bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Settlement of Intersecting Buildings in an Offshore Reclamation Project
Authors: Su Jing-Bo , Yu Zheng-yang , Lv Ya-Ru , Zhu Yi-Huan , Wang Hua-Qing
Published: March 2019

This paper addresses the problem of open gaps caused by differential settlement in the process of constructing sluice buildings in soft soil beach areas, combined with the construction of sluice and supporting facilities in a reclamation project. First, the change rules for the shear strength and compression modulus of soft soil under different consolidation degrees are studied by theoretical analysis. Then, an interaction model for soft soil and pile soil is established using the geotechnical finite element analysis software MIDAS/GTS NX. The change rules for the vertical and horizontal ultimate bearing capacities of a single pile with the degree of soil consolidation are studied. On this basis, a three‐dimensional numerical analysis model of drainage sluice, seawall, cofferdam, and foundation soil is established, and the relationship between the degree of soil consolidation and the development of structural gaps caused by differential settlement is obtained. The research results show that the bearing capacity of a single pile increases greatly with the consolidation of soil around the pile and that the gap width between the structures in the project decreases with increasing consolidation. This paper provides a theoretical basis for the prediction of pile bearing capacity in the preliminary design stage and the evaluation and calculation of differential settlement of intersecting buildings in soft soil beach areas.
Pharmacokinetic and Bioavailability Studies of Embelin after Intravenous and Oral Administration to Rats
Authors: Li Zhen , Chen Shu-jing , Yu Xie-an , Li Jin , Gao Xiu-mei , He Jun , Chang Yan-xu
Published: March 2019

Embelin exhibits the broad bioactivities such as antitumor, antifertility, antidiabetic, anti-inflammatory, antioxidant, anticonvulsant, anxiolytic, antimicrobial, and hepatoprotective activity. In order to further understand the pharmacokinetic characteristics and oral bioavailability of embelin in vivo, the concentration of embelin in rat plasma was determined by a sensitive high-performance liquid chromatography with diode array detector (HPLC-DAD). The preparation of samples was accomplished by a simple precipitating protein with methanol. Emodin was selected as the internal standard (IS). Embelin and IS were completely separated on an analytical column (Extend-C18, 4.6 × 250 mm, 5 μm) using 0.1% phosphoric acid in methanol and 0.1% phosphoric acid in aqueous solution (90:10, v/v) as the mobile phase. The lower limit of quantification was 0.15 μg/mL. Oral bioavailability of embelin was 30.2 ± 11.9%. This study could provide the information about pharmacokinetics and oral bioavailability of embelin, which was useful to assess the clinic efficacy and safety and promote further development of embelin.
Applicability of Smartphone for Dynamic Postural Stability Evaluation
Authors: Polechoński Jacek , Nawrocka Agnieszka , Wodarski Piotr , Tomik Rajmund
Published: March 2019

The purpose of this study was to determine the accuracy of smartphone’s gyroscope for dynamic postural stability among young healthy adults. The research included convenience sample of 85 healthy adults—37 women (mean age 22.1±1.6, body height 167.2±7.0) and 48 men (mean age 22.4±1.7, body height 176.1±13.8). In order to assess the accuracy of stabilometric measurement recorded by mobile phone, the raw data obtained at the same time by Sigma Balance Platform and Smartphone (SP) were correlated. Two thirty-second trials with one-minute interval break were performed (first in the frontal plane and second in the sagittal plane). A total of 170 measurements of postural stability were recorded (85 in frontal and 85 in the sagittal plane). The following parameters were included: the path of the stabilogram (in the case of SP, angular path) and the variation of the swing (standard deviation of the horizontal deflection of the platform). The results have shown strong and significant relationship between body sway variability measured by Sigma platform and smartphone in frontal (r=0.997) and sagittal (r=0.990) plane. For the geometric center of the platform and angular path distances, the correlation coefficient was also statistically significant and high, considering both lateral (r=0.999) and anterior-posterior sway (r=0.981). Our research shows that smartphones with gyroscope have potential for accurate assessment of postural balance, as an alternative for expensive and specialized equipment.
4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer
Authors: Wang Zhiyong , Feng Xiaodong , Molinolo Alfredo A. , Martin Daniel , Vitale-Cross Lynn , Nohata Nijiro , Ando Mizuo , Wahba Amy , Amornphimoltham Panomwat , Wu Xingyu , Gilardi Mara , Allevato Michael , Wu Victoria , Steffen Dana J. , Tofilon Philip , Sonenberg Nahum , Califano Joseph , Chen Qianming , Lippman Scott M. , Gutkind J. Silvio
Published: March 2019

