bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition
Authors: Okonska Agata , Bühler Saskja , Rao Vasundhara , Ronner Manuel , Blijlevens Maxime , van der Meulen-Muileman Ida H. , de Menezes Renee X. , Wipplinger Martin , Oehl Kathrin , Smit Egbert F. , Weder Walter , Stahel Rolf A. , Penengo Lorenza , van Beusechem Victor W. , Felley-Bosco Emanuela 
Published: October 2019

Abstract
Loss of function of BRCA1-associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy. A genetically engineered model was established expressing either functional or nonfunctional BAP1, and whole-genome siRNA synthetic lethality screens were performed assessing differentially impaired survival between the two cell lines. The whole-genome siRNA screen unexpectedly revealed 11 hits (FDR &lt; 0.05) that were more cytotoxic to BAP1-proficient cells. Two actionable targets, ribonucleotide reductase (RNR) catalytic subunit M1 (RRM1) and RNR regulatory subunit M2 (RRM2), were validated. In line with the screen results, primary mesothelioma (BAP1+/−) overexpressing BAP1 C91A (catalytically dead mutant) was more resistant to RNR inhibition, while BAP1 knockdown in the BAP1-proficient cell lines rescued the cells from their vulnerability to RNR depletion. Gemcitabine and hydroxyurea were more cytotoxic in BAP1-proficient cell line–derived spheroids compared with BAP1 deficient. Upregulation of RRM2 upon gemcitabine and hydroxyurea treatment was more profound in BAP1 mut/del cell lines. Increased lethality mediated by RNR inhibition was observed in NCI-H2452 cells reconstituted with BAP1-WT but not with BAP1 C91A. Upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared with control or C91A mutant. Together, we found that BAP1 is involved in the regulation of RNR levels during replication stress. Our observations reveal a potential clinical application where BAP1 status could serve as predictive or stratification biomarker for RNR inhibition-based therapy in MPM.
A TFAP2C Gene Signature Is Predictive of Outcome in HER2-Positive Breast Cancer
Authors: Wu Vincent T. , Kiriazov Boris , Koch Kelsey E. , Gu Vivian W. , Beck Anna C. , Borcherding Nicholas , Li Tiandao , Addo Peter , Wehrspan Zachary J. , Zhang Weizhou , Braun Terry A. , Brown Bartley J. , Band Vimla , Band Hamid , Kulak Mikhail V. , Weigel Ronald J. 
Published: October 2019

Abstract

The AP-2γ transcription factor, encoded by the TFAP2C gene, regulates the expression of estrogen receptor-alpha (ERα) and other genes associated with hormone response in luminal breast cancer. Little is known about the role of AP-2γ in other breast cancer subtypes. A subset of HER2+ breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2γ. Herein, we sought to define AP-2γ gene targets in HER2+ breast cancer and identify genes accounting for physiologic effects of growth and invasiveness regulated by AP-2γ. Comparing HER2+ cell lines that demonstrated differential response to growth and invasiveness with knockdown of TFAP2C, we identified a set of 68 differentially expressed target genes. CDH5 and CDKN1A were among the genes differentially regulated by AP-2γ and that contributed to growth and invasiveness. Pathway analysis implicated the MAPK13/p38δ and retinoic acid regulatory nodes, which were confirmed to display divergent responses in different HER2+ cancer lines. To confirm the clinical relevance of the genes identified, the AP-2γ gene signature was found to be highly predictive of outcome in patients with HER2+ breast cancer. We conclude that AP-2γ regulates a set of genes in HER2+ breast cancer that drive cancer growth and invasiveness. The AP-2γ gene signature predicts outcome of patients with HER2+ breast cancer and pathway analysis predicts that subsets of patients will respond to drugs that target the MAPK or retinoic acid pathways.

Implications:
A set of genes regulated by AP-2γ in HER2+ breast cancer that drive proliferation and invasion were identified and provided a gene signature that is predictive of outcome in HER2+ breast cancer.
E-Cigarettes and Cancer Risk
Authors: Mravec Boris , Tibensky Miroslav , Horvathova Lubica , Babal Pavel 
Published: October 2019

