bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter, randomized controlled, observer‐blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes—ProNOx1 study
Authors: Edmonds Michael E. , Bodansky Harvey J. , Boulton Andrew J.M. , Chadwick Paul J. , Dang Cuong N. , D'Costa Ryan , Johnston Atholl , Kennon Brian , Leese Graham , Rajbhandari Satyan M. , Serena Thomas E. , Young Matthew J. , Stewart Joanne E. , Tucker Arthur T. , Carter Marissa J. 
Published: April 2018

AbstractThe aim of this multicenter, prospective, observer‐blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting “real world” clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25–2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12‐week follow‐up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110—75; Control—73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention‐to‐treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice.
Development of a large‐volume human‐derived adipose acellular allogenic flap by perfusion decellularization
Authors: Giatsidis Giorgio , Guyette Jacques P. , Ott Harald C. , Orgill Dennis P. 
Published: April 2018

AbstractIn reconstructive surgery, transfer of patients’ tissue (autologous flaps) is routinely used to repair large soft tissue defects caused by surgery, trauma, chronic diseases, or malformations; unfortunately, this strategy is not always possible and often creates a secondary defect in the donor site of the tissue. Tissue‐engineered synthetic flaps are currently unable to repair clinically‐relevant, large‐volume defects; allogenic flaps from cadaveric donors could provide a ready‐to‐use biological alternative if treated with methods to avoid the immune‐rejection of the donor's cells. Here, we describe the successful decellularization of a large (> 800 cc) human‐derived adipose flap through a perfusion apparatus; we demonstrate the complete removal of the immunogenic cellular components of the flap with the retention of its structural components and vascular network. Our aim is to obtain a universally compatible, off‐the‐shelf acellular allogenic flap that could be recellularized with cells from recipient patients to provide a tissue‐engineered allogenic/autologous alternative for reconstruction of large‐volume soft‐tissue defects.
Draft Genome Sequence of Candida pseudohaemulonii Isolated from the Blood of a Neutropenic Patient
Authors: Mohd Tap Ratna , Kamarudin Nur Amalina , Ginsapu Stephanie Jane , Ahmed Bakri Ahmed Rafezzan , Ahmad Norazah , Amran Fairuz , Sipiczki Matthias 
Published: April 2018

ABSTRACT

Candida pseudohaemulonii
is phylogenetically close to the
C. haemulonii
complex and exhibits resistance to amphotericin B and azole agents. We report here the draft genome sequence of
C. pseudohaemulonii
UZ153_17 isolated from the blood culture of a neutropenic patient. The draft genome is 3,532,003,666 bp in length, with 579,838 reads, 130 contigs, and a G+C content of 47.15%.
Challenges in screening for latent tuberculosis in inflammatory bowel disease prior to biologic treatment: a UK cohort study
Authors: Thi Aye Aye , Abbara Aula , Bouri Sonia , Collin Simon M , Wolfson Paul , Owen Leah , Buell Kevin G , John Laurence , Hart Ailsa L 
Published: April 2018

ObjectiveThe aim of this study was to determine the occurrence of latent tuberculosis infections (LTBI) and active TB in a cohort of patients with inflammatory bowel disease (IBD) treated with biologics. We also examined the effects of immunosuppressive drugs on indeterminate interferon-gamma release assays (IGRA) in LTBI screening.DesignRetrospective study of patients treated with biologics between March 2007 and November 2015.SettingSt Mark’s Hospital, North West London, UK.Patients732 patients with IBD who were screened for LTBI using either tuberculin skin test or IGRA before starting a biologic treatment.MethodsRetrospective case note review of all patients with IBD who were screened for LTBI prior to initiating biologics. Patients who developed active TB were identified from the London TB register.ResultsOf 732 patients with IBD, 31 (4.2%) were diagnosed with and treated for LTBI with no significant side effects. Six of 596 patients (1.0%) who received biologic treatment developed active TB. There was a higher proportion of indeterminate IGRA in the immunosuppressive medication group compared with the non-immunosuppressive group (33% (59/181) compared with 9% (6/66), p<0.001). The combination of steroids and thiopurines had the highest proportion of indeterminate IGRA (64%, 16/25). High and low doses of steroids were equally likely to result in an indeterminate IGRA result (67% (8/12) and 57% (4/7), respectively).ConclusionsThis study highlights the challenges of LTBI screening prior to commencing biologic therapy and demonstrates the risk of TB in patients who have been screened and who are receiving prolonged and continuing doses of antitumour necrosis factor.
Emphasizing the “positive” in positive reinforcement: using nonbinary rewarding for training monkeys on cognitive tasks
Authors: Fischer Benjamin , Wegener Detlef 
Published: April 2018

