tbuckley/cabot-search huggingface dataset:
Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance
Authors: Justin R. Bailey, Lisa N. Wasilewski, Anna E. Snider, Ramy El-Diwany, William O. Osburn, Zhenyong Keck, Steven K.H. Foung, Stuart C. Ray
Journal: Journal of Clinical Investigation (2014)

For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization panel expressing diverse, naturally occurring HCV envelopes (E1E2s) and used this panel to characterize neutralizing breadth and resistance mechanisms of 18 previously described broadly neutralizing anti-HCV human mAbs. The observed mAb resistance could not be attributed to polymorphisms in E1E2 at known mAb-binding residues. Additionally, hierarchical clustering analysis of neutralization resistance patterns revealed relationships between mAbs that were not predicted by prior epitope mapping, identifying 3 distinct neutralization clusters. Using this clustering analysis and envelope sequence data, we identified polymorphisms in E2 that confer resistance to multiple broadly neutralizing mAbs. These polymorphisms, which are not at mAb contact residues, also conferred resistance to neutralization by plasma from HCV-infected subjects. Together, our method of neutralization clustering with sequence analysis reveals that polymorphisms at noncontact residues may be a major immune evasion mechanism for HCV, facilitating viral persistence and presenting a challenge for HCV vaccine development.
Metastasis-Suppressor Genes: a Review and Perspective on an Emerging Field
Authors: Barbara A. Yoshida, Mitchell M. Sokoloff, Danny R. Welch, Carrie W. Rinker-Schaeffer
Journal: JNCI Journal of the National Cancer Institute (2000)

Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will distinguish accurately those histologic lesions and disseminated cells with a high probability of causing clinically important metastatic disease from those that will remain indolent. While the development of new diagnostic markers of metastasis was the initial motivation for many studies, the biologic approach used to identify metastasis-suppressor genes has provided surprising insights into the in vivo mechanisms regulating the formation of metastases. This review and perspective describes the evolving view of the mechanisms that regulate metastasis and the importance of metastasis-suppressor genes in this process. The known metastasis-suppressor proteins or genes and the microcell-mediated chromosomal transfer strategy used to identify many of them are reviewed. New evidence for the role of these metastasis-suppressor proteins or genes in regulating the growth of disseminated cancer cells at the secondary site, the potential for the identification of novel therapeutic targets, and the multidisciplinary approach needed to translate this information into clinical tools for the treatment of metastatic disease are discussed.
Identification of Angiogenesis/Metastases Genes Predicting Chemoradiotherapy Response in Patients With Laryngopharyngeal Carcinoma
Authors: Ian Ganly, Simon Talbot, Diane Carlson, Agnes Viale, Ellie Maghami, Iman Osman, Eric Sherman, David Pfister, Shaokun Chuai, Ashok R. Shaha, Dennis Kraus, Jatin P. Shah, Nicholas D. Socci, Bhuvanesh Singh
Journal: Journal of Clinical Oncology (2007)

To identify genes related to angiogenesis/metastasis that predict locoregional failure in patients with laryngopharyngeal cancer (LPC) undergoing chemoradiotherapy (CRT) treatment.Tumor tissue was collected and snap-frozen from 35 sequential patients with histologically confirmed LPC being treated with CRT. Gene expression analysis was performed using a novel cDNA array consisting of 277 genes functionally associated with angiogenesis (n = 152) and/or metastasis (n = 125). Locoregional response was correlated to the gene expression profiles to identify genes associated with outcome. These genes were internally validated by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and validated externally by immunohistochemistry analysis on an independent set of patients.Locoregional failure occurred in nine of 35 patients. Seventeen genes from the cDNA microarray correlated with locoregional failure (two-sample t test, P < .05). Seven genes were chosen for additional analysis based on the availability of antibodies for immunohistochemistry. Of these seven genes, real-time RT-PCR validated four genes: MDM2, VCAM-1, erbB2, and H-ras (Wilcoxon rank sum test, P = .008, .02, .04, and .04, respectively). External validation by immunohistochemistry confirmed MDM2 and erbB2 as being predictive of locoregional response. Controlling for stage of disease, positivity for MDM2 or erbB2 was an independent negative predictor of locoregional disease-free survival.Genomic screening by cDNA microarray and validation internally by real-time RT-PCR and externally by immunohistochemistry have identified two genes (MDM2 and erbB2) as predictors of locoregional failure in LPC patients treated with CRT. The role of these genes in treatment selection and the functional basis for their activity in CRT response merit additional consideration.
Patient stratification in the management of acute bacterial exacerbation of chronic bronchitis: the role of levofloxacin 750 mg
Authors: F. J. Martinez
Journal: European Respiratory Journal (2005)

