bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of B-1 Cells Promotes Tumor Cell Killing in the Peritoneal Cavity
Authors: Haro Marcela A. , Dyevoich Allison M. , Phipps James P. , Haas Karen M. 
Published: September 2018

Abstract

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6′-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer–induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell–produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases.

Significance:
This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential.
See related commentary by Tripodo, p. 5
UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling
Authors: Dikshit Anushka , Jin Yingai J. , Degan Simone , Hwang Jihwan , Foster Matthew W. , Li Chuan-Yuan , Zhang Jennifer Y. 
Published: September 2018

Abstract
UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here, we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry–based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression, and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small-molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma.
Significance: These findings identify ubiquitin conjugase UBE2N and its variant partners as novel regulators of MAPK signaling and potential therapeutic targets in melanoma. Cancer Res; 78(22); 6462–72. ©2018 AACR.
Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof-of-Concept Study in Patients
Authors: Theruvath Ashok J. , Nejadnik Hossein , Muehe Anne M. , Gassert Felix , Lacayo Norman J. , Goodman Stuart B. , Daldrup-Link Heike E. 
Published: September 2018

Abstract

Purpose:
Osteonecrosis is a devastating complication of high-dose corticosteroid therapy in patients with cancer. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in osteonecrosis lesions.

Experimental Design:
In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MRI studies of nine hip joints of 7 patients with osteonecrosis before and after core decompression. Twenty-four to 48 hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron-labeled bone marrow cells were aspirated from the iliac crest, concentrated, and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation.

Results:
Iron-labeled cells could be detected in the access canal by a dark (negative) signal on T2-weighted MR images. T2* relaxation times of iron-labeled cell transplants were significantly lower compared with unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair.

Conclusions:
This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.
USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia
Authors: Jin Qi , Martinez Carlos A. , Arcipowski Kelly M. , Zhu Yixing , Gutierrez-Diaz Blanca T. , Wang Kenneth K. , Johnson Megan R. , Volk Andrew G. , Wang Feng , Wu Jian , Grove Charles , Wang Hui , Sokirniy Ivan , Thomas Paul M. , Goo Young Ah , Abshiru Nebiyu A. , Hijiya Nobuko , Peirs Sofie , Vandamme Niels , Berx Geert , Goosens Steven , Marshall Stacy A. , Rendleman Emily J. , Takahashi Yoh-hei , Wang Lu , Rawat Radhika , Bartom Elizabeth T. , Collings Clayton K. , Van Vlierberghe Pieter , Strikoudis Alexandros , Kelly Stephen , Ueberheide Beatrix , Mantis Christine , Kandela Irawati , Bourquin Jean-Pierre , Bornhauser Beat , Serafin Valentina , Bresolin Silvia , Paganin Maddalena , Accordi Benedetta , Basso Giuseppe , Kelleher Neil L. , Weinstock Joseph , Kumar Suresh , Crispino John D. , Shilatifard Ali , Ntziachristos Panagiotis 
Published: September 2018

Abstract

Purpose:
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes.

Experimental Design:
To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models.

Results:
We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo.

Conclusions:
These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma
Authors: Wei Yun , Maximov Victor , Morrissy Sorana A. , Taylor Michael D. , Pallas David C. , Kenney Anna Marie 
Published: September 2018

Abstract

Medulloblastomas, the most common malignant pediatric brain tumors, have been genetically defined into four subclasses, namely WNT-activated, Sonic Hedgehog (SHH)-activated, Group 3, and Group 4. Approximately 30% of medulloblastomas have aberrant SHH signaling and thus are referred to as SHH-activated medulloblastoma. The tumor suppressor gene TP53 has been recently recognized as a prognostic marker for patients with SHH-activated medulloblastoma; patients with mutant TP53 have a significantly worse outcome than those with wild-type TP53. It remains unknown whether p53 activity is impaired in SHH-activated, wild-type TP53 medulloblastoma, which is about 80% of the SHH-activated medulloblastomas. Utilizing the homozygous NeuroD2:SmoA1 mouse model with wild-type Trp53, which recapitulates human SHH-activated medulloblastoma, it was discovered that the endogenous Inhibitor 2 of Protein Phosphatase 2A (SET/I2PP2A) suppresses p53 function by promoting accumulation of phospho-MDM2 (S166), an active form of MDM2 that negatively regulates p53. Knockdown of I2PP2A in SmoA1 primary medulloblastoma cells reduced viability and proliferation in a p53-dependent manner, indicating the oncogenic role of I2PP2A. Importantly, this mechanism is conserved in the human medulloblastoma cell line ONS76 with wild-type TP53. Taken together, these findings indicate that p53 activity is inhibited by I2PP2A upstream of PP2A in SHH-activated and TP53-wildtype medulloblastomas.