AbstractFrom the time of their introduction, the popularity of e-cigarettes (electronic nicotine-delivery systems) has been rising. This trend may reflect the general belief that e-cigarettes are a less hazardous alternative to combustible cigarettes. However, the potential cancer-related effects of increased activation of the sympathoadrenal system induced by the inhalation of nicotine, the primary component of the e-cigarettes, are completely overlooked. Therefore, the aim of this review is to describe mechanisms that may connect the use of e-cigarettes and an increased risk for cancer development, as well as their stimulatory effect on cancer progression. Available preclinical data indicate that activation of the sympathetic nervous system by nicotine inhaled from e-cigarettes may stimulate cancer development and growth by several mechanisms. This issue might be especially important for oncological patients as they may have the misconception that compared with combustible cigarettes, e-cigarettes represent a risk-free alternative.
Морфологічні зміни в нирках за умов гострого поширеного перитоніту на тлі цукрового діабету
Authors: Dzubanovsky I. Ya. , Verveha B. M. , Pidruchna S. R. , Melnyk N. A. 
Published: October 2019

Мета роботи: дослідити морфологічні зміни в нирках піддослідних тварин при змодельованому гострому поширеному перитоніті на тлі цукрового діабету порівняно із тваринами з експериментальним гострим поширеним перитонітом.
Матеріали і методи. В експерименті використано 56 білих щурів. Цукровий діабет моделювали шляхом внутрішньоочеревинного введення стрептозотоцину фірми “Sigmal” з розрахунку 7 мг на 100 г маси тварини, гострий поширений перитоніт – введенням 0,5 мл 10 % профільтрованої калової суспензії в черевну порожнину досліджуваних тварин. Досліджували тканину нирки 1, 3, 7 доби від початку моделювання перитоніту.
Результати досліджень та їх обговорення. У тварин із гострим поширеним перитонітом на тлі цукрового діабету патоморфологічні зміни були більш виражені: судини венозного русла дещо розширювались, були повнокровні, візуалізувались дрібні периваскулярні точкові крововиливи. Більшість вивідних канальців були розширені, проте їх просвіти були вільні від ексудату. В петлях Генле і прямих канальцях ми спостерігали виражений набряк епітелію. У тварин із гострим поширеним перитонітом на тлі цукрового діабету спостерігалися більш виражені патоморфологічні зміни у тканині нирок у всі терміни спостереження порівняно із групою тварин, яким не моделювали цукровий діабет, що характеризувалися периваскулярним набряком, збільшенням та розширенням судинного просвіту, наявністю серозного ексудату.
Активність каталази та супероксиддисмутази на тлі експериментальної ішемії-реперфузії кінцівки
Authors: Volotovska N. V. , Zarichna O. Yo. , Kuzmak I. P. 
Published: October 2019

Мета роботи: встановити динаміку активності супероксиддисмутази та каталази нирок на тлі модифікацій ішемічнореперфузійного синдрому (ІРС).
Матеріали і методи. У експерименті використовували 210 нелінійних білих щурів-самців віком 5–5,5 місяця. Досліджено динаміку активності антиоксидних ферментів (каталаза (Кат), супероксиддисмутаза (СОД)) у тканині нирки в умовах моделювання модифікацій ішемічно-реперфузійного синдрому (ІРС). Забір зразків тканини здійснювали через 24 години, на 3, 7, 14 доби після травми. Щури виведені з експерименту методом тотального кровопускання з верхівки серця.
Результати досліджень та їх обговорення. У наших моделях ІРС рівень Кат в основному зменшувався в кожному періоді експерименту. Пік активності СОД спостерігався на 1, 3 добу або пригнічення (здебільшого на 3 добу) після експериментального ІРС – згідно з модифікаціями ступенів тяжкості травми. Таким чином, застосування кровоспинного джгута в поєднанні з втратою крові та механічною травмою спричиняли суттєві ураження антиоксидної системи нирок. При цьому навіть одноразове застосування джгута зумовлювало подібні хвилеподібні реакції. Загалом розвиток ІРС супроводжується сильним пригніченням антиоксидної системи нирки.
Гострі абсцеси легень та їх ускладнення: особливості перебігу та лікувальна тактика
Authors: Bedenyuk A. D. , Malovanyy V. V. , Viytovych L. E. 
Published: October 2019