This is the first prospective clinical trial in which patients with acute bacterial exacerbation of chronic bronchitis have been stratified by degree of underlying illness. Uncomplicated patients were randomised to levofloxacin 750 mg once daily (<i>q.d.</i>) for 3 days or azithromycin <i>q.d.</i> for 5 days. Complicated patients were randomised to levofloxacin 750 mg <i>q.d.</i> for 5 days or amoxicillin 875 mg/clavulanate 125 mg twice daily for 10 days. Regardless of therapy, complicated patients demonstrated lower clinical and microbiological success than uncomplicated patients. Clinical success for clinically evaluable patients was similar for levofloxacin and azithromycin (93.0 <i>versus</i> 90.1%, respectively), and levofloxacin and amoxicillin/clavulanate (79.2 <i>versus</i> 81.7%, respectively). For microbiologically evaluable patients, clinical response to levofloxacin for 3 days was superior to azithromycin for 5 days (96.3 <i>versus</i> 87.4%, respectively), and levofloxacin for 5 days was similar to amoxicillin/clavulanate for 10 days (81.4 <i>versus</i> 80.9%, respectively). Microbiological eradication was superior for levofloxacin for 3 days compared with azithromycin for 5 days (93.8 <i>versus</i> 82.8%, respectively), and similar for levofloxacin and amoxicillin/clavulanate for 10 days (81.4 <i>versus</i> 79.8%, respectively). In conclusion, levofloxacin 750 mg for 3 days was comparable to azithromycin for 5 days for uncomplicated patients with acute bacterial exacerbation of chronic bronchitis, while 5 days of 750 mg levofloxacin was comparable to 10 days of amoxicillin/clavulanate for complicated acute bacterial exacerbation of chronic bronchitis.
Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients
Authors: M Varettoni, A Corso, G Pica, S Mangiacavalli, C Pascutto, M Lazzarino
Journal: Annals of Oncology (2009)

There are few data on the incidence and prognosis of extramedullary (EM) multiple myeloma (MM). There are concerns about a possible increase of EM relapses with the expanding use of high-dose therapy (HDT) and biological agents.The incidence of EM disease, its relationship with prior exposure to HDT or novel agents, and its prognostic impact were analyzed in 1003 MM patients. Based on the different therapies available, three periods were considered: 1971-1993, conventional-dose chemotherapy; 1994-1999, HDT for younger patients; and 2000-2007, introduction of novel agents.Overall, 13% of patients had EM disease, 7% at diagnosis and 6% later. In the 2000-2007 period, there was a significant increase of EM involvement, at diagnosis (P = 0.02) and during follow-up (P = 0.03). The risk of EM spread was not significantly increased after HDT [hazard ratio (HR 0.6)], bortezomib (HR 1.62), or thalidomide/lenalidomide (HR 1.07). EM disease was associated with shorter overall (HR 3.26, P < 0.0001) and progression-free (HR 1.46, P = 0.04) survival.The incidence of EM disease has increased, probably due to the availability of more sensitive imaging techniques and the prolongation of patients' survival. HDT or novel agents seem not to increase the risk of EM disease. EM involvement confers a poor prognosis.
Author's response to letter on number needed to treat in COPD: exacerbations versus pneumonias: Table 1
Authors: Samy Suissa
Journal: Thorax (2013)

I thank Keene et al for their letter.1 I am pleased to clarify the issues they have raised about my paper.2 First, I agree that when dealing with recurrent events such as exacerbations, it is statistically more informative to analyse all events with tools such as incidence rates and rate differences. The point of my paper, however, was that inverting these rate differences and calling the result a number needed to treat (NNT) is simply wrong. For example, while the rates of chronic obstructive pulmonary disease (COPD) exacerbation from the TORCH trial are valid representations of …
Novel pharmacologic approach to enhance the epigenetic and immune priming effect of decitabine in patients with advanced non-small cell lung cancer
Authors: Vamsidhar Velcheti, Nathan A Pennell, Sagar Rakshit, James Stevenson, Marc Shapiro, Francisco A Almeida, Ram Gurajala, Kurt Alex Schalper, Yogen Saunthararajah
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts DNA methyl transferase 1 (DNMT-1) is a key epigenetic enzyme in cancer cells which inactivates proliferation terminating genes and downregulates the expression of cancer related proteins and neoantigens by hypermethylation. Prolonged exposure of tumor cells to DAC is required for
Efficacy of Sequential High-Dose Doxorubicin and Ifosfamide Compared With Standard-Dose Doxorubicin in Patients With Advanced Soft Tissue Sarcoma: An Open-Label Randomized Phase II Study of the Spanish Group for Research on Sarcomas
Authors: Joan Maurel, Antonio López-Pousa, Ramón de las Peñas, Joaquín Fra, Javier Martín, Josefina Cruz, Antonio Casado, Andrés Poveda, Javier Martínez-Trufero, Carmen Balañá, María Auxiliadora Gómez, Ricardo Cubedo, Oscar Gallego, Belen Rubio-Viqueira, Jordi Rubió, Raquel Andrés, Isabel Sevilla, Juan Jose de la Cruz, Xavier García del Muro, Jose María Buesa
Journal: Journal of Clinical Oncology (2009)

