tbuckley/cabot-search huggingface dataset:
Abstract P3-05-07: RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model
Authors: F Garner, J Brown, J Katzenellenbogen, CR Lyttle, G Hattersley
Journal: Cancer Research (2016)

Abstract Despite advances in the treatment of metastatic breast cancer, many women eventually relapse with more aggressive forms of endocrine-resistant disease. Mutations in the ESR1 gene encoding the estrogen receptor (ER) have recently emerged as a potential mechanism for the development of clinical resistance to conventional anti-estrogen therapies, such as fulvestrant. To overcome some of the pharmacokinetic limitations and intramuscular administration challenges associated with fulvestrant endocrine therapy and to combat the development of resistance, there is a significant need for the development of more durable and more effective ER-targeted therapies. Here, we begin to describe and characterize the preclinical efficacy of RAD1901, a novel, orally bioavailable small-molecule SERD, with significant therapeutic potential for treatment of breast cancer. RAD1901 selectively binds to and degrades the ER and is a potent antagonist of ER-positive breast cancer cell proliferation. Importantly, RAD1901 demonstrated profound tumor growth inhibition in MCF-7 xenograft models when compared to fulvestrant and tamoxifen. Importantly, RAD1901 also demonstrated marked single agent efficacy in a primary patient-derived xenograft (PDx) model harboring the ESR1 Y537S mutation indicating the utility of this SERD against clinically relevant ER mutants. Further biochemical binding studies and co-crystallization experiments of RAD1901 bound to the ER further confirms the ability of RAD1901 to bind to both mutant and wild type forms of the ER. RAD1901 is currently undergoing clinical testing in postmenopausal women with ER-positive advanced breast cancer. Citation Format: Garner F, Brown J, Katzenellenbogen J, Lyttle CR, Hattersley G. RAD1901, a novel oral, selective estrogen receptor degrader (SERD) with single agent efficacy in an ER+ primary patent derived ESR1 mutant xenograft model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-07.
Serologic and virologic surveillance of avian influenza in Nigeria, 2006-7
Authors: T M Joannis, C A Meseko, A T Oladokun, H G Ularamu, A N Egbuji, P Solomon, D C Nyam, D A Gado, P Luka, M E Ogedengbe, M B Yakubu, A D Tyem, O Akinyede, A I Shittu, L K Sulaiman, O A Owolodun, A K Olawuyi, E T Obishakin, F O Fasina
Journal: Eurosurveillance (2008)

Since January 2006, H5N1 avian influenza has affected Nigeria's poultry population causing enormous loss of resources. The current circulating virus is a potential candidate for pandemic influenza which may severely affect the human and animal population worldwide especially in the resource-poor countries. In this study, we report on our field and laboratory surveillance efforts in Nigeria. A total of 1,821 tissue samples, 8,638 tracheal swabs, 7,976 cloacal swabs and 7,328 avian sera were analysed over a period of two years, with 312 positive results [corrected] We recovered 299 isolates of highly pathogenic avian influenza virus H5N1 mainly from the diagnostic samples of poultry kept in backyard, small scale and free range farms. This finding emphasised the role played by these farming systems in the dissemination of avian influenza in Nigeria and highlights the need for a continued surveillance in humans since human-animal interaction is a key feature in Africa. Furthermore, there is a need for the strengthening of border controls. Since October 2007, there has been no reported and confirmed outbreak of avian influenza in Nigeria.
Abstract 12419: Preclinical Safety and Efficacy of a Novel Thrombolytic Agent Administered by Rapid Bolus Injection: Clot Specific Streptokinase (CSSK/SMRX-11)
Authors: Ronald J Shebuski, Kishore Joshi, Abhay Pande, Ravinder Sharma, Yatindra Prashar, John Kapeghian, Girish Sahni
Journal: Circulation (2015)

