bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of 12/15-lipoxygenase with fatty acids alters the leukocyte kinetics leading to improved postmyocardial infarction healing
Authors: Halade Ganesh V. , Kain Vasundhara , Ingle Kevin A. , Prabhu Sumanth D. 
Published: April 2017

The metabolic transformation of fatty acids to form oxylipids using 12/15-lipoxygenase (LOX) can promote either resolving or nonresolving inflammation. However, the mechanism of how 12/15-LOX interacts with polyunsaturated fatty acids (PUFA) in postmyocardial infarction (post-MI) healing is unclear. Here, we reported the role of 12/15-LOX in post-MI cardiac remodeling in a PUFA [10% (wt/wt), 22 kcal]-enriched environment. Wild-type (WT; C57BL/6J) and 12/15-LOX-null (12/15-LOX−/−) male mice of 8–12 wk of age were fed a PUFA-enriched diet for 1 mo and subjected to permanent coronary artery ligation. Post-MI mice were monitored for day 1 or until day 5 along with standard diet-fed MI controls. No-MI surgery mice served as naïve controls. PUFA-fed WT and 12/15-LOX−/−mice improved ejection fraction and reduced lung edema greater than WT mice at day 5 post-MI ( P < 0.05). Post-MI, neutrophil density was decreased in PUFA-fed WT and 12/15-LOX−/−mice at day 1 ( P < 0.05). Deletion of 12/15-LOX in mice led to increased cytochrome P-450-derived bioactive lipid mediator epoxyeicosatrienoic acids (EETs), i.e., 11,12-EpETrE and 14,15-EpETrE, which were further enhanced by acute PUFA intake post-MI. Macrophage density was decreased in WT + PUFA and 12/15-LOX−/−mice compared with their respective standard diet-fed WT controls at day 5 post-MI. 12/15-LOX−/−+ PUFA mice displayed an increased expression of chemokine (C-C motif) ligand 2 and reparative macrophages markers ( Ym-1, Mrc-1, and Arg-1, all P < 0.05) in the infarcted area. Furthermore, 12/15-LOX−/−mice, with or without PUFA, showed reduced collagen deposition at day 5 post-MI compared with WT mice. In conclusion, deletion of 12/15-LOX and short-term exposure of PUFA promoted leukocyte clearance, thereby limiting cardiac remodeling and promoting an effective resolution of inflammation.NEW & NOTEWORTHY This study determined that 1) deletion of 12/15-lipoxygenase (LOX) promotes the generation of epoxyeicosatrienoic acids, the cytochrome P-450-derived metabolites in postmyocardial infarction (post-MI) healing; 2) acute exposure of fatty acids to 12/15-LOX−/−mice drives leukocyte (neutrophils and macrophages) clearance post-MI; and 3) metabolic transformation of fats is the significant contributor in leukocyte clearance to drive either resolving or nonresolving inflammation post-MI.
Angiotensin-(1–7) attenuates angiotensin II-induced cardiac hypertrophy via a Sirt3-dependent mechanism
Authors: Guo Lirong , Yin Ankang , Zhang Qi , Zhong Tiecheng , O’Rourke Stephen T. , Sun Chengwen 
Published: April 2017

