tbuckley/cabot-search huggingface dataset:
Persistence of High-Grade Cervical Dysplasia and Cervical Cancer Requires the Continuous Expression of the Human Papillomavirus Type 16 <i>E7</i> Oncogene
Authors: Sean F. Jabbar, Linda Abrams, Adam Glick, Paul F. Lambert
Journal: Cancer Research (2009)

Several mucosotropic human papillomaviruses (HPV), including HPV type 16 (HPV-16), are etiologic agents of a subset of anogenital cancers and head and neck squamous cell carcinomas. In mice, HPV-16 E7 is the most potent of the papillomaviral oncogenes in the development of cervical disease. Furthermore, interfering specifically with the expression of E7 in HPV-positive cell lines derived from human cervical cancers inhibits their ability to proliferate, indicating that the expression of E7 is important in maintaining the transformed phenotype in vitro. To assess the temporal role of E7 in maintaining HPV-associated tumors and precancerous lesions in vivo, we generated Bi-L E7 transgenic mice that harbor a tetracycline-inducible transgene that expresses both HPV-16 E7 and firefly luciferase. When we crossed Bi-L E7 mice to a K5-tTA transgene-inducing line of mice, which expresses a tetracycline-responsive transactivator selectively in the stratified squamous epithelia, the resulting Bi-L E7/K5-tTA bitransgenic mice expressed E7 and luciferase in the skin and cervical epithelium, and doxycycline repressed this expression. Bitransgenic mice displayed several overt and acute epithelial phenotypes previously shown to be associated with the expression of E7, and these phenotypes were reversed on treatment with doxycycline. Repressing the expression of E7 caused the regression of high-grade cervical dysplasia and established cervical tumors, indicating that they depend on the continuous expression of E7 for their persistence. These results suggest that E7 is a relevant target not only for anticancer therapy but also for the treatment of HPV-positive dysplastic cervical lesions.
Richter's Syndrome With Aberrant CD2 and CD4 Expression
Authors: Sarah Barnhard, Ashok Pai, Helen K. Chew, Joo Young Song
Journal: Journal of Clinical Oncology (2012)

Richter's Syndrome With Aberrant CD2 and CD4 ExpressionCase Report An 81-year-old man with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was evaluated for rapidly enlarging and symptomatic lymphadenopathy.The patient was initially diagnosed 9 years earlier and was treated at varying intervals with chemotherapy that included fludarabine-cyclophosphamide-rituximab and bendamustine-rituximab; the most recent treatment ended 6 months before this presentation.The patient described a 1-week history of markedly increasing cervical lymphadenopathy, shortness of breath, and difficulty swallowing.Physical examination revealed massive cervical and supraclavicular lymphadenopathy, with the largest lymph node measuring 8 ϫ 10 cm in size.No stridor was noted.Laboratory data revealed a normal WBC count with no peripheral lymphocytosis and a slightly elevated lactate dehydrogenase level.A computed tomography scan demonstrated extensive bulky supraclavicular and mediastinal adenopathy with mass effect noted on the posterior pharyngeal and hypopharyngeal walls (Fig 1).An excisional biopsy of a cervical lymph node was evaluated by flow cytometry and showed two distinct abnormal populations on cytosmear (Fig 2).The first population (59% of the total cells) was small in size by forward scatter, positive for CD19, CD5 (dim), CD23, kappa restricted, and negative for FMC-7, consistent with CLL/SLL.The second lymphoid population (20% of the total cells) was large in size by forward scatter, positive for CD19 and FMC-7, kappa restricted, and negative for CD5 and CD23, which suggested a mature B-cell lymphoma.This group of cells also showed aberrant expression of CD2 and CD4, which is unusual because these
Profile of Preparticipation Cardiovascular Screening for High School Athletes
Authors: David W. Glover
Journal: JAMA (1998)

