bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microparticle-induced vascular injury in mice following decompression is inhibited by hyperbaric oxygen: effects on microparticles and interleukin-1β
Authors: Thom Stephen R. , Bhopale Veena M. , Yang Ming 
Published: February 2019

Hyperbaric oxygen (HBO2) became a mainstay for treating decompression sickness (DCS) because bubbles are associated with the disorder. Inflammatory processes including production of circulating microparticles (MPs) have now been shown to occur with DCS, leading to questions regarding pathophysiology and the role for HBO2. We investigated effects of HBO2on mice exposed to 790 kPa air pressure for 2 h, which triggers elevations of MPs ladened with interleukin (IL)-1β that cause diffuse vascular injuries. Exposure to 283 kPa O2(HBO2) inhibited MP elevations at 2 h postdecompression by 50% when applied either prophylactically or as treatment after decompression, and the MP number remained suppressed for 13 h in the prophylactic group. Particle content of IL-1β at 2 h postdecompression was 139.3 ± 16.2 [means ± SE; n = 11, P < 0.05) pg/million MPs vs. 8.2 ± 1.0 ( n = 15) in control mice, whereas it was 31.5 ± 6.1 ( n = 6, not significant vs. control (NS)] in mice exposed to HBO2prophylactically, and 16.6 ± 6.3 ( n = 7, NS) when HBO2was administered postdecompression. IL-1β content in MPs was similar in HBO2-exposed mice at 13 h postdecompression. HBO2also inhibited decompression-associated neutrophil activation and diffuse vascular leak. Immunoprecipitation studies demonstrated that HBO2inhibits high-pressure-mediated neutrophil nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome oligomerization. Furthermore, MPs isolated from decompressed mice cause vascular injuries when injected into naïve mice, but if decompressed mice were exposed to HBO2before MP harvest, vascular injuries were inhibited. We conclude that HBO2impedes high-pressure/decompression-mediated inflammatory events by inhibiting inflammasome formation and IL-1β production.NEW & NOTEWORTHY High pressure/decompression causes vascular damage because it stimulates production of microparticles that contain high concentrations of interleukin-1β, and hyperbaric oxygen can prevent injuries.
Cytochrome c Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer
Authors: Kumar Rahul , Bhat Tariq A. , Walsh Elise M. , Chaudhary Ajay K. , O'Malley Jordan , Rhim Johng S. , Wang Jianmin , Morrison Carl D. , Attwood Kristopher , Bshara Wiam , Mohler James L. , Yadav Neelu , Chandra Dhyan 
Published: February 2019

Abstract

Although African-American (AA) patients with prostate cancer tend to develop greater therapeutic resistance and faster prostate cancer recurrence compared with Caucasian-American (CA) men, the molecular mechanisms of this racial prostate cancer disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and prostate cancer aggressiveness in AA men. In AA prostate cancer cells, decreased nuclear accumulation of nuclear respiration factor 1 (Nrf1) and its subsequent loss of binding to the cytochrome c promoter mediated cytochrome c deficiency. The activation of cellular Myc (c-Myc) and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacologic inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to cytochrome c promoter, cytochrome c expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA prostate cancer cells contributed to defective cytochrome c release and increased resistance to apoptosis, indicating that restoration of cytochrome c alone may be insufficient to induce effective apoptosis. Cytochrome c deficiency promoted the acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas cytochrome c restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA prostate cancer cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring cytochrome c may overcome therapeutic resistance and prostate cancer aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in prostate cancer racial disparity.

Significance:
Mechanistic insights on prostate cancer health disparity among American men provide novel approaches to restore mitochondrial function, which can address therapeutic resistance and aggressiveness in African-American men with prostate cancer.
MDH1 and MPP7 Regulate Autophagy in Pancreatic Ductal Adenocarcinoma
Authors: New Maria , Van Acker Tim , Sakamaki Jun-Ichi , Jiang Ming , Saunders Rebecca E. , Long Jaclyn , Wang Victoria M.-Y. , Behrens Axel , Cerveira Joana , Sudhakar Padhmanand , Korcsmaros Tamas , Jefferies Harold B.J. , Ryan Kevin M. , Howell Michael , Tooze Sharon A. 
Published: February 2019

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival. Validation of two promising candidates, MPP7 (MAGUK p55 subfamily member 7, a scaffolding protein involved in cell–cell contacts) and MDH1 (cytosolic Malate dehydrogenase 1), revealed their role in early stages of autophagy during autophagosome formation. MPP7 was involved in the activation of YAP1 (a transcriptional coactivator in the Hippo pathway), which in turn promoted autophagy, whereas MDH1 was required for maintenance of the levels of the essential autophagy initiator serine–threonine kinase ULK1, and increased in the activity upon induction of autophagy. Our results provide a possible explanation for how autophagy is regulated by MPP7 and MDH1, which adds to our understanding of autophagy regulation in PDAC.

