tbuckley/cabot-search huggingface dataset:
Non-targeted transcription factors motifs are a systemic component of ChIP-seq datasets
Authors: Rebecca Worsley Hunt, Wyeth W Wasserman
Journal: Genome biology (2014)

Abstract Background The global effort to annotate the non-coding portion of the human genome relies heavily on chromatin immunoprecipitation data generated with high-throughput DNA sequencing (ChIP-seq). ChIP-seq is generally successful in detailing the segments of the genome bound by the immunoprecipitated transcription factor (TF), however almost all datasets contain genomic regions devoid of the canonical motif for the TF. It remains to be determined if these regions are related to the immunoprecipitated TF or whether, despite the use of controls, there is a portion of peaks that can be attributed to other causes. Results Analyses across hundreds of ChIP-seq datasets generated for sequence-specific DNA binding TFs reveal a small set of TF binding profiles for which predicted TF binding site motifs are repeatedly observed to be significantly enriched. Grouping related binding profiles, the set includes: CTCF-like, ETS-like, JUN-like, and THAP11 profiles. These frequently enriched profiles are termed ‘zingers’ to highlight their unanticipated enrichment in datasets for which they were not the targeted TF, and their potential impact on the interpretation and analysis of TF ChIP-seq data. Peaks with zinger motifs and lacking the ChIPped TF’s motif are observed to compose up to 45% of a ChIP-seq dataset. There is substantial overlap of zinger motif containing regions between diverse TF datasets, suggesting a mechanism that is not TF-specific for the recovery of these regions. Conclusions Based on the zinger regions proximity to cohesin-bound segments, a loading station model is proposed. Further study of zingers will advance understanding of gene regulation.
Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial
Authors: Bela F. Asztalos, Dorothea Collins, Katalin V. Horvath, Hanna E. Bloomfield, Sander J. Robins, Ernst J. Schaefer
Journal: Metabolism (2007)
C<scp>ERULOPLASMIN</scp> M<scp>ETABOLISM AND</scp> F<scp>UNCTION</scp>
Authors: Nathan E. Hellman, Jonathan D. Gitlin
Journal: Annual Review of Nutrition (2002)

Ceruloplasmin is a serum ferroxidase that contains greater than 95% of the copper found in plasma. This protein is a member of the multicopper oxidase family, an evolutionarily conserved group of proteins that utilize copper to couple substrate oxidation with the four-electron reduction of oxygen to water. Despite the need for copper in ceruloplasmin function, this protein plays no essential role in the transport or metabolism of this metal. Aceruloplasminemia is a neurodegenerative disease resulting from inherited loss-of-function mutations in the ceruloplasmin gene. Characterization of this disorder revealed a critical physiological role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and has provided new insights into human iron metabolism and nutrition.
Evaluation of amifostine for protection against cisplatin-induced serious hearing loss in children treated for average-risk or high-risk medulloblastoma
Authors: James G. Gurney, Johnnie K. Bass, Arzu Onar-Thomas, Jie Huang, Murali Chintagumpala, Eric Bouffet, Tim Hassall, Sridharan Gururangan, John A. Heath, Stewart Kellie, Richard Cohn, Michael J. Fisher, Atmaram Pai Panandiker, Thomas E. Merchant, Ashok Srinivasan, Cynthia Wetmore, Ibrahim Qaddoumi, Clinton F. Stewart, Gregory T. Armstrong, Alberto Broniscer, Amar Gajjar
Journal: Neuro-Oncology (2014)