Sudden death in young competitive athletes due to unsuspected cardiovascular disease has heightened concern and interest in the preparticipation screening available to high school athletes in the United States.To assess the potential adequacy of the preparticipation screening process for detecting or increasing the suspicion of cardiovascular abnormalities.Current guidelines and requirements for implementation of preparticipation screening from each of the high school jurisdictions in the 50 states and the District of Columbia were analyzed and compared with the 1996 American Heart Association (AHA) consensus panel guidelines on screening.Items contained on preparticipation screening questionnaires; the examiners designated to perform screening.Eight states (16%) have no approved history and physical examination questionnaires to guide examiners, including 1 state without a formal screening requirement. Of the remaining 43 states, several items relevant to cardiac-related problems were frequently omitted from the questionnaires. Exertional dyspnea or chest pain, prior limitation from sports, family history of heart disease, or Marfan syndrome were included in 0% to 56% of the state forms. Specific cardiovascular items on physical examination were included in forms from only 5% to 37% of states, including documentation of a heart murmur, irregular heart rhythm, peripheral pulses, or stigmata of Marfan syndrome. Seventeen (40%) of 43 states had history and physical questionnaires judged to be most adequate with at least 9 of the 13 AHA recommendations, whereas 12 states (28%) were least adequate with 4 or less of these recommended items. Therefore, a total of 20 (40%) of the 51 states have no approved history and physical examination questionnaires, or formal screening requirement, or forms that were judged to be inadequate. In addition to physicians, 21 states also permit nurses or physician assistants to administer examinations, and 11 states specifically provide for practitioners with limited cardiovascular training (such as chiropractors).Preparticipation athletic screening for cardiovascular disease with standard history and physical examination, as presently employed in US high schools, is highly dependent on the state-approved questionnaires, which frequently are abbreviated and may be inadequate; is implemented by a variety of health care workers with varying levels of expertise; and may be severely limited in its power to detect potentially lethal cardiovascular abnormalities. These observations should represent an impetus for change and improvement in the preparticipation cardiovascular screening process for high school athletes.
Rapid radiological progression in the first year of early rheumatoid arthritis is predictive of disability and joint damage progression during 8 years of follow-up
Authors: M van den Broek, L Dirven, J K de Vries-Bouwstra, A J Dehpoor, Y P M Goekoop-Ruiterman, A H Gerards, P J S M Kerstens, T W J Huizinga, WF Lems, C F Allaart
Journal: Annals of the Rheumatic Diseases (2012)

Several prediction models for rapid radiological progression (RRP) in the first year of rheumatoid arthritis have been designed to aid rheumatologists in their choice of initial treatment. The association was assessed between RRP and disability and joint damage progression in 8 years.Patients from the BeSt cohort were used. RRP was defined as an increase of ≥5 points in the Sharp/van der Heijde score (SHS) in year 1. Functional ability over 8 years, measured with the health assessment questionnaire (HAQ), was compared for patients with and without RRP using linear mixed models. Joint damage progression from years 1 to 8 was compared using logistic regression analyses.RRP was observed in 102/465 patients. Over 8 years, patients with RRP had worse functional ability: difference in HAQ score 0.21 (0.14 after adjustment for disease activity score (over time)). RRP was associated with joint damage progression ≥25 points in SHS in years 1-8: OR 4.6.RRP in year 1 is a predictor of worse functional ability over 8 years, independent of baseline joint damage and disease activity. Patients with RRP have more joint damage progression in subsequent years. RRP is thus a relevant outcome on which to base the initial treatment decision.
A Population-Based Prospective Study of Carcinogenic Human Papillomavirus Variant Lineages, Viral Persistence, and Cervical Neoplasia
Authors: Mark Schiffman, Ana Cecilia Rodriguez, Zigui Chen, Sholom Wacholder, Rolando Herrero, Allan Hildesheim, Rob Desalle, Brian Befano, Kai Yu, Mahboobeh Safaeian, Mark E. Sherman, Jorge Morales, Diego Guillen, Mario Alfaro, Martha Hutchinson, Diane Solomon, Philip E. Castle, Robert D. Burk
Journal: Cancer Research (2010)

Human papillomavirus (HPV) types differ profoundly in cervical carcinogenicity. For the most carcinogenic type HPV16, variant lineages representing further evolutionary divergence also differ in cancer risk. Variants of the remaining 10 to 15 carcinogenic HPV types have not been well studied. In the first prospective, population-based study of HPV variants, we explored whether, on average, the oldest evolutionary branches within each carcinogenic type predicted different risks of >2-year viral persistence and/or precancer and cancer [cervical intraepithelial neoplasia grade 3+ (CIN3+)]. We examined the natural history of HPV variants in the 7-year, 10,049-woman Guanacaste Cohort Study, using a nested case-control design. Infections were assigned to a variant lineage determined by phylogenetic parsimony methods based on URR/E6 sequences. We used the Fisher's combination test to evaluate significance of the risk associations, cumulating evidence across types. Globally, for HPV types including HPV16, the P value was 0.01 for persistence and 0.07 for CIN3+. Excluding HPV16, the P values were 0.04 and 0.37, respectively. For HPV16, non-European viral variants were significantly more likely than European variants to cause persistence [odds ratio (OR), 2.6; P = 0.01] and CIN3+ (OR, 2.4; P = 0.004). HPV35 and HPV51 variant lineages also predicted CIN3+. HPV variants generally differ in risk of persistence. For some HPV types, especially HPV16, variant lineages differ in risk of CIN3+. The findings indicate that continued evolution of HPV types has led to even finer genetic discrimination linked to HPV natural history and cervical cancer risk. Larger viral genomic studies are warranted, especially to identify the genetic basis for HPV16's unique carcinogenicity.
Inducible t cell costimulator ligand (ICOSLG) influences crohn's disease susceptibility in the scottish paediatric ibd population
Authors: P. Henderson, J. van Limbergen, N. H. Anderson, R. K. Russell, J. Satsangi, D. C. Wilson
Journal: Gut (2011)