Significance:
This study identifies and characterizes MPP7 and MDH1 as novel regulators of autophagy, which is thought to be responsible for pancreatic cancer cell survival.
BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells
Authors: Atay Cigdem , Kwak Taekyoung , Lavilla-Alonso Sergio , Donthireddy Laxminarasimha , Richards Allison , Moberg Valerie , Pilon-Thomas Shari , Schell Michael , Messina Jane L. , Rebecca Vito W. , Xiao Min , Tan Jiufeng , Zhang Gao , Weber Jeffrey S. , Herlyn Meenhard , Sarnaik Amod A. , Gabrilovich Dmitry I. 
Published: February 2019

Abstract

Purpose:
BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi.

Experimental Design:
Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT.

Results:
Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment.

Conclusions:
BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.
See related commentary by Goff and Rosenberg, p. 2682
A Variant of a Killer Cell Immunoglobulin-like Receptor Is Associated with Resistance to PD-1 Blockade in Lung Cancer
Authors: Trefny Marcel P. , Rothschild Sacha I. , Uhlenbrock Franziska , Rieder Dietmar , Kasenda Benjamin , Stanczak Michal A. , Berner Fiamma , Kashyap Abhishek S. , Kaiser Monika , Herzig Petra , Poechtrager Severin , Thommen Daniela S. , Geier Florian , Savic Spasenija , Jermann Philip , Alborelli Ilaria , Schaub Stefan , Stenner Frank , Früh Martin , Trajanoski Zlatko , Flatz Lukas , Mertz Kirsten D. , Zippelius Alfred , Läubli Heinz 
Published: February 2019

Abstract

Purpose:
PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways.

Experimental Design:
Peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and nonresponders to treatment. Findings were confirmed in additional cohorts of patients with NSCLC receiving immune checkpoint blockade.

Results:
We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR, 1.72; 95% confidence interval, 1.10–2.68; P = 0.017). No relationship was seen in cohorts of patients with NSCLC who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be due to NK-cell dysfunction.

Conclusions:
We identified an association of the KIR3DS1 allelic variant with response to PD-1–targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. Although the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive markers for response to PD-1–targeted immunotherapy.
Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells
Authors: Zhang Ping , Raju Jyothy , Ullah Md Ashik , Au Raymond , Varelias Antiopi , Gartlan Kate H. , Olver Stuart D. , Samson Luke D. , Sturgeon Elise , Zomerdijk Nienke , Avery Judy , Gargett Tessa , Brown Michael P. , Coin Lachlan J. , Ganesamoorthy Devika , Hutchins Cheryl , Pratt Gary R. , Kennedy Glen A. , Morton A. James , Curley Cameron I. , Hill Geoffrey R. , Tey Siok-Keen 
Published: February 2019

Abstract

Purpose:
Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies.

Patients and Methods:
Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5−1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism.

Results:
Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/μL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein–Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/μL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur.

Conclusions:
iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.
Liver Fibrosis, Not Steatosis, Associates with Long-Term Outcomes in Ischaemic Stroke Patients
Authors: Baik Minyoul , Kim Seung Up , Kang Sungwoo , Park Hyung Jong , Nam Hyo Suk , Heo Ji Hoe , Kim Beom Kyung , Park Jun Yong , Kim Do Young , Ahn Sang Hoon , Han Kwang-Hyub , Lee Hye Sun , Kim Young Dae 
Published: February 2019