Purpose To assess the progression-free survival (PFS) and antitumor response to standard-dose doxorubicin compared with sequential dose-dense doxorubicin and ifosfamide in first-line treatment of advanced soft tissue sarcoma. Patients and Methods Patients with measurable advanced soft tissue sarcoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) &lt; 2, between the ages 18 and 65 years, and with adequate bone marrow, liver, and renal function were entered in the study. The stratifications were: ECOG PS (0 v 1), location of metastases, and potentially resectable disease. Patients were randomly assigned to either doxorubicin 75 mg/m 2 given as a bolus injection every 3 weeks for 6 cycles (arm A) or doxorubicin at 30 mg/m 2 per day for 3 consecutive days once every 2 weeks for 3 cycles followed by ifosfamide at 12.5 g/m 2 delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles with filgastrim or pegfilgastrim support (arm B). Results Between December 2003 and September 2007, 132 patients were entered onto the study. Febrile neutropenia, asthenia, and mucositis were more frequent in the arm B. The interim preplanned analysis for futility allowed the premature closure. Objective responses were observed in 23.4% of assessable patients in arm A and 24.1% in arm B. PFS was 26 weeks in the arm A and 24 weeks in arm B (P = .88). Overall survival did not differ between the two therapeutic arms (P = .14). Conclusion Single-agent doxorubicin remains the standard treatment in fit patients with advanced soft tissue sarcoma.
Circulating immune complexes in sarcoidosis, a clinical role for the Raji assay?
Authors: DP Rooney, MB Finch, JS Elborn, CF Stanford
Journal: European Respiratory Journal (1990)

Many immunological abnormalities, including circulating immune complexes (CICs), have been described in patients with sarcoidosis. The relationship of these abnormalities to clinical states is uncertain. In 31 proven cases of sarcoidosis we used the Raji assay in the investigation of the relationship between disease activity and the presence of CICs. Circulating immune complexes (greater than 49 micrograms.ml-1) were found in 11 of 14 patients with evidence of recent significant disease deterioration, whereas only one of 17 patients with chronic stable sarcoidosis demonstrated CICs (p less than 0.001). At follow-up, it was found that eight of the 11 cases with active disease and detectable CICs had resolved clinically. Resolution was accompanied by normalization of CICs in seven and persistence in one. The remaining three patients did not improve clinically and continued to demonstrate CICs. Measurements of complement levels did not demonstrate any significant difference between the two groups of patients. It is concluded that elevated levels of CICs, as detected by the Raji assay, are commonly found in association with significantly deteriorating sarcoidosis, often normalize following disease improvement and, consequently, may have a useful clinical role as a marker of activity.
The Finnish Diabetes Prevention Study (DPS)
Authors: Jaana Lindström, Anne Louheranta, Marjo Mannelin, Merja Rastas, Virpi Salminen, Johan Eriksson, Matti Uusitupa, Jaakko Tuomilehto
Journal: Diabetes Care (2003)

