tbuckley/cabot-search huggingface dataset:
Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations
Authors: Jessy Cartier, Thomas Smith, John P. Thomson, Catherine M. Rose, Batbayar Khulan, Andreas Heger, Richard R. Meehan, Amanda J. Drake
Journal: Genome biology (2018)

Early life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring. These programmed effects are transmissible to a second generation through both male and female lines, suggesting germline transmission. We have previously shown that prenatal overexposure to the synthetic glucocorticoid dexamethasone (Dex) in rats reduces birth weight in the first generation (F1), a phenotype which is transmitted to a second generation (F2), particularly through the male line. We hypothesize that Dex exposure affects developing germ cells, resulting in transmissible alterations in DNA methylation, histone marks and/or small RNA in the male germline.We profile epigenetic marks in sperm from F1 Sprague Dawley rats expressing a germ cell-specific GFP transgene following Dex or vehicle treatment of the mothers, using methylated DNA immunoprecipitation sequencing, small RNA sequencing and chromatin immunoprecipitation sequencing for H3K4me3, H3K4me1, H3K27me3 and H3K9me3. Although effects on birth weight are transmitted to the F2 generation through the male line, no differences in DNA methylation, histone modifications or small RNA were detected between germ cells and sperm from Dex-exposed animals and controls.Although the phenotype is transmitted to a second generation, we are unable to detect specific changes in DNA methylation, common histone modifications or small RNA profiles in sperm. Dex exposure is associated with more variable 5mC levels, particularly at non-promoter loci. Although this could be one mechanism contributing to the observed phenotype, other germline epigenetic modifications or non-epigenetic mechanisms may be responsible for the transmission of programmed effects across generations in this model.
Loss of Chromosome 18q11.2-q12.1 Is Predictive for Survival in Patients With Metastatic Colorectal Cancer Treated With Bevacizumab
Authors: Erik van Dijk, Hedde D. Biesma, Martijn Cordes, Dominiek Smeets, Maarten Neerincx, Sudipto Das, Paul P. Eijk, Verena Murphy, Anna Barat, Orna Bacon, Jochen H.M. Prehn, Johannes Betge, Timo Gaiser, Bozena Fender, Gerrit A. Meijer, Deborah A. McNamara, Rut Klinger, Miriam Koopman, Matthias P.A. Ebert, Elaine W. Kay, Bryan T. Hennessey, Henk M.W. Verheul, William M. Gallagher, Darran P. O'Connor, Cornelis J.A. Punt, Fotios Loupakis, Diether Lambrechts, Annette T. Byrne, Nicole C.T. van Grieken, Bauke Ylstra
Journal: Journal of Clinical Oncology (2018)

Purpose Patients with metastatic colorectal cancer (mCRC) have limited benefit from the addition of bevacizumab to standard chemotherapy. However, a subset probably benefits substantially, highlighting an unmet clinical need for a biomarker of response to bevacizumab. Previously, we demonstrated that losses of chromosomes 5q34, 17q12, and 18q11.2-q12.1 had a significant correlation with progression-free survival (PFS) in patients with mCRC treated with bevacizumab in the CAIRO2 clinical trial but not in patients who did not receive bevacizumab in the CAIRO trial. This study was designed to validate these findings. Materials and Methods Primary mCRC samples were analyzed from two cohorts of patients who received bevacizumab as first-line treatment; 96 samples from the European multicenter study Angiopredict (APD) and 81 samples from the Italian multicenter study, MOMA. A third cohort of 90 samples from patients with mCRC who did not receive bevacizumab was analyzed. Copy number aberrations of tumor biopsy specimens were measured by shallow whole-genome sequencing and were correlated with PFS, overall survival (OS), and response. Results Loss of chromosome 18q11.2-q12.1 was associated with prolonged PFS most significantly in both the cohorts that received bevacizumab (APD: hazard ratio, 0.54; P = .01; PFS difference, 65 days; MOMA: hazard ratio, 0.55; P = .019; PFS difference, 49 days). A similar association was found for OS and overall response rate in these two cohorts, which became significant when combined with the CAIRO2 cohort. Median PFS in the cohort of patients with mCRC who did not receive bevacizumab and in the CAIRO cohort was similar to that of the APD, MOMA, and CAIRO2 patients without an 18q11.2-q12.1 loss. Conclusion We conclude that the loss of chromosome 18q11.2-q12.1 is consistently predictive for prolonged PFS in patients receiving bevacizumab. The predictive value of this loss is substantiated by a significant gain in OS and overall response rate.
Rationale, Opportunities, and Reality of Biosimilar Medications
Authors: Gary H. Lyman, Robin Zon, R. Donald Harvey, Richard L. Schilsky
Journal: New England Journal of Medicine (2018)