The objectives of the present study were to investigate the effect of ANG-(1–7) on the development of cardiac hypertrophy and to identify the intracellular mechanism underlying this action of ANG-(1–7). Blood pressure and heart rate were recorded using radiotelemetry before and after chronic subcutaneous infusion of control (PBS), ANG II, ANG-(1–7), or ANG II + ANG-(1–7) for 4 wk in normotensive rats. Chronic administration of ANG-(1–7) did not affect either basal blood pressure or the ANG II-induced elevation in blood pressure. However, ANG-(1–7) significantly attenuated ANG II-induced cardiac hypertrophy and perivascular fibrosis in these rats. These effects of ANG-(1–7) were confirmed in cultured cardiomyocytes, in which ANG-(1–7) significantly attenuated ANG II-induced increases in cell size. This protective effect of ANG-(1–7) was significantly attenuated by pretreatment with A779 (a Mas receptor antagonist) or Mito-TEMPO (a mitochondria-targeting superoxide scavenger) as well as blockade of Sirt3 (a deacetylation-acting protein) by viral vector-mediated overexpression of sirtuin (Sirt)3 short hairpin (sh)RNA. Western blot analysis demonstrated that treatment with ANG-(1–7) dramatically increased Sirt3 expression. In addition, ANG-(1–7) attenuated the ANG II-induced increase in mitochondrial ROS generation, an effect that was abolished by A779 or Sirt3 shRNA. Moreover, ANG-(1–7) increased FoxO3a deacetylation and SOD2 expression, and these effects were blocked by Sirt3 shRNA. In summary, the protective effects of ANG-(1–7) on ANG II-induced cardiac hypertrophy and increased mitochondrial ROS production are mediated by elevated SOD2 expression via stimulation of Sirt3-dependent deacetylation of FoxO3a in cardiomyocytes. Thus, activation of the ANG-(1–7)/Sirt3 signaling pathway could be a novel therapeutic strategy in the management of cardiac hypertrophy and associated complications. NEW & NOTEWORTHY Chronic subcutaneous ANG-(1–7) has no effect on ANG II-induced elevations in blood pressure but significantly attenuates ANG II-induced cardiac hypertrophy and fibrosis by a mitochondrial ROS-dependent mechanism. This protective effect of ANG-(1–7) against the action of ANG II action is mediated by stimulation of sirtuin-3-mediated deacetylation of FoxO3a, which triggers SOD2 expression.
Phase I Study of Fenretinide Delivered Intravenously in Patients with Relapsed or Refractory Hematologic Malignancies: A California Cancer Consortium Trial
Authors: Mohrbacher Ann M. , Yang Allen S. , Groshen Susan , Kummar Shivaani , Gutierrez Martin E. , Kang Min H. , Tsao-Wei Denice , Reynolds C. Patrick , Newman Edward M. , Maurer Barry J. 
Published: April 2017

Abstract
Purpose: A phase I study was conducted to determine the MTD, dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies.
Experimental Design: Fenretinide (80–1,810 mg/m2/day) was administered by continuous infusion on days 1 to 5, in 21-day cycles, using an accelerated titration design.
Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1–7), were enrolled and received the test drug. Ninety-seven courses were completed. An MTD was reached at 1,280 mg/m2/day for 5 days. Course 1 DLTs included 6 patients with hypertriglyceridemia, 4 of whom were asymptomatic; 2 patients experienced DLT thrombocytopenia (asymptomatic). Of 11 patients with response-evaluable peripheral T-cell lymphomas, two had complete responses [CR, progression-free survival (PFS) 68+ months; unconfirmed CR, PFS 14+ months], two had unconfirmed partial responses (unconfirmed PR, PFS 5 months; unconfirmed PR, PFS 6 months), and five had stable disease (2–12 cycles). One patient with mature B-cell lymphoma had an unconfirmed PR sustained for two cycles. Steady-state plasma levels were approximately 10 mcg/mL (mid-20s μmol/L) at 640 mg/m2/day, approximately 14 mcg/mL (mid-30s μmol/L) at 905 mg/m2/day, and approximately 22 mcg/mL (mid-50s μmol/L) at 1,280 mg/m2/day.
Conclusions: Intravenous fenretinide obtained significantly higher plasma levels than a previous capsule formulation, had acceptable toxicities, and evidenced antitumor activity in peripheral T-cell lymphomas. A recommended phase II dosing is 600 mg/m2 on day 1, followed by 1,200 mg/m2 on days 2 to 5, every 21 days. A registration-enabling phase II study in relapsed/refractory PTCL (ClinicalTrials.gov identifier: NCT02495415) is ongoing. Clin Cancer Res; 23(16); 4550–5. ©2017 AACR.
Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer
Authors: Zou Min , Toivanen Roxanne , Mitrofanova Antonina , Floch Nicolas , Hayati Sheida , Sun Yanping , Le Magnen Clémentine , Chester Daniel , Mostaghel Elahe A. , Califano Andrea , Rubin Mark A. , Shen Michael M. , Abate-Shen Cory 
Published: April 2017

