bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravaginal boric acid: is it an alternative therapeutic option for vaginal trichomoniasis?
Authors: Thorley Nicola , Ross Jonathan 
Published: December 2017

ObjectivesTrichomoniasis, caused by Trichomonas vaginalis (TV), is the most common curable sexually transmitted infection worldwide. Current guidance in the UK is to treat TV with a nitroimidazole antibiotic. The high prevalence of TV, high rate of antibiotic resistance and limited tolerability to nitroimidazoles suggest that alternative treatment regimens are needed. Intravaginal boric acid (BA) has been used safely for the treatment of candida vulvovaginitis and bacterial vaginosis, and in vitro studies suggest BA is active against TV. We review the evidence for the efficacy of BA in patients with TV.MethodsMEDLINE, EMBASE, CINAHL, AMED, HMIC and BNI and Grey literature databases, The Cochrane Library, Trial Registers, conference abstracts and proceedings were searched. Inclusion criteria were women aged 16 years or over with microbiological confirmation of TV infection and using BA as treatment. There were no restrictions on language, publication date or study design. The in vitro evidence for BA activity against TV was also reviewed.ResultsNo randomised controlled trials or case series were found. Four case reports demonstrated TV clearance with BA using a variety of dose regimens (dose 600 mg alternate nights to 600 mg two times per day; duration 1–5 months). In vitro studies suggest that BA has activity against TV which is independent of its effect on pH.DiscussionFurther evaluation of BA for the treatment of uncomplicated TV is required, but it may be useful when therapeutic options are limited. If shown to be safe and effective, intravaginal BA might provide a well-tolerated alternative anti-infective treatment which reduces community exposure to systemic antibiotics.
Nanoscale Tuning of VCAM-1 Determines VLA-4–Dependent Melanoma Cell Plasticity on RGD Motifs
Authors: Amschler Katharina , Kossmann Eugen , Erpenbeck Luise , Kruss Sebastian , Schill Tillmann , Schön Margarete , Möckel Sigrid M.C. , Spatz Joachim P. , Schön Michael P. 
Published: December 2017

Abstract
The biophysical fine-tuning of cancer cell plasticity is crucial for tumor progression but remains largely enigmatic. Although vascular cell adhesion molecule-1 (VCAM-1/CD106) has been implicated in melanoma progression, here its presentation on endothelial cells was associated with diminished melanoma cell spreading. Using a specific nanoscale modulation of VCAM-1 (tunable from 70 to 670 ligands/μm²) next to integrin ligands (RGD motifs) in a bifunctional system, reciprocal regulation of integrin α4 (ITGA4/VLA-4/CD49d)-dependent adhesion and spreading of melanoma cells was found. As the VCAM-1/VLA-4 receptor pair facilitated adhesion, while at the same time antagonizing RGD-mediated spreading, melanoma cell morphogenesis on these bifunctional matrices was directly regulated by VCAM-1 in a dichotomic and density-dependent fashion. This was accompanied by concordant regulation of F-actin cytoskeleton remodeling, Rac1-expression, and paxillin-related adhesion formation. The novel function of VCAM-1 was corroborated in vivo using two murine models of pulmonary metastasis. The regulation of melanoma cell plasticity by VCAM-1 highlights the complex regulation of tumor–matrix interactions.
Implications: Nanotechnology has revealed a novel dichotomic function of the VCAM-1/VLA-4 interaction on melanoma cell plasticity, as nanoscale tuning of this interaction reciprocally determines adhesion and spreading in a ligand density-dependent manner. Mol Cancer Res; 16(3); 528–42. ©2017 AACR.
TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer
Authors: Solberg Nina T. , Waaler Jo , Lund Kaja , Mygland Line , Olsen Petter A. , Krauss Stefan 
Published: December 2017

AbstractOveractivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor–sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo. At the highest doses, tumor xenograft growth was halted without affecting the body weight of the tested animals.Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543–53. ©2017 AACR.
Imprecision and DNA Break Repair Biased towards Incompatible End Joining in Leukemia
Authors: Gassner Franz Josef , Schubert Maria , Rebhandl Stefan , Spandl Karina , Zaborsky Nadja , Catakovic Kemal , Blaimer Stephanie , Hebenstreit Daniel , Greil Richard , Geisberger Roland 
Published: December 2017

