoption of alternative payment technologies, and lower bank credit growth. The cross-sectional responses cumulate to a contraction in aggregate employment and night lights–based output due to the the cash shortage of at least 2 percentage points and of bank credit of 2 percentage points in 2016Q4 relative to their counterfactual paths, effects that dissipate over the next few months. Our analysis rejects monetary neutrality using a large-scale natural experiment, something that is still rare in the vast literature on the effects of monetary policy.
Galectin‐1 interacts with the human endogenous retroviral envelope protein syncytin‐2 and potentiates trophoblast fusion in humans
Authors: Toudic Caroline , Vargas Amandine , Xiao Yong , St‐Pierre Guillaume , Bannert Norbert , Lafond Julie , Rassart Eric , Sato Sachiko , Barbeau Benoit
Published: September 2019

Syncytin (Syn)‐2 is an important fusogenic protein that contributes to the formation of the placental syncytiotrophoblast. Galectin (Gal)‐1, a soluble lectin, is also involved in trophoblast cell fusion and modulates the interaction of certain retroviral envelopes with their cellular receptor. This study aimed to investigate the association between Syn‐2 and Gal‐1 during human trophoblast cell fusion. This association was evaluated in vitro on primary villous cytotrophoblasts (vCTBs) and cell lines using recombinant Gal‐1 and Syn‐2‐pseudotyped viruses. Using lactose, a Gal antagonist, and Gal‐1‐specific small interfering RNA (siRNA) transfections, we confirmed the implication of Gal‐1 in vCTBs and BeWo cell fusion, although RT‐PCR and ELISA analyses suggested that Gal‐1 alone did not induce syncytialization. Infection assays showed a specific and significant effect of Gal‐1 on the infectivity of Syn‐2‐pseudotyped viruses that depended on the expression of major facilitator superfamily domain‐containing 2A (MFSD2a). Moreover, Gal‐3, another placental Gal, did not modulate the infectivity of Syn‐2‐positive viruses, strengthening the specific association between Gal‐1 and Syn‐2. Interestingly, Gal‐1 significantly reduced the infectivity of Syn‐1‐pseudotyped viruses, suggesting the opposite effects of Gal‐1 on Syn‐1 and ‐2. Finally, coimmunoprecipitation experiments showed a glycan‐dependent interaction between Syn‐2‐bearing virions and Gal‐1. We conclude that Gal‐1 specifically interacts with Syn‐2 and possibly regulates Syn‐2/MFSD2a interaction during syncytialization of trophoblastic cells.—Toudic, C., Vargas, A., Xiao, Y., St‐Pierre, G., Bannert, N., Lafond, J., Rassart, E., Sato, S., Barbeau, B. Galectin‐1 interacts with the human endogenous retroviral envelope protein syncytin‐2 and potentiates trophoblast fusion in humans. FASEB J. 33, 12873–12887 (2019). www.fasebj.org
Mechanoregulation of p38 activity enhances endoplasmic reticulum stress‐mediated inflammation by arterial endothelium
Authors: Bailey Keith A. , Moreno Emily , Haj Fawaz G. , Simon Scott I. , Passerini Anthony G.
Published: September 2019

Endothelial up‐regulation of VCAM‐1 at susceptible sites in arteries modulates the recruitment efficiency of inflammatory monocytes that initiates atherosclerotic lesion formation. We reported that hydrodynamic shear stress (SS) mechanoregulates inflammation in human aortic endothelial cells through endoplasmic reticulum (ER) stress via activation of the transcription factor x‐box binding protein 1 (XBP1). Here, a microfluidic flow channel that produces a linear gradient of SS along a continuous monolayer of endothelium was used to delve the mechanisms underlying transcriptional regulation of TNF‐α‐stimulated VCAM‐1 expression. High‐resolution immunofluorescence imaging enabled continuous detection of platelet endothelial cell adhesion molecule 1 (PECAM‐1)‐dependent, outside‐in signaling as a function of SS magnitude. Differential expression of VCAM‐1 and intercellular adhesion molecule 1 (ICAM‐1) was regulated by the spatiotemporal activation of MAPKs, ER stress markers, and transcription factors, which was dependent on the mechanosensing of SS through PECAM‐1 and PI3K. Inhibition of p38 specifically abrogated the rise to peak VCAM‐1 at low SS (2 dyn/cm2), whereas inhibition of ERK1/2 attenuated peak ICAM‐1 at high SS (12 dyn/cm2). A shear stress‐regulated temporal rise in p38 phosphorylation activated the nuclear translocation of XBP1, which together with the transcription factor IFN regulatory factor 1, promoted maximum VCAM‐1 expression. These data reveal a mechanism by which SS sensitizes the endothelium to a cytokine‐induced ER stress response to spatially regulate inflammation promoting atherosclerosis.—Bailey, K. A., Moreno, E., Haj, F. G., Simon, S. I., Passerini, A. G. Mechanoregulation of p38 activity enhances endoplasmic reticulum stress‐mediated inflammation by arterial endothelium. FASEB J. 33, 12888–12899 (2019). www.fasebj.org
Microaggression in Academia: Consequences and Considerations
Authors: Ro Kumhee , Villarreal Joshua
Published: September 2019