Implications:
This study suggests that I2PP2A represents a novel therapeutic option and its targeting could improve the effectiveness of current therapeutic regimens for SHH-activated or other subclasses of medulloblastoma with wild-type TP53.
Prospective, Tissue-Specific Optimization of Ablation for Multiwavelet Reentry
Authors: Carrick Richard T. , Benson Bryce E. , Bates Jason H.T. , Spector Peter S. 
Published: September 2018

Background—
Treatment of multiwavelet reentry (MWR) remains difficult. We previously developed a metric, the fibrillogenicity index, to assess the propensity of homogeneous, 2-dimensional tissues to support MWR. In this study, we demonstrate a method by which fibrillogenicity index can be generalized to heterogeneous tissues and validate an algorithm for prospective, tissue-specific optimization of ablation to reduce MWR burden.

Methods and Results—

We used a computational model to simulate and measure the duration of MWR in tissues with heterogeneously distributed action potential durations and then assessed the relative efficacy of a variety of ablation strategies for reducing tissues’ ability to support MWR. We then derived and tested a strategy in which multiple linear lesions partially divided a fibrillogenic tissue into functionally equivalent subsections. The composite action potential duration of heterogeneous tissue was well approximated by an inverse sum of cellular action potential durations (
R
2
=0.82). Linear ablation more efficiently reduced MWR duration than branching ablation patterns and optimally reduced disease burden when positioned at a tissue’s functional (rather than geometric) center. The duration of MWR after application of prospective, individually optimized ablation sets fell within 4.4% (95% confidence interval, 3–5.8) of the predicted target.

Conclusions—
We think that this study presents a novel approach for (1) quantifying the extent of a tissue’s electric derangement, (2) prospectively determining the amount of ablation required to minimize the burden of MWR, and (3) predicting the most efficient distribution of these ablation lesions in tissue refractory to standard ablation strategies.
Relation of Left Ventricular Mass to Prognosis in Initially Asymptomatic Mild to Moderate Aortic Valve Stenosis
Authors: Gerdts Eva , Rossebø Anne B. , Pedersen Terje R. , Cioffi Giovanni , Lønnebakken Mai Tone , Cramariuc Dana , Rogge Barbara P. , Devereux Richard B. 
Published: September 2018

Background—
The prognostic importance of left ventricular (LV) mass in nonsevere asymptomatic aortic stenosis has not been documented in a large prospective study.

Methods and Results—

Cox regression analysis was used to assess the impact of echocardiographic LV mass on rate of major cardiovascular events in 1656 patients (mean age, 67 years; 39.6% women) with mild-to-moderate asymptomatic aortic stenosis participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. Patients were followed during 4.3 years of randomized treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily or placebo. At baseline, LV mass index was 45.9
+
14.9 g/m
2.7
, and peak aortic jet velocity was 3.09
+
0.54 m/s. During follow-up, 558 major cardiovascular events occurred. In Cox regression analyses, 1 SD (15 g/m
2.7
) higher baseline LV mass index predicted increases in hazards of 12% for major cardiovascular events, 28% for ischemic cardiovascular events, 34% for cardiovascular mortality, and 23% for combined total mortality and hospitalization for heart failure (all
P
<0.01), independent of confounders. In time-varying models, taking the progressive increase in LV mass index during follow-up into account, 1 SD higher in-study LV mass index was consistently associated with 13% to 61% higher hazard for cardiovascular events (all
P
<0.01), independent of age, sex, body mass index, valvuloarterial impedance, LV ejection fraction and concentricity, and the presence of concomitant hypertension.