Мета роботи: підвищити ефективність комплексного лікування хворих на гострий абсцес легень.
Матеріали і методи. На базі відділення торакальної хірургії Тернопільської університетської лікарні за період 2014–2019 рр. проліковано 68 хворих із гострим абсцесом легень віком від 20 до 74 років.
Результати досліджень та їх обговорення. У лікуванні хворих використовували комплекс заходів, який включав антибактеріальну терапію, забезпечення дренажної функції бронхів, дезінтоксикацію та корекцію метаболічних порушень. За останні роки все частіше зустрічались тяжкі форми гнійних захворювань, які нерідко ускладнювались піопневмотораксом (у 18 хворих), емпіємою плеври (у 15 хворих), при яких проводилася пункція плевральної порожнини та дренування за Бюлау з подальшими санаціями антисептиками (діоксидин, хлоргексидин, декасан) тричі на день та активною аспірацією вмісту. При виникненні кровохаркання використовували препарати транексамової кислоти з гемостатичною метою. При арозивних кровотечах виконували ургентне операційне втручання (верхня лобектомія справа – у 2 пацієнтів). Тому перспективою подальших досліджень буде впровадження рентгенендоваскулярних методів зупинки арозивних кровотеч шляхом емболізації бронхіальних артерій, що надасть можливість стабілізувати стан хворого та підготувати до оперативного втручання, тим самим покращити прогноз лікування. Для покращення результатів лікування гострих абсцесів легень необхідний комплексний підхід з використанням сучасних консервативних та хірургічних методів.
Blood Pressure and Heart Rate Variability in Preschool Children Exposed to Smokeless Tobacco in Fetal Life
Authors: Nordenstam Felicia , Norman Mikael , Wickström Ronny 
Published: October 2019

Background
Maternal smoking during pregnancy has been associated with higher blood pressure and autonomic imbalance in the offspring. However, it has been difficult to determine the selective prenatal and postnatal contributions as children frequently have been exposed to smoking both before and after birth. The specific role of nicotine is also unclear. We aimed to determine whether exclusive prenatal exposure to nicotine from maternal use of smokeless tobacco (Swedish snus) in pregnancy was associated with blood pressure and autonomic heart rate control in their children.

Methods and Results

We measured oscillometric blood pressures in forty 5‐ to 6‐year‐old children with snus exposure in fetal life (n=21) and in tobacco‐free controls (n=19). Taking the child′s age and height into account, snus‐exposed children had 4.2 (95%
CI
, 0.2–8.1) mm Hg higher systolic blood pressure than controls (
P
=0.038). The corresponding sex‐, age‐, and height‐standardized systolic blood pressure centiles were 61 and 46 (95%
CI
of the difference, 2–28) (
P
=0.029). Heart rate variability was tested in 30 of the children. The spectral heart rate variability variable low‐frequency/high‐frequency ratio was higher (median, 0.69; interquartile range, 0.45–1.21) in snus‐exposed children than in controls (median, 0.21; interquartile range, 0.32–0.57;
P
=0.034).

Conclusions
Prenatal snus exposure was associated with higher systolic blood pressure and altered heart rate variability at 6 years of age. These findings may indicate adverse prenatal programming of nicotine, but implications for cardiovascular health in later life remain to be studied. Meanwhile, women should be recommended to abstain from all types of tobacco and nicotine products during pregnancy.
Abstract 348: Homeobox A4 Suppresses Vascular Smooth Muscle Cell Phenotypic Switching as a Novel Regulator of YAP/TEAD Transcriptional Activity
Authors: Kimura Masahiro , Horie Takahiro , Kimura Takeshi , Ono Koh 
Published: October 2019

The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes-associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD-mediated gene expressions in VSMCs remains to be elucidated, then we sought to investigate a novel regulator of YAP/TEAD transactivation involved in vascular diseases.
We first investigated novel YAP/TEAD regulators using lentiviral shRNA library in HEK 293T-based TEAD-responsive reporter cell line and detected Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity. HOXA4 attenuated YAP/TEAD-mediated gene expression independently of YAP phosphorylation, and co-immunoprecipitation assays revealed that HOXA4 interacts with TEADs but not YAP. Mechanistically, HOXA4 attenuated YAP/TEAD-mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD-induced phenotypic switching characterized by cell morphology, cell proliferation, and gene expression patterns. We generated Hoxa4-decifient mice and confirmed the downregulation of smooth muscle-specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo.
Our results demonstrate HOXA4 is a novel repressor of VSMC phenotypic switching by inhibiting YAP/TEAD-mediated transcription. These findings give us a better understanding of the vascular pathophysiology and a novel therapeutic approach for vascular remodeling.
Abstract 447: Development of CD47-nanomedicine as Novel Treatment for Specific Mitigation of Thrombospondin 1-Induced Vascular Dysfunction
Authors: Yao Mingyi , Ganguly Samayita , Ebrahimi Aren , Elbayoumi Tamer 
Published: October 2019

