bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of the Pla Protease Substrate α2-Antiplasmin on the Progression of Primary Pneumonic Plague
Authors: Eddy Justin L. , Schroeder Jay A. , Zimbler Daniel L. , Bellows Lauren E. , Lathem Wyndham W. 
Published: October 2015

ABSTRACT

Many pathogens usurp the host hemostatic system during infection to promote pathogenesis.
Yersinia pestis
, the causative agent of plague, expresses the plasminogen activator protease Pla, which has been shown
in vitro
to target and cleave multiple proteins within the fibrinolytic pathway, including the plasmin inhibitor α2-antiplasmin (A2AP). It is not known, however, if Pla inactivates A2AP
in vivo
; the role of A2AP during respiratory
Y. pestis
infection is not known either. Here, we show that
Y. pestis
does not appreciably cleave A2AP in a Pla-dependent manner in the lungs during experimental pneumonic plague. Furthermore, following intranasal infection with
Y. pestis
, A2AP-deficient mice exhibit no difference in survival time, bacterial burden in the lungs, or dissemination from wild-type mice. Instead, we found that in the absence of Pla, A2AP contributes to the control of the pulmonary inflammatory response during infection by reducing neutrophil recruitment and cytokine production, resulting in altered immunopathology of the lungs compared to A2AP-deficient mice. Thus, our data demonstrate that A2AP is not significantly affected by the Pla protease during pneumonic plague, and although A2AP participates in immune modulation in the lungs, it has limited impact on the course or ultimate outcome of the infection.
Airpnp: Auto- and Integrated Regulation of Polynucleotide Phosphorylase
Authors: Condon Ciarán 
Published: October 2015

ABSTRACT

The properties and expression of polynucleotide phosphorylase (PNPase), capable of both RNA degradation and polymerization, have been studied for 60 years. In this issue of the
Journal of Bacteriology
,
Park et al.
(H. Park, H. Yakhnin, M. Connolly, T. Romeo, and P. Babitzke, J Bacteriol 197:3751–3759, 2015,
http://dx.doi.org/10.1128/JB.00721-15
) write the latest chapter on the complex regulation of
pnp
gene expression involving CsrA. I describe how this new piece of the puzzle fits into the global scheme of PNPase autoregulation and how this is influenced by central carbon metabolism at both the posttranscriptional level and that of enzyme activity.
Evaluation of AUSDRISK as a screening tool for lifestyle modification programs: international implications for policy and cost-effectiveness
Authors: Malo Jonathan A , Versace Vincent L , Janus Edward D , Laatikainen Tiina , Peltonen Markku , Vartiainen Erkki , Coates Michael J , Dunbar James A 
Published: October 2015

ObjectiveTo evaluate the current use of Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK) as a screening tool to identify individuals at high risk of developing type 2 diabetes for entry into lifestyle modification programs.Research Design and MethodsAUSDRISK scores were calculated from participants aged 40–74 years in the Greater Green Triangle Risk Factor Study, a cross-sectional population survey in 3 regions of Southwest Victoria, Australia, 2004–2006. Biomedical profiles of AUSDRISK risk categories were determined along with estimates of the Victorian population included at various cut-off scores. Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and receiver operating characteristics were calculated for AUSDRISK in determining fasting plasma glucose (FPG) ≥6.1 mmol/L.ResultsIncreasing AUSDRISK scores were associated with an increase in weight, body mass index, FPG, and metabolic syndrome. Increasing the minimum cut-off score also increased the proportion of individuals who were obese and centrally obese, had impaired fasting glucose (IFG) and metabolic syndrome. An AUSDRISK score of ≥12 was estimated to include 39.5% of the Victorian population aged 40–74 (916 000), while a score of ≥20 would include only 5.2% of the same population (120 000). At AUSDRISK≥20, the PPV for detecting FPG≥6.1 mmol/L was 28.4%.ConclusionsAUSDRISK is powered to predict those with IFG and undiagnosed type 2 diabetes, but its effectiveness as the sole determinant for entry into a lifestyle modification program is questionable given the large proportion of the population screened-in using the current minimum cut-off of ≥12. AUSDRISK should be used in conjunction with oral glucose tolerance testing, fasting glucose, or glycated hemoglobin to identify those individuals at highest risk of progression to type 2 diabetes, who should be the primary targets for lifestyle modification.
Effective interprofessional simulation training for medical and midwifery students
Authors: Edwards S E , Platt S , Lenguerrand E , Winter C , Mears J , Davis S , Lucas G , Hotton E , Fox R , Draycott T , Siassakos D 
Published: October 2015