Biosimilars work like established therapeutic agents but have some dissimilarities based on differences in production. These agents should be less expensive than, but as effective as, their patented relatives, but several barriers keep the advantage from being realized.
Impact Of Posaconazol Liquid Vs. Tablet Formulation On Plasma Trough Levels In Lung Transplant Recipients
Authors: D. Stelzer, F. Ihle, A. Weber, N. Kneidinger, G. Zimmermann, F. Ceelen, R. Schramm, H. Winter, L. Frey, M. Andraschko, M. Vogeser, J. Behr, C. Neurohr
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Global governance of antimicrobial resistance
Authors: Connor Rochford, Devi Sridhar, Ngaire Woods, Zia Saleh, Lars Hartenstein, Hemant Ahlawat, Ed Whiting, Mark Dybul, Otto Cars, Eric Goosby, Andrew Cassels, German Velasquez, Steven Hoffman, Enis Baris, Jonathan Wadsworth, Martha Gyansa-Lutterodt, Sally Davies
Journal: The Lancet (2018)
Intramuscular tendon injury is not associated with an increased hamstring reinjury rate within 12 months after return to play
Authors: Anne D van der Made, Emad Almusa, Gustaaf Reurink, Rod Whiteley, Adam Weir, Bruce Hamilton, Mario Maas, Aston S H Ngai, Maarten H Moen, Gert Jan Goudswaard, Johannes L Tol
Journal: British Journal of Sports Medicine (2018)

Acute hamstring injury that includes intramuscular tendon injury has been suggested to be associated with increased reinjury risk. These observations were based on a relatively small number of retrospectively analysed cases.To determine whether intramuscular tendon injury is associated with higher reinjury rates in acute hamstring injury.MRIs of 165 athletes with an acute hamstring injury were obtained within 5 days of injury. Treatment consisted of a standardised criteria-based rehabilitation programme. Standardised MRI parameters and intramuscular tendon injury, the latter subdivided into tendon disruption and waviness, were scored. We prospectively recorded reinjuries, defined as acute onset of posterior thigh pain in the same leg within 12 months after return to play.Participants were predominantly football players (72%). Sixty-four of 165 (39%) participants had an index injury with intramuscular hamstring tendon disruption, and waviness was present in 37 (22%). In total, there were 32 (19%) reinjuries. There was no significant difference (HR: 1.05, 95% CI 0.52 to 2.12, P=0.898) in reinjury rate between index injuries with intramuscular tendon disruption (n=13, 20%) and without tendon disruption (n=19, 20%). There was no significant difference in reinjury rate (X²(1)=0.031, P=0.861) between index injuries with presence of waviness (n=7, 19%) and without presence of waviness (n=25, 20%).In athletes with an acute hamstring injury, intramuscular tendon injury was not associated with an increased reinjury rate within 12 months after return to play.
BET Inhibition Overcomes Receptor Tyrosine Kinase–Mediated Cetuximab Resistance in HNSCC
Authors: Brandon Leonard, Toni M. Brand, Rachel A. O'Keefe, Eliot D. Lee, Yan Zeng, Jacquelyn D. Kemmer, Hua Li, Jennifer R. Grandis, Neil E. Bhola
Journal: Cancer Research (2018)