Conclusions—
Higher LV mass index is independently associated with increased cardiovascular morbidity and mortality during progression of aortic stenosis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00092677.
Discordant Alternans as a Mechanism for Initiation of Ventricular Fibrillation In Vitro
Authors: Muñoz Laura M. , Gelzer Anna R. M. , Fenton Flavio H. , Qian Wei , Lin WeiYe , Gilmour Robert F. , Otani Niels F. 
Published: September 2018

Background
Ventricular tachyarrhythmias are often preceded by short sequences of premature ventricular complexes. In a previous study, a restitution‐based computational model predicted which sequences of stimulated premature complexes were most likely to induce ventricular fibrillation in canines in vivo. However, the underlying mechanism, based on discordant‐alternans dynamics, could not be verified in that study. The current study seeks to elucidate the mechanism by determining whether the spatiotemporal evolution of action potentials and initiation of ventricular fibrillation in in vitro experiments are consistent with model predictions.

Methods and Results

Optical mapping voltage signals from canine right‐ventricular tissue (n=9) were obtained simultaneously from the entire epicardium and endocardium during and after premature stimulus sequences. Model predictions of action potential propagation along a 1‐dimensional cable were developed using action potential duration versus diastolic interval data. The model predicted sign‐change patterns in action potential duration and diastolic interval spatial gradients with posterior probabilities of 91.1%, and 82.1%, respectively. The model predicted conduction block with 64% sensitivity and 100% specificity. A generalized estimating equation logistic‐regression approach showed that model‐prediction effects were significant for both conduction block (
P
<1×10
−15
, coefficient 44.36) and sustained ventricular fibrillation (
P
=0.0046, coefficient, 1.63) events.

Conclusions
The observed sign‐change patterns favored discordant alternans, and the model successfully identified sequences of premature stimuli that induced conduction block. This suggests that the relatively simple discordant‐alternans‐based process that led to block in the model may often be responsible for ventricular fibrillation onset when preceded by premature beats. These observations may aid in developing improved methods for anticipating block and ventricular fibrillation.
Advanced Practice Provider Versus Physician‐Only Outpatient Follow‐Up After Acute Myocardial Infarction
Authors: Rymer Jennifer A. , Chen Anita Y. , Thomas Laine , Stafford Judith , Enriquez Jonathan R. , Goyal Abhinav , Peterson Eric D. , Wang Tracy Y. 
Published: September 2018

Background

Physician shortages and reimbursement changes have led to greater use of advanced practice providers (
APP
s). Prevalence of and outcomes associated with
APP
care following myocardial infarction are unknown.

Methods and Results

We examined outpatient cardiology or primary care visits within 90 days post‐myocardial infarction among 29 477 Medicare‐insured patients aged ≥65 years from 364 hospitals in Acute Coronary Treatment Intervention Outcomes Network Registry. We compared medication adherence, all‐cause readmission risk, mortality, and major adverse cardiovascular events between patients seen by
APP
s versus physicians only. Overall, 11% of myocardial infarction patients were treated by an
APP
. Patients seen by
APP
s were more likely to have diabetes mellitus (37% versus 33%) and heart failure (20% versus 16%), be discharged to a nursing facility (21% versus 13%) and had more outpatient visits within 90 days post‐discharge (median 6 versus 5,
P
<0.01 for all) than those seen by physicians only. Adherence to evidence‐based medications (adjusted odds ratio, 0.98; 95% confidence interval, 0.89–1.08) and readmission risks (adjusted hazard ratio, 1.11; 95% confidence interval, 0.99–1.26) were similar between patients seen by
APP
s versus physicians only. Risks of 90‐day mortality (adjusted hazard ratio, 1.18; 95% confidence interval, 0.98–1.42) and major adverse cardiovascular events (adjusted hazard ratio, 1.06; 95% confidence interval, 0.90–1.23) were also similar between patients seen by
APP
s versus physicians only.

