tbuckley/cabot-search huggingface dataset:
Longitudinal genomic surveillance of multidrug-resistant Escherichia coli carriage in a long-term care facility in the United Kingdom
Authors: Hayley J. Brodrick, Kathy E. Raven, Teemu Kallonen, Dorota Jamrozy, Beth Blane, Nicholas M. Brown, Veronique Martin, M. Estée Török, Julian Parkhill, Sharon J. Peacock
Journal: Genome Medicine (2017)

Residents of long-term care facilities (LTCF) may have high carriage rates of multidrug-resistant pathogens, but are not currently included in surveillance programmes for antimicrobial resistance or healthcare-associated infections. Here, we describe the value derived from a longitudinal epidemiological and genomic surveillance study of drug-resistant Escherichia coli in a LTCF in the United Kingdom (UK). Forty-five of 90 (50%) residents were recruited and followed for six months in 2014. Participants were screened weekly for carriage of extended-spectrum beta-lactamase (ESBL) producing E. coli. Participants positive for ESBL E. coli were also screened for ESBL-negative E. coli. Phenotypic antibiotic susceptibility of E. coli was determined using the Vitek2 instrument and isolates were sequenced on an Illumina HiSeq2000 instrument. Information was collected on episodes of clinical infection and antibiotic consumption. Seventeen of 45 participants (38%) carried ESBL E. coli. Twenty-three of the 45 participants (51%) had 63 documented episodes of clinical infection treated with antibiotics. Treatment with antibiotics was associated with higher risk of carrying ESBL E. coli. ESBL E. coli was mainly sequence type (ST)131 (16/17, 94%). Non-ESBL E. coli from these 17 cases was more genetically diverse, but ST131 was found in eight (47%) cases. Whole-genome analysis of 297 ST131 E. coli from the 17 cases demonstrated highly related strains from six participants, indicating acquisition from a common source or person-to-person transmission. Five participants carried highly related strains of both ESBL-positive and ESBL-negative ST131. Genome-based comparison of ST131 isolates from the LTCF study participants with ST131 associated with bloodstream infection at a nearby acute hospital and in hospitals across England revealed sharing of highly related lineages between the LTCF and a local hospital. This study demonstrates the power of genomic surveillance to detect multidrug-resistant pathogens and confirm their connectivity within a healthcare network.
Glioblastoma in elderly patients: solid conclusions built on shifting sand?
Authors: Antje Wick, Tobias Kessler, Andrew E H Elia, Frank Winkler, Tracy T Batchelor, Michael Platten, Wolfgang Wick
Journal: Neuro-Oncology (2017)

Management of glioblastoma in the elderly population is challenging. In the near future, more than half of patients with this tumor will be over the age of 65. Clinicians have been historically reluctant to treat such patients with the same intensity as younger patients. Due to upper age limits or poor accrual of elderly patients in clinical trials, randomized data for this patient population have been relatively sparse until recently. In this review, we will discuss the concept of an elderly patient population, describe evidence for molecular differences in glioblastoma of elderly versus young patients, evaluate recent first-line trials studying glioblastoma in elderly patients, and discuss best therapeutic practices including the value of molecular testing.
Can toxicities induced by antituberculosis drugs be better managed in diabetic patients?
Authors: Wing Wai Yew, Denise P. Chan, Chi Chiu Leung, Ying Zhang, Ruibing Wang, Phoebe Ng, Simon M. Lee
Journal: European Respiratory Journal (2017)

The converging epidemics of tuberculosis and diabetes mellitus worldwide have immense healthcare implications [1]. Diabetes mellitus adversely impacts tuberculosis treatment outcomes, largely as delayed bacteriological conversion and lower cure, as well as higher relapse and mortality. Worsened drug resistance scenarios may also result. In addition, diabetic patients experience a higher risk of toxicities induced by drugs used for treating drug-susceptible tuberculosis and multidrug-resistant tuberculosis (table 1) [1, 2]. Clearly, these adverse reactions merit better management. Elucidating mechanisms of antituberculosis-drug-induced toxicities in diabetic patients helps in clinical management <http://ow.ly/92vA30cAlBW> Li Ka Shing Institute of Health Sciences is gratefully acknowledged for providing technical support to this research
Inhibition of ornithine decarboxylase to facilitate pegylated arginase treatment in lung adenocarcinoma xenograft model.
Authors: James C. M. Ho, Sze Kwan Lam, kin Pong U, Paul Ning-Man Cheng
Journal: Journal of Clinical Oncology (2016)