The purpose of this study was to evaluate amifostine for protection from cisplatin-induced serious hearing loss in patients with average-risk medulloblastoma by extending a previous analysis to a much larger sample size. In addition, this study aimed to assess amifostine with serious hearing loss in patients with high-risk medulloblastoma treated with cisplatin. Newly diagnosed medulloblastoma patients (n = 379; ages 3–21 years), enrolled on one of 2 sequential St. Jude clinical protocols that included 4 courses of 75 mg/m2 cisplatin, were compared for hearing loss by whether or not they received 600 mg/m2 of amifostine immediately before and 3 hours into each cisplatin infusion. Amifostine administration was not randomized. The last audiological evaluation between 5.5 and 24.5 months following protocol treatment initiation was graded using the Chang Ototoxicity Scale. A grade of ≥2b (loss requiring a hearing aid or deafness) was considered a serious event. Among average-risk patients (n = 263), amifostine was associated with protection from serious hearing loss (adjusted OR, 0.30; 95% CI, 0.14–0.64). For high-risk patients (n = 116), however, there was not sufficient evidence to conclude that amifostine prevented serious hearing loss (OR, 0.89; 95% CI, 0.31–2.54). Although patients in this study were not randomly assigned to amifostine treatment, we found evidence in favor of amifostine administration for protection against cisplatin-induced serious hearing loss in average-risk but not in high-risk, medulloblastoma patients.
Nuclear Factor-κB Induced by Doxorubicin Is Deficient in Phosphorylation and Acetylation and Represses Nuclear Factor-κB–Dependent Transcription in Cancer Cells
Authors: Wai Chi Ho, Kathleen M. Dickson, Philip A. Barker
Journal: Cancer Research (2005)

Abstract The primary goal of chemotherapy is to cause cancer cell death. However, a side effect of many commonly used chemotherapeutic drugs is the activation of nuclear factor-κB (NF-κB), a potent inducer of antiapoptotic genes, which may blunt the therapeutic efficacy of these compounds. We have assessed the effect of doxorubicin, an anthracycline in widespread clinical use, on NF-κB activation and expression of antiapoptotic genes in breast cancer cells. We show that doxorubicin treatment activates NF-κB signaling and produces NF-κB complexes that are competent for NF-κB binding in vitro. Surprisingly, these NF-κB complexes suppress, rather than activate, constitutive- and cytokine-induced NF-κB–dependent transcription. We show that doxorubicin treatment produces RelA, which is deficient in phosphorylation and acetylation and which blocks NF-κB signaling in a histone deacetylase–independent manner, and we show that NF-κB activated by doxorubicin does not remain stably bound to κB elements in vivo. Together these data show that NF-κB signaling induced by doxorubicin reduces expression of NF-κB–dependent genes in cancer cells.
Genome-wide mapping reveals single-origin chromosome replication in Leishmania, a eukaryotic microbe
Authors: Catarina A. Marques, Nicholas J. Dickens, Daniel Paape, Samantha J. Campbell, Richard McCulloch
Journal: Genome biology (2015)

