bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant FOXL2C134W Hijacks SMAD4 and SMAD2/3 to Drive Adult Granulosa Cell Tumors
Authors: Weis-Banke Stine E. , Lerdrup Mads , Kleine-Kohlbrecher Daniela , Mohammad Faizaan , Sidoli Simone , Jensen Ole N. , Yanase Toshihiko , Nakamura Tomoko , Iwase Akira , Stylianou Anthe , Abu-Rustum Nadeem R. , Aghajanian Carol , Soslow Robert , Da Cruz Paula Arnaud , Koche Richard P. , Weigelt Britta , Christensen Jesper , Helin Kristian , Cloos Paul A.C. 
Published: July 2020

Abstract

The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2C134W binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2C134W. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2C134W and its interaction with SMAD4 as potential therapeutic targets to this condition.

Significance:
FOXL2C134W hijacks SMAD4 and leads to the expression of genes involved in EMT, stemness, and oncogenesis in AGCT, making FOXL2C134W and the TGFβ pathway therapeutic targets in this condition.
Transcatheter Aortic Valve Implantation Represents an Anti-Inflammatory Therapy Via Reduction of Shear Stress–Induced, Piezo-1–Mediated Monocyte Activation
Authors: Baratchi Sara , Zaldivia Maria T.K. , Wallert Maria , Loseff-Silver Julia , Al-Aryahi Sefaa , Zamani Jalal , Thurgood Peter , Salim Agus , Htun Nay M. , Stub Dion , Vahidi Parisa , Duffy Stephen J. , Walton Antony , Nguyen Thanh Ha , Jaworowski Anthony , Khoshmanesh Khashayar , Peter Karlheinz 
Published: July 2020

Background:
Aortic valve stenosis is an increasingly prevalent degenerative and inflammatory disease. Transcatheter aortic valve implantation (TAVI) has revolutionized its treatment, thereby avoiding its life-threatening/disabling consequences. Whether aortic valve stenosis is accelerated by inflammation and whether it is itself a cause of inflammation are unclear. We hypothesized that the large shear forces exerted on circulating cells, particularly on the largest circulating cells, monocytes, while passing through stenotic aortic valves result in proinflammatory effects that are resolved with TAVI.

Methods:

TAVI provides a unique opportunity to compare the activation status of monocytes under high shear stress (before TAVI) and under low shear stress (after TAVI). The activation status of monocytes was determined with a single-chain antibody, MAN-1, which is specific for the activated β
2
-integrin Mac-1. Monocyte function was further characterized by the adhesion of myocytes to stimulated endothelial cells, phagocytic activity, uptake of oxidized low-density lipoprotein, and cytokine expression. In addition, we designed a microfluidic system to recapitulate the shear rate conditions before and after TAVI. We used this tool in combination with functional assays, Ca
2+
imaging, siRNA gene silencing, and pharmacological agonists and antagonists to identify the key mechanoreceptor mediating the shear stress sensitivity of monocytes. Last, we stained for monocytes in explanted stenotic aortic human valves.

Results:
The resolution of high shear stress through TAVI reduces Mac-1 activation, cellular adhesion, phagocytosis, oxidized low-density lipoprotein uptake, and expression of inflammatory markers in monocytes and plasma. Using microfluidics and pharmacological and genetic studies, we could recapitulate high shear stress effects on isolated human monocytes under highly controlled conditions, showing that shear stress–dependent calcium influx and monocyte adhesion are mediated by the mechanosensitive ion channel Piezo-1. We also demonstrate that the expression of this receptor is shear stress dependent and downregulated in patients receiving TAVI. Last, we show monocyte accumulation at the aortic side of leaflets of explanted aortic valves.

Conclusions:
We demonstrate that high shear stress, as present in patients with aortic valve stenosis, activates multiple monocyte functions, and we identify Piezo-1 as the mainly responsible mechanoreceptor, representing a potentially druggable target. We demonstrate an anti-inflammatory effect and therefore a novel therapeutic benefit of TAVI.
A new automated system for the preparation of sclerosant foam: A study of the physical characteristics produced and the device settings required
Authors: Roche Enric , Pons Ramon , Roche Oriol , Puig Antoni 
Published: July 2020