Abstract
Cancer is a genetic disease caused by mutations and chromosomal abnormalities that contribute to uncontrolled cell growth. In addition, cancer cells can rapidly respond to conventional and targeted therapies by accumulating novel and often specific genetic lesions leading to acquired drug resistance and relapsing disease. In chronic lymphocytic leukemia (CLL), however, diverse chromosomal aberrations often occur. In many cases, improper repair of DNA double-strand breaks (DSB) is a major source for genomic abnormalities. Therefore, this study examined the repair of DNA DSBs by nonhomologous end joining (NHEJ) in CLL by performing plasmid-based repair assays in primary CLL cells and normal B cells, isolated from patients, as well as TALEN/Cas9–induced chromosomal deletions in the CLL cell line Mec1. It is demonstrated that DNA repair is aberrant in CLL cells, featuring perturbed DNA break structure preference with efficient joining of noncohesive ends and more deletions at repair junctions. In addition, increased microhomology-mediated end joining (MMEJ) of DNA substrates was observed in CLL together with increased expression of MMEJ-specific repair factors. In summary, these data identify major differences in DNA repair efficiency between CLL cells and normal B cells isolated from patients.
Implications: This study suggests inherently aberrant DNA DSB repair in the acquisition of subclonal genomic structural variations important for clonal evolution and treatment resistance in CLL. Mol Cancer Res; 16(3); 428–38. ©2017 AACR.
Adiposity, Inflammation, and Breast Cancer Pathogenesis in Asian Women
Authors: Iyengar Neil M. , Chen I-Chun , Zhou Xi K. , Giri Dilip D. , Falcone Domenick J. , Winston Lisle A. , Wang Hanhan , Williams Samantha , Lu Yen-Shen , Hsueh Tsu-Hsin , Cheng Ann-Lii , Hudis Clifford A. , Lin Ching-Hung , Dannenberg Andrew J. 
Published: December 2017

Abstract
Obesity is associated with white adipose tissue (WAT) inflammation in the breast, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that predispose to breast cancer development. We examined whether WAT inflammation and its associated systemic effects correlate with body fat levels in an Asian population where body mass index (BMI) is not an accurate assessment of obesity and cancer risk. We also investigated whether biologic differences could account for the greater proportion of premenopausal estrogen receptor (ER)–positive breast cancer in Asian versus Western countries. Breast WAT and fasting blood were prospectively collected from Taiwanese women undergoing mastectomy for breast cancer treatment. Body composition was measured in a subgroup using bioelectrical impedance analysis. WAT inflammation was defined by the presence of crown-like structures of the breast, which are composed of dead or dying adipocytes surrounded by macrophages. Findings were compared with U.S. Caucasian women. In the Taiwanese cohort (n = 72), breast WAT inflammation was present in 31 (43%) women and was associated with elevated BMI (P &lt; 0.01) and increased levels of body fat (P &lt; 0.01), C-reactive protein (P = 0.02), triglycerides (P &lt; 0.01), insulin resistance scores (P = 0.04), and lower HDL cholesterol (P &lt; 0.01). ER+ tumors were associated with greater body fat versus other subtypes (P = 0.03). Compared with U.S. Caucasians (n = 267), Taiwanese women had larger breast adipocytes despite lower BMI after adjusting for BMI and menopausal status (P = 0.01). A subclinical inflammatory state associated with increased adiposity and metabolic dysfunction could contribute to breast cancer pathogenesis in Asian women. Cancer Prev Res; 11(4); 227–36. ©2017 AACR.
Pioglitazone Inhibits Periprostatic White Adipose Tissue Inflammation in Obese Mice
Authors: Miyazawa Miki , Subbaramaiah Kotha , Bhardwaj Priya , Zhou Xi Kathy , Wang Hanhan , Falcone Domenick J. , Giri Dilip D. , Dannenberg Andrew J. 
Published: December 2017

AbstractObesity is associated with an increased incidence of high-grade prostate cancer and poor prognosis for prostate cancer patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade prostate cancer. It is possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the development or progression of prostate cancer. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses anti-inflammatory properties. Here, our main objectives were to determine whether pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Treatment with pioglitazone reduced the density of CLS in periprostatic fat and suppressed levels of TNFα, TGFβ, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knockout mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNFα-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels, thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ–adiponectin–MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade prostate cancer or improve outcomes for men with prostate cancer. Cancer Prev Res; 11(4); 215–26. ©2017 AACR.
Postoperative Reverse Remodeling and Symptomatic Improvement in Normal-Flow Low-Gradient Aortic Stenosis After Aortic Valve Replacement
Authors: Carter-Storch Rasmus , Møller Jacob E. , Christensen Nicolaj L. , Irmukhadenov Akhmadjon , Rasmussen Lars M. , Pecini Redi , Øvrehus Kristian A. , Søndergård Eva V. , Marcussen Niels , Dahl Jordi S. 
Published: December 2017