The trans-membrane receptor CD47 is considered a central relay of thrombospondin 1 (TSP-1) mediated responses in human cells/tissues, and ubiquitously serves as a marker of self on hematopoietic cells.
Preliminary studies of TSP-1 binding with soluble human CD-47, serving as decoy recombinant protein (rhCD47p), demonstrated molar ratio ≥ 3 folds of rhCD47p abolished all TSP1-vascular CD47 receptor signaling. Accordingly, we attached multiple rh-CD47p ligands onto liposomes (NanoLip), as clinical prototype therapy. Novel rh-CD47p-NanoLip can avoid blood mononuclear cells, while binding many circulating TSP1 molecules, thus eliminating excessive plasma TSP-1, often implicated in pulmonary arterial hypertension (PAH) and ischemia-reperfusion injuries.
Direct coupling of rh-CD47p, onto NanoLip surface was achieved using a sulfo-NHS-reaction between amino groups on rh-CD47p and corbodiimide-activated NanoLip, followed by column purification and physico-chemical analysis. Pharmaceutically, rh-CD47p-NanoLip formulation (av. size = 86±6.0nm) engaged 67±11μg/mL of protein, while retaining 86% of native rh-CD47p activity. Western blots and TSP-1-ELISA revealed dosimetric binding of tirmeric human TSP-1: rh-CD47p-NanoLip. Activated macrophages showed substantial decrease in phagocytosis of labeled rh-CD47p-NanoLip, compared to plain- and IgG-NanoLip controls (5- and 4- folds, respectively), indicating self-marker function. Conversely, binding of exogenous TSP-1 caused significant upturn of internalized rh-CD47p-NanoLip (p<0.05, n=4), due to TSP-1/nano-complex formation. Therapeutically, in isolated mouse thoracic aorta model, mimicking high plasma levels of TSP1 in PAH patients, titrated doses of CD47p-NanoLip neutralized TSP1-impaired vasodilation, back to the same level as controls (p<0.001, vs. TSP-1, n=4).
This is the first report of its kind about CD47-based immunomodulatory nano-therapy specifically targeting TSP-1. The extracellular domains of native CD47 receptors of TSP1 were successfully “nano-modified” into a candidate systemic decoy pharmaceutical, rh-CD47p-NanoLip, to scavenge and eliminate pathologically elevated TSP-1 plasma levels, to abrogate TSP-1-associated vascular complications.
Abstract 494: Role of Slug / PIP Axis in Pulmonary Hypertension Secondary to Pulmonary Fibrosis
Authors: Ruffenach Gregoire , Vaillancourt Mylene , Hong Jason , Cao Nancy , Cunningham Christine , Saggar Rajan , Reddy Srininivasa , Umar Soban , Fishbein Gregory , Eghbali Mansoureh 
Published: October 2019

Pulmonary hypertension (PH) secondary to pulmonary fibrosis (PF-PH) is the second most common cause of PH. While never studied in detail, pathology reports suggest that vascular remodeling (VR) differs between PF and PF-PH. In PF, VR is mainly limited to fibrotic areas, whereas in PF-PH, it also exist in non-fibrotic areas. These histological differences suggest potential molecular differences. To better understand this mechanism, we investigated the expression of the transcription factor Slug which is known to play a role in PH and PF.
Using explanted rat (n=7/group) and human (n=7-14/group) lungs, we compared lung fibrosis, VR and Slug expression between non-fibrotic and fibrotic areas in PF and PF-PH. Online microarray data (GSE24988) were used to find the targets of Slug that are implicated in VR. A new animal model recapitulating our findings in patients was used to test the therapeutic potential of Slug inhibition (n=10/group). This model is based on intra-tracheal instillation of bleomycin (2.5mg/Kg) at day 0 and 2weeks later, an injection of monocrotaline (60mg/kg). PH was assessed by right ventricular systolic pressure (RVSP). P<0.05 are considered significant.
In both PF and PF-PH patients, fibrotic areas (PF29±4; PF-PH37±3) exhibit significantly increased VR when compared to non-fibrotic areas of the lung (PF 22±1; PF-PH 31±6). PF-PH patients have increased pulmonary vascular thickening in both areas vs PF patients. This is concomitant with an increased number of Ki67+ vascular cells in PF-PH (12±2%) vs PF (8±1%) as well as an upregulation of Slug in PF-PH patients (2.3±0.5) vs PF (1±0.1). Co-immunolabeling with CD68 demonstrate that macrophages are the main cell type responsible for Slug up-regulation in PF-PH. Human microarray data reveal an up-regulation of the Prolactin-induced protein (PIP) in PF-PH vs PF (9±3 vs 1±0.4). PIP is an extracellular transcriptional target of Slug, known to promote cell proliferation. In-vitro, PIP significantly increases pulmonary arterial smooth muscle cell proliferation in a dose dependent manner. Finally, Slug inhibition decreases RVSP (47±3 vs 62±3mmHg) in an animal model of PF-PH.
There are histological differences between PF-PH and PF lungs that are at least in part mediated by a Slug/PIP axis leading to VR.
Abstract 658: RNF20/40 Regulates Cardiomyocyte Maturation
Authors: Vandusen Nathan J , Lee Julianna Y , Gu Wei-liang , Sethi Isha , Suo Shengbao , King Justin , Zheng Yanjiang , Guo Yuxuan , Pu William T 
Published: October 2019

