bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors
Authors: Allegrezza Michael J. , Rutkowski Melanie R. , Stephen Tom L. , Svoronos Nikolaos , Tesone Amelia J. , Perales-Puchalt Alfredo , Nguyen Jenny M. , Sarmin Fahmida , Sheen Mee R. , Jeng Emily K. , Tchou Julia , Wong Hing C. , Fiering Steven N. , Conejo-Garcia Jose R. 
Published: March 2016

Abstract
Many signal transduction inhibitors are being developed for cancer therapy target pathways that are also important for the proper function of antitumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T-cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro. However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor rechallenge. Our work identifies a clinically actionable approach to overcome the T-cell–suppressive effects of MEK inhibitors and illustrates how to reconcile the deficiencies of signal transduction inhibitors, which impede desired immunologic effects in vivo. Cancer Res; 76(9); 2561–72. ©2016 AACR.
Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1
Authors: Zhang Xiaoying , Guo Cai , Wu Xiwei , Li Arthur X. , Liu Limin , Tsark Walter , Dammann Reinhard , Shen Hui , Vonderfecht Steven L. , Pfeifer Gerd P. 
Published: March 2016

Abstract
The tumor suppressor gene RASSF1A is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologs of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic inasmuch as Hippo pathway components are rarely mutated in tumors. Here we show that Rassf1a homozygous knockout mice develop liver tumors. However, heterozygous deletion of Sav1 or codeletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A-binding partners by mass spectrometry identified the Hippo kinases MST1, MST2, and the oncogenic IκB kinase TBK1 as the most enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a−/− livers was more deregulated than that of Sav1+/− livers, and the transcriptome of Rassf1a−/−, Sav1+/− livers was similar to that of Rassf1a−/− mice. We found that the levels of TBK1 protein were substantially upregulated in livers lacking Rassf1a. Furthermore, transcripts of several β-tubulin isoforms were increased in the Rassf1a-deficient livers presumably reflecting a role of RASSF1A as a microtubule-stabilizing protein. In human liver cancer, RASSF1A frequently undergoes methylation at the promoter but this was not observed for MST1, MST2, or SAV1. Our results suggest a multifactorial role of RASSF1A in suppression of liver carcinogenesis. Cancer Res; 76(9); 2824–35. ©2016 AACR.
Dietary Patterns and Plasma Sex Hormones, Prolactin, and Sex Hormone–Binding Globulin in Premenopausal Women
Authors: Hirko Kelly A. , Spiegelman Donna , Barnett Junaidah B. , Cho Eunyoung , Willett Walter C. , Hankinson Susan E. , Eliassen A. Heather 
Published: March 2016

Abstract
Background: Sex hormones are important for breast cancer, but it is unclear whether dietary patterns influence hormone concentrations.
Methods: Dietary pattern adherence scores for the alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Alternative Healthy Eating Index (AHEI) were calculated from semiquantitative food frequency questionnaires administered in 1995 and 1999. Premenopausal plasma concentrations of sex hormones were measured in samples collected in 1996 to 1999. We used generalized linear models to calculate geometric mean hormone concentrations across quartiles of dietary pattern scores among 1,990 women in the Nurses' Health Study II.
Results: We did not observe significant associations between sex hormone concentrations and the DASH pattern and only one suggestive association between follicular estrone concentrations and the aMED pattern [top vs. bottom quartile −4.4%, 95% confidence interval (CI), −10.6% to 2.1%; Ptrend = 0.06]. However, women in the top versus bottom quartile of AHEI score had lower concentrations of follicular (−9.1%; 95% CI, −16.1% to −1.4%; Ptrend = 0.04) and luteal (−7.5%; 95% CI, −13.6% to −0.9%; Ptrend = 0.01) estrone, luteal-free (−9.3%; 95% CI, −16.8% to −1.1%; Ptrend = 0.01) and total (−6.7 %; 95% CI, −14.3% to 1.5%; Ptrend = 0.04) estradiol, follicular estradiol (−14.2%; 95% CI, −24.6% to −2.4%; Ptrend = 0.05), and androstenedione (−7.8%; 95% CI, −15.4% to 0.4%; Ptrend = 0.03).
Conclusion: Diet quality measured by the AHEI is inversely associated with premenopausal estrogen concentrations. Given that we did not observe similar associations with the aMED or DASH patterns, our findings should be interpreted with caution.
Impact: Given the role of estrogens in breast cancer etiology, our findings add to the substantial evidence on the benefits of adhering to a healthy diet. Cancer Epidemiol Biomarkers Prev; 25(5); 791–8. ©2016 AACR.
Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 In Vivo
Authors: Dibra Denada , Mitra Abhisek , Newman Melisa , Xia Xueqing , Cutrera Jeffry J. , Gagea Mihai , Kleinerman Eugenie S. , Lozano Guillermina , Li Shulin 
Published: March 2016