Microaggression as a concept has received significant attention in the popular media as well as in literature. The concept has yet to be addressed, however, in the context of health care education or academia. In this article, current thoughts on racial microaggressions are reviewed with a focus on implications for nursing faculty and academia. The role of implicit bias and microaggressions on faculty diversity and promotion is discussed, and recommendations for next steps are reviewed.
The Effect of Surgical Decompression on Functional Balance Testing in Patients With Cervical Spondylotic Myelopathy
Authors: Haddas Ram , Ju Kevin L. , Boah Akwasi , Kosztowski Thomas , Derman Peter B.
Published: September 2019

Study Design:

A prospective cohort study.

Objective:

Quantify the extent of change in dynamic balance and stability in a group of patients with cervical spondylotic myelopathy (CSM) after cervical decompression surgery and to compare them with matched healthy controls.

Summary of Background Data:

CSM is a naturally progressive degenerative condition that commonly results in loss of fine motor control in the hands and upper extremities and in gait imbalance. Whereas this was previously thought of as an irreversible condition, more recent studies are demonstrating postoperative improvements in balance and stability.

Materials and Methods:

Thirty subjects with symptomatic CSM and 25 matched asymptomatic controls between the ages of 45 and 75 years underwent functional balance testing using a 3D motion capture system to gather kinematic and spatiotemporal parameters. CSM subjects underwent testing 1 week before surgery and again 3 months postoperatively.

Results:

Patients with CSM exhibited markedly diminished balance as indicated by increased sway on a Romberg test and requiring significantly more time and a wider stance to complete tandem gait tests. The surgical intervention resulted in improved balance at the 3-month postoperative time point; however, kinematic and spatiotemporal parameters did not completely normalize to the levels observed in asymptomatic controls.

Conclusions:

Human motion video capture can be used to robustly quantify balance parameters in the setting of CSM. Compared with healthy controls, such patients exhibited increased standing sway and poorer performance on a tandem gait task. The surgical intervention resulted in significant improvement in many of the measures of functional balance, but overall profiles had not completely returned to normal when measured 3 months after surgery. These data reinforce the importance of operative intervention in the treatment of symptomatic CSM with the goal of halting disease progress but the expectation that balance may actually improve postoperatively.
The Prevalence and Risk Factors for Keratoconus: A Systematic Review and Meta-Analysis
Authors: Hashemi Hassan , Heydarian Samira , Hooshmand Elham , Saatchi Mohammad , Yekta Abbasali , Aghamirsalim Mohamadreza , Valadkhan Mehrnaz , Mortazavi Mehdi , Hashemi Alireza , Khabazkhoob Mehdi
Published: September 2019

Purpose:

This study was conducted to determine the prevalence and risk factors for keratoconus worldwide.

Methods:

In this meta-analysis, using a structured search strategy from 2 sources, 4 electronic databases (PubMed, Web of Science, Google Scholar, and Scopus) and the reference lists of the selected articles were searched from inception to June 2018 with no restrictions and filters. The outcome of the study was the prevalence of keratoconus and its risk factors, including eye rubbing, family history of keratoconus, atopy, allergy, asthma, eczema, diabetes type I and type II, and sex.

Results:

In this study, 3996 articles were retrieved, of which 29 were analyzed. These 29 articles included 7,158,241 participants from 15 countries. The prevalence of keratoconus in the whole population was 1.38 per 1000 population [95% confidence interval (CI): 1.14–1.62 per 1000]. The prevalence of keratoconus was 20.6 per 1000 (95% CI: 11.68–28.44 per 1000) in men and 18.33 per 1000 (95% CI: 8.66–28.00 per 1000) in women in studies reporting sex. The odds ratio of eye rubbing, family history of keratoconus, allergy, asthma, and eczema was 3.09 (95% CI: 2.17–4.00), 6.42 (95% CI: 2.59–10.24), 1.42 (95% CI: 1.06–1.79), 1.94 (95% CI: 1.30–2.58), and 2.95 (95% CI: 1.30–4.59), respectively.