Aberrant activation of the PI3K–mTOR signaling pathway occurs in >80% of head and neck squamous cell carcinomas (HNSCC), and overreliance on this signaling circuit may in turn represent a cancer-specific vulnerability that can be exploited therapeutically. mTOR inhibitors (mTORi) promote tumor regression in genetically defined and chemically induced HNSCC animal models, and encouraging results have been recently reported. However, the mTOR-regulated targets contributing to the clinical response have not yet been identified. Here, we focused on EIF4E-BP1 (4E-BP1), a direct target of mTOR that serves as key effector for protein synthesis. A systematic analysis of genomic alterations in the PIK3CA–mTOR pathway in HNSCC revealed that 4E-BP1 is rarely mutated, but at least one 4E-BP1 gene copy is lost in over 35% of the patients with HNSCC, correlating with decreased 4E-BP1 protein expression. 4E-BP1 gene copy number loss correlated with poor disease-free and overall survival. Aligned with a tumor-suppressive role, 4e-bp1/2 knockout mice formed larger and more lesions in models of HNSCC carcinogenesis. mTORi treatment or conditional expression of a mutant 4E-BP1 that cannot be phosphorylated by mTOR was sufficient to disrupt the translation–initiation complex and prevent tumor growth. Furthermore, CRISPR/Cas9–targeted 4E-BP1 HNSCC cells resulted in reduced sensitivity to mTORi in vitro and in vivo. Overall, these findings indicate that in HNSCC, mTOR persistently restrains 4E-BP1 via phosphorylation and that mTORi can restore the tumor-suppressive function of 4E-BP1. Our findings also support 4E-BP1 expression and phosphorylation status as a mechanistic biomarker of mTORi sensitivity in patients with HNSCC.

Significance:

These findings suggest that EIF4E-BP1 acts as a tumor suppressor in HNSCC and that 4E-BP1 dephosphorylation mediates the therapeutic response to mTORi, providing a mechanistic biomarker for future precision oncology trials.
Citrullination in Cancer
Authors: Yuzhalin Arseniy E.
Published: March 2019

Posttranslational modifications of proteins have been implicated in pathogenesis of numerous diseases. Arginine deimination (also known as citrullination) has a principal role in progression of rheumatoid arthritis through generation of autoantibodies and exacerbation of the inflammatory response. Recently, multiple research groups provided solid evidence of citrullination being in control of cancer progression; however, there is no comprehensive overview of these findings. This article summarizes and critically reviews the influence of citrullination on different aspects of tumor biology, including (i) regulation of apoptosis and differentiation, (ii) promoting EMT and metastasis, and (iii) potential use of citrullinated antigens for immunotherapy. In addition, (iv) the role of citrullination as a cancer biomarker and (v) implication of neutrophil extracellular traps in tumorigenesis are discussed. In summary, current findings testify to the significance of arginine deimination in tumor biology and thus more basic and translational studies are needed to further explore this topic.
Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans
Authors: Jones Carissa C. , Bradford Yuki , Amos Christopher I. , Blot William J. , Chanock Stephen J. , Harris Curtis C. , Schwartz Ann G. , Spitz Margaret R. , Wiencke John K. , Wrensch Margaret R. , Wu Xifeng , Aldrich Melinda C.
Published: March 2019

Background:

Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans.

Methods:

We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status.

Results:

We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73–0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22–1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72–0.90).

Conclusions:

We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans.

Impact:

Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.
CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function
Authors: Mittal Deepak , Lepletier Ailin , Madore Jason , Aguilera Amelia Roman , Stannard Kimberley , Blake Stephen J. , Whitehall Vicki L.J. , Liu Cheng , Bettington Mark L. , Takeda Kazuyoshi , Long Georgina V. , Scolyer Richard A. , Lan Ruth , Siemers Nathan , Korman Alan , Teng Michele W.L. , Johnston Robert J. , Dougall William C. , Smyth Mark J.
Published: March 2019

CD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8+ T cell–dependent manner. DNAM-1/CD226, Batf3, IL12p35, and IFNγ were also critical, and CD96-deficient CD8+ T cells promoted greater tumor control than CD96-sufficient CD8+ T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8+ T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti–PD-1 increased the percentage of IFNγ-expressing CD8+ T lymphocytes. Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8+ T cells and IFNγ. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8+ T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth.
Successful Treatment of Dermatophytomas in 19 Patients Using Efinaconazole 10% Solution
Authors: Wang Casey , Cantrell Wendy , Canavan Theresa , Elewski Boni
Published: March 2019

Dermatophytomas represent a historically difficult-to-treat complication of onychomycosis and are characterized by adherent fungal masses encased in biofilm in the subungual space. In this study, we evaluated the efficacy of 10% efinaconazole solution in patients with onychomycosis complicated by dermatophytomas. Cure was achieved in 65% of target great toenails. All dermatophytomas resolved and did not recur during the study. The median time to dermatophytoma resolution was 16 weeks.
Role of Immunocytochemistry in the Cytological Diagnosis of Pulmonary Tumors
Authors: Metovic Jasna , Righi Luisella , Delsedime Luisa , Volante Marco , Papotti Mauro
Published: March 2019