e23184 Background: Arginine depletion has shown promising anticancer effects among arginine auxotrophic cancers that are deficient in argininosuccinate synthetase (ASS) and/or ornithine transcarbamylase (OTC). Pegylated arginase (PEG-BCT-100 (rhArg1peg5000)) works as an arginine depletor by converting arginine to ornithine. However, accumulated ornithine can be channeled via ornithine decarboxylase (ODC) to produce polyamines that are known to promote tumor growth. We postulate that ODC inhibition enhances anticancer effects of BCT-100 in lung adenocarcinoma. Methods: The activity of BCT-100 was tested in a panel of lung adenocarcinoma cell lines (H23, H358, HCC827, H1650, H1975, HCC2935 and HCC4006). Cell viability was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Protein expression was evaluated by Western Blot. Nude mice subcutaneous xenograft models(XMs) derived from these cell lines were used for in vivostudy. An ODC inhibitor (α-difluoromethylornithine or DFMO given orally) was combined with BCT-100 (intraperitoneal) in treatment of XMs. Results: BCT-100 reduced in vitrocell viability across different cell lines. However, BCT-100 could only suppress tumor growth in HCC4006 XM, while paradoxical growth stimulation was observed in H358, HCC827, H1650 and H1975 XMs. ASS was expressed in all XMs but OTC was found only in HCC827 XM. Upon BCT-100 treatment, ODC was induced in two solid tumor XMs (H1650 and H1975), while unaltered in cystic tumor XMs (H358 and HCC827) and the remaining solid tumor (HCC4006) XM. Using H1975 XM (tumor growth and ODC induced by BCT-100), combined BCT-100 and DFMO significantly suppressed tumor growth compared with control or single arm treatments (44% of control, 53% of DFMO and 30% of BCT-100 on day 12), with median survival doubled in BCT-100/DFMO (25 days) compared with control (12 days) (p < 0.0001). Apoptosis (cleavage of PARP and downregulation of survivin) and G1 (downregulation of cyclin E1, E2 and H) and G2/M arrest (downregulation of cyclin B1 and CDK7) were evident in the combination arm. Conclusions: Inhibition of ODC by DFMO is essential in BCT-100 treatment in lung adenocarcinoma.
P1.15: Comparison of Pulmonary Function After Robotic-Assisted Video-Thoracoscopic Lobectomies vs Segmentectomies
Authors: Maria F. Echavarria, Anna Cheng, Frank Velez, Emily Ng, Eric Toloza, Jacques-Pierre Fontaine, Carla Moodie, Joseph Garrett
Journal: Journal of Thoracic Oncology (2016)
Genetic and epigenetic regulation of YKL-40 in childhood
Authors: Stefano Guerra, Erik Melén, Jordi Sunyer, Cheng-Jian Xu, Iris Lavi, Marta Benet, Mariona Bustamante, Anne-Elie Carsin, Carlota Dobaño, Mònica Guxens, Christina Tischer, Martine Vrijheid, Inger Kull, Anna Bergström, Ashish Kumar, Cilla Söderhäll, Ulrike Gehring, Dorieke J. Dijkstra, Pieter van der Vlies, Magnus Wickman, Jean Bousquet, Dirkje S. Postma, Josep M. Anto, Gerard H. Koppelman
Journal: Journal of Allergy and Clinical Immunology (2017)
A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma
Authors: Donald M. O’Rourke, MacLean P. Nasrallah, Arati Desai, Jan J. Melenhorst, Keith Mansfield, Jennifer J. D. Morrissette, Maria Martinez-Lage, Steven Brem, Eileen Maloney, Angela Shen, Randi Isaacs, Suyash Mohan, Gabriela Plesa, Simon F. Lacey, Jean-Marc Navenot, Zhaohui Zheng, Bruce L. Levine, Hideho Okada, Carl H. June, Jennifer L. Brogdon, Marcela V. Maus
Journal: Science Translational Medicine (2017)

A trial of autologous T cells redirected to a specific mutation in glioblastoma patients illustrates mechanisms of resistance.
The antibiotic course has had its day
Authors: Martin J Llewelyn, Jennifer M Fitzpatrick, Elizabeth Darwin, None SarahTonkin-Crine, Cliff Gorton, John Paul, Tim E A Peto, Lucy Yardley, Susan Hopkins, Ann Sarah Walker
Journal: BMJ (2017)