Abstract
Purpose: p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. IL27 is an important immunomodulatory cytokine, but its impact on mutant p53-driven tumorigenesis has not been reported.
Experimental Design: IL27RA−/− mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA−/−p53H/+ and IL27RA−/−p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via IHC and Western blot analysis.
Results: This study unraveled that lack of IL27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL27 signaling is closely associated with increased mutant p53 stability in vivo from early age.
Conclusions: These results suggest that IL27 signaling modulates the oncogenic properties of mutant p53 in vivo. Clin Cancer Res; 22(15); 3876–83. ©2016 AACR.
Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms
Authors: Pratz Keith W. , Koh Brian D. , Patel Anand G. , Flatten Karen S. , Poh Weijie , Herman James G. , Dilley Robert , Harrell Maria I. , Smith B. Douglas , Karp Judith E. , Swisher Elizabeth M. , McDevitt Michael A. , Kaufmann Scott H. 
Published: March 2016

Abstract
Purpose: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo.
Experimental Design: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays.
Results: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage–induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes.
Conclusions: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894–902. ©2016 AACR.
Unplugging JAK/STAT in Chronic Myelomonocytic Leukemia
Authors: Solary Eric 
Published: March 2016

Abstract
The proliferative component of chronic myelomonocytic leukemia, related to an increased sensitivity of myeloid progenitors to granulocyte macrophage–colony stimulating factor, suggests dedicated therapeutic approaches. In this issue, ruxolitinib, a JAK1 and -2 inhibitory drug, is shown to induce objective responses in chronic myelomonocytic leukemia patients. Clin Cancer Res; 22(15); 3707–9. ©2016 AACR.
See related article by Padron et al., p. 3746
Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma
Authors: Matsushita Hirokazu , Sato Yusuke , Karasaki Takahiro , Nakagawa Tohru , Kume Haruki , Ogawa Seishi , Homma Yukio , Kakimi Kazuhiro 
Published: March 2016

Abstract
Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or β2-microglobulin(β2M) revealed that an A-neohi/HLA-Ahi or ABC-neohi/β2Mhi phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules [CD8A, perforin (PRF1) and granzyme A (GZMA)], however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PD-L2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high-priority targets for modulating immune responses in patients with ccRCC. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity. Cancer Immunol Res; 4(5); 463–71. ©2016 AACR.
Metabolite Profiles Predict Acute Kidney Injury and Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Elmariah Sammy , Farrell Laurie A. , Daher Maureen , Shi Xu , Keyes Michelle J. , Cain Carolyn H. , Pomerantsev Eugene , Vlahakes Gus J. , Inglessis Ignacio , Passeri Jonathan J. , Palacios Igor F. , Fox Caroline S. , Rhee Eugene P. , Gerszten Robert E. 
Published: March 2016

Background

Acute kidney injury (
AKI
) occurs commonly after transcatheter aortic valve replacement (
TAVR
) and is associated with markedly increased postoperative mortality. We previously identified plasma metabolites predictive of incident chronic kidney disease, but whether metabolite profiles can identify those at risk of
AKI
is unknown.

Methods and Results

We performed liquid chromatography–mass spectrometry–based metabolite profiling on plasma from patients undergoing
TAVR
and subjects from the community‐based Framingham Heart Study (N=2164).
AKI
was defined by using the Valve Academic Research Consortium‐2 criteria. Of 44 patients (mean age 82±9 years, 52% female) undergoing
TAVR
, 22 (50%) had chronic kidney disease and 9 (20%) developed
AKI
. Of 85 metabolites profiled, we detected markedly concordant cross‐sectional metabolic changes associated with chronic kidney disease in the hospital‐based
TAVR
and Framingham Heart Study cohorts. Baseline levels of 5‐adenosylhomocysteine predicted
AKI
after
TAVR
, despite adjustment for baseline glomerular filtration rate (odds ratio per 1‐
SD
increase 5.97, 95%
CI
1.62–22.0;
P
=0.007). Of the patients who had
AKI
, 6 (66.7%) subsequently died, compared with 3 (8.6%) deaths among those patients who did not develop
AKI
(
P
=0.0008) over a median follow‐up of 7.8 months. 5‐adenosylhomocysteine was predictive of all‐cause mortality after
TAVR
(hazard ratio per 1‐
SD
increase 2.96, 95%
CI
1.33–6.58;
P
=0.008), independent of baseline glomerular filtration rate.

