bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monitoring Tumor Burden in Response to FOLFIRINOX Chemotherapy Via Profiling Circulating Cell-Free DNA in Pancreatic Cancer
Authors: Wei Tao , Zhang Qi , Li Xiang , Su Wei , Li Guogang , Ma Tao , Gao Shunliang , Lou Jianying , Que Risheng , Zheng Lei , Bai Xueli , Liang Tingbo 
Published: October 2018

Abstract
We aimed to explore the application of circulating cell-free DNA (cfDNA) profiling in monitoring tumor burden in patients with pancreatic ductal adenocarcinoma (PDAC). Thirty-eight patients with advanced PDAC receiving first-line FOLFIRINOX chemotherapy were prospectively enrolled. Next-generation sequencing for a panel of 560 genes covering a wide range of cancer-related loci was performed to profile cfDNA. In total, 25 patients (65.8%) had at least one common driver gene alterations (KRAS, TP53, SMAD4, CDKN2A) detected within cfDNA. In contrast, no above tumor-related recurrent mutations were found in plasma from 13 healthy individuals. Concordant alterations in plasma cfDNA and tumor tissue DNA was confirmed in two of three patients with available tissues. Further analysis showed that mutant allele fraction (MAF) for altered loci in cfDNA correlated with tumor stage, metastatic burden, and overall survival. Serial blood samples were collected from 17 patients after chemotherapy. We found that allele fraction for specific altered loci declined in chemotherapy-responding subjects. For cases who were resistant to this therapeutic regimen, increased ctDNA MAF was observed at the time of disease progression. Meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden following chemotherapy. Collectively, we provide evidence that pretreatment ctDNA level correlates with tumor burden in PDAC, and serial cfDNA analysis is a robust tool for monitoring cancer response to chemotherapy.
Impact of Apolipoprotein(a) Isoform Size on Lipoprotein(a) Lowering in the HPS2-THRIVE Study
Authors: Parish Sarah , Hopewell Jemma C. , Hill Michael R. , Marcovina Santica , Valdes-Marquez Elsa , Haynes Richard , Offer Alison , Pedersen Terje R. , Baigent Colin , Collins Rory , Landray Martin , Armitage Jane 
Published: October 2018

Background:
Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear.

Methods:
HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin–laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified.

Results:

Allocation to niacin–laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin–laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size (
P
Trend
=4×10
−29
) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels.

Conclusions:
Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin–laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a).

Clinical Trial Registration:

URL:
https://clinicaltrials.gov
. Unique identifier: NCT00461630.
Functionally Conserved Noncoding Regulators of Cardiomyocyte Proliferation and Regeneration in Mouse and Human
Authors: Adamowicz Martyna , Morgan Claire C. , Haubner Bernhard J. , Noseda Michela , Collins Melissa J. , Abreu Paiva Marta , Srivastava Prashant K. , Gellert Pascal , Razzaghi Bonnie , O’Gara Peter , Raina Priyanka , Game Laurence , Bottolo Leonardo , Schneider Michael D. , Harding Sian E. , Penninger Josef , Aitman Timothy J. 
Published: October 2018

Background:
The adult mammalian heart has little regenerative capacity after myocardial infarction (MI), whereas neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI.

Methods and Results:
Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA (miRNA) expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and noncoding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two-thirds of each of the messenger RNAs, long noncoding RNAs, and miRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR-451a, and miR-6240 showed evidence of functional conservation in human cardiomyocytes.

Conclusions:
The sets of messenger RNAs, miRNAs, and long noncoding RNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.
Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy
Authors: El-Battrawy Ibrahim , Zhao Zhihan , Lan Huan , Li Xin , Yücel Gökhan , Lang Siegfried , Sattler Katherine , Schünemann Jan-Dierk , Zimmermann Wolfram-Hubertus , Cyganek Lukas , Utikal Jochen , Wieland Thomas , Bieback Karen , Bauer Ralf , Ratte Antonius , Pribe-Wolferts Regina , Rapti Kleopatra , Nowak Daniel , Wittig Janina , Thomas Dierk , Most Patrick , Katus Hugo A. , Ravens Ursula , Schmidt Constanze , Borggrefe Martin , Zhou Xiao-Bo , Müller Oliver J. , Akin Ibrahim 
Published: October 2018

Background:
Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis.

Methods:
Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs. The hiPSCs were differentiated into cardiomyocytes and used for biological and electrophysiological studies.

