bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vimentin Modulates Infectious Internalization of Human Papillomavirus 16 Pseudovirions
Authors: Schäfer Georgia , Graham Lisa M. , Lang Dirk M. , Blumenthal Melissa J. , Bergant Marušič Martina , Katz Arieh A. 
Published: June 2017

ABSTRACT

Human papillomavirus (HPV) infection is the most common viral infection of the reproductive tract, with virtually all cases of cervical cancer being attributable to infection by oncogenic HPVs. However, the exact mechanism and receptors used by HPV to infect epithelial cells are controversial. The current entry model suggests that HPV initially attaches to heparan sulfate proteoglycans (HSPGs) at the cell surface, followed by conformational changes, cleavage by furin convertase, and subsequent transfer of the virus to an as-yet-unidentified high-affinity receptor. In line with this model, we established an
in vitro
infection system using the HSPG-deficient cell line pgsD677 together with HPV16 pseudovirions (HPV16-PsVs). While pgsD677 cells were nonpermissive for untreated HPV16-PsVs, furin cleavage of the particles led to a substantial increase in infection. Biochemical pulldown assays followed by mass spectrometry analysis showed that furin-precleaved HPV16-PsVs specifically interacted with surface-expressed vimentin on pgsD677 cells. We further demonstrated that both furin-precleaved and uncleaved HPV16-PsVs colocalized with surface-expressed vimentin on pgsD677, HeLa, HaCaT, and NIKS cells, while binding of incoming viral particles to soluble vimentin protein before infection led to a substantial decrease in viral uptake. Interestingly, decreasing cell surface vimentin by small interfering RNA (siRNA) knockdown in HeLa and NIKS cells significantly increased HPV16-PsV infectious internalization, while overexpression of vimentin had the opposite effect. The identification of vimentin as an HPV restriction factor enhances our understanding of the initial steps of HPV-host interaction and may lay the basis for the design of novel antiviral drugs preventing HPV internalization into epithelial cells.

IMPORTANCE
Despite HPV being a highly prevalent sexually transmitted virus causing significant disease burden worldwide, particularly cancer of the cervix, cell surface events preceding oncogenic HPV internalization are poorly understood. We herein describe the identification of surface-expressed vimentin as a novel molecule not previously implicated in the infectious internalization of HPV16. Contrary to our expectations, vimentin was found to act not as a receptor but rather as a restriction factor dampening the initial steps of HPV16 infection. These results importantly contribute to our current understanding of the molecular events during the infectious internalization of HPV16 and open a new direction in the development of alternative drugs to prevent HPV infection.
Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus
Authors: Felt Sébastien A. , Droby Gaith N. , Grdzelishvili Valery Z. 
Published: June 2017

ABSTRACT
Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV). Although VSV is effective against a majority of pancreatic ductal adenocarcinoma cell (PDAC) cell lines, some PDAC cell lines are highly resistant to VSV, and the mechanisms of resistance are still unclear. JAK1/2 inhibitors (such as ruxolitinib and JAK inhibitor I) strongly stimulate VSV replication and oncolysis in all resistant cell lines but only partially improve the susceptibility of resistant PDACs to VSV. VSV tumor tropism is generally dependent on the permissiveness of malignant cells to viral replication rather than on receptor specificity, with several ubiquitously expressed cell surface molecules playing a role in VSV attachment to host cells. However, as VSV attachment to PDAC cells has never been tested before, here we examined if it was possibly inhibited in resistant PDAC cells. Our data show a dramatically weaker attachment of VSV to HPAF-II cells, the most resistant human PDAC cell line. Although sequence analysis of low-density lipoprotein (LDL) receptor (LDLR) mRNA did not reveal any amino acid substitutions in this cell line, HPAF-II cells displayed the lowest level of LDLR expression and dramatically lower LDL uptake. Treatment of cells with various statins strongly increased LDLR expression levels but did not improve VSV attachment or LDL uptake in HPAF-II cells. However, LDLR-independent attachment of VSV to HPAF-II cells was dramatically improved by treating cells with Polybrene or DEAE-dextran. Moreover, combining VSV with ruxolitinib and Polybrene or DEAE-dextran successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication.