Pulmonary cytology is a challenging diagnostic tool, and it is usually evaluated considering medical history and radiological findings in order to reach an accurate diagnosis. Since the majority of lung cancer patients have an advanced stage at diagnosis, a cytological specimen is frequently the only material available for diagnosis and further prognostic/predictive marker determination. Several types of specimens can be obtained from the respiratory system (including sputum, bronchoalveolar lavage, bronchial brushing, fine needle aspiration, and pleural fluid) with different technical preclinical management protocols and different diagnostic yields. Immunocytochemistry (ICC) has a pivotal role in the determination of diagnostic, prognostic, and predictive markers. Therefore, limited cytology samples are to be used with a cell-sparing approach, to allow both diagnostic ICC evaluation as well as predictive marker assessment by ICC or specific molecular assays. In this review, we describe the most common ICC markers used for the diagnosis and prognostic/predictive characterization of thoracic tumors in different cytological specimens.
Transplant of Adult Bone for Reconstruction of a Large Post-Traumatic Cranial Defect in a Very Young Baby
Authors: Talamonti Giuseppe , Crisà Francesco , Canzi Gabriele
Published: March 2019

Large cranial defects in very young patients are challenging. The ideal material for cranioplasty in this age group has not yet been identified. Cryopreserved autologous bone presents very high rates of failures, acrylic resins pose a number of compatibility problems, bioceramics may be contraindicated, and autografts may be not adequate for repair of large defects. We present an 18-month-old baby with a large post-traumatic cranial defect which was repaired by assembling a new bone flap on a sterile stereolithographic 3-D model. This customized newly assembled flap consisted of a scaffold of autologous bone (from vault duplication) sustaining 2 large grafts of homologous cadaveric bone. It was adequately modeled and contoured on the 3-D model using metallic plates and screws. Immediately after implantation on the skull, the metallic devices were progressively replaced by reabsorbable material, thus maintaining the previously obtained flap profile. In this paper we detail this original technique which was developed to manage this specific patient.
Withdrawal Confounding in Randomized Controlled Trials of Antipsychotic, Antidepressant, and Stimulant Drugs, 2000–2017
Authors: Récalt Alexander M. , Cohen David
Published: March 2019

Background: Results of relapse prevention randomized controlled trials (RCTs) which discontinue psychotropic drug treatment from some participants may be confounded by drug withdrawal symptoms. We test for the confound by calculating whether ≥50% of the difference in relapse risk between drug-discontinued and drug-maintained groups is present at discontinuation time points (DCTs) with “short” and “long” assumptions regarding onset and duration of withdrawal symptoms. Methods: In eligible RCTs of antidepressants, antipsychotics, and stimulants from 2000 to 2017 (n = 30) selected from a systematic review, differences in relapse risk were examined by arithmetic and graphical comparison of mean behavioral scores or survival plots. Results: Only 14 studies (46.6%) with 15 analyses of relapse risk provided sufficient data. Under short and long DCTs, 9 of 13 (69.2%) and 7 of 9 (77.8%) interpretable analyses, respectively, suggested a withdrawal confound. The proportion of endpoint placebo-maintenance group difference present by the DCT averaged 69.1% (range, 58.7–148.0%, n = 13) for short DCT assumptions, and 79.0% (range, 51.5–183.3%, n = 9) under long DCTs. One study (3.33%) controlled for withdraw al effects, and 1 yielded inconclusive results. Conclusions: These results support suggestions that withdrawal symptoms confound the results of relapse prevention RCTs. Accounting for such symptoms in RCTs is an ethical, scientific, and clinical imperative. Justifications for relapse prevention RCTs employing a discontinuation procedure require more scrutiny.
Clinical Monitoring of Sacrococcygeal Teratoma
Authors: Wohlmuth Christoph , Bergh Eric , Bell Cynthia , Johnson Anthony , Moise Jr. Kenneth J. , van Gemert Martin J.C. , van den Wijngaard Jeroen P.H.M. , Wohlmuth-Wieser Iris , Averiss Ian , Gardiner Helena M.
Published: March 2019