Introduction: Clot specific Streptokinase (CSSK), also known as SMRX-11, is a novel recombinant protein, produced and purified from a yeast system (Pichia pastoris). Novel fibrin binding domains attached to each end of streptokinase mask the ability of the streptokinase component of SMRX-11 to interact with blood plasminogen. As a result, SMRX-11 remains inactive in the blood circulation and does not convert blood plasminogen into plasmin until the fibrin binding domains are cleaved by clot-bound plasmin. This is in contrast to native Streptokinase (SK), which indiscriminately converts plasminogen into plasmin. The molecular weight of the glycosylated SMRX-11 protein is approximately 80kD, with a specific activity of 80,000 Units/mg of protein. Results. In vitro experiments comparing SMRX-11 to other fibrinolytics (SK and tPA), demonstrated that SMRX-11 lyses experimentally-preformed human blood clots without reducing residual plasma fibrinogen levels. Initial in vitro studies compared the activity of SMRX-11 to lyse human whole blood clots to native Streptokinase (SK) and tissue Plasminogen Activator (tPA). SMRX-11 had comparable clot lysis activity to SK, with tPA eliciting a slightly greater percent clot lysis. Additional in vitro studies determined the relative fibrinogenolytic effects of SMRX-11 versus tPA. SMRX-11 demonstrated superior fibrinogen sparing compared to tPA with minimal consumption of alpha-2 antiplasmin relative to native SK. In vivo, SMRX-11 (0.7-1.4 mg/kg as an iv bolus), lysed experimentally-induced femoral arterial thrombi in cynomolgus monkeys with relatively minor fluctuation in plasma fibrinogen, forearm bleeding time or hemodynamics. In GLP safety studies, treatment with SMRX-11 at doses of 1, 3 and 10 mg/kg/day for 5 consecutive days was generally well-tolerated in male and female cynomolgus monkeys. Thus, the low dose of 1 mg/kg was considered the No-Observed Adverse Effect Level (NOAEL) for daily repeat-dose administration of SMRX-11 administered via bolus i.v. injection in cynomolgus monkeys. Conclusion. SMRX-11 represents a novel pharmacophore with the appropriate preclinical safety and efficacy profile to warrant clinical investigation for acute treatment of myocardial infarction and stroke.
Childhood schizophrenia: present but not accounted for
Authors: S Cantor, J Evans, J Pearce, T Pezzot-Pearce
Journal: American Journal of Psychiatry (1982)

The subjects of this study were 19 children and 11 adolescents who had been psychotic since childhood and who satisfied DSM-III criteria for schizophrenia except for the stipulation that a "deterioration from a previous level of functioning" must have occurred. Seven subjects had had documented signs of psychosis before the age of 30 months. The presence of thought disorder precluded giving these 7 subjects the diagnosis of early infantile autism. The authors argue that only symptoms and signs, not age at onset, can define a disorder. They also emphasize that in children and adolescents, developmental issues influence the clinical presentation.
Recombinant granulocyte colony-stimulating factor administration to healthy volunteers: induction of immunophenotypically and functionally altered neutrophils via an effect on myeloid progenitor cells
Authors: JM Kerst, M de Haas, CE van der Schoot, IC Slaper-Cortenbach, M Kleijer, AE von dem Borne, RH van Oers
Journal: Blood (1993)
GIRK1 overexpression correlates with ER positive breast cancer subtypes and is associated with poor prognosis
Authors: S. Kammerer, A. Sokolowski, H. Hackl, D. Platzer, S. Jahn, F. Peintinger, F. Symmans, W. Schreibmayer, T. Bauernhofer
Journal: Annals of Oncology (2015)
Unravelling the Mirnome of MLL-Rearranged Acute Lymphoblastic Leukemia
Authors: Patricia Garrido Castro, Clara Bueno, Eddy HJ van Roon, Sandra S Mimoso Pinhancos, Pauline Schneider, Merel Willekes, Pablo Menendez, Rob Pieters, Ronald Stam
Journal: Blood (2014)
Exome Sequencing and the Management of Neurometabolic Disorders
Authors: Maja Tarailo-Graovac, Casper Shyr, Colin J. Ross, Gabriella A. Horvath, Ramona Salvarinova, Xin C. Ye, Lin-Hua Zhang, Amit P. Bhavsar, Jessica J.Y. Lee, Britt I. Drögemöller, Mena Abdelsayed, Majid Alfadhel, Linlea Armstrong, Matthias R. Baumgartner, Patricie Burda, Mary B. Connolly, Jessie Cameron, Michelle Demos, Tammie Dewan, Janis Dionne, A. Mark Evans, Jan M. Friedman, Ian Garber, Suzanne Lewis, Jiqiang Ling, Rupasri Mandal, Andre Mattman, Margaret McKinnon, Aspasia Michoulas, Daniel Metzger, Oluseye A. Ogunbayo, Bojana Rakic, Jacob Rozmus, Peter Ruben, Bryan Sayson, Saikat Santra, Kirk R. Schultz, Kathryn Selby, Paul Shekel, Sandra Sirrs, Cristina Skrypnyk, Andrea Superti-Furga, Stuart E. Turvey, Margot I. Van Allen, David Wishart, Jiang Wu, John Wu, Dimitrios Zafeiriou, Leo Kluijtmans, Ron A. Wevers, Patrice Eydoux, Anna M. Lehman, Hilary Vallance, Sylvia Stockler-Ipsiroglu, Graham Sinclair, Wyeth W. Wasserman, Clara D. van Karnebeek
Journal: New England Journal of Medicine (2016)

Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level.To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes.We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%).Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).
Community Engagement and Data Disclosure in Environmental Health Research
Authors: Erin N. Haynes, Sarah Elam, Roxanne Burns, Alonzo Spencer, Elissa Yancey, Pierce Kuhnell, Jody Alden, Mike Walton, Virgil Reynolds, Nicholas Newman, Robert O. Wright, Patrick J. Parsons, Meredith L. Praamsma, Christopher D. Palmer, Kim N. Dietrich
Journal: Environmental Health Perspectives (2016)

Federal funding agencies increasingly support stakeholder participation in environmental health studies, and yet there is very little published research on engagement of community members in the development of data disclosure (DD) strategies. The Ohio Environmental Protection Agency reported airborne manganese (Mn) concentrations in East Liverpool, Ohio, 30 times higher than the reference concentration, which led to an academic–community research partnership to address community concern about Mn exposure, particularly among children. Children and their families were recruited to participate in a pilot study. Samples of blood and hair were collected from the children and analyzed for metals. DD mechanisms were developed using an iterative approach between community and academic partners. Individual DD letters were mailed to each participating family, and a community meeting was held. A post-meeting survey was administered to gauge community perception of the DD strategies. The purpose of this article is to demonstrate the effectiveness of engaging community partners in the conduct of environmental health research and in the development of DD strategies for individuals and the community at large. Scientists should include community partners in the development of DD strategies to enhance translation of the research findings and support the right of study participants to know their individual results.
Can psychiatry police itself effectively? The experience of one district branch
Authors: A Zitrin, H Klein
Journal: American Journal of Psychiatry (1976)

The growing demand by consumers and government for greater accountability from psychiatry is challenging the traditional system of self-policing by which the profession's standards of ethical conduct are established and maintained. The authors describe the operations of a district branch ethics committee, including types of complaints recieved, investigatory procedures, disposition of cases, and factors limiting the committee's effectiveness. They conclude that in some cases lack of funds, lack of time, and the use of peers to judge alleged misconduct make unbiased and thorough evaluation of complaints difficult. They suggest that psychiatry must take steps to improve public confidence in its ability to police itself so that the power to regulate professional conduct will remain within the profession.
Film: Unknown White Male
Authors: Piyal Sen
Journal: BMJ (2006)

Ayoung British man wakes up on a subway train in New York City to realise that he has lost all memory of the past. He is a man without an identity. What follows is his search to rediscover himself. The chance discovery of a telephone number on his person leads him to a friend. He is thus able to find out about his home, job, friends, and family.