With little evidence that failing to complete a prescribed antibiotic course contributes to antibiotic resistance, it’s time for policy makers, educators, and doctors to drop this message, argue <b>Martin Llewelyn and colleagues</b>
Intratumor Heterogeneity Is Associated with Survival of Patients with Stage IA Lung Adenocarcinoma
Authors: K. Quek, J. Li, J. Fujimoto, J. Zhang, C.-W. Chow, C. Behrens, J. Zhang, A. Weissferdt, S. Swisher, J.J. Lee, J. Heymach, I.I. Wistuba, P.A. Futreal, J. Zhang
Journal: Journal of Thoracic Oncology (2017)
An Ascites Tumor Derived From the Novikoff Hepatoma&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Monroe Birns
Journal: JNCI Journal of the National Cancer Institute (1960)

A transplantable ascites tumor was derived for the first time from the Novikoff hepatoma. It has been carried as a free-cell population but can readily be converted to an island form.
Role of long non-coding RNAs in glucose metabolism in cancer
Authors: Chunmei Fan, Yanyan Tang, Jinpeng Wang, Fang Xiong, Can Guo, Yumin Wang, Shanshan Zhang, Zhaojian Gong, Fang Wei, Liting Yang, Yi He, Ming Zhou, Xiaoling Li, Guiyuan Li, Wei Xiong, Zhaoyang Zeng
Journal: Molecular Cancer (2017)

Long-noncoding RNAs (lncRNAs) are a group of transcripts that are longer than 200 nucleotides and do not code for proteins. However, this class of RNAs plays pivotal regulatory roles. The mechanism of their action is highly complex. Mounting evidence shows that lncRNAs can regulate cancer onset and progression in a variety of ways. They can not only regulate cancer cell proliferation, differentiation, invasion and metastasis, but can also regulate glucose metabolism in cancer cells through different ways, such as by directly regulating the glycolytic enzymes and glucose transporters (GLUTs), or indirectly modulating the signaling pathways. In this review, we summarized the role of lncRNAs in regulating glucose metabolism in cancer, which will help understand better the pathogenesis of malignant tumors. The understanding of the role of lncRNAs in glucose metabolism may help provide new therapeutic targets and novel diagnostic and prognosis markers for human cancer.
Postponement of death weighed against duration of treatment and toxicity as key components in shared decision making about last line oncologic treatment.
Authors: Lars Henrik Jensen, Natacha D Trabjerg, Torben Hansen, Anders Kristian Moeller Jakobsen, Karina Dahl Steffensen
Journal: Journal of Clinical Oncology (2017)

e21555 Background: Decisions about last-line treatment are challenging in oncology practice. The hope of prolonging life and reducing symptoms should be weighed against the time spend on treatment, side effects and cost. Standard oncology measures of effect such as median survival time and number needed to treat are not easily explained to patients. Postponement of symptoms or death has been shown to be superior to e.g. number needed to treat in communicating the benefit of treatment to patients. The aim of the present study was to develop a tool for shared decision making in last line treatment of patients with colorectal cancer. Methods: A literature review identified pivotal phase III trials about specific antineoplastic agents for metastatic colorectal cancer after standard treatments. Principles for determining the mean survival followed restricted mean survival time analysis. High-resolution survival curves were digitalized. Areas under the curves (AUC) were calculated for the experimental group and the control group. Results: Two drugs are approved for colorectal cancer after exposure to standard treatments; regorafenib and TAS102. AUC at one year for regorafenib was 30.1 weeks compared to 26.6 weeks for placebo resulting in a difference of 3.5 weeks. AUC at one year for TAS102 was 31.4 weeks compared to 25.7 weeks for placebo resulting in a difference of 5.7 weeks. Average time on treatment was 12 weeks for regorafenib and 14 weeks for TAS102. Risk of severe, medical significant or life-threatening (grade 3-4) adverse events increased from 14% to 54% (regorafenib) and from 52% to 69% (TAS102). Conclusions: Data was developed for shared decision making using restricted mean survival time. A patient with colorectal cancer after standard treatment can be advised: »This is a deadly disease irrespective of treatment. On average, taking medicine for about 12 weeks will postpone death for 4 to 6 weeks. Taking the medicine will cause 17 to 40 extra patients out of 100 experiencing severe or life-threatening side effects«. The concept of postponement will be further explored as a key component in patient empowerment for value based care.
Breast Stem Cells and Their Implications for Cancer
Authors: Jane Visvader, Marie-Liesse Asselin-Labat, Francois Vaillant, Mark Shackleton, Kate Sutherland, Toula Bouras, Jacqueline van der Wees, Frank Grosveld, Geoffrey Lindeman
Journal: Clinical Cancer Research (2007)