Background: Sacrococcygeal teratomas (SCT) are often highly vascularized and may result in high-output cardiac failure, polyhydramnios, fetal hydrops, and demise. Delivery is guided by the SCT to fetus volume ratio (SCTratio), SCT growth rate, and cardiac output indexed for weight (CCOi). Methods: We compared measurements and outcome in 12 consecutive fetuses referred with SCT. Adverse outcomes were: fetal surgery, delivery < 32 gestational weeks or neonatal demise. Only SCTratio and CCOi were used to manage the cases. SCT vascularization index (VI%) was derived from the 3D virtual organ computer-aided analysis (VOCAL) software. The SCTModel (modified from acardiac twins) calculated a hypothetical SCT draining vein size and derived a risk line, using diameters of the superior and inferior vena cava, the azygous and umbilical veins. VI% and a model of systemic and umbilical venous volumes (SCTModel) were tested as indicators for outcome in SCT. Results: Fetuses were monitored from 20.1 to 36.4 gestational weeks and 5/12 had adverse outcomes: 1 had successful open fetal surgery at 23.8 weeks and delivered at term, 4 delivered at < 32 weeks with 3/4 having neonatal demise between 25 and 29 weeks. VI% was significantly higher in cases with adverse outcomes (mean 10.3 [8.9–11.6] vs. 4.4 [3.4–5.3], p < 0.0001). The additional fraction of the fetal cardiac output required to perfuse the SCT-draining vein (XSCO%) (p = 0.46), SCTratio (p = 0.08), and CCOi (p = 0.64) were not significant. All cases with adverse outcome had VI% > 8%. The SCTModel risk line predicted nonadverse outcomes well but lacked data in 2/5 cases with adverse outcomes. Conclusions: VI% is a significant indicator of SCT cases with adverse outcomes and combined with SCTratio may guide timing of delivery better than current measures.
Prenatal Diagnosis of Enterolithiasis in 20 Cases
Authors: Mallmann Michael R. , Reutter Heiko , Gottschalk Ingo , Geipel Annegret , Berg Christoph , Gembruch Ulrich
Published: March 2019

Background: Enterolithiasis is a sonographic sign defined by hyperechogenic foci within the – often distended – fetal bowel. Objectives: We report on a series of 20 cases with enterolithiasis diagnosed prenatally and illustrate the spectrum of associated malformations. Method: This was a retrospective study involving 20 fetuses with enterolithiasis at two large tertiary referral centers in Germany over a 17-year period (2000–2017). Results: Median diagnosis was made with ultrasound at 18+2 weeks of gestation (IQR25,75: 14+5, 26+5). Additional malformations included urogenital malformations (cloacal malformation in 7/20 fetuses [35%] and kidney defects in 7/20 fetuses [35%]), cardiac malformations (3/20 fetuses [15%]), and vertebral malformations (5/20 fetuses [25%]). Of 20 fetuses, 14 could be attributed to the anorectal malformation spectrum, 3/20 fetuses presented with caudal regression syndrome, and 1 fetus with bilateral kidney agenesis, congenital diaphragmatic aplasia, and enterovesical fistula, respectively. Conclusion: Enterolithiasis is a rare prenatal sonographic feature. Because of the frequent occurrence of uro-recto-genital malformations, thorough prenatal counseling should be performed.
Diffuse Iris Melanoma: Conservative Treatment with Proton Beam Therapy after Limbal Stem Cell Preservation or Enucleation?
Authors: Leblanc Alice , Lumbroso-Le Rouic Livia , Desjardins Laurence , Dendale Rémi , Cassoux Nathalie
Published: March 2019

Objectives: Iris melanomas represent 2–3% of uveal melanomas; the diffuse variant accounts for approximately 10% of all iris melanomas. Different treatment modalities for diffuse iris melanomas (DIM) have been proposed depending on the local status as well as the age and general condition of the patient. Methods: This study is a single-centre retrospective case series describing the diagnosis, treatments and outcomes of DIM. Treatment consisted of enucleation or proton beam therapy (PT) of the whole anterior segment. Patients who were treated with PT benefitted from limbal stem cell preservation before irradiation. Results: Between 1996 and 2016, a total of 14 patients with DIM presented to our institution and were included in the database. The global survival was 86%. The median follow-up was 4.6 years (range 4 months to 15 years). Only 1 patient (7%) developed metastatic disease of the DIM (gastric location). No patient developed liver metastasis. Seven patients were treated by enucleation and 7 by PT after limbal stem cell preservation. After a conservative attempt, local tumour recurrence occurred in 2 patients at 2 years, requiring enucleation. The cornea was clear after irradiation in all patients. Cataract (n = 6) and glaucoma (n = 4) were the main complications after irradiation. Conclusions: DIM is a very rare tumour. The global survival is excellent. Conservative treatment with PT is an efficient alternative to enucleation and allows good local tumour control. Cataract and glaucoma are the main radiation-related complications, but the corneal status was excellent due to the stem cell harvest prior to radiotherapy.
Retroperitoneal Tumor: A Silent Trespasser – Role of Image-Guided Fine-Needle Aspiration Cytology with Histopathological Correlation in Early Diagnosis
Authors: Das Aditi , Gahine Renuka , Patre Vivek , Hussain Nighat
Published: March 2019