Background—

Severe aortic stenosis (AS) most often presents with reduced aortic valve area (<1 cm
2
), normal stroke volume index (≥35 mL/m
2
), and either high mean gradient (≥40 mm Hg; normal-flow high-gradient AS) or low mean gradient (normal-flow low-gradient [NFLG] AS). The benefit of aortic valve replacement (AVR) among NFLG patients is controversial. We compared the impact of NFLG condition on preoperative left ventricular (LV) remodeling and myocardial fibrosis and postoperative remodeling and symptomatic benefit.

Methods and Results—

Eighty-seven consecutive patients with reduced aortic valve area and normal stroke volume index undergoing AVR underwent echocardiography, magnetic resonance imaging, a 6-minute walk test, and measurement of natriuretic peptides before and 1 year after AVR. Myocardial fibrosis was assessed from magnetic resonance imaging. Patients were stratified as NFLG or normal-flow high-gradient. In total, 33 patients (38%) had NFLG. Before AVR, they were characterized by similar symptom burden but less severe AS measured by aortic valve area index (0.50±0.09 versus 0.40±0.08 cm
2
/m
2
;
P
<0.0001), lower LV mass index (74±18 versus 90±26 g/m
2
;
P
=0.01), but the same degree of myocardial fibrosis. After AVR, NFLG had a smaller reduction in LV mass index (−3±10 versus −±18 g/m
2
;
P
<0.0001) and a smaller reduction in natriuretic peptides. Both groups experienced similar symptomatic improvement. Normal-flow high-gradient condition independently predicted change in LV mass index.

Conclusions—
Patients with NFLG had less severe AS and LV remodeling than patients with normal-flow high-gradient. Furthermore, NFLG patients experienced less reverse remodeling but the same symptomatic benefit.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02316587.
GDF-15 (Growth Differentiation Factor 15) Is Associated With Lack of Ventricular Recovery and Mortality After Transcatheter Aortic Valve Replacement
Authors: Kim Juyong Brian , Kobayashi Yukari , Moneghetti Kegan J. , Brenner Daniel A. , O’Malley Ryan , Schnittger Ingela , Wu Joseph C. , Murtagh Gillian , Beshiri Agim , Fischbein Michael , Miller D. Craig , Liang David , Yeung Alan C. , Haddad Francois , Fearon William F. 
Published: December 2017

Background—
Recent data suggest that circulating biomarkers may predict outcome in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the association between inflammatory, myocardial, and renal biomarkers and their role in ventricular recovery and outcome after TAVR.

Methods and Results—

A total of 112 subjects undergoing TAVR were included in the prospective registry. Plasma levels of B-type natriuretic peptide, hs-TnI (high-sensitivity troponin I), CRP (C-reactive protein), GDF-15 (growth differentiation factor 15), GAL-3 (galectin-3), and Cys-C (cystatin-C) were assessed before TAVR and in 100 sex-matched healthy controls. Among echocardiographic parameters, we measured global longitudinal strain, indexed left ventricular mass, and indexed left atrial volume. The TAVR group included 59% male, with an average age of 84 years, and 1-year mortality of 18%. Among biomarkers, we found GDF-15 and CRP to be strongly associated with all-cause mortality (
P
<0.001). Inclusion of GDF-15 and CRP to the Society of Thoracic Surgeons score significantly improved C index (0.65–0.79;
P
<0.05) and provided a category-free net reclassification improvement of 106% at 2 years (
P
=0.01). Among survivors, functional recovery in global longitudinal strain (>15% improvement) and indexed left ventricular mass (>20% decrease) at 1 year occurred in 48% and 22%, respectively. On multivariate logistic regression, lower baseline GDF-15 was associated with improved global longitudinal strain at 1 year (hazard ratio=0.29;
P
<0.001). Furthermore, improvement in global longitudinal strain at 1 month correlated with lower overall mortality (hazard ratio=0.45;
P
=0.03).

