bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant
Authors: Richmond Jennifer , Robbins Alissa , Evans Kathryn , Beck Dominik , Kurmasheva Raushan T. , Billups Catherine A. , Carol Hernan , Heatley Sue , Sutton Rosemary , Marshall Glenn M. , White Deborah , Pimanda John , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: June 2016

Abstract
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579–91. ©2016 AACR.
Retail Pharmacy Policy to End the Sale of Tobacco Products: What Is the Impact on Disparity in Neighborhood Density of Tobacco Outlets?
Authors: Tucker-Seeley Reginald D. , Bezold Carla P. , James Peter , Miller Melecia , Wallington Sherrie F. 
Published: June 2016

AbstractBackground: Population-level research on the implications of retail pharmacy policies to end the sale of tobacco products is scant, and the impact of such policies on racial/ethnic and socioeconomic disparities across neighborhoods in access to tobacco products remains unexplored.Methods: We investigated the association between neighborhood sociodemographic characteristics and tobacco retail density in Rhode Island (RI; N = 240 census tracts). We also investigated whether the CVS Health (N = 60) policy to end the sale of tobacco products reduces the disparity in the density of tobacco retail across neighborhoods, and we conducted a prospective policy analysis to determine whether a similar policy change in all pharmacies in RI (N = 135) would reduce the disparity in tobacco retail density.Results: The results revealed statistically significant associations between neighborhood sociodemographic characteristics and tobacco retail outlet density across RI neighborhoods. The results when excluding the CVS Health locations, as well as all pharmacies as tobacco retailers, revealed no change in the pattern for this association.Conclusions: The results of this study suggest that while a commendable tobacco control policy, the CVS Health policy appears to have no impact on the neighborhood racial/ethnic and socioeconomic disparities in the density of tobacco retailers in RI. Prospective policy analyses showed no impact on this disparity even if all other pharmacies in the state adopted a similar policy.Impact: Policy efforts aimed at reducing the disparity in access to tobacco products should focus on reducing the density of tobacco outlets in poor and racial/ethnic neighborhoods. Cancer Epidemiol Biomarkers Prev; 25(9); 1305–10. ©2016 AACR.
A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer
Authors: Hoogstins Charlotte E.S. , Tummers Quirijn R.J.G. , Gaarenstroom Katja N. , de Kroon Cor D. , Trimbos J. Baptist M.Z. , Bosse Tjalling , Smit Vincent T.H.B.M. , Vuyk Jaap , van de Velde Cornelis J.H. , Cohen Adam F. , Low Philip S. , Burggraaf Jacobus , Vahrmeijer Alexander L. 
Published: June 2016

Abstract
Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in &gt;90% of epithelial ovarian cancers.
Experimental Design: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging.
Results: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha–positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation.
Conclusions: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929–38. ©2016 AACR.
Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma
Authors: Böhm Steffen , Montfort Anne , Pearce Oliver M.T. , Topping Joanne , Chakravarty Probir , Everitt Gemma L.A. , Clear Andrew , McDermott Jackie R. , Ennis Darren , Dowe Thomas , Fitzpatrick Amanda , Brockbank Elly C. , Lawrence Alexandra C. , Jeyarajah Arjun , Faruqi Asma Z. , McNeish Iain A. , Singh Naveena , Lockley Michelle , Balkwill Frances R. 
Published: June 2016

Abstract
Purpose: The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian high-grade serous carcinoma (HGSC), and its relationship to treatment response.
Experimental Design: We obtained pre- and posttreatment omental biopsies and blood samples from a total of 54 patients undergoing platinum-based NACT and 6 patients undergoing primary debulking surgery. We measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using IHC, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related our findings to the histopathologic treatment response.
Results: There was evidence of T-cell activation in omental biopsies after NACT: CD4+ T cells showed enhanced IFNγ production and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to NACT. The CD8+ T-cell and CD45RO+ memory cell density in the tumor microenvironment was unchanged after NACT but biopsies showing a good therapeutic response had significantly fewer FoxP3+ T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- versus pre-NACT samples that was more pronounced in good responders. Plasma levels of proinflammatory cytokines decreased in all patients after NACT. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased after NACT.
Conclusions: NACT may enhance host immune response but this effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. Sequential chemoimmunotherapy may improve disease control in advanced HGSC. Clin Cancer Res; 22(12); 3025–36. ©2016 AACR.
Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts
Authors: Sharma Priyanka , López-Tarruella Sara , García-Saenz Jose Angel , Ward Claire , Connor Carol S. , Gómez Henry L. , Prat Aleix , Moreno Fernando , Jerez-Gilarranz Yolanda , Barnadas Augusti , Picornell Antoni C. , del Monte-Millán Maria , Gonzalez-Rivera Milagros , Massarrah Tatiana , Pelaez-Lorenzo Beatriz , Palomero María Isabel , González del Val Ricardo , Cortes Javier , Fuentes Rivera Hugo , Bretel Morales Denisse , Márquez-Rodas Iván , Perou Charles M. , Wagner Jamie L. , Mammen Joshua M.V. , McGinness Marilee K. , Klemp Jennifer R. , Amin Amanda L. , Fabian Carol J. , Heldstab Jaimie , Godwin Andrew K. , Jensen Roy A. , Kimler Bruce F. , Khan Qamar J. , Martin Miguel 
Published: June 2016