IntroductionGood interprofessional teamworking is essential for high quality, efficient and safe clinical care. Undergraduate interprofessional training has been advocated for many years to improve interprofessional working. However, few successful initiatives have been reported and even fewer have formally assessed their educational impact.MethodsThis was a prospective observational study of medical and midwifery students at a tertiary-level maternity unit. An interprofessional training module was developed and delivered by a multiprofessional faculty to medical and midwifery students, including short lectures, team-building exercises and practical simulation-based training for one obstetric (shoulder dystocia) and three generic emergencies (sepsis, haemorrhage, collapse). Outcome measures were interprofessional attitudes, assessed with a validated questionnaire (UWE Interprofessional Questionnaire) and clinical knowledge, measured with validated multiple-choice questions.ResultsSeventy-two students participated (34 medical, 38 midwifery). Following training median interprofessional attitude scores improved in all domains (p<0.0001), and more students responded in positive categories for communication and teamwork (69–89%, p=0.004), interprofessional interaction (3–16%, p=0.012) and interprofessional relationships (74–89%, p=0.006). Scores for knowledge improved following training for medical students (65.5% (61.8–70%) to 82.3% (79.1–84.5%) (median (IQR)) p<0.0001) and student midwives (70% (64.1–76.4%) to 81.8% (79.1–86.4%) p<0.0001), and in all subject areas (p<0.0001).ConclusionsThis training was associated with meaningful improvements in students’ attitudes to teamwork, and knowledge acquisition. Integrating practical tasks and teamwork training, in authentic clinical settings, with matched numbers of medical and non-medical students can facilitate learning of both why and how to work together. This type of training could be adopted widely in undergraduate healthcare education.
Validation of the Modified Raymond–Roy classification for intracranial aneurysms treated with coil embolization
Authors: Stapleton Christopher J , Torok Collin M , Rabinov James D , Walcott Brian P , Mascitelli Justin R , Leslie-Mazwi Thabele M , Hirsch Joshua A , Yoo Albert J , Ogilvy Christopher S , Patel Aman B 
Published: October 2015

BackgroundThe Raymond–Roy Occlusion Classification (RROC) qualitatively assesses intracranial aneurysm occlusion following endovascular coil embolization. The Modified Raymond–Roy Classification (MRRC) was developed as a refinement of this classification scheme, and dichotomizes RROC III occlusions into IIIa (opacification within the interstices of the coil mass) and IIIb (opacification between the coil mass and aneurysm wall) closures.MethodsTo demonstrate in an external cohort the predictive accuracy of the MRRC, the records of 326 patients with 345 intracranial aneurysms treated with endovascular coil embolization from January 2007 to December 2013 were retrospectively analyzed.ResultsWithin this cohort, 84 (24.3%) and 83 aneurysms (24.1%) had MRRC IIIa and IIIb closures, respectively, during initial coil embolization. Progression to complete occlusion was more likely with IIIa than IIIb closures (53.6% vs 19.2%, p≤0.01), while recanalization was more likely with IIIb than IIIa closures (65.1% vs 27.4%, p<0.01). Kaplan–Meier estimates demonstrated a significant difference in the test of equality for progression to complete occlusion (p=0.02) and recurrence (p<0.01) between class IIIa and IIIb distributions. For the entire cohort, male gender (p<0.01), ruptured aneurysm (p=0.04), intraluminal thrombus (p<0.01), and MRRC IIIb closure (p<0.01) were identified as predictors of recanalization. For aneurysms with an initial RROC III occlusion, MRRC IIIa closure was found to be an independent predictor of progression to complete occlusion (p=0.02).ConclusionsThis study confirms that the MRRC enhances the predictive accuracy of the RROC.
Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment
Authors: Ponzetta Andrea , Benigni Giorgia , Antonangeli Fabrizio , Sciumè Giuseppe , Sanseviero Emilio , Zingoni Alessandra , Ricciardi Maria Rosaria , Petrucci Maria Teresa , Santoni Angela , Bernardini Giovanni 
Published: October 2015