Abstract
Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.
Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736–49. ©2017 AACR.
See related commentary by Sinha and Nelson, p. 673.
This article is highlighted in the In This Issue feature, p. 653
Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC
Authors: Tumeh Paul C. , Hellmann Matthew D. , Hamid Omid , Tsai Katy K. , Loo Kimberly L. , Gubens Matthew A. , Rosenblum Michael , Harview Christina L. , Taube Janis M. , Handley Nathan , Khurana Neharika , Nosrati Adi , Krummel Matthew F. , Tucker Andrew , Sosa Eduardo V. , Sanchez Phillip J. , Banayan Nooriel , Osorio Juan C. , Nguyen-Kim Dan L. , Chang Jeremy , Shintaku I. Peter , Boasberg Peter D. , Taylor Emma J. , Munster Pamela N. , Algazi Alain P. , Chmielowski Bartosz , Dummer Reinhard , Grogan Tristan R. , Elashoff David , Hwang Jimmy , Goldinger Simone M. , Garon Edward B. , Pierce Robert H. , Daud Adil 
Published: April 2017

AbstractWe explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P &lt; 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis− group, n = 1,441 ± 250.7; P &lt; 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417–24. ©2017 AACR.
Analysis of the reversibility of biliary cirrhosis in young rats submitted to biliary obstruction followed by desobstruction
Authors: Braz Maria Julia de Aro , Corbi Leonardo Ervolino , Tannuri Ana Cristina Aoun , Gonçalves Josiane de Oliveira , Serafini Suellen , Coelho Maria Cecília de Mendonça , Tannuri Uenis 
Published: April 2017

In this letter to the editor of Revista de Medicina, we present a summary of our study entitled “Analysis of the reversibility of biliary cirrhosis in young rats submitted to biliary obstruction followed by desobstruction”, presented at the XXXV COMU in 2016 - 1st place of Oswaldo Cruz award, surgical area.Biliary atresia and other liver conditions are relevant in pediatric clinic, due to its progression into biliary cirrhosis and eventually, necessity for liver transplant. It is known that the period during which biliary obstruction persists is determining for the development of cirrhosis and its reversibility after a biliary drainage procedure. However, there are no time or histological markers of biliary cirrhosis reversibility. An animal model of biliary obstruction and desobstruction was employed and after histologic and molecular analysis, we concluded that, considering the high mortality rate and the improvement in histologic and molecular changes after biliary drainage in most groups, cirrhosis and its histological and molecular changes occur early after biliary obstruction, are severe and potentially fatal, but can be reversed or at least delayed after biliary drainage.
Decifrando a proveniência dos folhelhos da formação Ponta Grossa na região de Rio Verde de Mato Grosso e Coxim (MS) através de métodos petrográficos e geoquímicos
Authors: Montibeller Cibele Carolina , Zanardo Antenor , Navarro Guillermo Rafael Beltran 
Published: April 2017

Na região de Rio Verde de Mato Grosso e Coxim (MS) ocorrem rochas sedimentares devonianas relacionadas à Formação Ponta Grossa. Nesta região, a Formação Ponta Grossa aflorante é constituída por um pacote de folhelhos e siltitos cinza a pretos, com níveis de siltitos argilosos sobrepostos por arenitos feldspáticos muito finos micáceos, de cores creme, verde e avermelhados. Acima dos arenitos ocorrem siltitos argilosos amarelos fracamente laminados. Quimicamente, os níveis pelíticos são classificados como folhelhos/argilitos e com composição matura, derivados principalmente de rochas ígneas intermediárias e/ou máficas. Através da utilização de diagramas discriminantes para ambientes tectônicos e de proveniência, não foi estabelecido um padrão único para as amostras da Formação Ponta Grossa, podendo ser tanto classificados como sedimentos depositados em margem passiva quanto em margem ativa. Entretanto, dado o contexto da Bacia do Paraná durante o Devoniano, os sedimentos da Formação Ponta Grossa provavelmente tiveram como fonte rochas formadas em margens ativas (arcos magmáticos), erodidas e depositadas em margem passiva (bacia intracratônica).
Socioeconomic Status Interacts with the Genetic Effect of a Chromosome 9p21.3 Common Variant to Influence Coronary Artery Calcification and Incident Coronary Events in the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcium, and Lifestyle)
Authors: Schmidt Börge , Frölich Stefanie , Dragano Nico , Frank Mirjam , Eisele Lewin , Pechlivanis Sonali , Forstner Andreas J. , Nöthen Markus M. , Mahabadi Amir A. , Erbel Raimund , Moebus Susanne , Jöckel Karl-Heinz 
Published: April 2017

Background—
Genetic variants of a locus within the chromosome 9p21.3 region are consistently associated with coronary artery disease and coronary artery calcification (CAC). The aim of this study was to examine whether a 9p21.3 common variant interacts with socioeconomic status (SES) to influence CAC and incident coronary events in a population-based cohort.