Abstract Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK), including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK. Bromodomain-containing protein-4 (BRD4) has been shown to regulate the transcription of various RTK in the context of resistance to PI3K and HER2 inhibition in breast cancer models. We hypothesized that, in HNSCC, targeting BRD4 could overcome cetuximab resistance by depleting alternative RTK expression. We generated independent models of cetuximab resistance in HNSCC cell lines and interrogated their RTK and BRD4 expression profiles. Cetuximab-resistant clones displayed increased expression and activation of several RTK, such as MET and AXL, as well as an increased percentage of BRD4-expressing cells. Both genetic and pharmacologic inhibition of BRD4 abrogated cell viability in models of acquired and intrinsic cetuximab resistance and was associated with a robust decrease in alternative RTK expression by cetuximab. Combined treatment with cetuximab and bromodomain inhibitor JQ1 significantly delayed acquired resistance and RTK upregulation in patient-derived xenograft models of HNSCC. These findings indicate that the combination of cetuximab and bromodomain inhibition may be a promising therapeutic strategy for patients with HNSCC. Significance: Inhibition of bromodomain protein BRD4 represents a potential therapeutic strategy to circumvent the toxicities and financial burden of targeting the multiple receptor tyrosine kinases that drive cetuximab resistance in HNSCC and NSCLC. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4331/F1.large.jpg. Cancer Res; 78(15); 4331–43. ©2018 AACR.
Disgust as a mechanism for externalization: Coordination and disassociation
Authors: Isaac Wiegman
Journal: Behavioral and Brain Sciences (2018)

I extend Stanford's proposal in two ways by focusing on a possible mechanism of externalization: disgust. First, I argue that externalization also has value for solving coordination problems where interests of different groups coincide. Second, Stanford's proposal also holds promise for explaining why people "over-comply" with norms through disassociation, or the avoidance of actions that merely appear to violate norms.
THE TREATMENT OF FEVERS: WITH SPECIAL REFERENCE TO VENTILATION
Authors: T. H. Barker
Journal: BMJ (1856)

the views of the Paris physiologists, thf following cae i qquite iniexplicable; a such, however, it'is one of imme S. M., aged 33, was admitted on June 28th into St.Bartholomew's Hospital.She complained of pain in the neck, with some obcure fullness and tenderness of the bones in that region, and, what unfortunately but too well marked the real nature of the disease, very considerable want of motion of the lower limbs, amounting to paaplegia, but no want of senation.This singular paraplegia of the lower limbs, with comparatively good use of the upper extremities, though the poor woman looked quite cheerful, and ate her food, and exerted herself in the occupations of hospital life, left something undefined about the case.The treatment did not present any peculiarity: she had had pains of the chest and abdomen, for which Mr. Lawrence ordered alkalis and bitters; blisters also had been applied, for what definite purpose is not ascer- tained, to the stomach and chest.During the last week of September, Mr. Lawrence ordered her the oleum jecoris aselli, as he then believed the disease to be scrofulous disease of the cervical vertebme.About this period also, some obscure swelling uuder the jaw was observed, not painful nor attended with any sore- ness.It then continued slowly to increase through the first week of October, and some deep seated inflammation under the carotid vesscls was now suspected for the first time.The paraplegic symptoms remain unchanged, the woman otherwise did not complain very much.The tumour now began to pulsate very forcibly, and if seen for the first time might have been taken for aneurism; Mr. Lawrence, however, remembering the quantity of loose cellular tissue in the parts adjoining the larynx, pharynx, and parts adjoining the sterno-mastoid muscle, made the diagnosis of abscess in connexion with disease (carious or otherwise) of the processes or spines of the cervical ver- tebree, implicating the theca, ifnot the very coverings ofthe medulla spinalis itself.The sensation of the lower and upper extremities was good, but paralysis of motion in the former existed.Suddenly, about a week since, on the 26th of October, intense difficulty of breathing and dys- phagia set in; the nurse at night made an alarm that the woman was choking; she shrieked and cried with pain.31r.Lawrence, seeing there was no time to spare, at once made an incision behind the edge of the sterno- mastoid muscle.About five ounces of well formed pus were discharged, the woman now feels quite relieved, and the paraplegic symptoms have disappeared.K.
Nanoparticles That Reshape the Tumor Milieu Create a Therapeutic Window for Effective T-cell Therapy in Solid Malignancies
Authors: Fan Zhang, Sirkka B. Stephan, Chibawanye I. Ene, Tyrel T. Smith, Eric C. Holland, Matthias T. Stephan
Journal: Cancer Research (2018)