Results:

Compared with hiPSC cardiomyocytes from the healthy donors, the hiPSC cardiomyocytes from the patient exhibited abnormal action potentials characterized by reduced amplitude and upstroke velocity. The peak and late Na channel currents (I
Na
) as well as the peak L-type calcium channel currents were significantly reduced. The expression of SCN5A and CACNA1C was reduced in DCM cardiomyocytes, consistent with reduction of I
Na
and L-type calcium channel currents. In addition, the rapidly activating delayed rectifier potassium current (I
Kr
) was reduced, whereas the transient outward current (I
to
) and slowly activating delayed rectifier potassium current (I
Ks
) were similar in DCM and control cardiomyocytes. Finally, a significant reduction of systolic and diastolic intracellular Ca
2+
concentrations was detected in DCM cardiomyocytes.

Conclusions:
This study demonstrates that patient-specific hiPSC cardiomyocytes can recapitulate some phenotypic properties of LGMD2I with DCM and provide a platform for studies on the cardiac events in LGMD.
A Screening Approach to Identify Clinically Actionable Variants Causing Congenital Heart Disease in Exome Data
Authors: Szot Justin O. , Cuny Hartmut , Blue Gillian M. , Humphreys David T. , Ip Eddie , Harrison Katrina , Sholler Gary F. , Giannoulatou Eleni , Leo Paul , Duncan Emma L. , Sparrow Duncan B. , Ho Joshua W.K. , Graham Robert M. , Pachter Nicholas , Chapman Gavin , Winlaw David S. , Dunwoodie Sally L. 
Published: October 2018

Background:
Congenital heart disease (CHD)—structural abnormalities of the heart that arise during embryonic development—is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD.

Methods:
Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.

RESULTS:

In 3 families (10%), we found pathogenic variants in known CHD genes
TBX5
,
TFAP2B
, and
PTPN11
, explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in
PBX1
,
CNOT1
,
ZFP36L2
,
TEK
,
USP34
,
UPF2
,
KDM5A
,
KMT2C
,
TIE1
,
TEAD2
, and
FLT4
.

Conclusions:
The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.
Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women
Authors: Tobias Deirdre K. , Lawler Patrick R. , Harada Paulo H. , Demler Olga V. , Ridker Paul M , Manson JoAnn E. , Cheng Susan , Mora Samia 
Published: October 2018

Background:
Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) are strong predictors of type 2 diabetes mellitus (T2D), but their association with cardiovascular disease (CVD) is uncertain. We hypothesized that plasma BCAAs are positively associated with CVD risk and evaluated whether this was dependent on an intermediate diagnosis of T2D.

Methods:
Participants in the Women’s Health Study prospective cohort were eligible if free of CVD at baseline blood collection (n=27 041). Plasma metabolites were measured via nuclear magnetic resonance spectroscopy. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for BCAAs with incident CVD (myocardial infarction, stroke, and coronary revascularization).

RESULTS:

We confirmed 2207 CVD events over a mean 18.6 years of follow-up. Adjusting for age, body mass index, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD: HR, 1.13; 95% CI, 1.08–1.18), comparable to LDL-C (low-density lipoprotein cholesterol) with CVD (per SD: HR, 1.12; 95% CI, 1.07–1.17). BCAAs were associated with coronary events (myocardial infarction: HR, 1.16; 95% CI, 1.06–1.26; revascularization: HR, 1.17; 95% CI, 1.11–1.25), and borderline significant association with stroke (HR, 1.07; 95% CI, 0.99–1.15). The BCAA–CVD association was greater (
P
interaction=0.036) among women who developed T2D before CVD (HR, 1.20; 95% CI, 1.08–1.32) versus women without T2D (HR, 1.08; 95% CI, 1.03–1.14). Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c and insulin resistance eliminated the associations of BCAAs with CVD.

Conclusions:
Circulating plasma BCAAs were positively associated with incident CVD in women. Impaired BCAA metabolism may capture the long-term risk of the common cause underlying T2D and CVD.
Predictors of Outcome After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy
Authors: Lu Minjie , Du Hui , Gao Zhan , Song Lei , Cheng Huaibing , Zhang Yan , Yin Gang , Chen Xiuyu , Ling Jian , Jiang Yong , Wang Hao , Li Jinghui , Huang Jinghan , He Zuoxiang , Zhao Shihua 
Published: October 2018

Background—
Alcohol septal ablation (ASA) is used for treatment of medically refractory hypertrophic obstructive cardiomyopathy patients with severe left ventricular outflow tract (LVOT) obstruction. The current recommendations restrict the procedure to adults with favorable anatomy and no other coexisting surgically amenable disease. Some patients remain symptomatic with residual LVOT obstruction, thus better patient selection is required.