Objectives To determine the quality of sclerosant foam produced with an automated preparation system with multiple combinations of sclerosing agents, gases, and device settings. Methods Single-use mixing capsules filled with air or O2/CO2 and polidocanol (0.25, 1, or 3%) or sodium tetradecyl sulfate (0.2 or 1%) were coupled to a customized magnetic stirrer. Stirring speed and time were adjusted between 1500 and 4000 r/min and 30 and 60 s, respectively, and characteristics of the foam produced were measured: half-life, bubble diameter, and gas-to-liquid ratio. Results With optimized device settings, the following foam characteristics were obtained: half-life range, 1.4 ± 0.9 to 5.2 ± 0.6 min; bubble diameter, 84 ± 14 to 119 ± 6 µm; and gas-to-liquid ratio, 5:1–7:1. Sodium tetradecyl sulfate foam was quicker to form than polidocanol but faster to degrade. Foams with low sclerosant concentrations and O2/CO2 required higher speed and longer time. Conclusions Suitable foam characteristics could be obtained with all combinations of sclerosing agent, concentration, and gas.
Non-contrast-enhanced magnetic resonance imaging: Objective figures in differentiation between acute and chronic deep venous thrombosis in the lower extremities
Authors: Kao Chih-Chen , Chen Chien-Wei , Tseng Yuan-Hsi , Tsai Yuan-Hsiung , Wang Shih-Chung , Huang Yao-Kuang 
Published: July 2020

Background Deep vein thrombosis is a severe health problem. Treatment options may differ between acute and chronic deep vein thrombosis. Thus, distinguishing acute from chronic deep vein thrombosis is essential for patients with deep vein thrombosis. Triggered angiography non-contrast enhanced is an innovative magnetic resonance imaging protocol that may provide objective evidence in differentiating acute from chronic deep vein thrombosis. Method We prospectively collected information on consecutive patients who had been evaluated through triggered angiography non-contrast enhanced magnetic resonance imaging for venous pathology in their lower extremities at a vascular wound care center in a tertiary hospital between April 2017 and January 2020. Patients included were divided into two groups with the onset time cutoff point of 21 days. All were undergone non-contrast-enhanced magnetic resonance imaging evaluation. Non-contrast-enhanced magnetic resonance imaging images were evaluated by a radiologist, and lower extremity venous thrombosis, collateral-vein development, and subcutaneous honeycombing were emphasized. Cohen’s kappa coefficient was used to measure interrater agreement between the development of collateral veins, subcutaneous honeycombing, and symptom onset over 21 days. Results Interrater agreement analysis revealed that the development of collateral veins was substantially correlated with the onset of symptoms over 21 days (Table 1). Additionally, the development of subcutaneous honeycombing detected through triggered angiography non-contrast enhanced magnetic resonance imaging also substantially agreed with the onset of symptoms over 21 days (Table 2). Conclusion The diagnostic power of triggered angiography non-contrast enhanced magnetic resonance imaging in deep vein thrombosis is rival to current gold standard, color Doppler sonography. Triggered angiography non-contrast enhanced magnetic resonance imaging provides objective information on onset timing in patients with deep vein thrombosis that could differentiate acute from chronic deep vein thrombosis and provides guidance for treatment planning.
Influence of Needs and Experiences of Haemato-Oncology Patients on Acceptability of a Telephone Intervention for Support and Symptom Management: A Qualitative Study
Authors: Liptrott Sarah J. , Lovell Karina , Bee Penny 
Published: July 2020

Healthcare technologies are increasingly used to address the unmet needs of patients with cancer; however new service developments must be acceptable to patients. The objective of this study was to determine the unmet needs of haemato-oncology patients and their influence on the perceived acceptability and participation in a telephone intervention delivering. A qualitative study was designed interviewing 20 participants having received the intervention. Data were analysed inductively and deductively using Framework Analysis. Three core themes emerged: (1) fluctuations in emotional distress and coping across the cancer trajectory with evidence of adaptive and maladaptive coping; (2) potential deficits in patient support, continuity of care and information provision; and (3) intervention acceptability analysis underpinned by the Theoretical Framework of Acceptability showed acceptability was influenced by participants’ subjective illness contexts and unmet needs. This work contributes to understanding of personal context as a determinant of intervention acceptability in order to enhance implementation strategies.
A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal–gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial
Authors: Merz Valeria , Zecchetto Camilla , Simionato Francesca , Cavaliere Alessandro , Casalino Simona , Pavarana Michele , Giacopuzzi Simone , Bencivenga Maria , Tomezzoli Anna , Santoro Raffaela , Fedele Vita , Contarelli Serena , Rossi Irene , Giacomazzi Serena , Pasquato Martina , Piazzola Cristiana , Milleri Stefano , de Manzoni Giovanni , Melisi Davide 
Published: July 2020