Objective: Retroperitoneal lesions present a great diagnostic challenge. Here we analyze the spectrum of retroperitoneal lesions and the utility of cytohistopathological correlation in early diagnosis. Study Design: This 7-year study was undertaken in 338 patients with a retroperitoneal mass (kidney/adrenal/ pancreas/retroperitoneal lymph node, or soft tissue origin). In a prospective analysis, 81 patients underwent image-guided fine-needle aspiration cytology (FNAC) and 70 of the 81 underwent Tru-cut biopsy/histopathological evaluation. Clinical, radiological, and pathological details of 257 patients were retrieved from institutional records for retrospective analysis. A total of 119 patients, i.e., 70 in the prospective analysis and 49 in the retrospective analysis, had cytohistopathological correlation. Results: Of the 338 cases, 88.4% were malignant (n = 274), 2.6% were benign (n = 8), 9% were nonneoplastic (n = 28), and 9% were inadequate (n = 28). Most were renal in origin (n = 106; 34.2%), followed by retroperitoneal soft tissue (n = 96; 31%). The most common nonneoplastic lesion was tubercular lymphadenitis (42.85%) and the most common benign lesion was paraganglioma (42.85%). The most common malignancy was renal cell carcinoma (21.16%), followed by Wilms’ tumor (13.86%). In infancy and early childhood, Wilms’ tumor, neuroblastoma, and germ cell tumor were the most common malignancies, while in middle age it was renal cell carcinoma, followed by pancreatic adenocarcinoma, and in the elderly age group it was metastatic carcinoma. Most malignancies were noted in the 5th to 6th decades. The overall sensitivity, specificity, and diagnostic accuracy of image-guided FNAC was 98.02, 72.22, and 94.12%, respectively. Conclusion: Image-guided FNAC is highly sensitive and specific for early diagnosis of an otherwise silent retroperitoneal mass. It saves patient from meticulous surgical procedures for diagnostic reasons and allows more rational planning of management. Knowledge of the distribution of tumors by age group helps to narrow down differential diagnoses.
Identification of MazF Homologue in Legionella pneumophila Which Cleaves RNA at the AACU Sequence
Authors: Shaku Mao , Park Jung-Ho , Inouye Masayori , Yamaguchi Yoshihiro
Published: March 2019

MazF is a sequence-specific endoribonuclease that is widely conserved in bacteria and archaea. Here, we found an MazF homologue (MazF-lp; LPO-p0114) in Legionella pneumophila. The mazF-lp gene overlaps 14 base pairs with the upstream gene mazE-lp (MazE-lp; LPO-p0115). The induction of mazF-lp caused cell growth arrest, while mazE-lp co-induction recovered cell growth in Escherichia coli. In vivo and in vitro primer extension experiments showed that MazF-lp is a sequence-specific endoribonuclease cleaving RNA at AACU. The endoribonuclease activity of purified MazF-lp was inhibited by purified MazE-lp. We found that MazE-lp and the MazEF-lp complex specifically bind to the palindromic sequence present in the 5′-untranslated region of the mazEF-lp operon. MazE-lp and MazEF-lp both likely function as a repressor for the mazEF-lp operon and for other genes, including icmR, whose gene product functions as a secretion chaperone for the IcmQ pore-forming protein, by specifically binding to the palindromic sequence in 5′-UTR of these genes.
Myocardial Telocyte-Like Cells: A Review Including New Evidence
Authors: Iancu Cristian B. , Rusu Mugurel C. , Mogoantă  Laurenţiu , Hostiuc Sorin , Grigoriu Mihai
Published: March 2019

Telocytes (TCs) are a controversial cell type characterized by the presence of a particular kind of prolongations, known as telopodes, which are long, thin, and moniliform. A number of attempts has been made to establish the molecular phenotype of cardiac TCs (i.e., expression of c-kit, CD34, vimentin, PDGRFα, PDGRFβ, etc.). We designed an immunohistochemical study involving cardiac tissue samples obtained from 10 cadavers with the aim of determining whether there are TC-like interstitial cells that populate the interstitial space other than the mural microvascular cells. We applied the markers for CD31, CD34, PDGRFα, CD117/c-kit, and α-smooth muscle actin (α-SMA). We found that, in relation to two-dimensional cuts, the endothelial tubes could be misidentified as TC-like cells, the difference being the positive identification of endothelial lumina. Moreover, we found that cardiac pericytes express PDGRFα, CD117/c-kit, and α-SMA, and that they could also be misidentified as TCs when using light microscopy. We reviewed the respective values of the previously identified markers for achieving a clear-cut identification of cardiac TCs, highlighting the critical lack of specificity.
Female Physicians Leading Health Care in the Arab World
Authors: Al Sabah Salman , AlHamdan Fajer , Qadhi Iman , Shuaibi Sameera , Younes Shaden , Al Haddad Eliana
Published: March 2019