Abstract A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an α-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T-cell therapy, vaccines, and BITE platforms. Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors. Cancer Res; 78(13); 3718–30. ©2018 AACR.
Targeted Therapies for Brain Tumors: Will They Ever Deliver?
Authors: Michael A. Vogelbaum
Journal: Clinical Cancer Research (2018)

Abstract The strategy of using biologically targeted therapeutics for cancer has yet to translate into effective treatment of gliomas. The neuro-oncology community is beginning to recognize that phase 0 studies should be performed to account for the impact of the blood–brain barrier on the ability of a therapeutic to reach its target(s). Clin Cancer Res; 24(16); 3790–1. ©2018 AACR. See related article by Sanai et al., p. 3820
Elective distribution of resistance to beta-lactams among Enterobacter cloacae genetic clusters
Authors: Simon Garinet, Vincent Fihman, Hervé Jacquier, Stéphane Corvec, Alban Le Monnier, Thomas Guillard, Vincent Cattoir, Jean-Ralph Zahar, Paul-Louis Woerther, Etienne Carbonnelle, Alain Wargnier, Solen Kernéis, Philippe C Morand
Journal: Journal of Infection (2018)
Abstract B13: The prevention of lymphoproliferative lesions arising in patient-derived cancer xenografts by anti-graft-versus-host-disease agents
Authors: Tsuyoshi Chijiwa, Akira Noguchi, Daisuke Komura, Makoto Katayama, Mizuha Haraguchi, Haruo Hashimoto, Hiroshi Suemizu, Yoshiyasu Nakamura, Daisuke Furukawa, Takayuki Isagawa, Hiroto Katoh, Takashi Moriya, Shumpei Ishikawa, Masato Nakamura, Yohei Miyagi
Journal: Cancer Research (2018)

Abstract Xenografts derived from engrafting fresh surgical specimens directly onto immunodeficient mice have enabled the development of more relevant in vivo models for human cancers. Such patient-derived xenograft (PDX) models retain similar morphology, heterogeneities, and molecular signatures with the original cancers. We reported the rapid and efficient establishment of PDXs using super-immunodeficient NOG mice (PDX/NOG models). During the establishment process, a transplantable lymphoproliferative lesion (LPL) that replaces the original tumor cells sometimes occurs. The occurrence of LPL is the most problematic aspect of the establishment of PDX. This phenomenon may arise because of the Epstein-Barr virus due to the severely immunodeficient nature of the animal model; however, the mechanisms underlying LPL have not yet been elucidated in detail. In the present study, we histologically analyzed and tried to prevent the occurrence of LPL in PDX/NOG. Over 100 lines of cancer xenografts were established in our previous studies. Throughout these processes, we also established 10 LPL-PDX lines. Some LPL-PDX lines consist of B cells, T cells, and differentiated plasma cells. These LPL lymphocytes exhibited negligible proliferative potency in vitro. The invasions of LPL in the liver, lung, and pancreas were observed immunohistochemically. NOG mice bearing LPL-PDX (LPL-PDX/NOG) were treated with the anti-graft-versus-host-disease (anti-GVHD) drugs FK506 (1.0 mg/kg/day) and mycophenolate mofetil (MMF, 120 mg/kg/day) for 4 weeks using intraperitoneal injections. The LPL proliferations were significantly suppressed with FK506 (p=0.011) and MMF (p=0.014) compared with the control. The occurrence of LPL during establishment of PDX may be based on the GVHD-like mechanism. This phenomenon can be prevented by using anti-GVHD agents in the severely immunodeficient mice. The LPL-PDX/NOG models are also proposed for the utilization of GVHD mouse models with organic damage, particularly chronic GVHD mouse models. Citation Format: Tsuyoshi Chijiwa, Akira Noguchi, Daisuke Komura, Makoto Katayama, Mizuha Haraguchi, Haruo Hashimoto, Hiroshi Suemizu, Yoshiyasu Nakamura, Daisuke Furukawa, Takayuki Isagawa, Hiroto Katoh, Takashi Moriya, Shumpei Ishikawa, Masato Nakamura, Yohei Miyagi. The prevention of lymphoproliferative lesions arising in patient-derived cancer xenografts by anti-graft-versus-host-disease agents [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B13.
Nutritional Influences on One-Carbon Metabolism: Effects on Arsenic Methylation and Toxicity
Authors: Anne K. Bozack, Roheeni Saxena, Mary V. Gamble
Journal: Annual Review of Nutrition (2018)