<h3>Introduction</h3> Inducible T cell costimulator ligand (ICOSLG) is intimately involved in the proliferation and differentiation of T lymphocytes. A locus on Chr. 21q22 harbouring the <i>ICOSLG</i> gene has been shown to influence susceptibility to adult and paediatric Crohn9s disease (CD) and ulcerative colitis (UC). Our aim was to perform a detailed analysis of <i>ICOSLG</i> using a genewide haplotype-tagging approach and to delineate the region of strongest association. <h3>Methods</h3> 416 patients diagnosed with inflammatory bowel disease (IBD) &lt;17 years within Scotland (278 CD, 101 UC and 37 IBD-U) and 735 parents (276 complete trios) were genotyped for 4 single nucleotide polymorphisms (SNPs) tagging the two haplotype blocks encoding <i>ICOSLG</i> as well as the region extending to rs762421 which achieved recent genomewide significance. Detailed phenotypic characteristics of this cohort were previously described. SNPs were selected using HapMap data (based on solid spine of LD, MAF &gt; 0.1). Detailed single marker and haplotype analysis by transmission disequilibrium testing (ParenTDT) was carried out using Haploview (permutation analysis, n=100 000). <h3>Results</h3> The two-marker haplotypes rs762421A/G – rs8126734A/G and rs283529G/C – rs4818890C/A (both located within the 39 UTR of <i>ICOSLG</i>) showed weak associations with overall IBD susceptibility (p&lt;0.05) which did not retain significance after permutation analysis. However after stringent permutation analysis the rs8126734 A allele showed significant overtransmission to affected CD patients (p=0.02, D9 and r<sup>2</sup> with rs762421 was 0.78 and 0.21, respectively). The two-marker haplotype consisting of rs762421A and rs8126734G also showed significant distortion of transmission (p=0.03). Using a sliding-2 marker haplotype analysis to assess the extent of the CD-association signal from the 39UTR to the 59 end of the <i>ICOSLG</i> coding sequence we found that association signals did not extend upstream from rs8126734, thus implicating the 39 interval between rs762421 and rs8126734 as a target region for deep sequencing. <h3>Conclusion</h3> We have applied the first family-based association analysis of <i>ICOSLG</i> in childhood onset CD (thus minimising the effect of population stratification) to demonstrate that the signal at the 21q22 locus is due to germline variation at the 39 end of <i>ICOSLG</i>. Our analysis makes it less likely for non-synonymous <i>ICOSLG</i> SNPs or for other genes in the region to contribute significantly to inherited CD susceptibility. Deep sequencing of the 39 UTR of the <i>ICOSLG</i> gene is now warranted to identify causative variants, potentially affecting mRNA stability.
Emerging and re-emerging infectious diseases: challenges and opportunities for militaries
Authors: Zheng Jie Ho, Yi Fu Hwang, Jian Ming Lee
Journal: Military Medical Research (2014)

The communal nature of living and training environments, alongside suboptimal hygiene and stressors in the field, place military personnel at higher risk of contracting emerging infectious diseases. Some of these diseases spread quickly within ranks resulting in large outbreaks, and personnel deployed are also often immunologically naïve to otherwise uncommonly-encountered pathogens. Furthermore, the chance of weaponised biological agents being used in conventional warfare or otherwise remains a very real, albeit often veiled, threat. However, such challenges also provide opportunities for the advancement of preventive and therapeutic military medicine, some of which have been later adopted in civilian settings. Some of these include improved surveillance, new vaccines and drugs, better public health interventions and inter-agency co-operations. The legacy of successes in dealing with infectious diseases is a reminder of the importance in sustaining efforts aimed at ensuring a safer environment for both military and the community at large.
Monotherapy for fever and neutropenia in cancer patients: a randomized comparison of ceftazidime versus imipenem.
Authors: A G Freifeld, T Walsh, D Marshall, J Gress, S M Steinberg, J Hathorn, M Rubin, P Jarosinski, V Gill, R C Young
Journal: Journal of Clinical Oncology (1995)

