bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of creative writing on mood in patients with cancer
Authors: Zhu Junjia , Hussain Muhammad , Joshi Aditya , Truica Cristina I , Nesterova Darya , Collins Jolene , Saunders Erika F H , Hayes Michael , Drabick Joseph J , Joshi Monika 
Published: March 2019

ObjectiveTo determine the feasibility of conducting creative writing workshops (CWW) for patients with cancer to promote improvement in mood.MethodWe piloted a prospective study to determine the feasibility of conducting CWW over a 4-week period. Patients were randomised 2:1 to either an intervention arm (IA) or to standard of care (SOC). Patients in the IA attended four 2-hour long weekly CWW × 4 weeks, whereas those receiving SOC did not participate in the CWW. We used a validated emotion thermometer scale (ETS) to assess changes in patient’s mental health before and after intervention. Patients with metastatic or unresectable cancer were included.Primary endpoint(1) Feasibility and (2) mood scores before and after CWW using ETS.ResultsA total of 16 patients were enrolled: 11 in the IA vs 5 in SOC. Seven out of 11 (63%) patients enrolled in the IA attended at least 75% of classes. Patients in the IA showed a trend towards mood improvement relative to the SOC when comparing initial and final ETS scores. Within the IA group significantly lower postclass total ETS scores were observed relative to preclass ETS scores. Also, a significant decreasing trend over time was observed in the preclass total ETS scores for participants in the IA group.ConclusionsIt is feasible for patients with cancer to attend CWW. Our results also show a positive effect on mood in the CWW arm. Further prospective clinical studies are needed to evaluate the effect of this intervention in patients with cancer.
Vestibular modulation of muscle sympathetic nerve activity assessed over a 100-fold frequency range of sinusoidal galvanic vestibular stimulation
Authors: Singh Natasha , Hammam Elie , Macefield Vaughan G. 
Published: February 2019

We have previously shown that sinusoidal galvanic vestibular stimulation (sGVS), delivered at 0.2–2.0 Hz, evokes a partial entrainment of muscle sympathetic nerve activity (MSNA). Moreover, at lower frequencies of stimulation (0.08–0.18 Hz) sGVS produces two peaks of modulation: one (primary) peak associated with the positive peak of the sinusoidal stimulus and a smaller (secondary) peak associated with the trough. Here we assessed whether sGVS delivered at 0.05 Hz causes a more marked modulation of MSNA than at higher frequencies and tested the hypothesis that the primary and secondary peaks are of identical amplitude because of the longer cycle length. MSNA was recorded via tungsten microelectrodes inserted into the left peroneal nerve in 11 seated subjects. Bipolar binaural sGVS (±2 mA, 100 cycles) was applied to the mastoid processes at 0.05, 0.5, and 5.0 Hz (500 cycles). Cross-correlation analysis revealed two bursts of modulation of MSNA for each cycle at 0.05 and 0.5 Hz but only one at 5 Hz. There was a significant inverse linear relationship between vestibular modulation (primary peak) and frequency ( P < 0.0001), with the amplitudes of the peaks being highest at 0.05 Hz. Moreover, the secondary peak at this frequency was not significantly different from the primary peak. These results indicate that vestibular modulation of MSNA operates over a large range of frequencies but is greater at lower frequencies of sGVS. We conclude that the vestibular apparatus, through its influence on muscle sympathetic outflow, preferentially contributes to the control of blood pressure at low frequencies. NEW & NOTEWORTHY Vestibulosympathetic reflexes have been documented in experimental animals and humans. Here we show that sinusoidal galvanic vestibular stimulation, a means of selectively exciting vestibular afferents in humans, induces greater modulation of muscle sympathetic nerve activity when delivered at a very low frequency (0.05 Hz) than at 0.5 or 5.0 Hz.
A Study of Pre-Analytical Variables and Optimization of Extraction Method for Circulating Tumor DNA Measurements by Digital Droplet PCR
Authors: Cavallone Luca , Aldamry Mohammed , Lafleur Josiane , Lan Cathy , Gonzalez Ginestet Pablo , Alirezaie Najmeh , Ferrario Cristiano , Aguilar-Mahecha Adriana , Basik Mark 
Published: March 2019