Background and Objectives: A global trend in female leadership roles in the medical profession is on the rise, and females have been taking up leadership roles in varying and increasing levels. This study aims to identify changes in trends in the medical field in terms of gender in the last decade in Kuwait. Methods: A case study was conducted, in which data on leadership positions in Kuwait’s government hospitals were obtained from hospital registries. Demographic data about female to male physicians were collected from statistics published by the Department of Manpower, Statistics and Planning of Kuwait’s Ministry of Health. In addition, statistics on medical graduates were obtained from the Faculty of Medicine (FOM), Kuwait University (KU). Results: In general, every government hospital in Kuwait has experienced an increase in leadership roles among females; in 2008, among all leadership positions in Kuwait’s general hospitals, males occupied a majority of positions (60%); whereas in 2016, the male to female ratio was 1:1. The most change in gender trends was witnessed at Mubarak Al-Kabeer Hospital, where female leaders went from 38% in 2008 to 73% in 2016. The specialties that have the highest number of females in leadership positions across all hospitals from 2008 to 2016 were nuclear medicine, radiology, and laboratory medicine. In KU’s FOM, female graduates outweighed male graduates, except in 2005–2006, where females reached a minimum of 48%. The number of female physicians has also increased from its lowest of 31% of the total number of physicians in 2004–2006, to 37% in 2015. Conclusion: While women make up more than half of medical graduates in Kuwait at present, significant barriers had restricted their entry into formal medical leadership roles in the past. However, it is now seen that females currently occupy more leadership positions in government hospitals in Kuwait.
Pitfalls in the Diagnostic Evaluation of Hyperprolactinemia
Authors: Vilar Lucio , Vilar Clarice Freitas , Lyra Ruy , Freitas Maria da Conceição
Published: March 2019

An appropriate diagnostic evaluation is essential for the most appropriate treatment to be performed. Currently, macroprolactinemia is the third most frequent cause of nonphysiological hyperprolactinemia after drugs and prolactinomas. Up to 40% of macroprolactinemic patients may present with hypogonadism symptoms, infertility, and/or galactorrhea. Thus, the screening for macroprolactin is indicated not only for asymptomatic subjects but also for those without an obvious cause for their prolactin (PRL) elevation. Before submitting patients to macroprolactin screening and pituitary magnetic resonance imaging, one should rule out pregnancy, drug-induced hyperprolactinemia, primary hypothyroidism, and renal failure. The magnitude of PRL elevation can be useful in determining the etiology of hyperprolactinemia. PRL values >250 ng/mL are highly suggestive of prolactinomas and virtually exclude nonfunctioning pituitary adenomas (NFPAs) and other sellar masses as the etiology of hyperprolactinemia. However, they can also be found in subjects with macroprolactinemia, drug-induced hyper­prolactinemia or chronic renal failure. By contrast, most patients with NFPAs, drug-induced hyperprolactinemia, macroprolactinemia, or systemic diseases present with PRL levels <100 ng/mL. However, exceptions to these rules are not rare. Indeed, up to 25% of patients harboring a microprolactinoma or a cystic macroprolactinoma may also have PRL <100 ng/mL. Falsely low PRL levels may result from the so-called “hook effect,” which should be considered in all cases of large (≥3 cm) pituitary adenomas associated with normal or mildly elevated PRL levels (≤250 ng/mL). The hook effect may be unmasked by repeating PRL measurement after a 1:100 serum sample dilution.
Orchid bees (Hymenoptera, Apidae, Euglossini) are seasonal in Seasonal Semideciduous Forest fragments, southern Brazil
Authors: Margatto Cleiton , Berno Vinicius Ortega , Gonçalves Rodrigo Barbosa , Faria Jr. Luiz Roberto Ribeiro
Published: March 2019

Seasonal fluctuations in the abundance of orchid bees have already been reported. The variations in population dynamics may be expected to occur in more predictable and pronounced manners in environments with a clear distinction between rainy and dry seasons, where climatic variables are regarded to be good predictors of populational patterns. The main goal of this paper is to investigate the seasonality of males of orchid bees in fragments of Seasonal Semideciduous Forest in southern Brazil. Data comprise bait samples from five one-year periods on four forest fragments. The seasonality of species abundance was tested with circular statistics. Results suggest two phenological patterns, one for Eufriesea violacea (Blanchard), Eulaema nigrita Lepeletier and Euglossa cordata (Linnaeus), whose abundances are concentrated in late spring and early-middle summer and another for Euglossa fimbriata Moure with a tendency to be collected in middle-late summer and early autumn. These patterns are discussed, as well the possible driven factors, (i) the species life cycle and nesting behavior, (ii) synchrony with resource, and (iii) climate. We can postulate an important impact of climate change in local euglossine assemblage due to the small populations and marked seasonality.
The Transcription Factor ERG Regulates Super-Enhancers Associated With an Endothelial-Specific Gene Expression Program
Authors: Kalna Viktoria , Yang Youwen , Peghaire Claire R. , Frudd Karen , Hannah Rebecca , Shah Aarti V. , Osuna Almagro Lourdes , Boyle Joseph J. , Göttgens Berthold , Ferrer Jorge , Randi Anna M. , Birdsey Graeme M.
Published: March 2019

Rationale:

The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers).

Objective:

To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers.

Methods and Results:

Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as
DLL4
(Delta-like protein 4),
CLDN5
(claudin-5),
VWF
(von Willebrand factor), and
CDH5
(VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-associated single nucleotide polymorphisms from genome-wide association studies lie within noncoding regions and perturb transcription factor recognition sequences in relevant cell types. Analysis of genome-wide association studies data shows significant enrichment of risk variants for cardiovascular disease and other diseases, at ERG endothelial enhancers and super-enhancers.