Abstract
Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1− NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1− NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma–bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma–promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth. Cancer Res; 75(22); 4766–77. ©2015 AACR.
Systemic Administration and Targeted Radiosensitization via Chemically Synthetic Aptamer–siRNA Chimeras in Human Tumor Xenografts
Authors: Ni Xiaohua , Zhang Yonggang , Zennami Kenji , Castanares Mark , Mukherjee Amarnath , Raval Raju R. , Zhou Haoming , DeWeese Theodore L. , Lupold Shawn E. 
Published: October 2015

Abstract
Radiation therapy is a highly effective tool for treating all stages of prostate cancer, from curative approaches in localized disease to palliative care and enhanced survival for patients with distant bone metastases. The therapeutic index of these approaches may be enhanced with targeted radiation-sensitizing agents. Aptamers are promising nucleic acid delivery agents for short interfering RNAs (siRNA) and short hairpin RNAs (shRNA). We have previously developed a radiation-sensitizing RNA aptamer–shRNA chimera that selectively delivers DNA-PK targeting shRNAs to prostate-specific membrane antigen (PSMA) positive cells in the absence of transfection reagents. Although these chimera are effective, their synthesis requires in vitro transcription and their evaluation was limited to intratumoral administration. Here, we have developed a second-generation aptamer–siRNA chimera that can be assembled through the annealing of three separate chemically synthesized components. The resulting chimera knocked down DNA-PK in PSMA-positive prostate cancer cells, without the need of additional transfection reagents, and enhanced the efficacy of radiation-mediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiation-sensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors. Mol Cancer Ther; 14(12); 2797–804. ©2015 AACR.
A TORC2–Akt Feed-Forward Topology Underlies HER3 Resiliency in HER2-Amplified Cancers
Authors: Amin Dhara N. , Ahuja Deepika , Yaswen Paul , Moasser Mark M. 
Published: October 2015

Abstract
The requisite role of HER3 in HER2-amplified cancers is beyond what would be expected as a dimerization partner or effector substrate and it exhibits a substantial degree of resiliency that mitigates the effects of HER2-inhibitor therapies. To better understand the roots of this resiliency, we conducted an in-depth chemical-genetic interrogation of the signaling network downstream of HER3. A unique attribute of these tumors is the deregulation of TORC2. The upstream signals that ordinarily maintain TORC2 signaling are lost in these tumors, and instead TORC2 is driven by Akt. We find that in these cancers HER3 functions as a buffering arm of an Akt–TORC2 feed-forward loop that functions as a self-perpetuating module. This network topology alters the role of HER3 from a conditionally engaged ligand-driven upstream physiologic signaling input to an essential component of a concentric signaling throughput highly competent at preservation of homeostasis. The competence of this signaling topology is evident in its response to perturbation at any of its nodes. Thus, a critical pathophysiologic event in the evolution of HER2-amplified cancers is the loss of the input signals that normally drive TORC2 signaling, repositioning it under Akt dependency, and fundamentally altering the role of HER3. This reprogramming of the downstream network topology is a key aspect in the pathogenesis of HER2-amplified cancers and constitutes a formidable barrier in the targeted therapy of these cancers. Mol Cancer Ther; 14(12); 2805–17. ©2015 AACR.
ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor
Authors: Nakanishi Yoshito , Mizuno Hideaki , Sase Hitoshi , Fujii Toshihiko , Sakata Kiyoaki , Akiyama Nukinori , Aoki Yuko , Aoki Masahiro , Ishii Nobuya 
Published: October 2015

Abstract
Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal–regulated kinase (ERK) gene signature was altered in several FGFR inhibitor–sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor–sensitive cell line. Because the mitogen-activated protein kinase (MAPK) pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor–sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers. Mol Cancer Ther; 14(12); 2831–9. ©2015 AACR.
BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis
Authors: Sanderson Michael P. , Apgar Joshua , Garin-Chesa Pilar , Hofmann Marco H. , Kessler Dirk , Quant Jens , Savchenko Alexander , Schaaf Otmar , Treu Matthias , Tye Heather , Zahn Stephan K. , Zoephel Andreas , Haaksma Eric , Adolf Günther R. , Kraut Norbert 
Published: October 2015