Background: Prognosis of patients affected by metastatic esophageal–gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. Methods: The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib. Discussion: Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance. Protocol number: CRC2017_02 EudraCT Number: 2017-004522-14
Radiologic Analysis of Balloon Sinuplasty in a Human Cadaver Model: Observed Effects on Sinonasal Anatomy
Authors: Lopez Erin M. , Farzal Zainab , Norris Meghan , Canfarotta Michael W. , Pappa Andrew K. , Santarelli Griffin D. , Hernandez Stephen C. , Thorp Brian D. , Senior Brent A. , Zanation Adam M. , Ebert Charles S. , Kimbell Julia S. , Kimple Adam J. 
Published: July 2020

Background Balloon sinuplasty is increasingly used in the outpatient clinic for treatment of chronic rhinosinusitis, but radiologic analysis of its effects on sinonasal anatomy is largely uncharacterized in the known literature. Objective The purpose of this study is to examine the anatomic effects of balloon sinuplasty in a cadaveric model. Methods Five fresh cadaver heads underwent sequential endoscopic balloon dilation of maxillary ostia, frontal recess outflow tracts, and sphenoid ostia bilaterally by fellowship-trained rhinologists. Pre- and post-procedural CT imaging was obtained. CT scans were imported into Mimics™ software and sinonasal anatomy was analyzed systematically. Results Visual confirmation of balloon dilation was achieved in all 3 sites bilaterally in each cadaver. Radiologic analysis demonstrated that the frontal sinus outflow tract was appropriately dilated 60% (6/10 sites) of the time while the agger was inadvertently dilated 30% of the time (3/10). The sphenoid os was successfully dilated 70% (7/10 sites) of the time. In two cases, a posterior sphenoethmoid (Onodi) cell was dilated instead of the sphenoid. Successful dilation of maxillary os was noted 60% of the time (6/10 sites). No significant change in maxillary os was noted after balloon dilation. Normal middle turbinates were significantly medialized following balloon dilation 75% (6/8 sites) of the time. Conclusions While the goal of balloon sinuplasty is to improve natural sinonasal drainage by dilating existing outflow tracts, as evidenced by radiologic evaluation the procedure appears not to achieve this in all cases, while occasionally creating unintended changes in sinonasal anatomy as well. These unrecognized changes in anatomy may be responsible for the post-procedure change in symptomatology that some patients experience.
Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans
Authors: Davis Alan K. , Averill Lynnette A. , Sepeda Nathan D. , Barsuglia Joseph P. , Amoroso Timothy 
Published: July 2020

Background U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans. Method We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%). Results Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives. Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary. Conclusion U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.
circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals
Authors: Zeng Xiang-Yang , Yuan Jing , Wang Chen , Zeng Da , Yong Jia-Hui , Jiang Xiao-Yan , Lan Hua , Xiao Song-Shu 
Published: July 2020

Abstract
Background
Ovarian cancer is one of the most common gynecologic cancers and has high mortality rate due to the lack of early diagnosis method and efficient therapeutic agents. circCELSR1 is up-regulated in ovarian cancer, but its role and mechanisms in ovarian cancer are unclear.

Methods
Gene expression of circCELSR1, miR-598 and BRD4 in ovarian cells was examined by qRT-PCR. Protein level was determined by Western blotting. Bioinformatic analysis and luciferase assay determined the molecular binding among circCELSR1, miR-598 and BRD4 3′ UTR. Cell proliferation, migration, invasion and apoptosis were determined by colony formation, wound healing assay, transwell assay and flow cytometry analysis, respectively. An abdominal cavity metastasis nude mice model was used to determine the in vivo function of circCELSR1.

Results
circCELSR1 and BRD4 were promoted, but miR-598 was suppressed in various ovarian cancer cells. circCELSR1 bound to miR-598 and promoted expression of its downstream target BRD4. Knockdown of circCELSR1 suppressed proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), but promoted apoptosis in ovarian cancer cells, and these effects were reversed by miR-598 inhibition or BRD4 overexpression. circCELSR1 inhibition decreased the expression of BRD4 and its downstream proliferation/migration related genes by targeting miR-598. Furthermore, knockdown of circCELSR1 suppressed ovarian cancer growth and metastasis in nude mice.