Conclusions:

The transcription factor ERG promotes endothelial homeostasis via regulation of lineage-specific enhancers and super-enhancers. Enrichment of cardiovascular disease-associated single nucleotide polymorphisms at ERG super-enhancers suggests that ERG-dependent transcription modulates disease risk.
Years of Potential Life Lost Because of Cardiovascular Disease in Asian‐American Subgroups, 2003–2012
Authors: Iyer Divya G. , Shah Nilay S. , Hastings Katherine G. , Hu Jiaqi , Rodriguez Fatima , Boothroyd Derek B. , Krishnan Aruna V. , Falasinnu Titilola , Palaniappan Latha
Published: March 2019

Background

Asian‐American subgroups (Asian‐Indian, Chinese, Filipino, Korean, Japanese, and Vietnamese) display varied cardiovascular disease mortality patterns, especially at younger ages. This study aims to examine the years of potential life lost because of ischemic heart disease and cerebrovascular disease among the 6 largest Asian‐American subgroups compared with non‐Hispanic whites.

Methods and Results

We used National Center for Health Statistics Multiple Causes of Death mortality files from 2003 to 2012 to calculate race‐specific life expectancy, mean years of potential life lost, and years of potential life lost per 100 000 population for each Asian subgroup and non‐Hispanic whites. Asian‐American subgroups display heterogeneity in cardiovascular disease burden. Asian‐Indians had a high burden of ischemic heart disease; Asian‐Indian men lost 724 years per 100 000 population in 2012 and a mean of 17 years to ischemic heart disease. Respectively, Vietnamese and Filipino men and women lost a mean of 17 and 16 years of life to cerebrovascular disease; Filipino men lost 352 years per 100 000 population in 2012. All Asian subgroups for both sexes had higher years of life lost to cerebrovascular disease compared with non‐Hispanic whites.

Conclusions

Cardiovascular disease burden varies among Asian subgroups, and contributes to greater premature mortality in certain subgroups. Asian‐Indian and Filipino populations have the highest years of life lost because of ischemic heart disease and Filipino and Vietnamese have the highest years of life lost because of cerebrovascular disease. Analysis of risk factors and development of subgroup‐specific interventions are required to address these health disparities.
Association of Circulating Tissue Inhibitor of Metalloproteinases‐1 and Procollagen Type III Aminoterminal Peptide Levels With Incident Heart Failure and Chronic Kidney Disease
Authors: Lieb Wolfgang , Song Rebecca J. , Xanthakis Vanessa , Vasan Ramachandran S.
Published: March 2019

Background

Tissue inhibitor of metalloproteinases‐1 (
TIMP
‐1) and procollagen type
III
aminoterminal peptide are established circulating markers of extracellular matrix remodeling and associated with cardiovascular disease. The association of both biomarkers with incident congestive heart failure and chronic kidney disease (
CKD
) in the community is not well studied.

Methods and Results

We measured plasma total
TIMP
‐1 and procollagen type
III
aminoterminal peptide levels in 922 Framingham participants (mean age, 57 years; 57% women) and related both biomarkers to the risk of incident
CKD
and congestive heart failure in multivariable‐adjusted Cox regression models. Plasma total
TIMP
‐1 levels were positively associated with risk of incident
CKD
(164 events; hazard ratio per 1 SD in log‐biomarker, 1.90; 95%
CI
, 1.53–2.37) in multivariable models, including adjustments for left ventricular mass, C‐reactive protein, and B‐type natriuretic peptide levels. The association of total
TIMP
‐1 with risk of congestive heart failure was statistically significant in an age‐ and sex‐adjusted model, but was attenuated upon adjustment for conventional risk factors. Blood procollagen type
III
aminoterminal peptide levels were not related to the risk of
CKD
or congestive heart failure.

Conclusions

Higher baseline levels of total
TIMP
‐1 conferred an increased risk for incident
CKD
, independent of conventional risk factors and circulating biomarkers of chronic systemic inflammation and neurohormonal activation. Our prospective observations in a large community‐based sample support the role of matrix remodeling in the pathogenesis of
CKD
.
Lack of Consensus Among Stroke Experts on the Optimal Management of Patients With Acute Tandem Occlusion
Authors: Jacquin Gregory , Poppe Alexandre Y. , Labrie Marilyn , Daneault Nicole , Deschaintre Yan , Gioia Laura C. , Odier Celine , Raymond Jean , Roy Daniel , Weill Alain , Stapf Christian
Published: March 2019

Background and Purpose—

In patients with acute stroke caused by tandem occlusion, the benefit of immediate revascularization (stenting) of the cervical internal carotid artery lesion during endovascular thrombectomy is uncertain. We sought to determine current practice patterns and whether consensus existed among physicians with stroke expertise.

Methods—

We distributed an online survey to stroke experts affiliated with the Canadian Stroke Consortium, the Canadian Interventional Neuro Group, the Society of Vascular and Interventional Neurology, and international ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) collaborators. Questions were based on clinical scenarios, and multiple choice responses across a Likert-type scale were provided. The survey was sent out in September 2017. After 2 months, data were extracted and then analyzed using descriptive statistics.