Conclusions:

The results of this study, as the most comprehensive meta-analysis of keratoconus prevalence and risk factors, showed that keratoconus had a low prevalence in the world and eye rubbing, family history of keratoconus, allergy, asthma, and eczema were the most important risk factors for keratoconus according to the available evidence.
Improving Skin Cancer Knowledge and Awareness in Cosmetology Students
Authors: Haughtigan Kara , House Sonya , Main Marie Eve
Published: September 2019

Skin cancer is the most common form of cancer in the United States and includes melanoma and nonmelanoma skin cancer. Cosmetologists have reoccurring access to individuals presenting for services, and the clients are seen in good lighting where skin changes in the head and neck could be observed. The purpose of this study was to evaluate an educational intervention to increase cosmetology students’ skin cancer knowledge, personal practices, and client-directed skin observation behaviors. A single-group pretest–posttest design was used to examine knowledge, personal practices, client-directed skin observation behaviors, and confidence. A 20-minute face-to-face presentation and printed educational handouts on skin cancer were provided for participants. Statistically significant increases in knowledge (p < .0001), personal practices (p < .0001), and confidence (p < .025) were found; however, no statistically significant increases were found in client-directed skin observation behaviors (p < .057). The results of this study suggest that an educational intervention can increase cosmetology students’ skin cancer knowledge and awareness. Skin cancer knowledge could be used to increase opportunistic monitoring of customer skin health and early detection of skin changes.
High Dose of Intratympanic Steroids for Sudden Sensorineural Hearing Loss Salvage
Authors: Taha Ahmed , Shlamkovitch Nathan , Abu-Eta Rani , Yeheskeli Eyal , Muallem-Kalmovich Limor , Gavriel Haim , Pitaro Jacob
Published: September 2019

Objective:

Intratympanic (IT) steroid administration for sudden sensorineural hearing loss is offered as salvage to patients who failed systemic steroid treatment. Our objective was to study the audiometric and clinical outcomes of patients given salvage therapy with high-dose IT steroids instilled via ventilation tube.

Study Design:

Retrospective case review.

Setting:

Academic secondary medical center.

Patients:

One hundred three patients >18 years of age with sudden sensorineural hearing loss who failed systemic steroids and received IT treatment between 2010 and 2018.

Intervention:

Following ventilation tube insertion, 1 ml of 10 mg/ml dexamethasone was instilled, twice daily, for 7 days.

Outcome Measures:

Hearing assessment immediately before and after treatment. Tinnitus and vertigo complaints and risk factors were also retrieved.

Results:

Tinnitus had improved in 53 (52%) patients, vertigo in 4 (4%), and aural fullness sensation in 56 (55%) (p < 0.001, p = 0.344, p < 0.001, respectively). The mean pure-tone threshold difference across frequencies following treatment was between 0 and 6 dB. A significant improvement was observed at 250, 500, 1000 Hz (p < 0.001 in all), and at 2000 Hz (p = 0.035). No significant difference was found at 4000 and 8000 Hz (p = 0.055, p = 0.983 respectively). Mean pure-tone average improvement of 4.5 dB was detected in 61 (59%) patients (p = 0.001). The mean speech discrimination score improved by 7% (p = 0.001). Four (22%) diabetic and nine (20%) hypertensive patients had pure-tone average ≥10 dB improvement (p = 0.759, p = 0.852 respectively).

Conclusion:

Although more than half of the patients improved clinically, the significance of the slight audiometric improvement should be weighed against the treatment protocol's complications.
Cognitive Performance in Chronic Tinnitus Patients: A Cross-Sectional Study Using the RBANS-H
Authors: Cardon Emilie , Jacquemin Laure , Mertens Griet , Van de Heyning Paul , Vanderveken Olivier M. , Topsakal Vedat , De Hertogh Willem , Michiels Sarah , Van Rompaey Vincent , Gilles Annick
Published: September 2019

Objective:

Many tinnitus patients report cognitive deficits such as concentration and attention difficulties. The aim of this study was to comprehensively assess cognitive functioning in tinnitus patients using a standardized test battery, the repeatable battery for the assessment of neuropsychological status adjusted for hearing impaired individuals (RBANS-H).

Study Design:

Cross-sectional study.

Setting:

Tertiary referral center.

Participants:

Twenty-eight chronic tinnitus patients and 28 control participants, matched for sex, age, hearing loss, and education level.

Intervention:

Diagnostic.

Main Outcome Measures:

All participants completed the RBANS-H, which includes subtests probing immediate and delayed memory, visuospatial capabilities, language, and attention. The tinnitus patients completed the tinnitus functional index (TFI), a visual analogue scale (VAS) measuring subjective mean tinnitus loudness and the hyperacusis questionnaire (HQ).