Conclusion
Knockdown of circCELSR1 inhibited BRD4-mediated proliferation/migration related signaling via sponging miR-598, thereby repressing ovarian cancer progression. This study provides a new regulatory mechanism of ovarian cancer may facilitate the development of therapeutic agents for ovarian cancer.
Rubus apetalus (Rosaceae) improves spermatozoa characteristics, antioxidant enzymes and fertility potential in unilateral cryptorchid rats
Authors: Alumeti Munyali Désiré , Tetsatsi Momo Aimé Césaire , Bonsou Fozin Georges Romeo , Deeh Defo Patrick Brice , Petnga Tchatat Yannick , Lieunang Boris , Watcho Pierre 
Published: July 2020

Abstract
Background
Cryptorchidism (CPT) is an important cause of male infertility. Rubus apetalus is a medicinal plant with a powerful antioxidant potential. We investigated the effects of aqueous and methanolic extracts of R. apetalus on spermatozoa parameters, antioxidant enzymes and fertility potential of rats with experimental unilateral CPT.

Method
Normal (n = 15), sham-operated (n = 15) and cryptorchid rats (n = 80; distributed into 16 groups of 5 rats/group) were treated for 2, 4 or 8 weeks with either distilled water (10 ml/kg/day), vitamin E (75 mg/kg/day), aqueous or methanolic extract of R. apetalus (12 and 60 mg/kg). Sex organ weights, spermatozoa parameters, testicular proteins, sex hormones, fertility potential, morphometric characteristics of testis and oxidative stress markers were measured.

Results
CPT significantly (p < 0.05–0.001) decreased testicular and epididymal weights, spermatozoa density, spermatozoa motility, spermatozoa normality, testicular proteins, LH, FSH and testosterone concentrations. In cryptorchid rats, peri-vascular fibrosis significantly increased (p < 0.001), while diameter of the seminiferous tube, germ cell thickness, gestation index and fertility index decreased when compared to control. Additionally, CPT induced oxidative stress by increasing lipid peroxidation and by reducing superoxide dismutase and catalase activities. These alterations were corrected by R. apetalus. For instance, a significantly increase (p < 0.05–0.001) in spermatozoa motility, normality, viability and density after 2, 4 and 8 weeks of treatment was noticed. R. apetalus also increased (p < 0.05–0.001) testicular proteins, gestation index (90–100%) and fertility index (90–100%), compared to the untreated cryptorchid rats.

Conclusion
R. apetalus boosts fertility potential in cryptorchid rats and could be considered as a promising alternative agent for the management of infertility associated with CPT.
Matrine inhibits the growth of natural killer/T-cell lymphoma cells by modulating CaMKIIγ-c-Myc signaling pathway
Authors: Gu Jianyou , Zhang Yu , Wang Xiao , Xiang Jingjing , Deng Shu , Wu Dijiong , Chen Junfa , Yu Lihong , Zhou Yan , Wang Yaokun , Shen Jianping 
Published: July 2020

Abstract
Background
C-Myc overexpression is associated with poor prognosis and aggressive progression of natural killer/T-cell lymphoma (NKTCL). Matrine, a main alkaloid of the traditional Chinese herb Sophora flavescens Ait, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The present study investigated the effects and possible mechanisms of matrine inhibiting the growth of natural killer/T-cell lymphoma cells.

Methods
The effects of matrine on the proliferation, apoptosis and expression of apoptotic molecules, STAT3, LMP1, RUNX3, EZH2 and activation of CaMKIIγ/c-Myc pathway were examined in cultured NKTCL cell line NK92 cells.

Results
In cultured NK92 cells, matrine inhibited the proliferation in a dose and time dependent manner. The IC50 value of matrine was 1.71 mM for 72 h post exposure in NK92 cells. Matrine induced apoptosis with decreased Bcl-2 expression and the proteasome-dependent degradation of c-Myc protein in NK92 cells. c-Myc protein half-life in NK92 was reduced from 80.7 min to 33.4 min after matrine treatment, which meant the stability of c-Myc was decreased after matrine exposure. Furthermore, we found that matrine downregulated c-Myc phosphorylation at Ser62 together with the inhibition of CaMKIIγ, a key regulator of c-Myc protein in NKTCL. The downregulation of c-Myc transcription by matrine was mediated through LMP1 inhibition. We also observed that anti-proliferative activity of matrine was irrelevant to STAT3, RUNX3 and EZH2.

Conclusions
The results of the present study indicated that matrine inhibits the growth of natural killer/T-cell lymphoma cells by modulating LMP1-c-Myc and CaMKIIγ-c-Myc signaling pathway.