Nonhuman primates constitute an indispensable model system for studying higher brain functions at the neurophysiological level. Studies involving these animals elucidated the neuronal mechanisms of various cognitive and executive functions, such as visual attention, working memory, and decision-making. Positive reinforcement training (PRT) constitutes the gold standard for training animals on the cognitive tasks employed in these studies. In the laboratory, PRT is usually based on application of a liquid reward as the reinforcer to strengthen the desired behavior and absence of the reward if the animal’s response is wrong. By trial and error, the monkey may adapt its behavior and successfully reduce the number of error trials, and eventually learn even very sophisticated tasks. However, progress and success of the training strongly depend on reasonable error rates. If errors get too frequent, they may cause a drop in the animal’s motivation to cooperate or its adaptation to high error rates and poor overall performance. We introduce in this report an alternative training regime to minimize errors and base the critical information for learning on graded rewarding. For every new task rule, the feedback to the animal is provided by different amounts of reward to distinguish the desired, optimal behavior from less optimal behavior. We applied this regime in different situations during training of visual attention tasks and analyzed behavioral performance and reaction times to evaluate its effectiveness. For both simple and complex behaviors, graded rewarding was found to constitute a powerful technique allowing for effective training without trade-off in accessible task difficulty or task performance. NEW & NOTEWORTHY Laboratory training of monkeys usually builds on providing a fixed amount of reward for the desired behavior, and no reward otherwise. We present a nonbinary, graded reward schedule to emphasize the positive, desired behavior and to keep errors on a moderate level. Using data from typical training situations, we demonstrate that graded rewards help to effectively guide the animal by success rather than errors and provide a powerful new tool for positive reinforcement training.
Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis
Authors: Tang Grace H. , Satkunam Meloja , Pond Gregory R. , Steinberg Gregory R. , Blandino Giovanni , Schünemann Holger J. , Muti Paola 
Published: April 2018

Abstract
Background: Preclinical data suggest that metformin may reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence of breast cancer and all-cause mortality in patients with type II diabetes (T2D).
Methods: A literature search was performed on Medline, EMBASE, and the Cochrane library from inception to November 2016. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall certainty of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. Meta-analyses were performed using the most fully adjusted ORs or HRs and 95% confidence intervals (95% CI) as effect measures.
Results: A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR = 0.93; 95% CI, 0.85–1.03; I2 = 35%). A 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI, 0.44–0.70; I2 = 81%). Presence of publication bias is strongly suspected for both outcomes using Egger's funnel plots.
Conclusions: The use of metformin may improve overall survival in patients with T2D and breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and resulting biases.
Impact: Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. Cancer Epidemiol Biomarkers Prev; 27(6); 627–35. ©2018 AACR.
Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent
Authors: Piulats Josep M. , Vidal August , García-Rodríguez Francisco J. , Muñoz Clara , Nadal Marga , Moutinho Catia , Martínez-Iniesta María , Mora Josefina , Figueras Agnés , Guinó Elisabet , Padullés Laura , Aytés Àlvaro , Molleví David G. , Puertas Sara , Martínez-Fernández Carmen , Castillo Wilmar , Juliachs Merce , Moreno Victor , Muñoz Purificación , Stefanovic Milica , Pujana Miguel A. , Condom Enric , Esteller Manel , Germà Josep R. , Capella Gabriel , Farré Lourdes , Morales Albert , Viñals Francesc , García-del-Muro Xavier , Cerón Julián , Villanueva Alberto 
Published: April 2018