Conclusions

In an elderly population with severe aortic stenosis undergoing
TAVR
, metabolite profiling improves the prediction of AKI. Given the multifactorial nature of
AKI
after
TAVR
, metabolite profiles may identify those patients with reduced renal reserve.
Prospective Association Between the Dietary Inflammatory Index and Cardiovascular Diseases in the SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) Cohort
Authors: Neufcourt Lola , Assmann Karen E. , Fezeu Léopold K. , Touvier Mathilde , Graffouillère Laurie , Shivappa Nitin , Hébert James R. , Wirth Michael D. , Hercberg Serge , Galan Pilar , Julia Chantal , Kesse‐Guyot Emmanuelle 
Published: March 2016

Background
Cardiovascular diseases (CVD) are the leading cause of death in the world, and diet plays a major role in CVD incidence, especially through lipid oxidation mechanisms. This, in turn, leads to tissue inflammation and formation of atheromatous plaques.

Methods and Results

Our objective was to evaluate the association between the inflammatory potential of the diet and the incidence of overall CVD or its subclasses. We included 7743 participants from the Supplémentation en Vitamines et Minéraux AntioXydants (SU.VI.MAX) cohort. All cardiovascular events were recorded using self‐reported information or clinical visits, and were validated. The dietary inflammatory index (DII) was computed using repeated 24‐hour dietary records (mean=9.5±3.4 records/subject). Hazard ratio and 95% CI for outcomes (CVD and subclasses) were estimated across sex‐specific quartiles of the DII using Cox proportional hazard models. A total of 292 cardiovascular events were recorded and validated during an average of 11.4 years of follow‐up: 93 myocardial infarctions, 58 strokes, 128 angina pectoris and revascularization interventions, and 13 sudden deaths. When considering CVD subclasses, a diet with pro‐inflammatory properties, as expressed by higher DII scores, was significantly associated with a higher risk of myocardial infarction (hazard ratio
Quartile 4 versus Quartile 1
=2.24, 95% CI: 1.08–4.67). No significant association was observed between the DII score and stroke or both angina pectoris and revascularization intervention.

Conclusions
A pro‐inflammatory diet, as measured by a higher DII score, was prospectively associated with a higher risk of myocardial infarction. Promotion of a diet exhibiting anti‐inflammatory properties may help prevent myocardial infarctions.
Incidence and In‐Hospital Mortality of Acute Kidney Injury (AKI) and Dialysis‐Requiring AKI (AKI‐D) After Cardiac Catheterization in the National Inpatient Sample
Authors: Brown Jeremiah R. , Rezaee Michael E. , Nichols Elizabeth L. , Marshall Emily J. , Siew Edward D. , Matheny Michael E. 
Published: March 2016

Background

Acute kidney injury (
AKI
) and dialysis‐requiring
AKI
(
AKI
‐D) are common, serious complications of cardiac procedures.

Methods and Results

We evaluated 3 633 762 (17 765 214 weighted population) cardiac catheterization or percutaneous coronary intervention (
PCI
) hospital discharges from the nationally representative National Inpatient Sample to determine annual population incidence rates for
AKI
and
AKI
‐D in the United States from 2001 to 2011. Odds ratios for both conditions and associated in‐hospital mortality were calculated for each year in the study period using multiple logistic regression. The number of cardiac catheterization or
PCI
cases resulting in
AKI
rose almost 3‐fold from 2001 to 2011. The adjusted odds of
AKI
and
AKI
‐D per year among cardiac catheterization and
PCI
patients were 1.11 (95%
CI
: 1.10–1.12) and 1.01 (95%
CI
: 0.99–1.02), respectively. Most importantly, in‐hospital mortality significantly decreased from 2001 to 2011 for
AKI
(19.6–9.2%) and
AKI
‐D (28.3–19.9%), whereas odds of associated in‐hospital mortality were 0.50 (95%
CI
: 0.45–0.56) and 0.70 (95%
CI
: 0.55–0.93) in 2011 versus 2001, respectively. The population‐attributable risk of mortality for
AKI
and
AKI
‐D was 25.8% and 3.8% in 2001 and 41.1% and 6.5% in 2011, respectively. Males and females had similar patterns of
AKI
increase, although males outpaced females.

Conclusions

The Incidence of
AKI
among cardiac catheterization and
PCI
patients has increased sharply in the United States, and this should be addressed by implementing prevention strategies. However, mortality has significantly declined, suggesting that efforts to manage
AKI
and
AKI
‐D after cardiac catheterization and
PCI
have reduced mortality.
Ultrathin Strut Biodegradable Polymer Sirolimus‐Eluting Stent Versus Durable‐Polymer Everolimus‐Eluting Stent for Percutaneous Coronary Revascularization: 2‐Year Results of the BIOSCIENCE Trial
Authors: Zbinden Rainer , Piccolo Raffaele , Heg Dik , Roffi Marco , Kurz David J. , Muller Olivier , Vuilliomenet André , Cook Stéphane , Weilenmann Daniel , Kaiser Christoph , Jamshidi Peiman , Franzone Anna , Eberli Franz , Jüni Peter , Windecker Stephan , Pilgrim Thomas 
Published: March 2016

