bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequencies and patterns of laboratory test requests from general practice: a service evaluation to inform point-of-care testing
Authors: Fanshawe Thomas R , Ordóñez-Mena José M , Turner Philip J , Bruel Ann Van den , Shine Brian , Hayward Gail N 
Published: September 2018

AimsThe demand for test requests from general practice to laboratory services remains high. Tests performed at the point of care could reduce turnaround time and speed up clinical decision making. Replicating laboratory testing in the community would require panels of tests to be performed simultaneously, which is now approaching technological feasibility. We assessed frequencies and combinations of test requests from community settings to inform the potential future development of multiplex point-of-care panels.MethodsWe assessed all laboratory test requests made from general practice in Oxfordshire, UK, from January 2014 to March 2017. We summarised test request frequency overall and in combination, using heatmaps and hierarchical cluster analysis. Results are also presented by age/sex subgroups. We further assessed patterns of tests requested within 7 and 14 days after an initial test request.Results11 763 473 test requests were made for 413 073 individuals (28% age >65). Of more than 500 test types, 62 were requested at least 5000 times, most commonly renal function tests (approximately 296 000/year), full blood count (278 000/year) and liver function tests (237 000/year). Cluster analysis additionally identified a clear grouping of tests commonly used to investigate anaemia. Follow-up test frequency was much lower than the frequency of multiple tests ordered at initial presentation.ConclusionsThe current high volume of single and combination test requests highlights an opportunity for reliable multiplex point-of-care panels to cover a core set of frequently requested tests. The impact on test use of introducing such panels to general practice requires additional research.
Vascular access training for REBOA placement: a feasibility study in a live tissue-simulator hybrid porcine model
Authors: Borger van der Burg Boudewijn L S , Hörer T M , Eefting D , van Dongen T T C F , Hamming J F , DuBose J J , Bowyer M , Hoencamp R 
Published: September 2018

BackgroundThe use of resuscitative endovascular balloon occlusion of the aorta (REBOA) in patients with severe haemorrhagic shock is increasing. Obtaining vascular access is a necessary prerequisite for REBOA placement in these situations.MethodsDuring the EVTM workshop (September 2017, Örebro, Sweden), 21 individuals participated in this study, 16 participants and five instructors. A formalised curriculum was constructed including basic anatomy of the femoral region and basic training in access materials for REBOA placement in zone 1. Key skills: (1) preparation of endovascular toolkit, (2) achieving vascular access in the model and (3) bleeding control with REBOA. Scoring ranged from 0 to 5 for non-anatomical skills. Identification of anatomical structures was either sufficient (score=1) or insufficient (score=0). Five consultants performed a second identical procedure as a post test.ResultsConsultants had significantly better overall technical skills in comparison with residents (p=0.005), while understanding of surgical anatomy showed no difference. Procedure times differed significantly (p<0.01), with residents having a median procedure time of 3 min and 24 s, consultants 2:33 and instructors 1:09.ConclusionThis comprehensive training model using a live tissue-simulator hybrid porcine model can be used for femoral access and REBOA placement training in medical personnel with different prior training levels. Higher levels of training are associated with faster procedure times. Further research in open and percutaneous access training is necessary to simulate real-life situations. This training method can be used in a multistep training programme, in combination with realistic moulage and perfused cadaver models.
A Limb Tracking Platform for Tele-Rehabilitation
Authors: Buonocunto Pasquale , Giantomassi Andrea , Marinoni Mauro , Calvaresi Davide , Buttazzo Giorgio 
Published: September 2018

The adoption of motor-rehabilitative therapies is highly demanded in a society where the average age of the population is constantly increasing. A recent trend to contain costs while providing high quality of healthcare services is to foster the adoption of self-care procedures, performed primarily in patients’ environments rather than in hospitals or healthcare structures, especially in the case of intensive and chronic patients’ rehabilitation.
This work presents a platform to enhance limb functional recovery through telerehabilitation sessions. It relies on a sensing system based on inertial sensors and data fusion algorithms, a module to provide bio-feedback tailored to the users, and a module dedicated to the physicians’ practices. The system design had to face several cyber-physical challenges due to the tight interaction between patient and sensors. For instance, integrating the body kinematics into the sensory processing improved the precision of measurements, simplified the calibration procedure, and made it possible to generate bio-feedback signals. The precision of the proposed system is presented through a set of experiments, showing a resolution below one degree in monitoring joint angles. A validation of the proposed solution has been performed through a medical trial on 50 patients affected by osteo-articular diseases.
The presented framework has been designed to operate in other application fields, such as neurological rehabilitation (e.g., Parkinson, Stroke, etc.), sports training, and fitness activities.
Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
Authors: Stangl Stefan , Tei Lorenzo , De Rose Francesco , Reder Sybille , Martinelli Jonathan , Sievert Wolfgang , Shevtsov Maxim , Öllinger Rupert , Rad Roland , Schwaiger Markus , D'Alessandria Calogero , Multhoff Gabriele 
Published: September 2018