Abstract

Background:
Circulating free DNA (cfDNA) is an exciting novel method to diagnose, monitor, and predict resistance and response to cancer therapies, with the potential to radically alter the management of cancer patients. To fulfill its potential, greater knowledge about preanalytical variables is required to optimize and standardize the collection process, and maximize the yield and utility of the small quantities of cfDNA extracted.

Methods:
To this end, we have compared the cfDNA extraction efficiency of three different protocols, including a protocol developed in house (Jewish General Hospital). We evaluated the impact on cfDNA levels of preanalytical variables including speed and timing of the second centrifugation and the use of k-EDTA and CTAD blood collection tubes. Finally, we analyzed the impact on fractional abundance of targeted pre-amplification and whole genome amplification on tumor and circulating tumor DNA (ctDNA) from patients with breast cancer.

Results:
Making use of a novel protocol for cfDNA extraction we increased cfDNA quantities, up to double that of commercial kits. We found that a second centrifugation at 3,000 g on frozen plasma is as efficient as a high-speed (16,000 g) centrifugation on fresh plasma and does not affect cfDNA levels.

Conclusions:
These results allow for the implementation of protocols more suitable to the clinical setting. Finally, we found that, unlike targeted gene amplification, whole genome amplification resulted in altered fractional abundance of selected ctDNA variants.

Impact:
Our study of the preanalytical variables affecting cfDNA recovery and testing will significantly enhance the quality and application of ctDNA testing in clinical oncology.
Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib–treated Patients with BRAFV600-mutated Metastatic Melanoma
Authors: Yan Yibing , Wongchenko Matthew J. , Robert Caroline , Larkin James , Ascierto Paolo A. , Dréno Brigitte , Maio Michele , Garbe Claus , Chapman Paul B. , Sosman Jeffrey A. , Shi Zhen , Koeppen Hartmut , Hsu Jessie J. , Chang Ilsung , Caro Ivor , Rooney Isabelle , McArthur Grant A. , Ribas Antoni 
Published: March 2019

Abstract
Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti–programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAFV600-mutated metastatic melanoma.
Patients and Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.
Results: Whole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response–related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.
Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.
L-Type Cav 1.2 Calcium Channel-α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma
Authors: Zhang Jiu-Yang , Zhang Pei-Pei , Zhou Wen-Ping , Yu Jia-Yu , Yao Zhi-Hua , Chu Jun-Feng , Yao Shu-Na , Wang Cheng , Lone Waseem , Xia Qing-Xin , Ma Jie , Yang Shu-Jun , Liu Kang-Dong , Dong Zi-Gang , Guo Yong-Jun , Smith Lynette M. , McKeithan Timothy W. , Chan Wing C. , Iqbal Javeed , Liu Yan-Yan 
Published: March 2019

Abstract

Purpose:
One third of patients with diffuse large B-cell lymphoma (DLBCL) succumb to the disease partly due to rituximab resistance. Rituximab-induced calcium flux is an important inducer of apoptotic cell death, and we investigated the potential role of calcium channels in rituximab resistance.

Experimental Design:
The distinctive expression of calcium channel members was compared between patients sensitive and resistant to rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone (RCHOP) regimen. The observation was further validated through mechanistic in vitro and in vivo studies using cell lines and patient-derived xenograft mouse models.