Conclusions

APP
s were likely used to provide more frequent monitoring of high‐risk post‐
MI
patients. Medication adherence, readmission risk, mortality, and major adverse cardiovascular events did not differ substantially between patients seen by physician‐
APP
teams than those seen by physicians only.
Phase Angle as a Biomarker for Frailty and Postoperative Mortality: The BICS Study
Authors: Mullie Louis , Obrand Alexandrine , Bendayan Melissa , Trnkus Amanda , Ouimet Marie‐Claude , Moss Emmanuel , Chen‐Tournoux Annabel , Rudski Lawrence G. , Afilalo Jonathan 
Published: September 2018

Background
Phase angle (PA) is a bioimpedance measurement that is determined lean body mass and hydration status. Patients with low PA values are more likely to be frail, sarcopenic, or malnourished. Previous work has shown that low PA predicts adverse outcomes after cardiac surgery, but the effect of PA on survival has not previously been assessed in this setting.

Methods and Results

The BICS (Bioimpedance in Cardiac Surgery) study recruited 277 patients undergoing major cardiac surgery at 2 university‐affiliated hospitals in Montreal, QC, Canada. Bioimpedance measurements as well as frailty and nutritional assessments were performed preoperatively. The primary outcome was all‐cause mortality. Secondary outcomes were 30‐day mortality, postoperative morbidity, and hospital length of stay. There were 10 deaths at 1 month of follow‐up and 16 deaths at 12 months of follow‐up.
PA
was associated with age, sex, body mass index, comorbidities, and frailty, as measured by the Short Physical Performance Battery and Fried scales. After adjusting for Society of Thoracic Surgeons–predicted mortality, lower
PA
was associated with higher mortality at 1 month (adjusted odds ratio, 3.57 per 1° decrease in
PA
; 95% confidence interval, 1.35–9.47) and at 12 months (adjusted odds ratio, 3.03 per 1° decrease in
PA
; 95% confidence interval, 1.30–7.09), a higher risk of overall morbidity (adjusted hazard ratio, 2.51 per 1° decrease in
PA
; 95% confidence interval, 1.32–4.75), and a longer hospital length of stay (adjusted β, 4.8 days per 1° decrease in
PA
; 95% confidence interval, 1.3–8.2 days).

Conclusions

Low
PA
is associated with frailty and is predictive of mortality, morbidity, and length of stay after major cardiac surgery. Further work is needed to determine the responsiveness of
PA
to interventions aimed at reversing frailty.
Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction
Authors: Motloch Lukas J. , Cacheux Marine , Ishikawa Kiyotake , Xie Chaoqin , Hu Jun , Aguero Jaume , Fish Kenneth M. , Hajjar Roger J. , Akar Fadi G. 
Published: September 2018

Background

SERCA
2a gene transfer (
GT
) improves mechano‐electrical function in animal models of nonischemic heart failure Whether
SERCA
2a
GT
reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.
SERCA
2a
GT
following myocardial infarction (
MI
).

Methods and Results

Pigs developed mechanical dysfunction 1 month after anterior
MI
, at which point they received intracoronary adeno‐associated virus serotype 1.
SERCA
2a (
MI
+
SERCA
2a) or saline (
MI
) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo
ECG
‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (
AP
) mapping in controls,
MI
, and
MI
+
SERCA
2a preparations. In vivo
ECG
measurements revealed comparable
QT
durations between groups. In contrast, prolonged
QRS
duration and increased frequency of R′ waves were present in
MI
but not
MI
+
SERCA
2a pigs relative to controls.
SERCA
2a
GT
reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from
MI
but not
MI
+
SERCA
2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in
MI
versus
MI
+
SERCA
2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in
MI
+
SERCA
2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather,
SERCA
2a
GT
decreased phosphoactive
CAMKII
‐delta levels by >50%, leading to improved excitability at fast rates.

Conclusions

SERCA
2a
GT
increases conduction velocity reserve, likely by preventing
CAMKII
overactivation. Our findings suggest a primary effect of
SERCA
2a
GT
on myocardial excitability, independent of altered mechanical function.