Results:

The total RBANS-H scores did not differ between tinnitus patients and controls. However, on the language subscale, mean scores of the tinnitus group (97.6 ± 11.0) were significantly lower than those of controls (104.4 ± 12.0), with correction for sex, age, hearing level, and education level (general linear model: p = 0.034). Post hoc t tests revealed a specific deficit concerning the semantic fluency subtest (tinnitus: 19.5 ± 6.2; control: 23.1 ± 5.9; p = 0.015). VAS scores for tinnitus loudness were negatively correlated to scores on the RBANS-H attention subscale (r = –0.48, p = 0.012).

Conclusions:

The current study successfully employed the RBANS-H to provide a broader view on cognitive functioning in tinnitus patients. The results showed a specific negative influence of tinnitus on verbal fluency, which could be related to a deficit in executive cognitive control. Moreover, patients experiencing louder tinnitus performed worse on specific subtests concerning attention.
Long-term Implant Usage and Quality-of-Life in Sequential Bilateral Pediatric Cochlear Implantation
Authors: Low David , Shipp David , Gordon Karen , Kuroiwa-Rivero Maya , Cushing Sharon , Papsin Blake , Le Trung , Lin Vincent , Chen Joseph
Published: September 2019

Objectives:

Our primary objective was to investigate the long-term usage of cochlear implants (CIs) in children who underwent sequential bilateral CI (SeqBCI), and to study factors that impact usage. Our secondary objective was to understand the difference in subjective benefit and educational/employment status, between users and non-users of the second CI (CI2).

Study Design:

Prospective case series.

Setting:

Tertiary academic centers.

Patients:

Sixty-eight young adults who underwent SeqBCI as children.

Interventions:

Pediatric SeqBCI.

Main Outcome Measures:

The main outcome measures were the current usage of the first CI (CI1) and CI2, factors that determine usage, current perceptions of their CIs, educational/employment status, and Speech, Spatial and Qualities of Hearing scale (SSQ12) scores.

Results:

Sixty five (95.6%) participants were using CI1 for over 8 h/d and the rest were using CI1 for 4 to 8 h/d. Fourty four (64.7%) participants used CI2 for at least 4 h/d, 10 (15%) indicated that they rarely used CI2 (<4 h/d) and 14 (21%) were not using CI2 at all. On multivariate analysis, the only independent predictor of long-term usage of CI2 was the inter-implant interval (odds ratio [OR] 0.78, standard deviation [SD] 0.65–0.91, p = 0.002). There was no significant difference in the SSQ12 scores of users and non-users of CI2.

Conclusion:

The finding of increasing rates of non-usage of CI2 with lengthening inter-implant interval is clinically relevant and critical to health-economic assessment. From a usage point of view, the evidence is sufficiently robust to recommend that in children with bilateral deafness, bilateral CI should be done simultaneously, and if not, soon after the first CI. In the context of a longer inter-implant interval, clinicians should weigh the marginal benefits of CI2 against the surgical risks vis-a-vis non-usage and bilateral vestibular hypofunction.
Integration of Informatics Content in Baccalaureate and Graduate Nursing Education
Authors: Bove Lisa Anne
Published: September 2019

Background

The American Association of Colleges of Nursing identified informatics and health care technology as an essential component of baccalaureate, master's, and doctoral education, but schools still struggle to effectively deliver this core knowledge.

Purpose

The purpose of this study was to provide an update of the 2013 status report on the integration of informatics in nursing education.

Method

The top twenty-five 2018 US News & World Report Best Online Nursing Programs were reviewed for courses with technology, computers, informatics, statistics, or research in the title.

Findings

Sixty-seven percent of the schools with master's programs and more than 80% of the DNP programs included at least 1 informatics course. Schools with online BSN courses had about the same number of programs with informatics courses as the 2013 report.

Conclusion

While there was some improvement in the number of informatics courses in the programs reviewed, faculty need support to overcome barriers to teaching informatics.
Pathologic Characteristics of Spitz Melanoma With MAP3K8 Fusion or Truncation in a Pediatric Cohort
Authors: Newman Scott , Pappo Alberto , Raimondi Susana , Zhang Jinghui , Barnhill Raymond , Bahrami Armita
Published: September 2019

