bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma
Authors: Cohen Adam D. , Raje Noopur , Fowler Jessica A. , Mezzi Khalid , Scott Emma C. , Dhodapkar Madhav V. 
Published: October 2019

Abstract

The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell–dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell–associated changes during the evolution of multiple myeloma and provides an overview of T-cell–dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti–multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell–dependent immuno-oncology strategies in multiple myeloma.
A Solution to the Dilution: The Role for Biomarkers in Advanced Ovarian Cancer
Authors: Handley Katelyn F. , Sood Anil K. 
Published: October 2019

AbstractReliable approaches to predict residual disease prior to primary debulking surgery have been sought to further personalize surgical approaches. Reliance on molecular biomarkers alone in a complex clinical environment is challenging and algorithms that incorporate both molecular and clinical features may need to be considered.See related article by Heitz et al., p. 213
Radiation Responses of 2D and 3D Glioblastoma Cells: A Novel, 3D-specific Radioprotective Role of VEGF/Akt Signaling through Functional Activation of NHEJ
Authors: Gomez-Roman Natividad , Chong Ming Y , Chahal Sandeep K. , Caragher Seamus P. , Jackson Mark R. , Stevenson Katrina H. , Dongre Sidhartha A. , Chalmers Anthony J. 
Published: October 2019

AbstractGlioblastoma is resistant to conventional treatments and has dismal prognosis. Despite promising in vitro data, molecular targeted agents have failed to improve outcomes in patients, indicating that conventional two-dimensional (2D) in vitro models of GBM do not recapitulate the clinical scenario. Responses of primary glioblastoma stem-like cells (GSC) to radiation in combination with EGFR, VEGF, and Akt inhibition were investigated in conventional 2D cultures and a three-dimensional (3D) in vitro model of GBM that recapitulates key GBM clinical features. VEGF deprivation had no effect on radiation responses of 2D GSCs, but enhanced radiosensitivity of GSC cultures in 3D. The opposite effects were observed for EGFR inhibition. Detailed analysis of VEGF and EGF signaling demonstrated a radioprotective role of Akt that correlates with VEGF in 3D and with EGFR in 2D. In all cases, positive correlations were observed between increased radiosensitivity, markers of unrepaired DNA damage and persistent phospho-DNA-PK nuclear foci. Conversely, increased numbers of Rad51 foci were observed in radioresistant populations, indicating a novel role for VEGF/Akt signaling in influencing radiosensitivity by regulating the balance between nonhomologous end-joining and homologous recombination–mediated DNA repair. Differential activation of tyrosine kinase receptors in 2D and 3D models of GBM explains the well documented discrepancy between preclinical and clinical effects of EGFR inhibitors. Data obtained from our 3D model identify novel determinants and mechanisms of DNA repair and radiosensitivity in GBM, and confirm Akt as a promising therapeutic target in this cancer of unmet need.
Glutamine Deprivation Induces PD-L1 Expression via Activation of EGFR/ERK/c-Jun Signaling in Renal Cancer
Authors: Ma Guofeng , Liang Ye , Chen Yuanbin , Wang Liping , Li Dan , Liang Zhijuan , Wang Xiao , Tian Dongxu , Yang Xuecheng , Niu Haitao 
Published: October 2019

Abstract

The programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) pathway plays a pivotal role in the immune escape of tumors. Many tumor cells show “glutamine dependence.” However, the relationship between glutamine metabolism and PD-L1 expression has not been reported. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glutamine deprivation and recovery. Although PD-L1 expression differed in two renal cancer cell lines, both cell lines upregulated PD-L1 during glutamine deprivation, and the upregulated PD-L1 was restored to normal after glutamine recovery. Mechanistically, glutamine deprivation resulted in activation of EGFR signaling via ERKs 1 and 2 (ERK1/2) and c-Jun. In addition, treatment of renal cancer cells with EGF also induced PD-L1 expression and ERK1/2 phosphorylation. Finally, inhibitors of EGFR, ERK, and c-Jun all inhibited phosphorylation of c-Jun and downregulated PD-L1 expression induced by glutamine deprivation. Taken together, the data suggest that glutamine regulates the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer.