Doctors investigate his condition and find a pituitary tumour. The tumour is taken out but this does not improve his memory. His procedural memory is completely preserved. What he has lost is semantic memory, memory for past events. The most likely diagnosis is psychogenic amnesia. He is advised that his memory will return, but he does not know when. Undaunted, he sets about trying to rebuild his life.

Unknown White Male is a feature documentary based on the experience of Doug Bruce. The director, Rupert Murray, an old friend of Doug, spent more than a year filming various episodes in Doug's life, including his reunion with family and friends, his visits to doctors, his attempt to relaunch his career, and the start of a new relationship. He also spoke to people who knew Doug from before and also to experts, both doctors and philosophers. The result is not just a fascinating case history, but also a balanced exploration of how identity can be a double edged sword.

Psychogenic generalised amnesia is an extremely uncommon condition. It tends to follow markedly stressful life events. Recovery is usually complete. There was no obvious precipitant for Doug, though his amnesia makes this hard to corroborate. One could speculate whether this was due to deliberate avoidance of unpleasant memories, or unconscious repression.

Doug wishes to spend more time building up his new life instead of finding out why he lost his old one. Friends, family, and work supervisors find the new Doug to be more reflective, less cynical, but miss his old sparkling wit and sense of humour. There is a sense, however, that he is reclaiming some of his old personality traits with time. He does feel a connection with his older sister and regrets losing all memories of his dead mother.

Philosophers discuss whether Doug is the same man, but a different person. Some profound questions are raised about the nature of identity. Carl Jung coined the term “collective unconscious,” which links every individual's personality development to numerous life experiences from birth. The adult personality is formed by a dynamic interaction between the genetic endowment at birth and formative life experiences. However, like Doug, if one loses the total life experience from conscious memory, does the experience remain in the unconscious and influence the future personality, or does one start with only the genetic endowment and build up a collective unconscious all over again?​again?



Figure 1

Doug Bruce: a fascinating case history



This film might provide some answers. Most of all, it reminds us of the educational power of individual case reports in rare conditions. A psychiatrist named Freud would have been pleased.
Abstract PR08: GC skew defines distinct RNA polymerase pause sites in CpG island promoters
Authors: Joshua SK Bell, Wendy A. Kellner, Paula M. Vertino
Journal: Cancer Research (2016)

Abstract Promoter-proximal pausing of RNA Pol II (Pol II) is a near universal feature of human genes and plays a central role in governing levels of transcription and modulating rapid response to stimuli. Here we show that at CpG island (CGI)- associated promoters, Pol II encounters an additional barrier to elongation distinct from the promoter-proximal pause that occurs at the downstream boundary of the CGI domain. For most CGI associated promoters, Pol II exhibits a dominant pause at either the promoter-proximal or this distal site that correlates, both in position and in intensity, with local regions of high GC skew, a sequence feature known to promote the formation of unique secondary structures. Indeed, we find that distally paused genes manifest longer or more stable R-loops, a structure suggested to protect CGI domains from DNA methylation. Interestingly, the link between GC-skew and Pol II pausing is conserved in Drosophila. Upon signal-induced gene activation, long-range enhancer contacts at the dominant pause site are selectively enhanced, suggesting a new role for enhancers at CGI boundaries. Consistent with this idea, we find a correlation between enrichment of the cohesin complex, important for DNA looping, and the position of the dominant pause site. These findings unearth a novel transcriptional regulatory step at CGI-associated genes that is dictated by the underlying DNA sequenceand linked to the integrity of the CGI domain. Citation Format: Joshua SK Bell, Wendy A. Kellner, Paula M. Vertino. GC skew defines distinct RNA polymerase pause sites in CpG island promoters. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR08.
Detection of Breast Tumors by Nuclear Magnetic Resonance Imaging
Authors: B Pastakia
Journal: JNCI Journal of the National Cancer Institute (1979)