Spitz melanoma is a rare variant of melanoma defined by distinct clinical, histologic, and genetic features and affecting patients of all ages. Half of these tumors are driven by fusion of kinase genes including ALK, NTRK1/3, ROS1, RET, MET, or BRAF. We recently reported recurrent fusion or truncation of the potentially targetable serine-threonine kinase gene MAP3K8 in 33% of Spitz melanomas. Here we describe the histologic features of these MAP3K8-rearranged tumors (16 pediatric Spitz melanomas; 1 atypical Spitz tumor), using hematoxylin-eosin slides, p16 immunohistochemistry, and CDKN2A fluorescence in situ hybridization. The lesions consisted of a compound melanocytic proliferation, ranging in thickness from 1.5 to 13.4 mm (median, 3.1 mm), with 8 having a predominant dermal and 3 having a predominant junctional component. The predominant cell type was epithelioid (94%). The epithelioid melanocytes were generally monomorphic and amelanotic, arranged in expansile epithelial aggregates, confluent hypercellular nests, or enlarged syncytial nodules in the dermis. Ulceration was present in 9 of 17 tumors (53%) and deep mitotic figures were seen in 15 of 17 tumors (88%). Complete loss of p16 expression and homozygous CDKN2A deletion were observed in 82% and 70% of tumors, respectively. Recognition of MAP3K8-altered Spitz melanoma may thus be facilitated by these morphologic features, most notably presence of cohesive cellular nodules in the dermis and an epithelioid-cell phenotype.
Pan-TRK Immunohistochemistry
Authors: Harrison Beth T. , Fowler Elizabeth , Krings Gregor , Chen Yunn-Yi , Bean Gregory R. , Vincent-Salomon Anne , Fuhrmann Laetitia , Barnick Sandra E. , Chen Beiyun , Hosfield Elizabeth M. , Hornick Jason L. , Schnitt Stuart J.
Published: September 2019

Secretory carcinoma is a special-type breast carcinoma underpinned by a recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion. Immunohistochemistry (IHC) using a pan-TRK antibody has been recently shown to help identify NTRK rearrangements in other tumor types. The purpose of this study was to assess the diagnostic utility of pan-TRK IHC in secretory carcinoma of the breast. Pan-TRK IHC was performed using a rabbit monoclonal antibody on whole sections of 24 breast secretory carcinomas and tissue microarray sections of other breast carcinoma types (n=203) and histologic mimics (n=15). Cases were assessed for staining intensity and localization. The 24 patients with secretory carcinoma had a median age of 44 years and a median tumor size of 1.0 cm. ETV6 fluorescence in situ hybridization was positive in all cases tested (n=20). Twenty-three cases (95.8%) showed staining with pan-TRK, which was exclusively nuclear in 19, primarily nuclear with weak cytoplasmic staining in 3, and primarily cytoplasmic with focal nuclear staining in 1. The nuclear staining was diffuse in 17 and at least focally strong in 17. The only pan-TRK negative case was a core biopsy with limited tumor. Among the 203 nonsecretory carcinomas, 21 (10.3%) showed focal, weak nuclear staining in <5% of tumor cells and 1 (0.5%) showed focal membranous staining. All histologic mimics were negative. In conclusion, diffuse and/or at least focally strong nuclear pan-TRK staining is a sensitive and specific marker for secretory carcinoma of the breast.
Increased T1 Signal Intensity of the Anterior Pituitary Gland on Unenhanced Magnetic Resonance Images After Chronic Exposure to Gadodiamide
Authors: Mallio Carlo A. , Lo Vullo Gianguido , Messina Laura , Beomonte Zobel Bruno , Parizel Paul M. , Quattrocchi Carlo C.
Published: September 2019

Objective

The aim of this study was to assess the signal intensity of the anterior pituitary (AP) gland on unenhanced T1-weighted images in patients with history of serial intravenous injections of gadodiamide and normal renal function.

Materials and Methods

We included 53 patients who had undergone at least 5 injections of gadodiamide and a control group of 15 subjects who underwent at least 5 brain magnetic resonance imaging without gadolinium-based contrast agents. Using unenhanced sagittal T1-weighted images, values of mean signal intensity of the AP and of the central pons were obtained. Anterior pituitary–to–pons signal intensity ratios were calculated dividing the values of the AP by those of the pons. Then, the ratios were compared between the first and the last magnetic resonance imaging scans for all the subjects. To assess the difference between the first and the last ratios, nonparametric Wilcoxon signed-rank test with Monte Carlo resampling was applied. APvalue less than 0.05 was considered as statistically significant.

Results

The comparison between the first and the last scan revealed a statistically significant increase of AP-to-pons ratio in the last scan for the gadolinium-exposed group (P< 0.001), whereas nonsignificant results were found for the control group (P= nonsignificant).