Implications:
This study reveals glutamine deprivation induces PD-L1 expression via activation of EGFR/ERK/c-Jun signaling in renal cancer and provides novel markers for the treatment of renal cancer.
Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia
Authors: Figliolini Federico , Ranghino Andrea , Grange Cristina , Cedrino Massimo , Tapparo Marta , Cavallari Claudia , Rossi Andrea , Togliatto Gabriele , Femminò Saveria , Gugliuzza Maria Vittoria , Camussi Giovanni , Brizzi Maria Felice 
Published: October 2019

Objectives:
Critical hindlimb ischemia is a severe consequence of peripheral artery disease. Surgical treatment does not prevent skeletal muscle impairment or improve long-term patient outcomes. The present study investigates the protective/regenerative potential and the mechanism of action of adipose stem cell-derived extracellular vesicles (ASC-EVs) in a mouse model of hindlimb ischemia.

Approach and Results:
We demonstrated that ASC-EVs exert a protective effect on muscle damage by acting both on tissue microvessels and muscle cells. The genes involved in muscle regeneration were up-regulated in the ischemic muscles of ASC-EV-treated animals. MyoD expression has also been confirmed in satellite cells. This was followed by a reduction in muscle function impairment in vivo. ASC-EVs drive myoblast proliferation and differentiation in the in vitro ischemia/reoxygenation model. Moreover, ASC-EVs have shown an anti-apoptotic effect both in vitro and in vivo. Transcriptomic analyses have revealed that ASC-EVs carry a variety of pro-angiogenic mRNAs, while proteomic analyses have demonstrated an enrichment of NRG1 (neuregulin 1). A NRG1 blocking antibody used in vivo demonstrated that NRG1 is relevant to ASC-EV-induced muscle protection, vascular growth, and recruitment of inflammatory cells. Finally, bioinformatic analyses on 18 molecules that were commonly detected in ASC-EVs, including mRNAs and proteins, confirmed the enrichment of pathways involved in vascular growth and muscle regeneration/protection.

Conclusions:
This study demonstrates that ASC-EVs display pro-angiogenic and skeletal muscle protective properties that are associated with their NRG1/mRNA cargo. We, therefore, propose that ASC-EVs are a useful tool for therapeutic angiogenesis and muscle protection.
Medical Therapy Utilization and Long-Term Outcomes Following Percutaneous Coronary Intervention
Authors: Xie Joe X. , Gunzburger Elise C. , Kaun Lindsay , Plomondon Mary E. , Barón Anna E. , Waldo Stephen W. , Virani Salim S. , Maddox Thomas M. , Mavromatis Kreton 
Published: October 2019

Background:
Optimal medical therapy is endorsed by national guidelines in the management of ischemic heart disease; however, few studies have examined its long-term utilization following percutaneous coronary intervention (PCI) and association with clinical outcomes. We sought to assess longitudinal trends in medical therapy use after PCI and its prognostic significance.

Methods and Results:

From the Veteran Affairs Clinical Assessment, Reporting, and Tracking System Program, we retrospectively identified 57 900 Veteran’s Affairs patients undergoing PCI from January 2005 to May 2014. Using prescription fill dates, the utilization of 4 classes of medical therapy including statins, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, P2Y12 inhibitors, and their composites were assessed at discharge, 6 months, 1, 3, and 5 years post-PCI. Multivariable Cox regression models were developed to assess the association between medical therapy status and major adverse cardiovascular events, defined as all-cause mortality, rehospitalization for myocardial infarction, rehospitalization for stroke, or repeat revascularization. At discharge following PCI, 58.3% of patients received all 4 classes of medical therapy. Utilization of statins, β-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased from 89%, 84.9%, and 72.2% on discharge, respectively, to 72.7%, 67.9%, and 57.9% at 5 years. Prescription refills of P2Y12 inhibitors declined from 96.5% on discharge to 28.3% at 5 years, driven by a large decline in P2Y12 inhibitor use after 1 year. Use of each class of medical therapy, and its composite use, was associated with a significant reduction in major adverse cardiovascular events at 5 years, with the largest effect size seen by the use of statins (HR, 0.77; 95% CI, 0.75–0.79;
P
<0.0001) and P2Y12 inhibitors (HR, 0.82; 95% CI, 0.79–0.85;
P
<0.0001).