Abstract
Purpose: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC.
Experimental Design: The study population includes 190 patients with stage I–III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m2) given every 21 days × 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated.
Results: Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event.
Conclusions: The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline–taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649–57. ©2016 AACR.
Postdischarge Bleeding After Percutaneous Coronary Intervention and Subsequent Mortality and Myocardial Infarction
Authors: Valle Javier A. , Shetterly Susan , Maddox Thomas M. , Ho P. Michael , Bradley Steven M. , Sandhu Amneet , Magid David , Tsai Thomas T. 
Published: June 2016

Background—
Bleeding after hospital discharge from percutaneous coronary intervention (PCI) is associated with increased risk of subsequent myocardial infarction (MI) and death; however, the timing of adverse events after these bleeding events is poorly understood. Defining this relationship may help clinicians identify critical periods when patients are at highest risk.

Methods and Results—
All patients undergoing PCI from 2004 to 2007 who survived to hospital discharge without a bleeding event were identified from the HMO Research Network-Stent (HMORN-Stent) Registry. Postdischarge rates and timing of bleeding-related hospitalizations, MI, and death were defined. We then assessed the association between postdischarge bleeding–related hospitalizations with death and MI using Cox proportional hazards models. Among 8137 post-PCI patients surviving to hospital discharge without in-hospital bleeding, 391 (4.8%) had bleeding-related hospitalization after discharge, with the highest incidence of bleeding-related hospitalizations occurring within 30 days of discharge (n=79, 20.2%). Postdischarge bleeding–related hospitalization after PCI was associated with subsequent death or MI (hazard ratio, 3.09; 95% confidence interval, 2.41–3.96), with the highest risk for death or MI occurring in the first 60 days after bleeding-related hospitalization (hazard ratio, 7.16; confidence interval, 3.93–13.05).

Conclusions—
Approximately 1 in 20 post-PCI patients are readmitted for bleeding, with the highest incidence occurring within 30 days of discharge. Patients having postdischarge bleeding are at increased risk for subsequent death or MI, with the highest risk occurring within the first 60 days after a bleeding-related hospitalization. These findings suggest a critical period after bleeding events when patients are most vulnerable for further adverse events.
Transcatheter Replacement of Failed Bioprosthetic Valves
Authors: Simonato Matheus , Webb John , Kornowski Ran , Vahanian Alec , Frerker Christian , Nissen Henrik , Bleiziffer Sabine , Duncan Alison , Rodés-Cabau Josep , Attizzani Guilherme F. , Horlick Eric , Latib Azeem , Bekeredjian Raffi , Barbanti Marco , Lefevre Thierry , Cerillo Alfredo , Hernández José María , Bruschi Giuseppe , Spargias Konstantinos , Iadanza Alessandro , Brecker Stephen , Palma José Honório , Finkelstein Ariel , Abdel-Wahab Mohamed , Lemos Pedro , Petronio Anna Sonia , Champagnac Didier , Sinning Jan-Malte , Salizzoni Stefano , Napodano Massimo , Fiorina Claudia , Marzocchi Antonio , Leon Martin , Dvir Danny 
Published: June 2016

Background—
Transcatheter valve implantation inside failed bioprosthetic surgical valves (valve-in-valve [ViV]) may offer an advantage over reoperation. Supra-annular transcatheter valve position may be advantageous in achieving better hemodynamics after ViV. Our objective was to define targets for implantation that would improve hemodynamics after ViV.