<b><i>Background:</i></b> To investigate whether there are differences in long-term all-cause and cardiovascular mortality according to the burden of liver fibrosis or steatosis in patients with ischaemic stroke or transient ischaemic attack (TIA). ­<b><i>Methods:</i></b> Consecutive patients with acute ischaemic stroke or TIA who underwent transient elastography (TE) from January 2014 to December 2014 were considered eligible. The influence of liver fibrosis or steatosis, assessed via TE, on long-term outcomes was investigated using Cox proportional hazard models. <b><i>Results:</i></b> Among 395 patients included in this study, there were 37 (9%) patients with significant fibrosis (&#x3e; 8.0 kPa) and 164 (41.5%) patients with fatty liver (&#x3e; 250 dB/m). During the follow-up period (median 2.7 years), all-cause and cardiovascular mortality occurred in 28 (7.1%) and 20 (5.1%) patients. On multivariate analyses, significant liver fibrosis was independently associated with increased risk of all-cause (hazard ratio [HR] 8.14, 95% CI 3.03–21.90, <i>p</i> &#x3c; 0.001) and cardiovascular (HR 4.29, 95% CI 1.10–16.73, <i>p</i> = 0.036) mortality, whereas fatty liver was not (all <i>p</i> &#x3e; 0.05). <b><i>Conclusions:</i></b> This study found that the burden of liver fibrosis but not that of steatosis, assessed via TE, was an independent predictor of all-cause and cardiovascular mortality during long-term follow-up in patients with ischaemic stroke.
Temporal Patterns of 14 Blood Biomarker candidates of Cardiac Remodeling in Relation to Prognosis of Patients With Chronic Heart Failure—The Bio‐SHiFT Study
Authors: Bouwens Elke , Brankovic Milos , Mouthaan Henk , Baart Sara , Rizopoulos Dimitris , van Boven Nick , Caliskan Kadir , Manintveld Olivier , Germans Tjeerd , van Ramshorst Jan , Umans Victor , Akkerhuis K. Martijn , Kardys Isabella 
Published: February 2019

Background

Remodeling biomarkers carry high potential for predicting adverse events in chronic heart failure (
CHF
) patients. However, temporal patterns during the course of
CHF
, and especially the trajectory before an adverse event, are unknown. We studied the prognostic value of temporal patterns of 14 cardiac remodeling biomarker candidates in stable patients with CHF from the Bio‐SHiFT (Serial Biomarker Measurements and New Echocardiographic Techniques in Chronic Heart Failure Patients Result in Tailored Prediction of Prognosis) study.

Methods and Results

In 263
CHF
patients, we performed trimonthly blood sampling during a median follow‐up of 2.2 years. For the analysis, we selected all baseline samples, the 2 samples closest to the primary end point (
PE
), or the last sample available for end point–free patients. Thus, in 567 samples, we measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2, 3, and 9, tissue inhibitor metalloproteinase‐4, perlecan, aminopeptidase‐N, caspase‐3, cathepsin‐D, cathepsin‐Z, and cystatin‐B. The
PE
was a composite of cardiovascular mortality, heart transplantation, left ventricular assist device implantation, and
HF
hospitalization. Associations between repeatedly measured biomarker candidates and the
PE
were investigated by joint modeling. Median age was 68 (interquartile range: 59–76) years with 72% men; 70 patients reached the
PE
. Repeatedly measured suppression of tumorigenicity‐2, galectin‐3, galectin‐4, growth differentiation factor‐15, matrix metalloproteinase‐2 and 9, tissue inhibitor metalloproteinase‐4, perlecan, cathepsin‐D, and cystatin‐B levels were significantly associated with the
PE
, and increased as the
PE
approached. The slopes of biomarker trajectories were also predictors of clinical outcome, independent of their absolute level. Associations persisted after adjustment for clinical characteristics and pharmacological treatment. Suppression of tumorigenicity‐2 was the strongest predictor (hazard ratio: 7.55 per
SD
difference, 95%
CI
: 5.53–10.30), followed by growth differentiation factor‐15 (4.06, 2.98–5.54) and matrix metalloproteinase‐2 (3.59, 2.55–5.05).

Conclusions

Temporal patterns of remodeling biomarker candidates predict adverse clinical outcomes in
CHF
.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
01851538.
Association Between Norepinephrine Levels and Abnormal Iron Status in Patients With Chronic Heart Failure: Is Iron Deficiency More Than a Comorbidity?
Authors: Moliner Pedro , Enjuanes Cristina , Tajes Marta , Cainzos‐Achirica Miguel , Lupón Josep , Garay Alberto , Jimenez‐Marrero Santiago , Yun Sergi , Farré Núria , Cladellas Mercé , Díez Carles , Gonzalez‐Costello Jose , Comin‐Colet Josep 
Published: February 2019

Background
Mechanisms underlying iron homeostasis dysregulation in patients with chronic heart failure remain unsettled. In cardiomyocyte models, norepinephrine may lead to intracellular iron depletion, but the potential association between catecholamines (sympathetic activation markers) and iron metabolism biomarkers in chronic heart failure is unknown.