PURPOSE To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem. PATIENTS AND METHODS Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection. RESULTS Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P &lt; .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients. CONCLUSION Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.
Contribution of Cubilin and Amnionless to Processing and Membrane Targeting of Cubilin–Amnionless Complex
Authors: Gwénae[Combining Diaeresis]lle Coudroy, Jakub Gburek, Renata Kozyraki, Mette Madsen, Germain Trugnan, Søren K. Moestrup, Pierre J. Verroust, Miche[Combining Grave Accent]le Maurice
Journal: Journal of the American Society of Nephrology (2005)

Cubilin is a peripheral apical membrane receptor for multiple ligands that are taken up in several absorptive epithelia. Recently, amnionless (AMN) was identified to form a functional receptor complex with cubilin. By expression in transfected polarized MDCK cells of AMN and several cubilin fragments, including a functional "mini" version of cubilin, the processing, sorting, and membrane anchoring of the complex to the apical membrane were investigated. The results show that truncation mutants, including the N-terminal domain of cubilin, did not appear at the plasma membrane but instead were retained in the endoplasmic reticulum or partially secreted into the medium. Coexpression with AMN led to efficient transport to the apical cell surface of the cubilin constructs, which included the EGF domains, and prevented release into the medium. AMN co-precipitated with cubilin and co-localized with cubilin at the apical cell surface. Apical sorting was observed for a broad set of nonoverlapping cubilin fragments without the N-terminal region, in the absence of AMN. The preference for apical sorting disappeared when glycosylation was inhibited by tunicamycin. In conclusion, it is shown that both units contribute to the processing of the cubilin–AMN complex to the apical membrane: AMN interacts with the EGF domains of cubilin and is responsible for membrane attachment and export of the complex from the endoplasmic reticulum, whereas the extracellular cubilin molecule is responsible for apical sorting of the complex in a carbohydrate-dependent manner.
Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741
Authors: Marc L. Citron, Donald A. Berry, Constance Cirrincione, Clifford Hudis, Eric P. Winer, William J. Gradishar, Nancy E. Davidson, Silvana Martino, Robert Livingston, James N. Ingle, Edith A. Perez, John Carpenter, David Hurd, James F. Holland, Barbara L. Smith, Carolyn I. Sartor, Eleanor H. Leung, Jeffrey Abrams, Richard L. Schilsky, Hyman B. Muss, Larry Norton
Journal: Journal of Clinical Oncology (2003)

Purpose: Using a 2 × 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node–positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. Patients and Methods: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A × 4 (doses) → T × 4 → C × 4 with doses every 3 weeks, (II) sequential A × 4 → T × 4 → C × 4 every 2 weeks with filgrastim, (III) concurrent AC × 4 → T × 4 every 3 weeks, or (IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim. Results: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P = .010), and OS (RR = 0.69; P = .013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. Conclusion: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.
Intestinal epithelial cell secretion of RELM-β protects against gastrointestinal worm infection
Authors: De'Broski R. Herbert, Jun-Qi Yang, Simon P. Hogan, Kathryn Groschwitz, Marat Khodoun, Ariel Munitz, Tatyana Orekov, Charles Perkins, Quan Wang, Frank Brombacher, Joseph F. Urban, Marc E. Rothenberg, Fred D. Finkelman
Journal: The Journal of Experimental Medicine (2009)

Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decreases H. polygyrus adenosine triphosphate content and fecundity. Importantly, RELM-β–driven immunity does not require T or B cells, alternative macrophage activation, or increased gut permeability. Thus, we demonstrate a novel mechanism for host protection at the mucosal interface that explains how stimulation of epithelial cells by IL-4 and IL-13 contributes to protection against parasitic helminthes that dwell in the intestinal lumen.
Facilitated engraftment of human hematopoietic cells in severe combined immunodeficient mice following a single injection of Cl2MDP liposomes
Authors: W Terpstra, PJM Leenen, C van den Bos, A Prins, WAM Loenen, MMA Verstegen, S van Wyngaardt, N van Rooijen, AW Wognum, G Wagemaker, JJ Wielenga, B Löwenberg
Journal: Leukemia (1997)