Conclusions:
Consistent declines in medical therapy use following PCI were observed over time, which is associated with worse outcomes. Further efforts are needed to promote long-term adherence to secondary prevention therapies after revascularization.
Blood Pressure Normalization–Independent Cardioprotective Effects of Endogenous, Physical Activity–Induced αCGRP (α Calcitonin Gene-Related Peptide) in Chronically Hypertensive Mice
Authors: Skaria Tom , Mitchell Katharyn Jean , Vogel Olga , Wälchli Thomas , Gassmann Max , Vogel Johannes 
Published: October 2019

Rationale:
αCGRP (α calcitonin gene-related peptide), one of the strongest vasodilators, is cardioprotective in hypertension by reducing the elevated blood pressure.

Objective:
However, we hypothesize that endogenous, physical activity–induced αCGRP has blood pressure–independent cardioprotective effects in chronic hypertension.

Methods and Results:

Chronically hypertensive (one-kidney-one-clip surgery) wild-type and αCGRP
−/−
sedentary or voluntary wheel running mice were treated with vehicle, αCGRP, or the αCGRP receptor antagonist CGRP8-37. Cardiac function and myocardial phenotype were evaluated echocardiographically and by molecular, cellular, and histological analysis, respectively. Blood pressure was similar among all hypertensive experimental groups. Endogenous αCGRP limited pathological remodeling and heart failure in sedentary, chronically hypertensive wild-type mice. In these mice, voluntary wheel running significantly improved myocardial phenotype and function, which was abolished by CGRP8-37 treatment. In αCGRP
−/−
mice, αCGRP treatment, in contrast to voluntary wheel running, improved myocardial phenotype and function. Specific inhibition of proliferation and myofibroblast differentiation of primary, murine cardiac fibroblasts by αCGRP suggests involvement of these cells in αCGRP-dependent blunting of pathological cardiac remodeling.

Conclusions:
Endogenous, physical activity–induced αCGRP has blood pressure–independent cardioprotective effects and is crucial for maintaining cardiac function in chronic hypertension. Consequently, inhibiting endogenous αCGRP signaling, as currently approved for migraine prophylaxis, could endanger patients with hypertension.
Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart
Authors: Otani Kentaro , Tokudome Takeshi , Kamiya Chizuko A. , Mao Yuanjie , Nishimura Hirohito , Hasegawa Takeshi , Arai Yuji , Kaneko Mari , Shioi Go , Ishida Junji , Fukamizu Akiyoshi , Osaki Tsukasa , Nagai-Okatani Chiaki , Minamino Naoto , Ensho Takuya , Hino Jun , Murata Shunsuke , Takegami Misa , Nishimura Kunihiro , Kishimoto Ichiro , Miyazato Mikiya , Harada-Shiba Mariko , Yoshimatsu Jun , Nakao Kazuwa , Ikeda Tomoaki , Kangawa Kenji 
Published: October 2019

Background:
The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood.

Methods:
To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function.

Results:
In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy–lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin–nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti–interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice.