Methods and Results

In this cross‐sectional analysis, we studied the association between plasma norepinephrine levels and serum iron status biomarkers indicating iron storage (ferritin), iron transport (transferrin saturation), and iron demand (soluble transferrin receptor) in a prospective cohort of 742 chronic heart failure patients (mean age, 72±11 years; 56% male). Impaired iron status was defined as ferritin <100 μg/L or transferrin saturation <20%. Impaired iron status was observed in 69% of patients. In multivariate models, greater norepinephrine levels were associated with impaired iron transport (transferrin saturation <20%, odds ratio=2.28; 95% CI [1.19–4.35];
P
=0.013), but not with impaired iron storage (ferritin <100 μg/L, odds ratio=1.25; 95% CI [0.73–2.16];
P
=0.415). Norepinephrine was a significant predictor of increased iron demand (soluble transferrin receptor, standardized β‐coefficient=0.12;
P
=0.006) and low transferrin saturation (standardized β‐coefficient=−0.12;
P
=0.003). However, norepinephrine levels were not associated with iron or ferritin levels (
P
>0.05). Adjusted norepinephrine marginal means were significantly higher in patients with impaired iron status compared with those with normal iron status (528 pg/mL [505–551] versus 482 pg/mL [448–518], respectively;
P
=0.038).

Conclusions
In chronic heart failure patients, increased sympathetic activation estimated with norepinephrine levels is associated with impaired iron status and, particularly, dysregulation of biomarkers suggesting impaired iron transport and increased iron demand. Whether the relationship between norepinephrine and iron metabolism is bidirectional and entails causality need to be elucidated in future research.
The Nyquist Issue in Linear Inverse Modeling
Authors: Penland Cécile 
Published: February 2019

AbstractLinear inverse modeling (LIM) is a statistical technique based on covariance statistics that estimates the best-fit linear Markov process to a multivariate time series. An integral, often-ignored part of the technique is a test of whether or not the linear assumptions are valid. One test for linearity is the so-called tau test. While this test can be trusted when it passes, it sometimes fails when it ought to pass. In this article, we discuss one of the reasons for spurious failure, the “Nyquist issue,” which occurs when the lagged covariance matrix used in the analysis is numerically performed at a lag greater than or nearly equal to half the period of a natural mode of variability represented in the time series. As an illustration relevant to a system with many degrees of freedom, but simple enough to solve analytically, we consider a four-dimensional system consisting of two modal pairs. Within this framework, we suggest one solution that can be applied if the time series are long enough. It is hoped that awareness of this issue can prevent misinterpretation of LIM results.
The experiences and needs of primary family caregivers of patients with multiple myeloma: A qualitative analysis
Authors: Quiñoa-Salanova Carmen , Porta-Sales Josep , Monforte-Royo Cristina , Edo-Gual Montserrat 
Published: February 2019

Background: Family caregivers play a key role in the lives of patients with multiple myeloma. However, very little is known about the impact that the disease (its diagnosis, course and prognosis) has on the main family caregiver. Aim: To achieve a deeper understanding of the lived experience of individuals who are the primary caregiver of a relative with multiple myeloma and to shed light on their needs. Design: Interpretative phenomenological study. Setting and participants: A total of 12 individuals who were the main family caregivers of a relative with multiple myeloma who was under outpatient follow-up at a cancer unit in Barcelona were recruited via purposive sampling until data saturation was reached. In semi-structured in-depth interviews, participants described their experiences of caring for their relative with multiple myeloma. Interviews were recorded, transcribed and analysed using ATLAS.ti v7.2. The seven steps proposed by Colaizzi were used for data analysis, and the relationships among emerging themes were examined. Findings: Four main themes emerged: (a) a new life, adapting to the disease, (b) commitment to the patient, (c) the emotional sphere and (d) experiences in relation to the care and support received. The analysis also revealed a core overarching theme: uncertainty. Conclusion: Primary family caregivers experienced intense uncertainty, and they described a strong need to air their feelings. Specific practical initiatives, targeting both health-related and logistical aspects of care, need to be developed in order to support family caregivers of myeloma patients.