DNA replication initiates on defined genome sites, termed origins. Origin usage appears to follow common rules in the eukaryotic organisms examined to date: all chromosomes are replicated from multiple origins, which display variations in firing efficiency and are selected from a larger pool of potential origins. To ask if these features of DNA replication are true of all eukaryotes, we describe genome-wide origin mapping in the parasite Leishmania. Origin mapping in Leishmania suggests a striking divergence in origin usage relative to characterized eukaryotes, since each chromosome appears to be replicated from a single origin. By comparing two species of Leishmania, we find evidence that such origin singularity is maintained in the face of chromosome fusion or fission events during evolution. Mapping Leishmania origins suggests that all origins fire with equal efficiency, and that the genomic sites occupied by origins differ from related non-origins sites. Finally, we provide evidence that origin location in Leishmania displays striking conservation with Trypanosoma brucei, despite the latter parasite replicating its chromosomes from multiple, variable strength origins. The demonstration of chromosome replication for a single origin in Leishmania, a microbial eukaryote, has implications for the evolution of origin multiplicity and associated controls, and may explain the pervasive aneuploidy that characterizes Leishmania chromosome architecture.
Feeding and Eating Disorders in DSM-5
Authors: Evelyn Attia, Anne E. Becker, Rachel Bryant-Waugh, Hans W. Hoek, Richard E. Kreipe, Marsha D. Marcus, James E. Mitchell, Ruth H. Striegel, B. Timothy Walsh, G. Terence Wilson, Barbara E. Wolfe, Stephen Wonderlich
Journal: American Journal of Psychiatry (2013)
Absence of Gender Effects on Attention Deficit Hyperactivity Disorder: Findings in Nonreferred Subjects
Authors: Joseph Biederman, Anne Kwon, Megan Aleardi, Virginie-Anne Chouinard, Teresa Marino, Heather Cole, Eric Mick, Stephen V. Faraone
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: In a previous study, the authors found that, compared with referred boys with attention deficit hyperactivity disorder (ADHD), girls are less likely to manifest comorbid disruptive behavior disorders and learning disabilities—characteristics that could adversely affect identification of ADHD in girls. However, because referral bias can affect outcome, these findings require replication in nonreferred groups of ADHD subjects. METHOD: The authors evaluated gender effects in a large group of nonreferred siblings (N=577) of probands with ADHD and non-ADHD comparison subjects. Ninety-eight of the nonreferred siblings (N=73 males, N=25 females) met the criteria for diagnosis of ADHD, and 479 (N=244 males, N=235 females) did not meet those criteria. All siblings were systematically and comprehensively assessed with measures of emotional, school, intellectual, interpersonal, and family functioning. The assessment battery used for the siblings was the same as that used for the probands. RESULTS: The nonreferred males and females with ADHD did not differ in DSM-IV subtypes of ADHD, psychiatric comorbidity, or treatment history. They also showed similar levels of cognitive, psychosocial, school, and family functioning. CONCLUSIONS: These findings suggest that the clinical correlates of ADHD are not influenced by gender and that gender differences reported in groups of subjects seen in clinical settings may be caused by referral biases.
Personalizing Colon Cancer Adjuvant Therapy: Selecting Optimal Treatments for Individual Patients
Authors: Rodrigo Dienstmann, Ramon Salazar, Josep Tabernero
Journal: Journal of Clinical Oncology (2015)

For more than three decades, postoperative chemotherapy—initially fluoropyrimidines and more recently combinations with oxaliplatin—has reduced the risk of tumor recurrence and improved survival for patients with resected colon cancer. Although universally recommended for patients with stage III disease, there is no consensus about the survival benefit of postoperative chemotherapy in stage II colon cancer. The most recent adjuvant clinical trials have not shown any value for adding targeted agents, namely bevacizumab and cetuximab, to standard chemotherapies in stage III disease, despite improved outcomes in the metastatic setting. However, biomarker analyses of multiple studies strongly support the feasibility of refining risk stratification in colon cancer by factoring in molecular characteristics with pathologic tumor staging. In stage II disease, for example, microsatellite instability supports observation after surgery. Furthermore, the value of BRAF or KRAS mutations as additional risk factors in stage III disease is greater when microsatellite status and tumor location are taken into account. Validated predictive markers of adjuvant chemotherapy benefit for stage II or III colon cancer are lacking, but intensive research is ongoing. Recent advances in understanding the biologic hallmarks and drivers of early-stage disease as well as the micrometastatic environment are expected to translate into therapeutic strategies tailored to select patients. This review focuses on the pathologic, molecular, and gene expression characterizations of early-stage colon cancer; new insights into prognostication; and emerging predictive biomarkers that could ultimately help define the optimal adjuvant treatments for patients in routine clinical practice.
Molecular biology. Setting the stage in colorectal cancer?
Authors: H E Mulcahy, D P O'Donoghue
Journal: Gut (1993)

Leading articleMolecular biology.Setting the stage in colorectal cancer?Over 18 000 people die each year in the UK from colorectal cancer.The mortality has remained largely unchanged over the decades despite greater public awareness and better diagnostic facilities.Improving the outlook for patients will require either diagnosing cancer at an asymptomatic and, presumably, earlier phase or offering more effective treat- ment for those with advanced disease.Recent studies have expressed cautious optimism both for screening and for the use of adjuvant therapy, yet closer examination raises as many doubts as hopes.
The Ubiquitin–CXCR4 Axis Plays an Important Role in Acute Lung Infection–Enhanced Lung Tumor Metastasis
Authors: Libo Yan, Qingchun Cai, Yan Xu
Journal: Clinical Cancer Research (2013)