Abstract
High precision in vivo PET/CT imaging of solid tumors improves diagnostic credibility and clinical outcome of patients. An epitope of the oligomerization domain of Hsp70 is exclusively exposed on the membrane of a large variety of tumor types, but not on normal cells, and thus provides a universal tumor-specific target. Here we developed a novel PET tracer TPP-PEG24-DFO[89Zr] based on the tumor cell–penetrating peptide probe TPP, which specifically recognizes membrane Hsp70 (mHsp70) on tumor cells. The implemented PEG24 moiety supported tracer stability and improved biodistribution characteristics in vivo. The Kd of the tracer ranged in the low nanomolar range (18.9 ± 11.3 nmol/L). Fluorescein isothiocyanate (FITC)-labeled derivatives TPP-[FITC] and TPP-PEG24-[FITC] revealed comparable and specific binding to mHsp70-positive 4T1, 4T1+, a derivative of the 4T1 cell line sorted for high Hsp70 expression, and CT26 tumor cells, but not to mHsp70-negative normal fibroblasts. The rapid internalization kinetics of mHsp70 into the cytosol and the favorable biodistribution of the peptide-based tracer TPP-PEG24-DFO[89Zr] in vivo enabled a tumor-specific accumulation with a high tumor-to-background contrast and renal body clearance. The tumor-specific enrichment of the tracer in 4T1+ (6.2 ± 1.1%ID/g), 4T1 (4.3 ± 0.7%ID/g), and CT26 (2.6 ± 0.6%ID/g) mouse tumors with very high, high, and intermediate mHsp70 densities, respectively, reflected mHsp70 expression profiles of the different tumor types, whereas benign mHsp70-negative fibroblastic hyperplasia showed no tracer accumulation (0.2 ± 0.03%ID/g). The ability of our chemically optimized peptide-based tracer TPP-PEG24-DFO[89Zr] to detect mHsp70 in vivo suggests its broad applicability in targeting and imaging with high specificity for any tumor type that exhibits surface expression of Hsp70.
Significance: A novel peptide-based PET tracer against the oligomerization domain of Hsp70 has potential for universal tumor-specific imaging in vivo across many tumor type. Cancer Res; 78(21); 6268–81. ©2018 AACR.
Circulating Growth and Sex Hormone Levels and Breast Tissue Composition in Young Nulliparous Women
Authors: Denholm Rachel , De Stavola Bianca L. , Hipwell John H. , Doran Simon J. , Holly Jeff M.P. , Folkerd Elizabeth , Dowsett Mitch , Leach Martin O. , Hawkes David J. , dos-Santos-Silva Isabel 
Published: September 2018

Abstract

Background:
Endogenous hormones are associated with breast cancer risk, but little is known about their role on breast tissue composition, a strong risk predictor. This study aims to investigate the relationship between growth and sex hormone levels and breast tissue composition in young nulliparous women.

Methods:
A cross-sectional study of 415 young (age ∼21.5 years) nulliparous women from an English prebirth cohort underwent a MRI examination of their breasts to estimate percent-water (a proxy for mammographic percent density) and provided a blood sample to measure plasma levels of growth factors (insulin-like growth factor-I, insulin-like growth factor-II, insulin growth factor-binding protein-3, growth hormone) and, if not on hormonal contraception (n = 117) sex hormones (dehydroepiandrosterone, androstenedione, testosterone, estrone, estadiol, sex hormone–binding globulin, prolactin). Testosterone (n = 330) and sex hormone–binding globulin (n = 318) were also measured at age 15.5 years. Regression models were used to estimate the relative difference (RD) in percent-water associated with one SD increment in hormone levels.