Methods and Results—

One-hundred and two consecutive subjects with hypertrophic obstructive cardiomyopathy who underwent cardiovascular magnetic resonance imaging, transthoracic echocardiography, and ASA were enrolled in this study. Successful ASA was defined as reduction of LVOT gradient ≥50% of baseline by echocardiographic follow-up 6 months post ASA. The relationships between segmental thickness assessed by cardiovascular magnetic resonance imaging and echocardiography and outcomes of ASA were compared between the 2 groups. The survival rate after ablation was 100% at 6-month follow-up. The LVOT gradient decreased ≥50% of baseline in 72% (73/102) patients. There were good correlations between the reduction of postoperative LVOT gradient and the thickness of basal anterior segment (
r
=0.371;
P
<0.001), basal anteroseptal segment (
r
=0.527;
P
<0.001), and total thickness of the above 2 segments (
r
=0.672;
P
<0.001). The area under the receiver operating curves were 0.68, 0.79 and 0.89 for predictive analysis (all
P
<0.001). The cutoff thickness of the segment 1+2 was 50.9 mm, which yielded a sensitivity of 86% and specificity of 77%.

Conclusions—
Both echocardiography and cardiovascular magnetic resonance imaging can be used effectively as noninvasive tools for patient selection for ASA procedure. A significantly thickened septum among hypertrophic obstructive cardiomyopathy patients may be associated with a poor outcome after ASA.
Cluster Randomized Clinical Trial of FAITH (Faith-Based Approaches in the Treatment of Hypertension) in Blacks
Authors: Schoenthaler Antoinette M. , Lancaster Kristie J. , Chaplin William , Butler Mark , Forsyth Jessica , Ogedegbe Gbenga 
Published: October 2018

Background:
Therapeutic lifestyle change (TLC) is a recommended treatment for patients with hypertension, but its effectiveness in community-based settings remains untested, particularly in black churches—an influential institution for health promotion in black communities.

Methods and Results:

The FAITH study (Faith-Based Approaches in the Treatment of Hypertension) evaluated the comparative effectiveness of a TLC intervention plus motivational interviewing (MINT) sessions versus health education (HE) alone, on blood pressure (BP) reduction among blacks with uncontrolled hypertension. Data were collected on 373 participants meeting eligibility criteria (self-identification as black, age ≥18 years, self-reported diagnosis of hypertension, and uncontrolled BP [BP ≥140/90 or ≥130/80 mm Hg with diabetes mellitus or chronic kidney disease]) from 32 New York City churches. The MINT-TLC intervention plus motivational interviewing treatment comprised 11 weekly group sessions on TLC plus 3 MINT sessions delivered monthly by lay health advisors. The HE control group received 1 TLC session plus 10 sessions on health topics delivered by local experts. The outcomes were BP reduction at 6 months (primary) and BP control and BP reduction at 9 months (secondary). The sample mean age was 63 years; 76% women, with mean BP of 153/87 mm Hg. Using linear mixed-effects regression models, the MINT-TLC intervention plus motivational interviewing group had a significantly greater systolic BP reduction of 5.79 mm Hg compared with the HE group at 6 months (
P
=0.029). The treatment effect on systolic BP persisted at 9 months but had reduced significance (5.21 mm Hg;
P
=0.068). The between-group differences in diastolic BP reduction (0.41 mm Hg) and mean arterial pressure (2.24 mm Hg) at 6 months were not significant. Although the MINT-TLC intervention plus motivational interviewing group had greater BP control than the HE group at 9 months, the difference was not statistically significant (57.0% versus 48.8%; odds ratio, 1.43; 95% CI, 0.90–2.28).

Conclusions:
A community-based lifestyle intervention delivered in churches led to significantly greater reduction in systolic BP in hypertensive blacks compared with HE alone.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01065831.
Dynamics of Spatio-Temporal Binding in Rats
Authors: Malet-Karas Aurore , Noulhiane Marion , Doyère Valérie 
Published: October 2018