IMPORTANCE
Oncolytic virus (OV) therapy is an anticancer approach that uses viruses that selectively infect and kill cancer cells. This study focuses on oncolytic vesicular stomatitis virus (VSV) against pancreatic ductal adenocarcinoma (PDAC) cells. Although VSV is effective against most PDAC cells, some are highly resistant to VSV, and the mechanisms are still unclear. Here we examined if VSV attachment to cells was inhibited in resistant PDAC cells. Our data show very inefficient attachment of VSV to the most resistant human PDAC cell line, HPAF-II. However, VSV attachment to HPAF-II cells was dramatically improved by treating cells with polycations. Moreover, combining VSV with polycations and ruxolitinib (which inhibits antiviral signaling) successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication. We envision that this novel triple-combination approach could be used in the future to treat PDAC tumors that are highly resistant to OV therapy.
Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56–60
Authors: Lamin Helena , Eklund Carina , Elfström Klara Miriam , Carlsten-Thor Agneta , Hortlund Maria , Elfgren Kristina , Törnberg Sven , Dillner Joakim 
Published: June 2017

ObjectiveThe aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme.ParticipantsResident women in the Stockholm/Gotland region of Sweden, aged 56–60 years were randomised to either (1) screening with cervical cytology, with HPV test in triage of low-grade cytological abnormalities (old policy) or (2) screening with HPV testing, with cytology in triage of HPV positives (new policy).OutcomeThe primary evaluation was the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+).ResultsDuring January 2012–May 2014, the organised screening programme sent 42 752 blinded invitations with a prebooked appointment time to the women in the target age group. 7325 women attended in the HPV policy arm and 7438 women attended in the cytology arm. In the new policy, the population HPV prevalence was 5.5%, using an accredited HPV test (Cobas 4800). HPV16 prevalence was 1.0% (73/7325) and HPV18 prevalence was 0.3% (22/7325). In the HPV policy arm, 78/405 (19%) HPV-positive women were also cytology positive. There were 19 cases of CIN2+ in histopathology, all among women who were both HPV positive and cytology positive. The positive predictive value for CIN2+ in this group was 33.3% (19/57). In the cytology policy, 153 women were cytology positive and there were 18 cases of CIN2+ in histopathology. Both the total number of cervical biopsies and the number of cervical biopsies with benign histopathology were much lower in thepositive predictive value policy (49 benign, 87 total vs 105 benign, 132 total).ConclusionPrimary HPV screening had a similar detection rate for CIN2+ as cytology-based screening, already before follow-up of HPV-positive, cytology-negative women with new HPV test and referral of women with persistence.Trial registration numberNCT01511328.
Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans
Authors: Maman Stephan R. , Vargas Alvaro F. , Ahmad Tariq Ali , Miller Amanda J. , Gao Zhaohui , Leuenberger Urs A. , Proctor David N. , Muller Matthew D. 
Published: June 2017

During exercise, β-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of β-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that β1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective β-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t-tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; P = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective β1 blockade reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia. NEW & NOTEWORTHY In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary β1 and β2 adrenergic receptors in humans.
UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level
Authors: Flück Daniela , Morris Laura E. , Niroula Shailesh , Tallon Christine M. , Sherpa Kami T. , Stembridge Mike , Ainslie Philip N. , McManus Ali M. 
Published: June 2017

Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia. NEW & NOTEWORTHY Cerebral blood flow is lower in Sherpa children compared with children residing at sea level; this may reflect a cerebral hemodynamic pattern, potentially due to adaptation to a hypoxic environment.
A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant
Authors: Ronald John A. , Kim Byung-Su , Gowrishankar Gayatri , Namavari Mohammad , Alam Israt S. , D'Souza Aloma , Nishikii Hidekazu , Chuang Hui-Yen , Ilovich Ohad , Lin Chih-Feng , Reeves Robert , Shuhendler Adam , Hoehne Aileen , Chan Carmel T. , Baker Jeanette , Yaghoubi Shahriar S. , VanBrocklin Henry F. , Hawkins Randall , Franc Benjamin L. , Jivan Salma , Slater James B. , Verdin Emily F. , Gao Kenneth T. , Benjamin Jonathan , Negrin Robert , Gambhir Sanjiv Sam 
Published: June 2017

Abstract
A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2′-deoxy-2′-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893–902. ©2017 AACR.
Unmet Needs in Clinical Research in Breast Cancer: Where Do We Need to Go?
Authors: Partridge Ann H. , Carey Lisa A. 
Published: June 2017