Methods and Results—

Cases from the Valve-in-Valve International Data (VIVID) registry were analyzed using centralized core laboratory assessment blinded to clinical events. Multivariate analysis was performed to identify independent predictors of elevated postprocedural gradients (mean ≥20 mm Hg). Optimal implantation depths were defined by receiver operating characteristic curve. A total of 292 consecutive patients (age, 78.9±8.7 years; 60.3% male; 157 CoreValve Evolut and 135 Sapien XT) were evaluated. High implantation was associated with significantly lower rates of elevated gradients in comparison with low implantation (CoreValve Evolut, 15% versus 34.2%;
P
=0.03 and Sapien XT, 18.5% versus 43.5%;
P
=0.03, respectively). Optimal implantation depths were defined: CoreValve Evolut, 0 to 5 mm; Sapien XT, 0 to 2 mm (0–10% frame height); sensitivities, 91.3% and 88.5%, respectively. The strongest independent correlate for elevated gradients after ViV was device position (high: odds ratio, 0.22; confidence interval, 0.1–0.52;
P
=0.001), in addition to type of device used (CoreValve Evolut: odds ratio, 0.5; confidence interval, 0.28–0.88;
P
=0.02) and surgical valve mechanism of failure (stenosis/mixed baseline failure: odds ratio, 3.12; confidence interval, 1.51–6.45;
P
=0.002).

Conclusions—
High implantation inside failed bioprosthetic valves is a strong independent correlate of lower postprocedural gradients in both self- and balloon-expandable transcatheter valves. These clinical evaluations support specific implantation targets to optimize hemodynamics after ViV.
Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats
Authors: Lee Jin Hwan , Wei Ling , Gu Xiaohuan , Won Soonmi , Wei Zheng Zachory , Dix Thomas A. , Yu Shan Ping 
Published: June 2016

Background and Purpose—
Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke.

Methods—
Wistar rats were subjected to 90-minute middle cerebral artery occlusion by insertion of an intraluminal filament. Mild-to-moderate hypothermia was induced 120 minutes after the onset of stroke by PC alone, a neurotensin receptor 1 (NTR1) agonist HPI-201 (formally ABS-201) alone or the combination of both. The outcomes of stroke were evaluated at 3 and 21 days after stroke.

Results—
PC or HPI-201 each showed hypothermic effect and neuroprotection in stroke rats. The combination of PC and HPI-201 exhibited synergistic effects in cooling process, reduced infarct formation, cell death, and blood-brain barrier damages and improved functional recovery after stroke. Importantly, coapplied HPI-201 completely inhibited PC-associated shivering and tachycardia.

Conclusions—
The centrally acting hypothermic drug HPI-201 greatly enhanced the efficiency and efficacy of conventional PC; this combined cooling therapy may facilitate clinical translation of hypothermic treatment for stroke.
Interaction of Recanalization, Intracerebral Hemorrhage, and Cerebral Edema After Intravenous Thrombolysis
Authors: Cheripelli Bharath Kumar , Huang Xuya , MacIsaac Rachael , Muir Keith W. 
Published: June 2016

Background and Purpose—
Both intracerebral hemorrhage (ICH) and brain edema have been attributed to reperfusion after intravenous thrombolysis. We explored the interaction of recanalization and core size for imaging outcomes (ICH and vasogenic brain edema).

Methods—
In patients with anterior circulation occlusion given intravenous thrombolysis <4.5 hours and imaged with computed tomographic (CT) perfusion and CT angiography, we defined volumes of core (relative delay time >2 s and relative cerebral blood flow <40%) and penumbra (relative delay time >2 s). CT and CT angiography at 24 hours were reviewed for ICH (European Cooperative Acute Stroke Study [ECASS]-2 definition), early vasogenic edema (third International Stroke Trial [IST-3] criteria), and recanalization (thrombolysis in myocardial infarction 2–3). Independent effects of recanalization, core volume and potential interactions on edema, ICH and day 90 outcomes were estimated by logistic regression.

Results—

In 123 patients, there was a trend for recanalization to be associated with H1/2 ICH (odds ratio [OR], 2.3 [0.97–5.5];
P
=0.06) but not with PH1/2 ICH (OR, 1.7 [0.33–8.8];
P
=0.5), any edema, or significant brain edema (OR, 1.45 [0.4–4.9];
P
=0.55). Ischemic core (>50 mL) was associated with any ICH (OR, 4.0 [1.6–9.5];
P
=0.003), edema (OR, 5.4 [2–14];
P
<0.01), and significant brain edema (OR, 17.4 [5.3–57];
P
<0.01) but not with PH1/2 ICH (OR, 1.2 [0.23–6.5];
P
=0.8), after controlling for recanalization. There was no significant interaction of recanalization and large core for any adverse outcomes.