Results:
Estradiol at age 21.5 and sex hormone–binding globulin at age 21.5 were positively associated with body mass index (BMI)-adjusted percent-water [RD (95% confidence interval (CI)): 3% (0%–7%) and 3% (1%–5%), respectively]. There was a positive nonlinear association between androstenedione at age 21.5 and percent-water. Insulin-like growth factor-I and growth hormone at age 21.5 were also positively associated with BMI-adjusted percent-water [RD (95% CI): 2% (0%–4%) and 4% (1%–7%), respectively].

Conclusions:
The findings suggest that endogenous hormones affect breast tissue composition in young nulliparous women.

Impact:
The well-established associations of childhood growth and development with breast cancer risk may be partly mediated by the role of endogenous hormones on breast tissue composition.
Prognostic Role of Circulating Exosomal miR-425-3p for the Response of NSCLC to Platinum-Based Chemotherapy
Authors: Yuwen Daolu , Ma Yuzhu , Wang Deqiang , Gao Jian , Li Xin , Xue Wenwen , Fan Minmin , Xu Qiang , Shen Yan , Shu Yongqian 
Published: September 2018

Abstract

Background:
Platinum-based doublets with a third-generation agent are the recommended option for many patients with non–small cell lung cancer (NSCLC) with no contraindications to platinum compounds. Unfortunately, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance.

Methods:
Circulating exosomal miRNAs were isolated and used to perform HiSeq deep-sequencing analyses on serum pool samples from platinum-resistant or platinum-sensitive patients, and six exosomal miRNAs were further validated for their predictive utility by qRT-PCR in 170 serum samples of patients with advanced NSCLC. Gain- and loss-of-function experiments clarified the responsiveness regulating role of the clinically relevant miRNA. IHC analyses were performed to evaluate the association between basal autophagy in lung cancer tissues and responsiveness in 203 patients with NSCLC receiving platinum-based chemotherapy.

Results:
Six circulating exosomal miRNAs (miR-425-3p, miR-1273h, miR-4755-5p, miR-9-5p, miR-146a-5p, and miR-215-5p) were found to be differentially expressed with the largest fold change in platinum-resistant patients compared with platinum-sensitive patients. High miR-425-3p proved to be a potent predictive biomarker for low responsiveness and poor progression-free survival (PFS). Mechanistically, miR-425-3p upregulated the autophagic levels via targeting AKT1, leading to the decrease in therapeutic response. Concordantly, high levels of basal autophagy in lung cancer tissues correlate with low responsiveness in patients with NSCLC within the early and advanced disease stages.

Conclusions:
Our study highlights circulating exosomal miR-425-3p as a potential biomarker for improved predictions of the clinical response to platinum-based chemotherapy in patients with NSCLC.

Impact:
This study provides the first evidence that miR-425-3p in NSCLC patient–derived exosomes can be a marker for predicating the clinical response to platinum-based chemotherapy.
Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC
Authors: Le Xiuning , Puri Sonam , Negrao Marcelo V. , Nilsson Monique B. , Robichaux Jacqulyne , Boyle Theresa , Hicks J. Kevin , Lovinger Katherine L. , Roarty Emily , Rinsurongkawong Waree , Tang Ming , Sun Huiying , Elamin Yasir , Lacerda Lara C. , Lewis Jeff , Roth Jack A. , Swisher Stephen G. , Lee J. Jack , William William N. , Glisson Bonnie S. , Zhang Jianjun , Papadimitrakopoulou Vassiliki A. , Gray Jhanelle E. , Heymach John V. 
Published: September 2018

Abstract

Purpose:
Osimertinib was initially approved for T790M-positive non–small cell lung cancer (NSCLC) and, more recently, for first-line treatment of EGFR-mutant NSCLC. However, resistance mechanisms to osimertinib have been incompletely described.

Experimental Design:
Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.

Results:
In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months, P = 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months, P = 0.02).

Conclusions:
Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.
See related commentary by Devarakonda and Govindan, p. 6112.
Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin
Authors: Yang Dian , Denny Sarah K. , Greenside Peyton G. , Chaikovsky Andrea C. , Brady Jennifer J. , Ouadah Youcef , Granja Jeffrey M. , Jahchan Nadine S. , Lim Jing Shan , Kwok Shirley , Kong Christina S. , Berghoff Anna S. , Schmitt Anna , Reinhardt H. Christian , Park Kwon-Sik , Preusser Matthias , Kundaje Anshul , Greenleaf William J. , Sage Julien , Winslow Monte M. 
Published: September 2018