Conclusions

We found an increased signal intensity of the AP on unenhanced T1-weighted images in patients with history of serial intravenous injections of gadodiamide and normal renal function, suggesting gadolinium deposition or long-term retention within the AP gland. Our findings need to be confirmed by further histochemical analysis of AP gland tissue samples.
Does the Artery-first Approach Improve the Rate of R0 Resection in Pancreatoduodenectomy?
Authors: Sabater Luis , Cugat Esteban , Serrablo Alejandro , Suarez-Artacho Gonzalo , Diez-Valladares Luis , Santoyo-Santoyo Julio , Martín-Pérez Elena , Ausania Fabio , Lopez-Ben Santiago , Jover-Navalon Jose Maria , Garcés-Albir Marina , Garcia-Domingo Maria Isabel , Serradilla Mario , Pérez-Aguirre Elia , Sánchez-Pérez Belinda , Di Martino Marcello , Senra-del-Rio Paula , Falgueras-Verdaguer Laia , Carabias Alberto , Gómez-Mateo Mari Carmen , Ferrandez Antonio , Dorcaratto Dimitri , Muñoz-Forner Elena , Fondevila Constantino , Padillo Javier
Published: September 2019

Objective:

To compare the rates of R0 resection in pancreatoduodenectomy (PD) for pancreatic and periampullary malignant tumors by means of standard (ST-PD) versus artery-first approach (AFA-PD).

Background:

Standardized histological examination of PD specimens has shown that most pancreatic resections thought to be R0 resections are R1. “Artery-first approach” is a surgical technique characterized by meticulous dissection of arterial planes and clearing of retropancreatic tissue in an attempt to achieve a higher rate of R0. To date, studies comparing AFA-PD versus ST-PD are retrospective cohort or case-control studies.

Methods:

A multicenter, randomized, controlled trial was conducted in 10 University Hospitals (NCT02803814, ClinicalTrials.gov). Eligible patients were those who presented with pancreatic head adenocarcinoma and periampullary tumors (ampulloma, distal cholangiocarcinoma, duodenal adenocarcinoma). Assignment to each group (ST-PD or AFA-PD) was randomized by blocks and stratified by centers. The primary end-point was the rate of tumor-free resection margins (R0); secondary end-points were postoperative complications and mortality.

Results:

One hundred seventy-nine patients were assessed for eligibility and 176 randomized. After exclusions, the final analysis included 75 ST-PD and 78 AFA-PD. R0 resection rates were 77.3% (95% CI: 68.4–87.4) with ST-PD and 67.9% (95% CI: 58.3–79.1) with AFA-PD, P=0.194. There were no significant differences in postoperative complication rates, overall 73.3% versus 67.9%, and perioperative mortality 4% versus 6.4%.

Conclusions:

Despite theoretical oncological advantages associated with AFA-PD and evidence coming from low-level studies, this multicenter, randomized, controlled trial has found no difference neither in R0 resection rates nor in postoperative complications in patients undergoing ST-PD versus AFA-PD for pancreatic head adenocarcinoma and other periampullary tumors.
The role of polymers in cross-kingdom bioadhesion
Authors: Morales-García A. L. , Bailey R. G. , Jana S. , Burgess J. G.
Published: September 2019

The secretion of extracellular polymeric substances provides an evolutionary advantage found in many organisms that can adhere to surfaces and cover themselves in a protective matrix. This ability is found in prokaryotes, archaea and eukaryotes, all of which use functionally similar polysaccharides, proteins and nucleic acids to form extracellular matrices, mucus and bioadhesive substances. These macromolecules have been investigated from the perspective of polymer biophysics, and theories to help understand adhesion, viscosity and gelling have been developed. These properties can be measured experimentally using straightforward methods such as cell counting as well as more advanced techniques such as atomic force microscopy and rheometry. An integrated understanding of the properties and uses of adhesive macromolecules across kingdoms is also important and can provide the basis for a range of biotechnological and medical applications.

This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.
Temporary adhesion of the proseriate flatworm
Minona ileanae
Authors: Pjeta Robert , Wunderer Julia , Bertemes Philip , Hofer Teresa , Salvenmoser Willi , Lengerer Birgit , Coassin Stefan , Erhart Gertraud , Beisel Christian , Sobral Daniel , Kremser Leopold , Lindner Herbert , Curini-Galletti Marco , Stelzer Claus-Peter , Hess Michael W. , Ladurner Peter
Published: September 2019

Flatworms can very rapidly attach to and detach from many substrates. In the presented work, we analysed the adhesive system of the marine proseriate flatworm
Minona ileanae
. We used light-, scanning- and transmission electron microscopy to analyse the morphology of the adhesive organs, which are located at the ventral side of the tail-plate. We performed transcriptome sequencing and differential RNA-seq for the identification of tail-specific transcripts. Using
in situ
hybridization expression screening, we identified nine transcripts that were expressed in the cells of the adhesive organs. Knock-down of five of these transcripts by RNA interference led to a reduction of the animal's attachment capacity. Adhesive proteins in footprints were confirmed using mass spectrometry and antibody staining. Additionally, lectin labelling of footprints revealed the presence of several sugar moieties. Furthermore, we determined a genome size of about 560 Mb for
M. ileanae
. We demonstrated the potential of Oxford Nanopore sequencing of genomic DNA as a cost-effective tool for identifying the number of repeats within an adhesive protein and for combining transcripts that were fragments of larger genes. A better understanding of the molecules involved in flatworm bioadhesion can pave the way towards developing innovative glues with reversible adhesive properties.