Conclusions—
Large ischemic core was associated with poorer outcomes and both early vasogenic brain edema and ICH, but recanalization on 24-hour CT angiography was associated with clinically favorable outcome. There was no significant interaction of recanalization and large core volume for any outcomes. The association of hemorrhage or brain edema with post-thrombolysis reperfusion is unclear.
Majority of 30-Day Readmissions After Intracerebral Hemorrhage Are Related to Infections
Authors: Lord Aaron S. , Lewis Ariane , Czeisler Barry , Ishida Koto , Torres Jose , Kamel Hooman , Woo Daniel , Elkind Mitchell S.V. , Boden-Albala Bernadette 
Published: June 2016

Background and Purpose—
Infections are common after intracerebral hemorrhage, but little is known about the risk of serious infection requiring readmission after hospital discharge.

Methods—

To determine if infections are prevalent in patients readmitted within 30 days of discharge, we performed a retrospective cohort study of patients discharged from nonfederal acute care hospitals in California with a primary diagnosis of intracerebral hemorrhage between 2006 and 2010. We excluded patients who died during the index admission, were discharged against medical advice, or were not California residents. Our main outcome was 30-day unplanned readmission with primary infection–related
International Classification of Diseases
, Ninth Revision, Clinical Modification code.

Results—

There were 24 540 index intracerebral hemorrhage visits from 2006 to 2010. Unplanned readmissions occurred in 14.5% (n=3550) of index patients. Of 3550 readmissions, 777 (22%) had an infection-related primary diagnosis code. When evaluating primary and all secondary diagnosis codes, infection was associated with 1826 (51%) of readmissions. Other common diagnoses associated with readmission included stroke-related codes (n=840, 23.7%) and aspiration pneumonitis (n=154, 4.3%). The most common infection-related primary diagnosis codes were septicemia (n=420, 11.8%), pneumonia (n=124, 3.5%), urinary tract infection (n=141, 4.0%), and gastrointestinal infection (n=42, 1.2%). Patients with a primary infection–related
International Classification of Diseases
, Ninth Revision, Clinical Modification code on readmission had higher in-hospital mortality compared with other types of readmission (15.6% versus 8.0%,
P
<0.001). After controlling for other predictors of mortality, primary infection–related readmissions remained associated with in-hospital mortality (relative risk, 1.7; 95% confidence interval, 1.3–2.2).

Conclusions—
Infections are associated with a majority of 30-day readmissions after intracerebral hemorrhage and increased mortality. Efforts should be made to reduce infection-related complications after hospital discharge.
PPM1A
Methylation Is Associated With Vascular Recurrence in Aspirin-Treated Patients
Authors: Gallego-Fabrega Cristina , Carrera Caty , Reny Jean-Luc , Fontana Pierre , Slowik Agnieszka , Pera Joanna , Pezzini Alessandro , Serrano-Heras Gemma , Segura Tomás , Bin Dukhyil Abdul-Aziz A. , Martí-Fàbregas Joan , Muiño Elena , Cullell Natalia , Montaner Joan , Krupinski Jerzy , Fernandez-Cadenas Israel 
Published: June 2016

Background and Purpose—
Despite great efforts by pharmacogenetic studies, the causes of aspirin failure to prevent the recurrence of ischemic events remain unclear. Our aim was to study whether epigenetics could be associated with the risk of vascular recurrence in aspirin-treated stroke patients.

Methods—
We performed an epigenetic joint analysis study in 327 patients treated with aspirin. In the discovery stage, we performed a nested case–control study in 38 matched ischemic stroke patients in whom 450 000 methylation sites were analyzed. Nineteen patients presented vascular recurrence after stroke, and 19 matched patients did not present vascular recurrence during the first year of follow-up. In a second stage, 289 new patients were analyzed by EpiTYPER.

Results—

The following 3 differentially methylated candidate CpG sites, were identified in the discovery stage and analyzed in the second stage: cg26039762 (
P
=9.69×10
−06
,
RAF1
), cg04985020 (
P
=3.47×10
−03
,
PPM1A
), and cg08419850 (
P
=3.47×10
−03
,
KCNQ1
). Joint analysis identified an epigenome-wide association for cg04985020 (
PPM1A
;
P
=1.78×10
−07
), with vascular recurrence in patients treated with aspirin.

Conclusions—

The pattern of differential methylation in
PPM1A
is associated with vascular recurrence in aspirin-treated stroke patients.