Our goals were to test the effect of acute lung infection on tumor metastasis and to investigate the underlying mechanisms.We combined bacteria-induced and lipopolysaccharide (LPS)-induced acute lung injury/inflammation (ALI) mouse models with mouse metastatic models to study the effect of acute inflammation on lung metastasis in mice. The mechanisms were investigated in ex vivo, in vitro, and in vivo studies.Both bacteria- and LPS-induced ALI significantly enhanced lung metastasis of four tail vein-injected mouse tumor cell lines. Bacteria also enhanced lung metastasis when 4T1 cells were orthotopically injected. The bronchoalveolar lavage fluid (BALF) from LPS- or bacteria-injected mice stimulated migration of tumor cells. In vivo tracking of metastatic RM-9 cells showed that bacterial injection enhanced early dissemination of tumor cells to the lung. The majority of the BALF migratory activity could be blocked by AMD3100, a chemokine receptor 4 (CXCR4) inhibitor. All tested cell lines expressed CXCR4. The levels of extracellular ubiquitin, but not stromal cell-derived factor-1, in BALF were significantly increased by LPS. Ubiquitin was able to induce AMD3100-sensitive migration of tumor cells. Finally, the antibacterial agent amoxicillin and the CXCR4 inhibitor AMD3100 blocked the enhancement effect of bacterial infection on tumor metastasis.Acute lung infection dramatically increased cancer cell homing to the lung and lung metastasis. This change may be due to an alteration of the lung microenvironment and preparation of a favorable metastatic "niche." This effect was seen in multiple cancer types and thus may have broad applications for cancer patients in prevention and/or treatment of metastasis.
Multicenter Phase II Study of Fertility-Sparing Treatment With Medroxyprogesterone Acetate for Endometrial Carcinoma and Atypical Hyperplasia in Young Women
Authors: Kimio Ushijima, Hideaki Yahata, Hiroyuki Yoshikawa, Ikuo Konishi, Toshiharu Yasugi, Toshiaki Saito, Toru Nakanishi, Hiroshi Sasaki, Fumitaka Saji, Tsuyoshi Iwasaka, Masayuki Hatae, Shoji Kodama, Tsuyoshi Saito, Naoki Terakawa, Nobuo Yaegashi, Masamichi Hiura, Atsuhiko Sakamoto, Hitoshi Tsuda, Masaharu Fukunaga, Toshiharu Kamura
Journal: Journal of Clinical Oncology (2007)

To assess the efficacy of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC) and atypical endometrial hyperplasia (AH) in young women.This multicenter prospective study was carried out at 16 institutions in Japan. Twenty-eight patients having EC at presumed stage IA and 17 patients with AH at younger than 40 years of age were enrolled. All patients were given a daily oral dose of 600 mg of MPA with low-dose aspirin. This treatment continued for 26 weeks, as long as the patients responded. Histologic change of endometrial tissue was assessed at 8 and 16 weeks of treatment. Either estrogen-progestin therapy or fertility treatment was provided for the responders after MPA therapy. The primary end point was a pathologic complete response (CR) rate. Toxicity, pregnancy rate, and progression-free interval were secondary end points.CR was found in 55% of EC cases and 82% of AH cases. The overall CR rate was 67%. Neither therapeutic death nor irreversible toxicities were observed; however, two patients had grade 3 body weight gain, and one patient had grade 3 liver dysfunction. During the 3-year follow-up period, 12 pregnancies and seven normal deliveries were achieved after MPA therapy. Fourteen recurrences were found in 30 patients (47%) between 7 and 36 months.The efficacy of fertility-sparing treatment with a high-dose of MPA for EC and AH was proven by this prospective trial. Even in responders, however, close follow-up is required because of the substantial rate of recurrence.
Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease
Authors: Isabelle Cleynen, Emilie Vazeille, Marta Artieda, Hein W Verspaget, Magdalena Szczypiorska, Marie-Agnès Bringer, Peter L Lakatos, Frank Seibold, Kirstie Parnell, Rinse K Weersma, Jestinah M Mahachie John, Rebecca Morgan-Walsh, Dominiek Staelens, Ingrid Arijs, Gert De Hertogh, Stefan Müller, Atilla Tordai, Daniel W Hommes, Tariq Ahmad, Cisca Wijmenga, Sylvia Pender, Paul Rutgeerts, Kristel Van Steen, Daniel Lottaz, Severine Vermeire, Arlette Darfeuille-Michaud
Journal: Gut (2013)

Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up.We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis.Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (p(FDR)=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly.Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.
The National Organ Procurement and Transplantation Network
Authors: John C. McDonald
Journal: JAMA (1988)

The development of the immunosuppressive agent cyclosporin revolutionized the field of organ transplantation, resulting in an increased demand for organs and a strong public interest in how organs are procured and distributed. Federal legislation in 1984 led to the creation of the National Organ Procurement and Transplantation Network (NOPTN) through a contract with the United Network for Organ Sharing (UNOS). McDonald seeks to clarify for his medical colleagues the current situation with regard to public involvement through NOPTN with organ procurement and distribution. He lists the ten tasks contracted for with UNOS, and explains three of the tasks and their implications for professionals and facilities involved in transplantation. McDonald emphasizes the advantages of NOPTN and assures physicians that its operation will not interfere with their capacity to care for patients.
P222 Multi-Disciplinary Team Attitudes Towards End-of-Life Care in Severe COPD
Authors: B. Turnpenny, K. Shepherd, R. Barraclough, C. Haskins
Journal: Thorax (2011)

<h3>Introduction</h3> Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death globally. The physical and psychological symptom burden in severe COPD is significant and yet many of these symptoms go untreated (Elkington <i>et al</i>, 2005). Patients with COPD have far less specialist palliative care input than patients with lung cancer despite a symptom burden at the end of life similar, or indeed greater, than patients with lung cancer (Gore <i>et al</i>, 2000). <h3>Methods</h3> An anonymous questionnaire was completed by respiratory healthcare professionals including respiratory doctors of all grades, physiotherapists and nurses of different backgrounds. The questions focused on perceived ease of predicting prognosis in severe COPD, the initiating of end-of-life discussions in this group, and training received in palliative care. <h3>Results</h3> 100 questionnaires were completed. 67 participants were doctors, from house officers to consultants, 5 physiotherapists, 9 respiratory specialist nurses, 8 Macmillan nurses and 12 respiratory ward nurses. The questionnaire found 76% of participants felt it was a very important or important part of their role to initiate end-of-life discussions in severe COPD and 2% felt it was not, or definitely not part of their role. Participants initiated such discussions frequently or very frequently in 20%, and infrequently or very infrequently in 55%. Prognosis in severe COPD was difficult or very difficult in 63% and straightforward or very straightforward in 6%. This is consistent with literature (Gott <i>et al</i>, 2009). Training participants had received in palliating symptoms in this patient group was significant or extensive in 25% and minimal or little in 41%. Training in initiating end-of-life discussions was significant or extensive in 19% and minimal or little in 44%. Training in services available to this group of patients was significant or extensive in 17% and minimal or little in 42%. <h3>Conclusion</h3> The need to initiate end-of-life discussions in severe COPD is felt to be important to the multidisciplinary team9s role in palliating such patients, yet very few regularly have such discussions. A lack of training and self-reported difficulty in predicting prognosis in this group are perceived to be great, and are suggested as possible reasons for this imbalance.
Research in Walk-In Psychiatric Services in General Hospitals
Authors: JULES V. COLEMAN
Journal: American Journal of Psychiatry (1968)

Emergency treatment services in the general hospitals of urban centers have grown spectacularly in recent years, reflecting in effect a medical care vacuum for the slum poor. The medical and psychiatric needs of this population are known to be great, and a unique opportunity is presented to meet a changing pattern of medical-psychiatric demand. To do so, the emergency service as an accident accommodation must be replaced by its development as a primary clinic treating patients with illnesses associated with poverty.