Methods and Results—

9p21.3 single nucleotide polymorphism rs2891168 was genotyped in 4116 participants of the Heinz Nixdorf Recall study. SES indicators (education and income) and CAC were assessed at baseline. Incident coronary events were ascertained over a median follow-up of 9.3 years. Multiple regression models were fitted to estimate genetic effects on log
e
(CAC+1) and incident coronary events. Genetic effects were highest in the lower income tertile with a 53.1% (95% confidence interval, 30.6%–79.6%;
P
=1.8×10

–
7

) increase in CAC and a hazard ratio of 1.44 (95% confidence interval, 1.01–2.07;
P
=0.049) for incident coronary events per additional risk allele. After including genotype×SES interaction terms in the regression models, genotype×income interactions were observed for CAC (exp[β
g×income
]=0.85 [95% confidence interval, 0.74–0.98;
P
g×income
=0.02] per 1000€/mo increase and additional risk allele) and for incident coronary events (hazard ratio
g×income
=0.69 [95% confidence interval, 0.48–0.98;
P
g×income
=0.04] per 1000€/mo increase and additional risk allele). No interaction was observed using education as SES indicator.

Conclusions—
A 9p21.3 common variant seems to interact with SES to influence CAC and incident coronary events in a population-based cohort. This supports the hypothesis that better material, psychosocial, and lifestyle conditions enable higher SES groups to reduce the expression of their genetic susceptibility to coronary artery disease.
Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning
Authors: de Couto Geoffrey , Gallet Romain , Cambier Linda , Jaghatspanyan Ervin , Makkar Nupur , Dawkins James Frederick , Berman Benjamin P. , Marbán Eduardo 
Published: April 2017

Background:

Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction by distinctive macrophage (Mϕ) polarization. Here we demonstrate that CDC-secreted exosomes (CDC
exo
) recapitulate the cardioprotective effects of CDC therapy known as cellular postconditioning.

Methods:

Rats and pigs underwent myocardial infarction induced by ischemia/reperfusion before intracoronary infusion of CDC
exo
, inert fibroblast exosomes (Fb
exo
; control), or vehicle. Two days later, infarct size was quantified. Macrophages were isolated from cardiac tissue or bone marrow for downstream analyses. RNA sequencing was used to determine exosome content and alterations in gene expression profiles in Mϕ.

Results:

Administration of CDC
exo
but not Fb
exo
after reperfusion reduces infarct size in rat and pig models of myocardial infarction. Furthermore, CDC
exo
reduce the number of CD68+ Mϕ within infarcted tissue and modify the polarization state of Mϕ so as to mimic that induced by CDCs. CDC
exo
are enriched in several miRNAs (including miR-146a, miR-181b, and miR-126) relative to Fb
exo
. Reverse pathway analysis of whole-transcriptome data from CDC
exo
-primed Mϕ implicated miR-181b as a significant (
P
=1.3x10
−21
) candidate mediator of CDC-induced Mϕ polarization, and PKCδ (protein kinase C δ) as a downstream target. Otherwise inert Fb
exo
loaded selectively with miR-181b alter Mϕ phenotype and confer cardioprotective efficacy in a rat model of myocardial infarction. Adoptive transfer of PKCδ-suppressed Mϕ recapitulates cardioprotection.