Conclusions:
These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system plays an important role in protecting the maternal heart from interleukin-6–induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.
Temporal Trends and Clinical Outcomes of Transcatheter Aortic Valve Replacement in Nonagenarians
Authors: Mentias Amgad , Saad Marwan , Desai Milind Y. , Horwitz Phillip A. , Rossen James D. , Panaich Sidakpal , Elbadawi Ayman , Qazi Abdul , Sorajja Paul , Jneid Hani , Kapadia Samir , London Barry , Vaughan Sarrazin Mary S. 
Published: October 2019

Background

Contemporary outcomes of transcatheter aortic valve replacement (
TAVR
) in nonagenarians are unknown.

Methods and Results

We identified 13 544 nonagenarians (aged 90–100 years) who underwent
TAVR
between 2012 and 2016 using Medicare claims. Generalized estimating equations were used to study the change in short‐term outcomes among nonagenarians over time. We compared outcomes between nonagenarians and non‐nonagenarians undergoing
TAVR
in 2016. A mixed‐effect multivariable logistic regression was performed to determine predictors of 30‐day mortality in nonagenarians in 2016. A center was defined as a
high‐volume center
if it performed ≥100
TAVR
procedures per year. After adjusting for changes in patients’ characteristics, risk‐adjusted 30‐day mortality declined in nonagenarians from 9.8% in 2012 to 4.4% in 2016 (
P
<0.001), whereas mortality for patients <90 years decreased from 6.4% to 3.5%. In 2016, 35 712
TAVR
procedures were performed, of which 12.7% were in nonagenarians. Overall, in‐hospital mortality in 2016 was higher in nonagenarians compared with younger patients (2.4% versus 1.7%,
P
<0.05) but did not differ in analysis limited to high‐volume centers (2.2% versus 1.7%; odds ratio: 1.33; 95%
CI
, 0.97–1.81;
P
=0.07). Important predictors of 30‐day mortality in nonagenarians included in‐hospital stroke (adjusted odds ratio [aOR]: 8.67; 95%
CI
, 5.03–15.00), acute kidney injury (
aOR
: 4.11; 95%
CI
, 2.90–5.83), blood transfusion (
aOR
: 2.66; 95%
CI
, 1.81–3.90), respiratory complications (
aOR
: 2.96; 95%
CI
, 1.52–5.76), heart failure (
aOR
: 1.86; 95%
CI
, 1.04–3.34), coagulopathy (
aOR
: 1.59; 95%
CI
, 1.12–2.26;
P
<0.05 for all).

Conclusions

Short‐term outcomes after
TAVR
have improved in nonagenarians. Several procedural complications were associated with increased 30‐day mortality among nonagenarians.
Lower Blood Pressure After Transcatheter or Surgical Aortic Valve Replacement is Associated with Increased Mortality
Authors: Lindman Brian R. , Goel Kashish , Bermejo Javier , Beckman Joshua , O'Leary Jared , Barker Colin M. , Kaiser Clayton , Cavalcante João L. , Elmariah Sammy , Huang Jian , Hickey Graeme L. , Adams David H. , Popma Jeffrey J. , Reardon Michael J. 
Published: October 2019

Background

Blood pressure (
BP
) guidelines for patients with aortic stenosis or a history of aortic stenosis treated with aortic valve replacement (
AVR
) match those in the general population, but this extrapolation may not be warranted.

Methods and Results

Among patients enrolled in the Medtronic intermediate, high, and extreme risk trials, we included those with a transcatheter
AVR
(n=1794) or surgical
AVR
(n=1103) who were alive at 30 days. The associations between early (average of discharge and 30 day post‐
AVR
) systolic
BP
(
SBP
) and diastolic
BP
(
DBP
) measurements and clinical outcomes between 30 days and 1 year were evaluated. Among 2897 patients, after adjustment, spline curves demonstrated an association between lower
SBP
(<120 mm Hg, representing 21% of patients) and
DBP
(<60 mm Hg, representing 30% of patients) and increased all‐cause and cardiovascular mortality and repeat hospitalization. These relationships were unchanged when patients with moderate‐to‐severe aortic regurgitation post‐
AVR
were excluded. After adjustment, compared with
DBP
60 to <80 mm Hg,
DBP
30 to <60 mm Hg was associated with increased all‐cause (adjusted hazard ratio 1.62, 95%
CI
1.23–2.14) and cardiovascular mortality (adjusted hazard ratio 2.13, 95%
CI
1.52–3.00), but
DBP
80 to <100 mm Hg was not. Similarly, after adjustment, compared with
SBP
120 to <150 mm Hg,
SBP
90 to <120 mm Hg was associated with increased all‐cause (adjusted hazard ratio 1.63, 95%
CI
1.21–2.21) and cardiovascular mortality (adjusted hazard ratio 1.81, 95%
CI
1.25–2.61), but
SBP
150 to <180 mm Hg was not.