Results:
A significant inverse correlation was observed between CACNA1C expression and RCHOP resistance in two independent DLBCL cohorts, and CACNA1C expression was an independent prognostic factor for RCHOP resistance after adjusting for International Prognostic Index, cell-of-origin classification, and MYC/BCL2 double expression. Loss of CACNA1C expression reduced rituximab-induced apoptosis and tumor shrinkage. We further demonstrated direct interaction of CACNA1C with CD20 and its role in CD20 stabilization. Functional modulators of L-type calcium channel showed expected alteration in rituximab-induced apoptosis and tumor suppression. Furthermore, we demonstrated that CACNA1C expression was directly regulated by miR-363 whose high expression is associated with worse prognosis in DLBCL.

Conclusions:
We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.
EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer
Authors: Martini Giulia , Cardone Claudia , Vitiello Pietro Paolo , Belli Valentina , Napolitano Stefania , Troiani Teresa , Ciardiello Davide , Della Corte Carminia Maria , Morgillo Floriana , Matrone Nunzia , Sforza Vincenzo , Papaccio Gianpaolo , Desiderio Vincenzo , Paul Mariel C. , Moreno-Viedma Veronica , Normanno Nicola , Rachiglio Anna Maria , Tirino Virginia , Maiello Evaristo , Latiano Tiziana Pia , Rizzi Daniele , Signoriello Giuseppe , Sibilia Maria , Ciardiello Fortunato , Martinelli Erika 
Published: March 2019

Abstract
The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1–G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4–10.8; vs. 12.3 months; CI 95%, 10.4–14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.
Nanobody Targeting of Epidermal Growth Factor Receptor (EGFR) Ectodomain Variants Overcomes Resistance to Therapeutic EGFR Antibodies
Authors: Tintelnot Joseph , Baum Natalie , Schultheiß Christoph , Braig Friederike , Trentmann Marie , Finter Johannes , Fumey William , Bannas Peter , Fehse Boris , Riecken Kristoffer , Schuetze Kerstin , Bokemeyer Carsten , Rösner Thies , Valerius Thomas , Peipp Matthias , Koch-Nolte Friedrich , Binder Mascha 
Published: March 2019

Abstract
Epidermal growth factor receptor (EGFR) ectodomain variants mediating primary resistance or secondary treatment failure in cancer patients treated with cetuximab or panitumumab support the need for more resistance-preventive or personalized ways of targeting this essential pathway. Here, we tested the hypothesis that the EGFR nanobody 7D12 fused to an IgG1 Fc portion (7D12-hcAb) would overcome EGFR ectodomain–mediated resistance because it targets a very small binding epitope within domain III of EGFR. Indeed, we found that 7D12-hcAb bound and inhibited all tested cell lines expressing common resistance-mediating EGFR ectodomain variants. Moreover, we assessed receptor functionality and binding properties in synthetic mutants of the 7D12-hcAb epitope to model resistance to 7D12-hcAb. Because the 7D12-hcAb epitope almost completely overlaps with the EGF-binding site, only position R377 could be mutated without simultaneous loss of receptor functionality, suggesting a low risk of developing secondary resistance toward 7D12-hcAb. Our binding data indicated that if 7D12-hcAb resistance mutations occurred in position R377, which is located within the cetuximab and panitumumab epitope, cells expressing these receptor variants would retain sensitivity to these antibodies. However, 7D12-hcAb was equally ineffective as cetuximab in killing cells expressing the cetuximab/panitumumab-resistant aberrantly N-glycosylated EGFR R521K variant. Yet, this resistance could be overcome by introducing mutations into the Fc portion of 7D12-hcAb, which enhanced immune effector functions and thereby allowed killing of cells expressing this variant. Taken together, our data demonstrate a broad range of activity of 7D12-hcAb across cells expressing different EGFR variants involved in primary and secondary EGFR antibody resistance.
Cholesterol Sulfotransferase SULT2B1b Modulates Sensitivity to Death Receptor Ligand TNFα in Castration-Resistant Prostate Cancer
Authors: Vickman Renee E. , Yang Jiang , Lanman Nadia A. , Cresswell Gregory M. , Zheng Faye , Zhang Chi , Doerge R. W. , Crist Scott A. , Mesecar Andrew D. , Hu Chang-Deng , Ratliff Timothy L. 
Published: March 2019