This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.
Elasticity and energy dissipation in the double network hydrogel adhesive of the slug
Arion subfuscus
Authors: Fung T.-M. , Gallego Lazo C. , Smith A. M.
Published: September 2019

The slug
Arion subfuscus
produces a mucus-based defensive secretion that is remarkably tough. This glue appears to be a double network hydrogel, gaining its toughness through the synergistic actions of two networks of polymers, a relatively stiff network and a relatively deformable network. The double network mechanism has great potential to guide the development of synthetic adhesives. Mechanical tests were performed to analyse key predictions of the mechanism. Stress relaxation tests and tensile tests support the presence of stable cross-links. Cyclic stress–strain tests demonstrate that the glue dissipates a great deal of energy through the failure of these cross-links as sacrificial bonds. Energy dissipation by failure of sacrificial bonds rather than viscous processes is supported by the minimal effect of the time course of the experiments on the measured properties. These sacrificial bonds appear able to reform within minutes after failure. Finally, the glue's stiffness decreases at pH values below 5.5, whereas magnesium and calcium rapidly dissociate from the glue at all pH values tested. Thus, these ions may not be the primary cross-linkers generating the glue's stiffness.

This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.
Learning from Northern clingfish (Gobiesox maeandricus): bioinspired suction cups attach to rough surfaces
Authors: Ditsche Petra , Summers Adam
Published: September 2019

While artificial suction cups only attach well to smooth surfaces, the Northern clingfish can attach to surfaces ranging from nanoscale smooth to rough stone. This ability is highly desirable for technical applications. The morphology of the fish's suction disc and its ability to attach to rough and slimy surfaces have been described before, and here we aim to close gaps in the biomechanical understanding, and transfer the biomechanical principles to technical suction cups. We demonstrate that the margin of the suction disc is the critical feature enabling attachment to rough surfaces. Second, friction measurements show that friction of the disc rim is increased on rough substrates and contributes to high tenacity. Increased friction causes a delay in failure of the suction cup and increases the attachment force. We were able to implement these concepts to develop the first suction cups bioinspired by Northern clingfish. These cups attach with tenacities up to 70 kPa on surfaces as rough as 270 µm grain size. The application of this technology is promising in fields such as surgery, industrial production processes and whale tagging.

This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems'.
Single cell ATAC-seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures
Authors: Rai Vivek , Quang Daniel X. , Erdos Michael R. , Cusanovich Darren A. , Daza Riza M. , Narisu Narisu , Zou Luli S. , Didion John P. , Guan Yuanfang , Shendure Jay , Parker Stephen C.J. , Collins Francis S.
Published: September 2019

Objective

Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood glucose levels. Genome wide association studies (GWAS) have identified >400 independent signals that encode genetic predisposition. More than 90% of the associated single nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined islet enhancer elements, indicating a strong transcriptional regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types that express distinct hormonal programs, and so each cell type may contribute differentially to the underlying regulatory processes that modulate T2D-associated transcriptional circuits. Existing chromatin profiling methods such as ATAC-seq and DNase-seq, applied to islets in bulk, produce aggregate profiles that mask important cellular and regulatory heterogeneity.

Methods

We present genome-wide single cell chromatin accessibility profiles in >1,600 cells derived from a human pancreatic islet sample using single-cell-combinatorial-indexing ATAC-seq (sci-ATAC-seq). We also developed a deep learning model based on the U-Net architecture to accurately predict open chromatin peak calls in rare cell populations.

Results

We show that sci-ATAC-seq profiles allow us to deconvolve alpha, beta, and delta cell populations and identify cell-type-specific regulatory signatures underlying T2D. Particularly, we find that T2D GWAS SNPs are significantly enriched in beta cell-specific and cross cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. We also demonstrate, using less abundant delta cells, that deep-learning models can improve signal recovery and feature reconstruction of rarer cell populations. Finally, we use co-accessibility measures to nominate the cell-specific target genes at 104 non-coding T2D GWAS signals.