Background

No data are available on the long‐term performance of ultrathin strut biodegradable polymer sirolimus‐eluting stents (
BP
‐
SES
). We reported 2‐year clinical outcomes of the
BIOSCIENCE
(Ultrathin Strut Biodegradable Polymer Sirolimus‐Eluting Stent Versus Durable Polymer Everolimus‐Eluting Stent for Percutaneous Coronary Revascularisation) trial, which compared
BP
‐
SES
with durable‐polymer everolimus‐eluting stents (
DP
‐
EES
) in patients undergoing percutaneous coronary intervention.

Methods and Results

A total of 2119 patients with minimal exclusion criteria were assigned to treatment with
BP
‐
SES
(n=1063) or
DP
‐
EES
(n=1056). Follow‐up at 2 years was available for 2048 patients (97%). The primary end point was target‐lesion failure, a composite of cardiac death, target‐vessel myocardial infarction, or clinically indicated target‐lesion revascularization. At 2 years,
target‐lesion failure
occurred in 107 patients (10.5%) in the
BP
‐
SES
arm and 107 patients (10.4%) in the
DP
‐
EES
arm (risk ratio [
RR
] 1.00, 95%
CI
0.77–1.31,
P
=0.979). There were no significant differences between
BP
‐
SES
and
DP
‐
EES
with respect to cardiac death (
RR
1.01, 95%
CI
0.62–1.63,
P
=0.984), target‐vessel myocardial infarction (
RR
0.91, 95%
CI
0.60–1.39,
P
=0.669),
target‐lesion revascularization
(
RR
1.17, 95%
CI
0.81–1.71,
P
=0.403), and definite stent thrombosis (
RR
1.38, 95%
CI
0.56–3.44,
P
=0.485). There were 2 cases (0.2%) of definite very late stent thrombosis in the
BP
‐
SES
arm and 4 cases (0.4%) in the
DP
‐
EES
arm (
P
=0.423). In the prespecified subgroup of patients with
ST
‐segment elevation myocardial infarction,
BP
‐
SES
was associated with a lower risk of
target‐lesion failure
compared with
DP
‐
EES
(
RR
0.48, 95%
CI
0.23–0.99,
P
=0.043,
P
interaction
=0.026).

Conclusions

Comparable safety and efficacy profiles of
BP
‐
SES
and
DP
‐
EES
were maintained throughout 2 years of follow‐up.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
01443104.
Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning
Authors: Cuomo Ornella , Pignataro Giuseppe , Sirabella Rossana , Molinaro Pasquale , Anzilotti Serenella , Scorziello Antonella , Sisalli Maria Josè , Di Renzo Gianfranco , Annunziato Lucio 
Published: March 2016

Background and Purpose—
The small ubiquitin-like modifier (SUMO), a ubiquitin-like protein involved in posttranslational protein modifications, is activated by several conditions, such as heat stress, hypoxia, and hibernation and confers neuroprotection. Sumoylation enzymes and substrates are expressed also at the plasma membrane level. Among the numerous plasma membrane proteins controlling ionic homeostasis during cerebral ischemia, 1 of the 3 brain sodium/calcium exchangers (NCX3), exerts a protective role during ischemic preconditioning. In this study, we evaluated whether NCX3 is a target for sumoylation and whether this posttranslational modification participates in ischemic preconditioning-induced neuroprotection. To test these hypotheses, we analyzed (1) SUMO1 conjugation pattern after ischemic preconditioning; (2) the effect of SUMO1 knockdown on the ischemic damage after transient middle cerebral artery occlusion and ischemic preconditioning, (3) the possible interaction between SUMO1 and NCX3 and (4) the molecular determinants of NCX3 sequence responsible for sumoylation.

Methods—
Focal brain ischemia and ischemic preconditioning were induced in rats by middle cerebral artery occlusion. SUMOylation was evaluated by western blot and immunohistochemistry. SUMO1 and NCX3 interaction was analyzed by site-directed mutagenesis and immunoprecipitation assay.

Results—
We found that (1) SUMO1 knockdown worsened ischemic damage and reduced the protective effect of preconditioning; (2) SUMO1 bound to NCX3 at lysine residue 590, and its silencing increased NCX3 degradation; and (3) NCX3 sumoylation participates in SUMO1 protective role during ischemic preconditioning. Thus, our results demonstrate that NCX3 sumoylation confers additional neuroprotection in ischemic preconditioning.

Conclusions—
Finally, this study suggests that NCX3 sumoylation might be a new target to enhance ischemic preconditioning-induced neuroprotection.