PL05-02  Interest in mammary stem cells (MaSCs) has been stimulated by their potential role in breast tumorigenesis. We have isolated discrete populations of mouse mammary epithelial cells on the basis of expression of the cell surface markers (CD29 and CD24) and transplanted these into cleared fat pads of recipient mice to identify the mammary stem cell. A population that expresses ‘basal’ markers and is highly enriched for mammary stem cells was defined. An absolute expansion in the number of mammary stem cells was observed in the pre-neoplastic phase in the MMTV-wnt-1 mammary tumor model, suggesting that these tumors originate within mammary stem cells. Interestingly, the basal stem cell-enriched population was found to be ‘triple negative’ for ER, PR and ErbB2. This phenotype is reminiscent of human basal tumors, inferring that the mammary stem cell may be the ‘cell of origin’ for this poor prognosis subset. We have recently further subdivided the luminal epithelial cell-containing population on the basis of CD61 (β3-integrin) expression. The CD61+ subset contained luminal progenitors, as defined by colony forming assays, and is the earliest identified cell-type to express ER. Since the GATA-3 transcription factor is a key marker of ‘luminal’ breast tumors, we studied its role in normal mammary gland development. Utilising conditionally targeted mice, Gata-3 was found to be essential for mammary gland morphogenesis in both the embryo and adult. Gata-3 deficiency resulted in an expansion of CD61+ luminal progenitors and a concomitant block in epithelial differentiation in both virgin and pregnant glands. These findings provide evidence for the existence of an epithelial hierarchy within the mammary gland and reveal that GATA-3is a critical regulator of luminal cell differentiation. It is likely that high expression of GATA-3 in luminal tumors confers a favourable prognosis due to the promotion of differentiation. Conversely, GATA-3 loss could result in a more clinically aggressive phenotype.
The Memphis breast cancer disparity-screening program.
Authors: Gregory A. Vidal, Zaquishia Green, Cynthia Tankersley, Zachary Hidinger, Rafael Miranda, Bobby Baker, Paula Jacobson, Kimberly Lamar, Edward Rafalski, Kurt W. Tauer
Journal: Journal of Clinical Oncology (2015)

e12577 Background: Despite the higher incidence of breast cancer in the white population, the mortality rates are higher in blacks. This is most apparent in the city of Memphis, TN, with the largest mortality disparity of large cities. Memphis also has the distinction of having the highest number of deaths from breast cancer in Tennessee. Conventional risk factors play a role, but they do not fully explain this difference. Socioeconomic factors are contributory. The city of Memphis, which is predominantly black, has a 20% poverty level and a dismal uninsured rate. The rate of annual screening mammograms is low in this population. We hypothesized that a screening program targeted at the uninsured may help reduce the breast cancer mortality. Methods: Through a cooperative partnership between the Methodist Le Bonheur Healthcare System and West Cancer Center, we utilized the Congregational Health Network (CHN) and a Community Outcome and Relations Coordinator (CORC) to seamlessly transition participants from the community to the clinic. The CHN is comprised of 8 patient navigators and over 600 trained liaisons that identify potential candidates for screening through patient centered care that begins in the congregation. The CORC works within the community centers and other areas of the city. Together, we efficiently schedule all imaging and consultations as well as track appointments to ensure compliance. Our funding partners are the Susan G Komen Memphis Mid-South and the Avon Foundation. Results: From September 2014 to January 2015, 586 women were initially contacted, 27 were ineligible and 152 are pending call back. Of the remaining 407 women, 325 have been screened—222 screening and 103 diagnostic mammograms. Our estimated adherence rate was 80%. This resulted in a 5.8% call back biopsy rate (19/325) of which 15 have been completed. Two malignant lesions have been detected. 67% of women were black, 29% Hispanic and 1% white. 77% of women were between the ages of 40-60 years Conclusions: We have described a successful, seamless network involving health care professionals and community stakeholders working together in a pilot project to attack this increasing cancer mortality in a vulnerable population
BERNIE: Open-label, randomized, phase II study of bevacizumab plus chemotherapy in pediatric metastatic rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
Authors: Julia C. Chisholm, Johannes H. Merks, Michela Casanova, Gianni Bisogno, Daniel Orbach, Jean-Claude Gentet, Anne-Sophie Thomassin Defachelles, Pascal B. Chastagner, Steve Lowis, Milind Ronghe, Kieran McHugh, Rick R. van Rijn, Magalie Hilton, Jeanette Bachir, Sabine Fürst-Recktenwald, Birgit Geoerger, Odile Oberlin
Journal: Journal of Clinical Oncology (2016)