Conclusions

Lower
BP
in the first month after transcatheter AVR or surgical AVR is common and associated with increased mortality and repeat hospitalization. Clarifying optimal
BP
targets in these patients ought to be a priority and may improve patient outcomes.

Clinical Trial Registration Information

URL:
http://www.clinicaltrials.gov
. Unique identifiers:
NCT
01586910,
NCT
01240902.
The Origins of Plurilateralism in International Trade Law
Authors: Lewis Meredith Kolsky 
Published: October 2019

Abstract
This article examines the historical experience with and understanding of plurilateral trade agreements throughout the General Agreement on Tariffs and Trade (GATT) and World Trade Organization (WTO) to better contextualise assessments of the continued viability of the single undertaking and the recent resurgence of plurilateralism in international trade law. Plurilateral agreements have been playing a significant role in international trade relations for the past fifty years. As such, the current wave of plurilateral agreements does not represent a sea change in approach to trade liberalisation, but rather a continuation of a process that originated many decades ago. Further, while the WTO agreements are multilateral in that they apply to all members, they can also be seen as plurilateral in that not all WTO members have identical responsibilities under such agreements. The article concludes that plurilateralism and multilateralism have much in common, and hence may be mutually supportive rather than binary choices.
Diversity of anatomical structure of tension wood among 242 tropical tree species
Authors: Ghislain Barbara , Engel Julien , Clair Bruno 
Published: October 2019

ABSTRACT
Angiosperm trees produce tension wood to actively control their vertical position. Tension wood has often been characterised by the presence of an unlignified inner fibre wall layer called the G-layer. Using this definition, previous reports indicate that only one-third of all tree species have tension wood with G-layers. Here we aim to (i) describe the large diversity of tension wood anatomy in tropical tree species, taking advantage of the recent understanding of tension wood anatomy and (ii) explore any link between this diversity and other ecological traits of the species. We sampled tension wood and normal wood in 432 trees from 242 species in French Guiana. The samples were observed using safranin and astra blue staining combined with optical microscopy. Species were assigned to four anatomical groups depending on the presence/absence of G-layers, and their degree of lignification. The groups were analysed for functional traits including wood density and light preferences. Eighty-six% of the species had G-layers in their tension wood which was lignified in most species, with various patterns of lignification. Only a few species did not have G-layers. We found significantly more species with lignified G-layers among shade-tolerant and shade-demanding species as well as species with a high wood density. Our results bring up-to-date the incidence of species with/without G-layers in the tropical lowland forest where lignified G-layers are the most common anatomy of tension wood. Species without G-layers may share a common mechanism with the bark motor taking over the wood motor. We discuss the functional role of lignin in the G-layer.
<p><strong><em>Begonia medicinalis</em> (Begoniaceae), a new species from Sulawesi, Indonesia</strong></p>
Authors: ARDI WISNU H. , ZUBAIR MUHAMMAD S. , - RAMADANIL , THOMAS DANIEL C. 
Published: October 2019

A new species of Begonia, Begonia medicinalis Ardi & D.C.Thomas, is described from Sulawesi, Indonesia. A photo plate and distribution map are provided. The new species is endemic to Sulawesi and belongs to Begonia section Petermannia.