Abstract
This CCR Focus highlights areas in breast cancer research with the greatest potential for clinical and therapeutic application. The articles in this CCR Focus address the state of the science in a broad range of areas with a focus on “hot” although sometimes controversial topics, unanswered questions, and unmet need. From mutational signatures, the cancer genomic revolution, and new inroads in immunotherapy for breast cancer to unique concerns of vulnerable populations as well as national and global health disparities, these works represent much of the promise of breast cancer research as well as the challenges in the coming years. Each review focuses not only on recent discoveries but also on putting the topic in context, including limitations to overcome. This overview is designed to further contextualize the highlighted issues within the broader research landscape. We also present new information from a poll of ALLIANCE for Clinical Trials in Oncology Breast Committee members regarding the most needed and viable potential future National Cancer Institute (NCI)–supported clinical trials in breast cancer. The great challenge is to translate the potential benefits of greater scientific knowledge reflected in this CCR Focus section into improvements in outcomes for individuals and populations with breast cancer. A unifying theme across the six articles contained in this CCR Focus is the increasingly recognized value and necessity of collaboration across disciplines from bench to bedside to populations. Only continued and iteratively amplified scientific, clinical, and governmental commitment to creating, testing, and implementing new knowledge will reduce the global morbidity and mortality of breast cancer. Clin Cancer Res; 23(11); 2611–6. ©2017 AACR.
See all articles in this CCR Focus section, “Breast Cancer Research: From Base Pairs to Populations.”
JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines
Authors: Kani Kian , Garri Carolina , Tiemann Katrin , Malihi Paymaneh D. , Punj Vasu , Nguyen Anthony L. , Lee Janet , Hughes Lindsey D. , Alvarez Ruth M. , Wood Damien M. , Joo Ah Young , Katz Jonathan E. , Agus David B. , Mallick Parag 
Published: June 2017

Abstract
Mutations or deletions in exons 18–21 in the EGFR) are present in approximately 15% of tumors in patients with non–small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib-resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC50 from 49 nmol/L to 8 μmol/L (P &lt; 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC50 from 49 nmol/L to 2 nmol/L; P &lt; 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line (P &lt; 0.01). Analysis of gene expression in patient tumors with EGFR-activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, P &lt; 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. Mol Cancer Ther; 16(8); 1645–57. ©2017 AACR.
Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas
Authors: King Amanda R. , Corso Christopher D. , Chen Evan M. , Song Eric , Bongiorni Paul , Chen Zhe , Sundaram Ranjini K. , Bindra Ranjit S. , Saltzman W. Mark 
Published: June 2017

AbstractHigh-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood–brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456–69. ©2017 AACR.
Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension
Authors: Prins Kurt W. , Tian Lian , Wu Danchen , Thenappan Thenappan , Metzger Joseph M. , Archer Stephen L. 
Published: June 2017

Background

Pulmonary arterial hypertension (
PAH
) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (
RV
) dysfunction. Although
RV
function predicts outcomes in
PAH
, mechanisms of
RV
dysfunction are poorly understood, and
RV
‐targeted therapies are lacking. We hypothesized that in
PAH
, abnormal microtubular structure in
RV
cardiomyocytes impairs
RV
function by reducing junctophilin‐2 (
JPH
2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase
JPH
2 expression and enhance
RV
function in monocrotaline‐induced
PAH
.

Methods and Results

Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics,
RV
function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline
RV
, but not the left ventricle, microtubule density is increased, and
JPH
2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases
JPH
2 expression, and improves t‐tubule morphology in
RV
cardiomyocytes. Colchicine therapy diminishes
RV
hypertrophy, improves
RV
function, and enhances
RV
–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.

Conclusions

Monocrotaline‐induced PAH causes
RV
‐specific derangement of microtubules marked by reduction in
JPH
2 and t‐tubule disarray. Colchicine reduces microtubule density, increases
JPH
2 expression, and improves both t‐tubule architecture and
RV
function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a
RV
‐directed therapy for
PAH
.
A Discussion of M. Bonazzi, À la recherche des idées
Authors: Petrucci Federico M. 
Published: June 2017

AbstractThis paper discusses Mauro Bonazzi’s excellent book on Middle Platonism, its relationship with Hellenistic philosophy and Plotinus. The overall evaluation is extremely positive: the book detects fundamental aspects of Middle Platonism by focusing on its (often disregarded) epistemology and carefully analysing puzzling—and telling—stages of its philosophical development.