Conclusions—
Elevated GDF-15 correlates with lack of reverse remodeling and increased mortality after TAVR and improves risk prediction of mortality when added to the Society of Thoracic Surgeons score.
A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia
Authors: Logue Omar C. , Mahdi Fakhri , Chapman Heather , George Eric M. , Bidwell Gene L. 
Published: December 2017

Background

Preeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms‐like tyrosine kinase‐1, is believed to sequester vascular endothelial growth factor (
VEGF
), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms‐like tyrosine kinase‐1 while simultaneously preventing fetal exposure to
VEGF
, we fused
VEGF
to elastin‐like polypeptide, a biopolymer carrier that does not cross the placental barrier (
ELP
‐
VEGF
).

Methods and Results

ELP
‐
VEGF
restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long‐term administered
ELP
‐
VEGF
in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long‐term administration of
ELP
‐
VEGF
in a placental ischemia rat model achieved dose‐dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day.
ELP
‐
VEGF
infusion increased total plasma soluble fms‐like tyrosine kinase‐1 levels but dramatically reduced free plasma soluble fms‐like tyrosine kinase‐1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling.
ELP
‐
VEGF
at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose‐dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump.

Conclusions

ELP
‐
VEGF
has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.
Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes
Authors: Rivaud Mathilde R. , Agullo‐Pascual Esperanza , Lin Xianming , Leo‐Macias Alejandra , Zhang Mingliang , Rothenberg Eli , Bezzina Connie R. , Delmar Mario , Remme Carol Ann 
Published: December 2017

Background
Cardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region‐specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure.

Methods and Results

Mice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham–operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole‐cell sodium current (I
Na
) density was decreased by 30% in TAC versus sham–operated on cardiomyocytes. On macropatch analysis, I
Na
in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter‐]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z‐groove ratios). Using scanning ion conductance microscopy, cell‐attached recordings in LM subdomains revealed decreased I
Na
and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α‐tubulin and Glu‐tubulin expression). Superresolution microscopy showed reduced average Na
V
1.5 cluster size at the LM of TAC cells, in line with reduced I
Na
.

Conclusions

Heart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in Na
V
1.5 clustering and I
Na
within distinct subcellular microdomains of failing cardiomyocytes.
Contrasting Conceptions of Asylum in Deuteronomy 19 and Numbers 35
Authors: Mattison Kevin 
Published: December 2017

Abstract
This essay argues that the Deuteronomic and Holiness laws granting asylum to unintentional killers (Deut 19:1-13; Num 35:9-34) differ markedly in their procedures and purposes. The differences between these laws reflect different underlying conceptions of bloodguilt. For Deuteronomy, bloodguilt is created only in the presence of homicidal intention. For the Holiness legislators, bloodguilt is created whenever human blood is shed. These differing conceptions of bloodguilt are reflected in the status each law accords to the manslayer, the role of the blood avenger, the purpose and duration of asylum, and the features of asylum locations.
A Text-Linguistics Approach to the Literary Structure and Coherence of 2 Kings 17:7-23
Authors: Lovell Nathan 
Published: December 2017

Abstract
This paper examines 2 Kgs 17:7-23 which is often understood as a fragmented text, compounding various theological reactions to the fall of Samaria. Applying a text-linguistics approach, I find vv7-20 to be a unit that makes sense in its present form, complementing a second unit beginning in v21. My reading understands the relationship between vv6 and 7 differently to what is usually understood, and to the standard English translations. I argue based on the Hebrew syntax that vv7-20 form a narrative unit that summarises the history of both northern and southern kingdoms together, as a history of idolatrous activity. Thus, the concern of the narrator is to explore the theological reason for the series of Assyrian invasions of the last quarter of the 8th Century bc, and the different fates of Israel and Judah.
Toward the Identification of the Goddess of Ekron
Authors: Fantalkin Alexander 
Published: December 2017

AbstractThe article puts forward a new hypothesis concerning the origin of the goddess of Ekron, mentioned in Ekron’s royal dedicatory inscription from the early 7th centurybce. Contrary to a widely held view, it is suggested that the origin of the Philistine Goddess of Ekron should not be sought in the Aegean world but rather in northern Syria.
Mapping Shia Muslim Communities in Europe
Authors: Shanneik Yafa , Heinhold Chris , Ali Zahra 
Published: December 2017

AbstractThis article provides an introduction to the special issue onMapping Shia Muslim Communities in Europe.1 With six empirically rich case studies on Shia Muslim communities in various European countries, this issue intends: first, to illustrate the historical developments and emergence of the Shia presence in Europe; second, to highlight the local particularities of the various Shia communities within each nation state and demonstrate their transnational links; and third, to provide for the first time an empirical comparative study on the increasingly visible presence of Shia communities in Europe that fills an important gap in research on Muslims in Europe.