Conclusions:
Our data support the hypothesis that exosomal transfer of miR-181b from CDCs into Mϕ reduces PKCδ transcript levels and underlies the cardioprotective effects of CDCs administered after reperfusion.
Long‐Term Follow‐up of the PADI Trial: Percutaneous Transluminal Angioplasty Versus Drug‐Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia
Authors: Spreen Marlon I. , Martens Jasper M. , Knippenberg Bob , van Dijk Lukas C. , de Vries Jean‐Paul P. M. , Vos Jan Albert , de Borst Gert Jan , Vonken Evert‐Jan P. A. , Bijlstra Okker D. , Wever Jan J. , Statius van Eps Randolph G. , Mali Willem P. Th. M. , van Overhagen Hendrik 
Published: April 2017

Background

Clinical outcomes reported after treatment of infrapopliteal lesions with drug‐eluting stents (DESs) have been more favorable compared with percutaneous transluminal angioplasty with a bailout bare metal stent (
PTA
‐
BMS
) through midterm follow‐up in patients with critical limb ischemia. In the present study, long‐term results of treatment of infrapopliteal lesions with
DESs
are presented.

Methods and Results

Adults with critical limb ischemia (Rutherford category ≥4) and infrapopliteal lesions were randomized to receive
PTA
‐
BMS
or
DESs
with paclitaxel. Long‐term follow‐up consisted of annual assessments up to 5 years after treatment or until a clinical end point was reached. Clinical end points were major amputation (above ankle level), infrapopliteal surgical or endovascular reintervention, and death. Preserved primary patency (≤50% restenosis) of treated lesions was an additional morphological end point, assessed by duplex sonography. In total, 74 limbs (73 patients) were treated with
DESs
and 66 limbs (64 patients) were treated with
PTA
‐
BMS
. The estimated 5‐year major amputation rate was lower in the
DES
arm (19.3% versus 34.0% for
PTA
‐
BMS
;
P
=0.091). The 5‐year rates of amputation‐ and event‐free survival (survival free from major amputation or reintervention) were significantly higher in the
DES
arm compared with
PTA
‐BMS (31.8% versus 20.4%,
P
=0.043; and 26.2% versus 15.3%,
P
=0.041, respectively). Survival rates were comparable. The limited available morphological results showed higher preserved patency rates after
DESs
than after
PTA
‐
BMS
at 1, 3, and 4 years of follow‐up.

Conclusions

Both clinical and morphological long‐term results after treatment of infrapopliteal lesions in patients with critical limb ischemia are improved with
DES
compared with
PTA
‐
BMS
.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00471289.
Differences in Short‐ and Long‐Term Mortality Associated With BMI Following Coronary Revascularization
Authors: Terada Tasuku , Forhan Mary , Norris Colleen M. , Qiu Weiyu , Padwal Raj , Sharma Arya M. , Nagendran Jayan , Johnson Jeffrey A. 
Published: April 2017

Background

The association between obesity and mortality risks following coronary revascularization is not clear. We examined the associations of BMI (kg/m
2
) with short‐, intermediate‐, and long‐term mortality following coronary artery bypass graft surgery (
CABG
) and percutaneous coronary intervention (
PCI
) in patients with different coronary anatomy risks and diabetes mellitus status.

Methods and Results

Data from the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry were analyzed. Using normal
BMI
(18.5–24.9) as a reference, multivariable‐adjusted hazard ratios for all‐cause mortality within 6 months, 1 year, 5 years, and 10 years were individually calculated for
CABG
and
PCI
with 4 prespecified
BMI
categories: overweight (25.0–29.9), obese class I (30.0–34.9), obese class
II
(35.0–39.9), and obese class
III
(≥40.0). The analyses were repeated after stratifying for coronary risks and diabetes mellitus status. The cohorts included 7560 and 30 258 patients for
CABG
and
PCI
, respectively. Following
PCI
, overall mortality was lower in patients with overweight and obese class I compared to those with normal
BMI
; however, 5‐ and 10‐year mortality rates were significantly higher in patients with obese class
III
with high‐risk coronary anatomy, which was primarily driven by higher mortality rates in patients without diabetes mellitus (5‐year adjusted hazard ratio, 1.78 [95%
CI
, 1.11–2.85] and 10‐year adjusted hazard ratio, 1.57 [95% CI, 1.02–2.43]). Following
CABG
, overweight was associated with lower mortality risks compared with normal
BMI
.

Conclusions

Overweight was associated with lower mortality following
CABG
and
PCI
. Greater long‐term mortality in patients with obese class
III
following
PCI
, especially in those with high‐risk coronary anatomy without diabetes mellitus, warrants further investigation.