11054 Background: Thephase II BERNIE study evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic RMS/NRSTS. Methods: Eligible patients aged ≥6 months and <18 years were randomized to receive 18 months of induction chemotherapy (4x 21-day cycles of IVADo [ifosfamide, vincristine, actinomycin-D, doxorubicin] + 5x cycles of IVA; ± bevacizumab 7.5mg/kg q3w) with local therapy, followed by maintenance chemotherapy (12x 28-day cycles of cyclophosphamide + vinorelbine; ± bevacizumab 5.0mg/kg q2w). The primary objective was independent review committee (IRC)-assessed event-free survival (EFS). Secondary objectives included: pharmacokinetics; safety; overall response rate (ORR); and overall survival (OS). Results: 154 patients were randomized to receive chemotherapy (n=80) or bevacizumab plus chemotherapy (n=74). Baseline characteristics were balanced. The cut-off for the results shown below was May 31, 2015, 19 months after the last patient was enrolled. Conclusions: The addition of bevacizumab to the chemotherapy backbone appeared tolerable and enhanced ORR in children and adolescents with metastatic RMS/NRSTS, but the primary and secondary efficacy endpoints were not met. Long-term observation continues. Clinical trial information: NCT00643565. Chemotherapy (n=80) Bevacizumab + chemo- therapy (n=74) Hazard ratio (95% CI) Median survival follow-up, months 20.5 24.95 - Patients with an event, n (%) 42 (52.5) 51 (68.9) - Median EFS by IRC, months 14.9 20.6 0.93 (0.61−1.41); p=0.72 Median EFS by investigator, months 12.5 18.9 0.71 (0.47−1.07); p=0.10 Median OS, months 42.2 32.3 0.79 (0.49−1.26); p=0.32 ORR by IRC, % 36.0 54.0 Difference 18.0% (95% Hauck-Anderson CI: 0.64−35.30); p=0.04 Grade 3/4 AEs (mainly hematologic), % patients 100 98.6 - Grade 3/4 AEs of special interest for bevacizumab, % patients 12.7 12.7 - Deaths due to AEs, % 0 0 -
Distinct Trajectories of Massive Recent Gene Gains and Losses in Populations of a Microbial Eukaryotic Pathogen
Authors: Fanny E. Hartmann, Daniel Croll
Journal: Molecular Biology and Evolution (2017)

Differences in gene content are a significant source of variability within species and have an impact on phenotypic traits. However, little is known about the mechanisms responsible for the most recent gene gains and losses. We screened the genomes of 123 worldwide isolates of the major pathogen of wheat Zymoseptoria tritici for robust evidence of gene copy number variation. Based on orthology relationships in three closely related fungi, we identified 599 gene gains and 1,024 gene losses that have not yet reached fixation within the focal species. Our analyses of gene gains and losses segregating in populations showed that gene copy number variation arose preferentially in subtelomeres and in proximity to transposable elements. Recently lost genes were enriched in virulence factors and secondary metabolite gene clusters. In contrast, recently gained genes encoded mostly secreted protein lacking a conserved domain. We analyzed the frequency spectrum at loci segregating a gene presence-absence polymorphism in four worldwide populations. Recent gene losses showed a significant excess in low-frequency variants compared with genome-wide single nucleotide polymorphism, which is indicative of strong negative selection against gene losses. Recent gene gains were either under weak negative selection or neutral. We found evidence for strong divergent selection among populations at individual loci segregating a gene presence-absence polymorphism. Hence, gene gains and losses likely contributed to local adaptation. Our study shows that microbial eukaryotes harbor extensive copy number variation within populations and that functional differences among recently gained and lost genes led to distinct evolutionary trajectories.
Appearance of antidesmocollin 1 autoantibodies leading to a vegetative lesion in a patient with pemphigus vulgaris
Authors: Y. Yamaguchi, S. Shinkuma, N. Ishii, S. Takashima, K. Natsuga, H. Ujiie, H. Iwata, T. Nomura, Y. Fujita, A. Hamasaka, K. Hamasaka, T. Hashimoto, H. Shimizu
Journal: British Journal of Dermatology (2017)
Prevalence of primary immunodeficiencies in France is underestimated
Authors: Nizar Mahlaoui, Jean-Philippe Jais, Pauline Brosselin, Cecile Mignot, Beatrice Beaurain, Carolina Brito, Laurence Costes, Virginie Courteille, Nathalie De Vergnes, Alexandre Alcaïs, Alain Fischer
Journal: Journal of Allergy and Clinical Immunology (2017)