Abstract

Cholesterol sulfotransferase, SULT2B1b, has been demonstrated to modulate both androgen receptor activity and cell growth properties. However, the mechanism(s) by which SULT2B1b alters these properties within prostate cancer cells has not been described. Furthermore, specific advantages of SULT2B1b expression in prostate cancer cells are not understood. In these studies, single-cell mRNA sequencing was conducted to compare the transcriptomes of SULT2B1b knockdown (KD) versus Control KD LNCaP cells. Over 2,000 differentially expressed genes were identified along with alterations in numerous canonical pathways, including the death receptor signaling pathway. The studies herein demonstrate that SULT2B1b KD increases TNFα expression in prostate cancer cells and results in NF-κB activation in a TNF-dependent manner. More importantly, SULT2B1b KD significantly enhances TNF-mediated apoptosis in both TNF-sensitive LNCaP cells and TNF-resistant C4-2 cells. Overexpression of SULT2B1b in LNCaP cells also decreases sensitivity to TNF-mediated cell death, suggesting that SULT2B1b modulates pathways dictating the TNF sensitivity capacity of prostate cancer cells. Probing human prostate cancer patient datasets further supports this work by providing evidence that SULT2B1b expression is inversely correlated with TNF-related genes, including TNF, CD40LG, FADD, and NFKB1. Together, these data provide evidence that SULT2B1b expression in prostate cancer cells enhances resistance to TNF and may provide a growth advantage. In addition, targeting SULT2B1b may induce an enhanced therapeutic response to TNF treatment in advanced prostate cancer.

Implications:
These data suggest that SULT2B1b expression enhances resistance to TNF and may promote prostate cancer.
Acceptability of Localized Cancer Risk Reduction Interventions Among Individuals at Average or High Risk for Cancer
Authors: Samimi Goli , Heckman-Stoddard Brandy M. , Kay Shelley S. , Bloodgood Bonny , Coa Kisha I. , Robinson Jennifer L. , Tennant Bethany , Ford Leslie G. , Szabo Eva , Minasian Lori 
Published: March 2019

Abstract
Individuals at high risk for cancer, including those already diagnosed with premalignant lesions, can potentially benefit from chemopreventive interventions to reduce cancer risk. However, uptake and acceptability have been hindered due to the risk of systemic toxicity and other adverse effects. Locally delivered chemopreventive agents, where direct action on the primary organ may limit systemic toxicity, are emerging as an option for high-risk individuals. While a number of clinical trials support the development of chemopreventive agents, it is crucial to understand the factors and barriers that influence their acceptability and use. We conducted 36 focus groups with 198 individuals at average and high risk of breast/ovarian, gynecologic, and head/neck/oral and lung cancers to examine the perceptions and acceptability of chemopreventive agents. Participants' willingness to use chemopreventive agents was influenced by several factors, including perceived risk of cancer, skepticism around prevention, previous knowledge of chemopreventive agents, support from trusted sources of health information, participation in other cancer-related risk-reduction activities, previous experience with similar modalities, cost, regimen, side effects, and perceived effectiveness of the preventive intervention. Our findings indicate that individuals may be more receptive to locally delivered chemopreventive agents if they perceive themselves to be at high risk for cancer and are given the necessary information regarding regimen and side effects to make an informed decision. Clinical trials that collect additional patient-centered data including side effects and how these interventions fit into an individual's lifestyle are imperative to improve uptake of chemopreventive agents.
Gly101Val BCL2 Mutation: One Step Closer to Understanding Venetoclax Resistance in CLL
Authors: Thangavadivel Shanmugapriya , Byrd John C. 
Published: March 2019