Results—

Responses from 162 stroke experts were analyzed; most were stroke physicians (n=65, 40.1%) and neurointerventionalists (n=74, 45.7%), from Canada (n=95, 58.6%), the United States (n=42, 25.9%), and other countries (n=25, 15.4%). Over half (n=96, 59.3%) of respondents consider acute stenting of the cervical internal carotid artery as a treatment option, whereas 40.7% (n=66) would never use it. Most respondents (n=113, 69.8%) agree that there exists uncertainty about the optimal acute management of patients with tandem occlusion. A majority (n=88, 54.3%) of physicians surveyed would include patients in a randomized trial addressing this question.

Conclusions—

This survey shows high variability in practice about acute management of tandem occlusion. The existence of community equipoise underscores the importance of a randomized trial evaluating the benefit of acute internal carotid artery stenting in patients with tandem occlusion undergoing endovascular thrombectomy.
Infratentorial Intracerebral Hemorrhage
Authors: Chen Ruiqi , Wang Xia , Anderson Craig S. , Robinson Thompson , Lavados Pablo M. , Lindley Richard I. , Chalmers John , Delcourt Candice ,   for the INTERACT Investigators
Published: March 2019

Background and Purpose—

Infratentorial intracerebral hemorrhage (ICH) has a poor outcome but is rarely analyzed by cerebellar versus brain stem location. We evaluated this relationship and clinical outcomes among participants of the INTERACT 1 and 2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials).

Methods—

Participants with brain stem and cerebellar ICH were compared. Logistic regression models were used to compare outcomes of death or major disability and quality of life.

Results—

Of 195 included patients, 92 (47%) and 103 (53%) had brain stem and cerebellar ICH, respectively. Patients with brain stem ICH were younger (mean [SD] age, 59±13 versus 70±11 years), less female (28.3% versus 50.5%), with higher admission National Institutes of Health Stroke Scale scores (median [interquartile range], 6 [4–10) versus 3 [2–8]), less prior ICH (3% versus 17%), smaller ICH volumes (1.6 mL [1.0–2.8 mL] versus 5.1 mL [2.6–10.7 mL]), and less intraventricular extension (3% versus 39%) than those with cerebellar ICH. Brain stem ICH had higher mortality (odds ratio, 37.1; 95% CI, 1.99–692.27) and worse scores in the European Quality of Life Scale (EQ-5D) pain domain (odds ratio, 3.36; 95% CI, 1.38–8.20).

Conclusions—

Cerebellar and brain stem ICH differ in their clinical characteristics and prognosis, with the latter being associated with higher case fatality and worse EQ-5D scores in the pain domain.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT00226096 and NCT00716079.
Novel Event Detection and Classification for Historical Texts
Authors: Sprugnoli Rachele , Tonelli Sara
Published: March 2019

Event processing is an active area of research in the Natural Language Processing community, but resources and automatic systems developed so far have mainly addressed contemporary texts. However, the recognition and elaboration of events is a crucial step when dealing with historical texts Particularly in the current era of massive digitization of historical sources: Research in this domain can lead to the development of methodologies and tools that can assist historians in enhancing their work, while having an impact also on the field of Natural Language Processing. Our work aims at shedding light on the complex concept of events when dealing with historical texts. More specifically, we introduce new annotation guidelines for event mentions and types, categorized into 22 classes. Then, we annotate a historical corpus accordingly, and compare two approaches for automatic event detection and classification following this novel scheme. We believe that this work can foster research in a field of inquiry as yet underestimated in the area of Temporal Information Processing. To this end, we release new annotation guidelines, a corpus, and new models for automatic annotation.
Incorporating Source-Side Phrase Structures into Neural Machine Translation
Authors: Eriguchi Akiko , Hashimoto Kazuma , Tsuruoka Yoshimasa
Published: March 2019

Neural machine translation (NMT) has shown great success as a new alternative to the traditional Statistical Machine Translation model in multiple languages. Early NMT models are based on sequence-to-sequence learning that encodes a sequence of source words into a vector space and generates another sequence of target words from the vector. In those NMT models, sentences are simply treated as sequences of words without any internal structure. In this article, we focus on the role of the syntactic structure of source sentences and propose a novel end-to-end syntactic NMT model, which we call a tree-to-sequence NMT model, extending a sequence-to-sequence model with the source-side phrase structure. Our proposed model has an attention mechanism that enables the decoder to generate a translated word while softly aligning it with phrases as well as words of the source sentence. We have empirically compared the proposed model with sequence-to-sequence models in various settings on Chinese-to-Japanese and English-to-Japanese translation tasks. Our experimental results suggest that the use of syntactic structure can be beneficial when the training data set is small, but is not as effective as using a bi-directional encoder. As the size of training data set increases, the benefits of using a syntactic tree tends to diminish.