Between birth and adulthood, cardiomyocytes (CMs) undergo profound changes in size, ultrastructure, metabolism, and gene expression, a process collectively referred to as CM maturation. Although highly coordinated, the transcriptional network that governs this process is not understood. This lack of understanding is a barrier to cardiac regenerative medicine, where our current inability to mature CMs differentiated from non-myocytes limits their use for disease modeling or replacement therapy. In addition, disruption of maturation by abnormal hemodynamic loads in neonates who have undergone surgery to correct congenital heart defects likely contributes to their high incidence of heart failure in adulthood. A sound understanding of the regulatory network governing CM maturation will inspire hypothesis driven attempts to surmount these challenges.
In mice, a key hallmark of CM maturation is sarcomere isoform switching, including the well documented neonatal switch from Myosin Heavy Chain 7 (Myh7) to Myosin Heavy Chain 6 (Myh6). We have conducted and validated an in vivo high throughput CRISPR screen for transcriptional regulators of CM maturation, using the Myh7/6 isoform switch as the readout. Two top candidates from this screen, Rnf20 and Rnf40, form a complex which deposits the epigenetic mark H2bub1 (histone-2B mono-ubiquitinated on lysine 120). Defects in RNF20/40 and H2Bub1 regulation have been associated with human congenital heart disease, but their mechanistic function in the heart has not been studied. We performed ChIP and RNA-sequencing experiments in control and RNF loss-of-function models to characterize the role of H2Bub1 in transcriptional control of CM maturation. The resulting mechanistic insights into how gene expression is coordinately controlled during maturation will inform efforts to improve CM production protocols and develop targeted therapies.
Abstract 736: Increased Cell Death in Regions of Elevated Aortic Wall Shear Stress in Bicuspid Valve Aortopathy
Authors: Maredia Ashna K , Iqbal Fatima , Guzzardi David G , Barker Alex J , McCarthy Patrick M , Fedak Paul W , Greenway Steven C 
Published: October 2019

Bicuspid aortic valve (BAV) is a common congenital malformation associated with aortopathy and potential rupture. Identifying those patients at greatest risk for dissection is difficult at present. Abnormal hemodynamics in the ascending aorta creates regions of increased wall shear stress (WSS) which causes extracellular matrix dysregulation and may affect cell death. Dying cells release fragmented DNA into the blood and levels of aorta-specific cell-free DNA (cfDNA), identified by the presence of tissue-specific differentially methylated regions (DMRs), could be leveraged as a biomarker. Our objective was to determine if a relationship between elevated WSS and apoptosis in the ascending aorta existed and identify aorta-specific DMRs in the cfDNA of BAV patients. We hypothesized that areas of increased WSS would demonstrate increased cell death that would correlate with increases in aorta-specific cfDNA from patient blood.

BAV patients undergoing 4D-flow cardiac magnetic resonance imaging (CMR) and surgery for ascending aorta dilation (range 36-63 mm) were recruited. Blood was collected from 23 patients at the time of CMR and used for the isolation of plasma cfDNA. Aortic wall samples (n = 30) corresponding to regions of high and low WSS were collected at surgery from 15 patients and stained for cell death using the TUNEL assay. Publicly-available methylomes and Metilene were used to identify aorta-specific DMRs
in silico
.

Regions of elevated WSS were seen in all individuals regardless of absolute aortic dimension. These regions of elevated WSS by CMR showed significantly greater cell death when compared to the region of normal WSS in the ascending aorta (0.14 ± 0.05 vs. 0.08 ± 0.06, p=0.00006). Levels of cell death did not correlate with maximal aortic diameter. Twenty-three aorta-specific DMRs were identified. Of the four that were tested, three were found to be hypomethylated in genomic DNA from the aorta compared to 14 other tissues. Levels of aorta-specific cfDNA based on our DMRs did not correlate with maximal aortic diameter.
Increased regional cell death corresponding to elevated WSS may implicate abnormal hemodynamic flow in the progression of aortopathy and provides a biological rationale for the use of cfDNA as a biomarker for aortopathy.