Journal Article Detection of Breast Tumors by Nuclear Magnetic Resonance Imaging Get access Behram Pastakia, M.B., B.S. Behram Pastakia, M.B., B.S. William S. Middleton Memorial Veterans Administration Hospital2500 Overlook Terrace Madison, Wisconsin 53705 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 63, Issue 2, August 1979, Page 273, https://doi.org/10.1093/jnci/63.2.273 Published: 01 August 1979
NCCN Guidelines Updates: Breast Cancer
Authors: Sharon H Giordano, Anthony D Elias, William J Gradishar
Journal: Journal of the National Comprehensive Cancer Network (2018)

<section class="abstract"><p id="P1">The emergence of CDK4/6 inhibitors has changed the treatment algorithm for advanced/metastatic estrogen receptor–positive breast cancer. In pivotal trials of palbociclib, ribociclib, and abemaciclib, doubling in progression-free survival has been seen. All 3 agents in this class are now included in the NCCN Guidelines for Breast Cancer, and clinicians should be incorporating these agents into their treatment algorithms. The other important issue in this breast cancer setting is extended duration of endocrine therapy. Most of the benefit is modest and toxicity is an issue; therefore, extended-duration endocrine therapy should be highly individualized. For triple-negative disease, platinum agents and PARP inhibitors are helping some patients, but immunotherapies and other novel classes of drugs now in development hold the promise of even better outcomes. In HER2-positive early-stage disease, dual HER2 blockade is of modest benefit, and extended treatment with neratinib may be a good option for some high-risk patients. </section>
Effects of the German skin cancer screening programme on melanoma incidence and indicators of disease severity
Authors: F. Trautmann, F. Meier, A. Seidler, J. Schmitt
Journal: British Journal of Dermatology (2016)

In Germany a nationwide melanoma screening programme for adults aged ≥ 35 years was introduced in July 2008. Evidence on utilization and effects is limited. To examine the uptake and effects of the German nationwide screening programme. This analysis is based on pseudonymized outpatient routine data of a German health insurance company covering data of > 2 million individuals from Saxony for the years 2005–2012. Cases of melanoma and nonmelanoma skin cancer (NMSC) were identified using an algorithm based on the International Classification of Diseases, 10th Revision. Cross‐sectional and longitudinal analyses were applied to determine the utilization of the screening programme and effects on skin cancer incidence and disease severity as a proxy for prognosis. Overall, 38·0% of eligible persons (≥ 35 years) were screened at least once between July 2008 and December 2012. The annual participation rate was 12·4%. Out of 533 393 persons screened, melanoma and NMSC were diagnosed in 0·3% and 2·5%, respectively. The 6‐month melanoma incidence per 100 000 insured persons decreased from 12·8 before screening introduction (January to June 2008) to 10·2 after introduction (July to December 2008). NMSC incidence increased from 173·8 to 175·5 per 100 000. The numbers of screening participants receiving interferon alpha and/or being diagnosed with lymph node and/or distant metastasis (8·6%, 5·9%, 1·5%, respectively) were lower than in nonparticipants (11·2%, 8·5%, 3·5%). These differences were not significant. The results suggest that the introduction of a generic skin cancer screening programme in Germany was not associated with significant changes in incidence. No firm conclusions regarding the effects of skin cancer screening on prognosis can be drawn. Longer follow‐up and linkage with clinical registry data are necessary to clarify the effect of screening participation on incidence and prognosis.
Placental Malaria
Authors: I J Miller, S R Telford
Journal: New England Journal of Medicine (1996)

Figure 1. A 40-year-old Nigerian woman with a history of malaria was admitted at 36 weeks of pregnancy after 4 days of intermittent fever, with temperatures up to 40°C (104°F), and lower abdominal pain. The base-line fetal heart rate was 108 beats per minute, with late decelerations. An emergency cesarean section was performed, and a healthy-appearing baby boy was born, with Apgar scores of 6 at one minute and 9 at five minutes. Maternal malaria due to a mixed infection with Plasmodium falciparum and P. malariae was diagnosed on the basis of a peripheral-blood smear. The mother was treated successfully . . .