Abstract

Summary:
In this issue, Blombery and colleagues show that the chronic lymphocytic leukemia (CLL) cells bearing Gly101Val mutation confer resistance to venetoclax by reducing the affinity of BCL2 for venetoclax by 180-fold in cell lines and in patient cells. Detection of this mutation provides a potential biomarker for impending disease progression and an opportunity for targeted and combinational therapy to treat CLL.
See related article by Blombery et al., p. 342.
High‐Sensitivity Cardiac Troponin I Improves Cardiovascular Risk Prediction in Older Men: HIMS (The Health in Men Study)
Authors: Lan Nick S. R. , Bell Damon A. , McCaul Kieran A. , Vasikaran Samuel D. , Yeap Bu B. , Norman Paul E. , Almeida Osvaldo P. , Golledge Jonathan , Hankey Graeme J. , Flicker Leon 
Published: March 2019

Background
The Framingham Risk Score estimates the 10‐year risk of cardiovascular events. However, it performs poorly in older adults. We evaluated the incremental benefit of adding high‐sensitivity cardiac troponin I (hs‐cTnI) to the Framingham Risk Score.

Methods and Results

The HIMS (Health in Men Study) is a cohort study of community‐dwelling men aged 70 to 89 years in Western Australia. Participants were identified from the electoral roll, with a subset undergoing plasma analysis. Hs‐
cTnI
(Abbott Architect i2000
SR
) was measured in 1151 men without prior cardiovascular disease. The Western Australia Data Linkage System was used to identify incident cardiovascular events. After 10 years of follow‐up, 252 men (22%) had a cardiovascular event (
CVE
+) and 899 did not (CVE–). The Framingham Risk Score placed 148 (59%)
CVE
+ and 415 (46%)
CVE–
in the high‐risk category. In
CVE
– men, adding hs‐
cTnI
affected the risk categories of 244 (27.2%) men, with 64.8% appropriately reclassified to a lower and 35.2% to a higher category, which decreased the number of high‐risk men in the
CVE–
to 39%. In
CVE
+ men, adding hs‐
cTnI
affected the risk categories of 61 (24.2%), with 50.8% appropriately reclassified to a higher and 49.2% to a lower category and 82.5% remaining above the 15% risk treatment threshold. The net reclassification index was 0.305 (
P
<0.001). Adding hs‐
cTnI
increased the C‐statistic modestly from 0.588 (95%
CI
, 0.552–0.624) to 0.624 (95%
CI
, 0.589–0.659) and improved model fit (likelihood ratio test,
P
<0.001).

Conclusions

Adding hs‐
cTnI
to the Framingham Risk Score provided incremental prognostic benefit in older men, especially aiding reclassification of individuals into a lower risk category.
Observed Variations of the Atmospheric Boundary Layer and Stratocumulus over a Warm Eddy in the Kuroshio Extension
Authors: Wang Qian , Zhang Su-Ping , Xie Shang-Ping , Norris Joel R. , Sun Jian-Xiang , Jiang Yu-Xi 
Published: March 2019

Abstract
A research vessel sailing across a warm eddy in the Kuroshio Extension on 13 April 2016 captured an abrupt development of stratocumulus under synoptic high pressure. Shipboard observations and results from regional atmospheric model simulations indicate that increased surface heat flux over the ocean eddy lowered surface pressure and thereby accelerated southeasterly winds. The southeasterly winds transported moisture toward the low pressure and enhanced the air–sea interface heat flux, which in turn deepened the low pressure and promoted low-level convergence and rising motion over the warm eddy. The lifting condensation level lowered and the top of the marine atmospheric boundary layer (MABL) rose, thereby aiding the development of the stratocumulus. Further experiments showed that 6°C sea surface temperature anomalies associated with the 400-km-diameter warm eddy accounted for 80% of the total ascending motion and 95% of total cloud water mixing ratio in the marine atmospheric boundary layer during the development of stratocumulus. The synthesis of in situ soundings and modeling contributes to understanding of the mechanism by which the MABL and marine stratocumulus respond to ocean eddies.