Abstract
The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms.
Significance: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1316–31. ©2018 AACR.
See related commentary by Pozo et al., p. 1216.
This article is highlighted in the In This Issue feature, p. 1195
Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer
Authors: O'Malley Grace , Treacy Oliver , Lynch Kevin , Naicker Serika D. , Leonard Niamh A. , Lohan Paul , Dunne Philip D. , Ritter Thomas , Egan Laurence J. , Ryan Aideen E. 
Published: September 2018

Abstract
Stromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFα-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells. Using CD274 shRNA and antibody-mediated approaches, we showed that stromal cell PD-L1 potentiated enhanced immunosuppression, characterized by inhibition of activated CD8+ granzyme B-secreting T cells in vitro, and the inhibition of CD8+ effector cells was associated with enhanced tumor progression. Stromal cell immunosuppressive and tumor-promoting effects could be reversed with administration of anti–PD-1 in vivo. We validated our findings of stromal cell CD274 expression in two cohorts of clinical samples and also observed PD-L1 induction on human stromal cells in response to exposure to the inflammatory secretome from human colon cancer cells, irrespective of microsatellite instability. Collectively, our data showed that tumor-associated stromal cells support T-cell suppression by PD-L1 induction, which is dependent on colon cancer inflammatory signaling. Our findings reveal a key role of mesenchymal stromal cells PD-L1 in suppression of CD8+ antitumor immune responses and potentiation of colorectal cancer progression. Cancer Immunol Res; 6(11); 1426–41. ©2018 AACR.
Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status
Authors: Hamada Tsuyoshi , Zhang Xuehong , Mima Kosuke , Bullman Susan , Sukawa Yasutaka , Nowak Jonathan A. , Kosumi Keisuke , Masugi Yohei , Twombly Tyler S. , Cao Yin , Song Mingyang , Liu Li , da Silva Annacarolina , Shi Yan , Gu Mancang , Li Wanwan , Koh Hideo , Nosho Katsuhiko , Inamura Kentaro , Keum NaNa , Wu Kana , Meyerhardt Jeffrey A. , Kostic Aleksandar D. , Huttenhower Curtis , Garrett Wendy S. , Meyerson Matthew , Giovannucci Edward L. , Chan Andrew T. , Fuchs Charles S. , Nishihara Reiko , Giannakis Marios , Ogino Shuji 
Published: September 2018

Abstract
The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor–immune microenvironment between MSI-high and non–MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses’ Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (Pinteraction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22–0.92], but positively associated with TIL in non–MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12–3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327–36. ©2018 AACR.
See related Spotlight on p. 1290.
Survival after Endoscopic Valve Therapy in Patients with Severe Emphysema
Authors: Gompelmann Daniela , Benjamin Nicola , Bischoff Elena , Kontogianni Konstantina , Schuhmann Maren , Hoffmann Hans , Heussel Claus Peter , Herth Felix J.F. , Eberhardt Ralf 
Published: September 2018

<b><i>Background:</i></b> Endoscopic valve therapy leads to an improvement of lung function, exercise tolerance, and quality of life in a selected cohort of patients with advanced emphysema. So far, only few data exist on the long-term outcome. <b><i>Objectives:</i></b> This analysis evaluated the impact of valve therapy on the survival of emphysema patients. <b><i>Methods:</i></b> Survival rates of emphysema patients who underwent valve therapy were assessed according to their radiological outcome following valve placement. <b><i>Results:</i></b> From 2005 to 2013, 449 emphysema patients (mean age 64 ± 7 years) underwent valve therapy and were followed for a mean time of 37.3 ± 21.3 months. A total of 128 patients (29%) developed complete lobar atelectasis, 34 out of these also experienced a pneumothorax; 50 patients (11%) developed pneumothorax without lobar atelectasis, and 261 patients (58%) target lobe volume reduction or no volume change. Patients with atelectasis showed significantly better baseline forced expiratory volume in 1 second (%), residual volume (L), total lung capacity (L), and transfer factor for carbon monoxide (%; all <i>p</i> &#x3c; 0.05), but there was no significant difference in the BODE score (<i>p</i> = 0.195). Patients with valve-induced lobar atelectasis had a significant survival benefit compared to patients without atelectasis (<i>p</i> = 0.009; 5-year survival rate 65.3 vs. 43.9%). The advent of pneumothorax in 84 patients did not influence survival (<i>p</i> = 0.52). <b><i>Conclusions:</i></b> Lobar atelectasis following endoscopic valve therapy is associated with a survival benefit.