Exposure to inorganic arsenic (InAs) via drinking water and/or food is a considerable worldwide problem. Methylation of InAs generates monomethyl (MMAsIII+V)- and dimethyl (DMAsIII+V)-arsenical species in a process that facilitates urinary As elimination; however, MMAs is considerably more toxic than either InAs or DMAs. Emerging evidence suggests that incomplete methylation of As to DMAs, resulting in increased MMAs, is associated with increased risk for a host of As-related health outcomes. The biochemical pathway that provides methyl groups for As methylation, one-carbon metabolism (OCM), is influenced by folate and other micronutrients, including choline and betaine. Individuals and species differ widely in their ability to methylate As. A growing body of research, including cell-culture, animal-model, and epidemiological studies, has demonstrated the role of OCM-related micronutrients in As methylation. This review examines the evidence that nutritional status and nutritional interventions can influence the metabolism and toxicity of As, with a primary focus on folate.
The Drug-Intoxication Epidemic and Solid-Organ Transplantation
Authors: Mandeep R Mehra, John A Jarcho, Wida Cherikh, Muthiah Vaduganathan, Rebecca R Lehman, Jacqueline Smits, Josef Stehlik
Journal: New England Journal of Medicine (2018)

Survival with Organs from Drug-Intoxicated Donors The proportion of solid-organ donors who died from drug intoxication increased from 1% in 2000 to 14% in 2016 in the United States. Allograft survival did not differ significantly between donors who died from drug intoxication and those who died from other causes.
Factors associated with pain and osteoarthritis at the hip and knee in Great Britain’s Olympians: a cross-sectional study
Authors: Dale J Cooper, Brigitte E Scammell, Mark E Batt, Debbie Palmer
Journal: British Journal of Sports Medicine (2018)

Knowledge of the epidemiology and potentially modifiable factors associated with musculoskeletal disease is an important first step in injury prevention among elite athletes.This study investigated the prevalence and factors associated with pain and osteoarthritis (OA) at the hip and knee in Great Britain's (GB) Olympians aged 40 and older.This is a cross-sectional study. A survey was distributed to 2742 GB Olympians living in 30 countries. Of the 714 (26.0%) who responded, 605 were eligible for analysis (ie, aged 40 and older).The prevalence of hip and knee pain was 22.4% and 26.1%, and of hip and knee OA was 11.1% and 14.2%, respectively. Using a multivariable model, injury was associated with OA at the hip (adjusted OR (aOR) 10.85; 95% CI 3.80 to 30.96) and knee (aOR 4.92; 95% CI 2.58 to 9.38), and pain at the hip (aOR 5.55; 95% CI 1.83 to 16.86) and knee (aOR 2.65; 95% CI 1.57 to 4.46). Widespread pain was associated with pain at the hip (aOR 7.63; 95% CI 1.84 to 31.72) and knee (aOR 4.77; 95% CI 1.58 to 14.41). Older age, obesity, knee malalignment, comorbidities, hypermobility and weight-bearing exercise were associated with hip and knee OA and/or pain.This study detected an association between several factors and hip and knee pain/OA in retired GB Olympic athletes. These associations require further substantiation in retired athletes from other National Olympic Committees, and through comparison with the general population. Longitudinal follow-up is needed to investigate the factors associated with the onset and progression of OA/pain, and to determine if modulation of such factors can reduce the prevalence of pain and OA in this population.