Abstract
Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.
Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.
Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin-resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin-refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32-q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo-PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.
Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755–66. ©2018 AACR.
Risk Assessment after Neoadjuvant Chemotherapy in Luminal Breast Cancer Using a Clinicomolecular Predictor
Authors: Loibl Sibylle , Weber Karsten , Huober Jens , Krappmann Kristin , Marmé Frederik , Schem Christian , Engels Knut , Pfitzner Berit Maria , Kümmel Sherko , Furlanetto Jenny , Hartmann Arndt , Darb-Esfahani Silvia , Müller Volkmar , Staebler Annette , von Minckwitz Gunter , Kronenwett Ralf , Denkert Carsten 
Published: April 2018

Abstract
Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathologic tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen receptor (ER)–positive/HER2-negative breast cancer. We also compared the prognostic power of the mEPclin with that of the CPS-EG score.
Experimental Design: A total of 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cut-off values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS).
Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse [HR, 2.16; 95% confidence interval (CI), 1.86–2.51; P &lt; 0.001] and death (HR, 2.28; 95% CI, 1.90–2.75; P &lt; 0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer DFS and overall survival compared with those at low risk. In contrast with CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR, 2.13; 95% CI, 1.73–2.63; P &lt; 0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; P &lt; 0.001).
Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies. Clin Cancer Res; 24(14); 3358–65. ©2018 AACR.
Prevalent Homozygous Deletions of Type I Interferon and Defensin Genes in Human Cancers Associate with Immunotherapy Resistance
Authors: Ye Zhenqing , Dong Haidong , Li Ying , Ma Tao , Huang Haojie , Leong Hon Sing , Eckel-Passow Jeanette , Kocher Jean-Pierre A. , Liang Han , Wang Liguo 
Published: April 2018

Abstract
Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done.
Experimental Design: We performed integrative analyses of the copy-number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project.
Results: We found that the type-I interferon, α-, and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%–31%, median = 12%; interquartile range = 10%–16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy.
Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance. Clin Cancer Res; 24(14); 3299–308. ©2018 AACR.
Change in Topoisomerase 1–Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol
Authors: Rugo Hope S. , Cortes Javier , Awada Ahmad , O'Shaughnessy Joyce , Twelves Chris , Im Seock-Ah , Hannah Alison , Lu Lin , Sy Sherwin , Caygill Katie , Zajchowski Deborah A. , Davis Darren W. , Tagliaferri Mary , Hoch Ute , Perez Edith A. 
Published: April 2018

Abstract
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).
Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan–Meier analyses.
Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47–63 CTCs/mL; range, 0–2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).
Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348–57. ©2018 AACR.
Characteristics of Ice Impedance Recorded From a Ring Electrode Placed at the Anterior Surface of the Cryoballoon
Authors: Avitall Boaz , Kalinski Arthur , Kocheril G. Stephen , Lizama Ken S. , Coulombe Nicolas , Laske Timothy 
Published: April 2018

Background:
The success of cryoablation of the pulmonary vein isolation (PVI) is dependent on transmural and circumferential ice formation. We hypothesize that rising impedance recorded from a ring electrode placed 2 mm from the cryoballoon signifies ice formation covering the balloon surface and indicates ice expansion. The impedance level enables titration of the cryoapplication time to avoid extracardiac damage while ensuring PVI.

Methods and Results:
In 12 canines, a total of 57 pulmonary veins were targeted for isolation. Two cryoapplications were delivered per vein with a minimum of 90 and maximum of 180-second duration. Cryoapplication was terminated on reaching a 500 Ω change from baseline. Animals recovered 38±6 days post-procedure, and veins were assessed electrically for isolation. Heart tissue was histologically analyzed. Extracardiac structures were examined for damage. PVI was achieved in 100% of the veins if the impedance reached 500 Ω in <90 seconds with freeze time of 90 seconds. When 500 Ω was reached >90 to 180 seconds (142.60±29.3 seconds), 90% PVI was achieved. When the final impedance was between 200 and 500 Ω with 180 seconds of freeze time, PVI was achieved in 86.8%. For impedance of <200 Ω, PVI was achieved in 14%. No extracardiac damage was recorded.

Conclusions:
Impedance rise of 500 Ω at <90 seconds with freeze time of 90 seconds resulted in 100% PVI. Impedance measurements from the nose of the balloon is a direct measure of ice formation on the balloon. It provides real-time feedback on the quality of the ablation and defines the cryoapplication termination time based on ice formation, limiting ice expansion to extracardiac tissues.