Time and space are commonly approached as two distinct dimensions, and rarely combined together in a single task, preventing a comparison of their interaction. In this project, using a version of a timing task with a spatial component, we investigate the learning of a spatio-temporal rule in animals. To do so, rats were placed in front of a five-hole nose-poke wall in a Peak Interval (PI) procedure to obtain a reward, with two spatio-temporal combination rules associated with different to-be-timed cues and lighting contexts. We report that, after successful learning of the discriminative task, a single Pavlovian session was sufficient for the animals to learn a new spatio-temporal association. This was seen as evidence for a beneficial transfer to the new spatio-temporal rule, as compared to control animals that did not experience the new spatio-temporal association during the Pavlovian session. The benefit was observed until nine days later. The results are discussed within the framework of adaptation to a change of a complex associative rule involving interval timing processes.
Characterisation and possible hazard of an atypical asbestiform sepiolite associated with aliphatic hydrocarbons from Sassello, Ligurian Apennines, Italy
Authors: Giustetto Roberto , Macaluso Loredana , Berlier Gloria , Ganjkhanlou Yadolah , Barale Luca 
Published: October 2018

AbstractAn unusual occurrence of asbestiform sepiolite, filling veins in the antigorite serpentinites of the Voltri Unit exposed in a borrow pit (now reclaimed) in the Deiva forest, near Sassello, NW Italy, was investigated with an in-depth analytical approach aimed at studying its crystal-chemistry and structure and evaluating its possible hazards for human health. Optical microscopy and scanning electron microscopy (energy-dispersive spectroscopy mode) proved that these sepiolite fibres, apparently up to several cm long, are made up of bundles of thinner fibrils (or laths: average length &gt; 100 µm; thickness ≈ 80 nm), with a composition consistent to that reported in the literature. The dehydration process was monitored through thermo-gravimetric analyses and Fourier-transform infrared spectroscopy, performed at increasingT; the latter, in particular, showed the presence of moderate amounts of aliphatic hydrocarbons – not yet identified thoroughly – associated with the sample. The crystal structure refinement with the Rietveld method showed no relevant difference from the literature models, although a peculiar distribution of zeolitic H2O molecules was observed. The geological context suggests that the Sassello sepiolite precipitated from hydrothermal fluids, which were saturated in Mg and silica by the interaction of the host serpentinites. The same setting favoured formation of abiotic hydrocarbons, by means of the Fischer–Tropsch reaction. The extremely long and flexible fibrils (length/width aspect ratio &gt;&gt; 3) of this sepiolite specimen could represent a serious hazard for human health if air dispersed and inhaled; also, its atypical association with hydrocarbons (only reported once previously) might even favour further fragmentation in thinner units.
Accelerated, but not conventional, radiotherapy of murine B-cell lymphoma induces potent T cell–mediated remissions
Authors: Dutt Suparna , Atallah Michelle B. , Minamida Yoshitaka , Filatenkov Alexander , Jensen Kent P. , Iliopoulou Bettina P. , Tamosiuniene Rasa , Waters Jeffrey , Engleman Edgar G. , Strober Samuel 
Published: October 2018

Abstract
Conventional local tumor irradiation (LTI), delivered in small daily doses over several weeks, is used clinically as a palliative, rather than curative, treatment for chemotherapy-resistant diffuse large B-cell lymphoma (DLBCL) for patients who are ineligible for hematopoietic cell transplantation. Our goal was to test the hypothesis that accelerated, but not conventional, LTI would be more curative by inducing T cell–mediated durable remissions. We irradiated subcutaneous A20 and BL3750 lymphoma tumors in mice with a clinically relevant total radiation dose of 30 Gy LTI, delivered in 10 doses of 3 Gy over 4 days (accelerated irradiation) or as 10 doses of 3 Gy over 12 days (conventional irradiation). Compared with conventional LTI, accelerated LTI resulted in more complete and durable tumor remissions. The majority of these mice were resistant to rechallenge with lymphoma cells, demonstrating the induction of memory antitumor immunity. The increased efficacy of accelerated LTI correlated with higher levels of tumor cell necrosis vs apoptosis and expression of “immunogenic cell death” markers, including calreticulin, heat shock protein 70 (Hsp70), and Hsp90. Accelerated LTI–induced remissions were not seen in immunodeficient Rag-2−/− mice, CD8+ T-cell–depleted mice, or Batf-3−/− mice lacking CD8α+ and CD103+ dendritic cells. Accelerated, but not conventional, LTI in immunocompetent hosts induced marked increases in tumor-infiltrating CD4+ and CD8+ T cells and MHCII+CD103+CD11c+ dendritic cells and corresponding reductions in exhausted PD-1+Eomes+CD8+ T cells and CD4+CD25+FOXP3+ regulatory T cells. These findings raise the possibility that accelerated LTI can provide effective immune control of human DLBCL.