Conclusions

Collectively, we identify the islet cell type of action across genetic signals of T2D predisposition and provide higher-resolution mechanistic insights into genetically encoded risk pathways.
Sexual-dimorphism in human immune system aging
Authors: Márquez Eladio J. , Chung Cheng-han , Marches Radu , Rossi Robert J. , Nehar-Belaid Djamel , Eroglu Alper , Mellert David J , Kuchel George A , Banchereau Jacques , Ucar Duygu
Published: September 2019

Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow-cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cell and increasing monocyte/cytotoxic cell functions. These changes were greater in magnitude in men and accompanied by a male-specific genomic decline in B-cell specific loci. Age-related epigenomic changes first spike around late-thirties with similar timing and magnitude between sexes, whereas the second spike is earlier and stronger in men. Unexpectedly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. Impact of age and sex on immune cell genomes can be visualized at https://immune-aging.jax.org to provide insights into future studies.
The distribution of neuronal primary cilia immunoreactive to melanin-concentrating hormone receptor 1 (MCHR1) in the murine prosencephalon
Authors: Diniz Giovanne B. , Battagello Daniella S. , Bono Bianca S. M. , Ferreira Jozélia G. P. , Klein Marianne O. , Motta-Teixeira Livia C. , Duarte Jessica C. G. , Presse Françoise , Nahon Jean-Louis , Adamantidis Antoine , Chee Melissa J. , Sita Luciane V. , Bittencourt Jackson C.
Published: September 2019

Melanin-concentrating hormone (MCH) is a ubiquitous vertebrate neuropeptide predominantly synthesized by neurons of the diencephalon that can act through two G protein-coupled receptors, called MCHR1 and MCHR2. The expression of Mchr1 has been investigated in both rats and mice, but its synthesis remains poorly described. After identifying an antibody that detects MCHR1 with high specificity, we employed immunohistochemistry to map the distribution of MCHR1 in the CNS of rats and mice. Multiple neurochemical markers were also employed to characterize some of the neuronal populations that synthesize MCHR1. Our results show that MCHR1 is abundantly found in a sensory subcellular structure called the neuronal primary cilium, which has been associated with the detection of free neurochemical agents released to act through volume transmission. Ciliary MCHR1 was found in a wide range of areas, including the olfactory bulb, cortical mantle, striatum, hippocampal formation, amygdala, midline thalamic nuclei, periventricular hypothalamic nuclei, and midbrain areas. No differences were observed between male and female mice, and rats and mice diverged in two key areas: the caudate-putamen nucleus and the subgranular zone of the dentate gyrus. Ciliary MCHR1 was found in close association to several neurochemical markers, including tyrosine hydroxylase, calretinin, kisspeptin, estrogen receptor, oxytocin, vasopressin, and corticotropin-releasing factor. Given the role of neuronal primary cilia in sensing free neurochemical messengers in the extracellular fluid, the widespread distribution of ciliary MCHR1, and the diverse neurochemical populations who synthesize MCHR1, our data indicates that volume transmission may play a prominent role in the normal function of the MCH system.
Functional connectome contractions in temporal lobe epilepsy: microstructural underpinnings and associations to surgical outcome
Authors: Larivière Sara , Weng Yifei , Vos de Wael Reinder , Frauscher Birgit , Wang Zhengge , Bernasconi Andrea , Bernasconi Neda , Schrader Dewi V. , Zhang Zhiqiang , Bernhardt Boris C.
Published: September 2019

Abstract

Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. While commonly related to hippocampal pathology, increasing evidence suggests structural changes beyond the mesiotemporal lobe. Functional anomalies and their link to underlying structural alterations, however, remain incompletely understood. We studied 30 drug-resistant TLE patients and 57 healthy controls using multimodal magnetic resonance imaging analyses. We developed a novel framework that parameterizes functional connectivity distance, consolidating functional and geometric properties of macroscale networks. Compared to controls, TLE showed connectivity distance reductions in temporo-insular and prefrontal networks, suggesting topological segregation of functional networks. Our novel approach furthermore allowed for the testing of morphological and microstructural associations, and revealed that functional connectivity contractions occurred independently from TLE-related cortical atrophy but were mediated by microstructural changes in the underlying white matter. All patients underwent a comparable resective surgery after our study and a regularized supervised machine learning paradigm with 5-fold cross-validation demonstrated that patient-specific functional anomalies predicted post-surgical seizure outcome with 74±8% accuracy, outperforming classifiers operating on clinical and structural imaging features. Our findings suggest connectivity distance contractions as a clinically relevant pathoconnectomic substrate of TLE. Functional topological isolation may represent a microstructurally mediated network mechanism that tilts the balance towards epileptogenesis.