Abstract
Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP-competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance. BI 885578, administered daily per os, displayed an acceptable tolerability profile in mice at doses that significantly reduced the growth of xenografted human GEO and CL-14 colon carcinoma tumors. We found that treatment with BI 885578 is accompanied by increases in circulating glucose and insulin levels, which in turn leads to compensatory hyperphosphorylation of muscle INSRs and subsequent normalization of blood glucose within a few hours. In contrast, the normalization of IGF1R and INSR phosphorylation in GEO tumors occurs at a much slower rate. In accordance with this, BI 885578 led to a prolonged inhibition of cell proliferation and induction of apoptosis in GEO tumors. We propose that the remarkable therapeutic window observed for BI 885578 is achieved by virtue of the distinctive pharmacokinetic properties of the compound, capitalizing on the physiologic mechanisms of glucose homeostasis and differential levels of IGF1R and INSR expression in tumors and normal tissues. Mol Cancer Ther; 14(12); 2762–72. ©2015 AACR.
Safety and Effectiveness of Stent Placement for Iliofemoral Venous Outflow Obstruction
Authors: Razavi Mahmood K. , Jaff Michael R. , Miller Larry E. 
Published: October 2015

Background—
Endovenous recanalization of iliofemoral stenosis or occlusion with angioplasty and stent placement has been increasingly used to maintain long-term venous patency in patients with iliofemoral venous outflow obstruction. The purpose of this systematic review and meta-analysis was to determine safety and effectiveness of venous stent placement in patients with iliofemoral venous outflow obstruction.

Methods and Results—
We searched MEDLINE and EMBASE for studies evaluating safety or effectiveness of stent placement in patients with iliofemoral venous outflow obstruction. Data were extracted by disease pathogenesis: nonthrombotic, acute thrombotic, or chronic post-thrombotic. Main outcomes included technical success, periprocedural complications, symptom relief at final follow-up, and primary/secondary patency through 5 years. A total of 37 studies reporting 45 treatment effects (nonthrombotic, 8; acute thrombotic, 19; and chronic post-thrombotic, 18) from 2869 patients (nonthrombotic, 1122; acute thrombotic, 629; and chronic post-thrombotic, 1118) were included. Technical success rates were comparable among groups, ranging from 94% to 96%. Complication rates ranged from 0.3% to 1.1% among groups for major bleeding, from 0.2% to 0.9% for pulmonary embolism, from 0.1% to 0.7% for periprocedural mortality, and from 1.0% to 6.8% for early thrombosis. Patient symptom relief data were reported inconsistently. At 1 year, primary and secondary patency were 96% and 99% for nonthrombotic, 87% and 89% for acute thrombotic, and 79% and 94% for chronic post-thrombotic.

Conclusions—
Stent placement for iliofemoral venous outflow obstruction results in high technical success and acceptable complication rates regardless of cause of obstruction.
Changes in Diet Quality Scores and Risk of Cardiovascular Disease Among US Men and Women
Authors: Sotos-Prieto Mercedes , Bhupathiraju Shilpa N. , Mattei Josiemer , Fung Teresa T. , Li Yanping , Pan An , Willett Walter C. , Rimm Eric B. , Hu Frank B. 
Published: October 2015

Background—
Adherence to several diet quality scores, including the Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension, has been associated with lower risk of cardiovascular disease (CVD), but little is known about how changes in these scores over time influence subsequent CVD risk.

Methods and Results—

We analyzed the association between 4-year changes in the 3 diet quality scores (Alternative Healthy Eating Index, Alternative Mediterranean Diet score, and Dietary Approach to Stop Hypertension) and subsequent cardiovascular disease (CVD) risk among 29 343 men in the Health Professionals Follow-up Study and 51 195 women in the Nurses’ Health Study (1986–2010). During 1 394 702 person-years of follow-up, we documented 11 793 CVD cases. Compared with participants whose diet quality remained relatively stable in each 4-year period, those with the greatest improvement in diet quality scores had a 7% to 8% lower CVD risk in the subsequent 4-year period (pooled hazard ratio, 0.92 [95% confidence interval (CI), 0.87–0.99] for the Alternative Healthy Eating Index; 0.93 [95% CI, 0.85–1.02] for the Alternative Mediterranean Diet score; and 0.93 [95% CI, 0.87–0.99] for the Dietary Approach to Stop Hypertension; all
P
for trend <0.05). In the long term, increasing the diet scores from baseline to the first 4-year follow-up was associated with lower CVD risk during the next 20 years (7% [95% CI, 1–12] for the Alternative Healthy Eating Index, and 9% [95% CI, 3–14] for the Alternative Mediterranean Diet score). A decrease in diet quality scores was associated with significantly elevated risk of CVD in subsequent time periods.

Conclusions—
Improving adherence to diet quality scores over time is associated with significantly lower CVD risk in both the short term and long term.