OBJECTIVE—To describe the 1) lifestyle intervention used in the Finnish Diabetes Prevention Study, 2) short- and long-term changes in diet and exercise behavior, and 3) effect of the intervention on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS—There were 522 middle-aged, overweight subjects with impaired glucose tolerance who were randomized to either a usual care control group or an intensive lifestyle intervention group. The control group received general dietary and exercise advice at baseline and had an annual physician’s examination. The subjects in the intervention group received additional individualized dietary counseling from a nutritionist. They were also offered circuit-type resistance training sessions and advised to increase overall physical activity. The intervention was the most intensive during the first year, followed by a maintenance period. The intervention goals were to reduce body weight, reduce dietary and saturated fat, and increase physical activity and dietary fiber. RESULTS—The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 and 0.9 kg in the control group, respectively. Measures of glycemia and lipemia improved more in the intervention group. CONCLUSIONS—The intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, and clinical and biochemical parameters and reduced diabetes risk. This type of intervention is a feasible option to prevent type 2 diabetes and should be implemented in the primary health care system.
FGFR Signaling Promotes the Growth of Triple-Negative and Basal-Like Breast Cancer Cell Lines Both <i>In Vitro</i> and <i>In Vivo</i>
Authors: Rachel Sharpe, Alex Pearson, Maria T. Herrera-Abreu, Damian Johnson, Alan Mackay, Jonathan C. Welti, Rachael Natrajan, Andrew R. Reynolds, Jorge S. Reis-Filho, Alan Ashworth, Nicholas C. Turner
Journal: Clinical Cancer Research (2011)

The oncogenic drivers of triple-negative (TN) and basal-like breast cancers are largely unknown. Substantial evidence now links aberrant signaling by the fibroblast growth factor receptors (FGFR) to the development of multiple cancer types. Here, we examined the role of FGFR signaling in TN breast cancer.We examined the sensitivity of a panel of 31 breast cancer cell lines to the selective FGFR inhibitor PD173074 and investigated the potential mechanisms underlying sensitivity.TN breast cancer cell lines were more sensitive to PD173074 than comparator cell lines (P = 0.011), with 47% (7/15) of TN cell lines showing significantly reduced growth. The majority of TN cell lines showed only modest sensitivity to FGFR inhibition in two-dimensional growth but were highly sensitive in anchorage-independent conditions. PD173074 inhibited downstream mitogen-activated protein kinase and PI3K-AKT signaling and induced cell-cycle arrest and apoptosis. Basal-like breast cancer cell lines were found to express FGF2 ligand (11/21 positive) and, similarly, 62% of basal-like breast cancers expressed FGF2, as assessed by immunohistochemistry compared with 5% of nonbasal breast cancers (P < 0.0001). RNA interference targeting of FGF2 in basal-like cell lines significantly reduced growth in vitro and reduced down stream signaling, suggesting an autocrine FGF2 signaling loop. Treatment with PD173074 significantly reduced the growth of CAL51 basal-like breast cancer cell line xenografts in vivo.Basal-like breast cancer cell lines, and breast cancers, express autocrine FGF2 and show sensitivity to FGFR inhibitors, identifying a potential novel therapeutic approach for these cancers.
Recommendations for the Return of Research Results to Study Participants and Guardians: A Report From the Children's Oncology Group
Authors: Conrad V. Fernandez, Kathleen Ruccione, Robert J. Wells, Jay B. Long, Wendy Pelletier, Mary C. Hooke, Rebecca D. Pentz, Robert B. Noll, Justin N. Baker, Maura O'Leary, Gregory Reaman, Peter C. Adamson, Steven Joffe
Journal: Journal of Clinical Oncology (2012)

The Children's Oncology Group (COG) strongly supports the widely recognized principle that research participants should be offered a summary of study results. The mechanism by which to do so in a cooperative research group setting has not been previously described.On the basis of a review of the available empirical and theoretic literature and on iterative, multidisciplinary discussion, a COG Return of Results Task Force (RRTF) offered detailed recommendations for the return of results to research study participants.The RRTF established guidelines for the notification of research participants and/or their parents/guardians about the availability of research results, a mechanism for and timing of sharing results via registration on the COG public Web site, the scope of the research to be shared, the target audience, and a process for creating and vetting lay summaries of study results. The RRTF recognized the challenges in adequately conveying complex scientific results to audiences with varying levels of health literacy and recommended that particularly sensitive or complex results be returned using direct personal contact. The RRTF also recommended evaluation of the cost, effectiveness, and impact of sharing results.These recommendations provide a framework for the offering and returning of results to participants. They can be used by individual investigators, multi-investigator research collaboratives, and large cooperative groups.
Surgical Outcome of Discrete Subaortic Stenosis in Adults
Authors: Denise van der Linde, Jolien W. Roos-Hesselink, Dimitris Rizopoulos, Helena J. Heuvelman, Werner Budts, Arie P.J. van Dijk, Maarten Witsenburg, Sing C. Yap, Angela Oxenius, Candice K. Silversides, Erwin N. Oechslin, Ad J.J.C. Bogers, Johanna J.M. Takkenberg
Journal: Circulation (2013)

Discrete subaortic stenosis is notable for its unpredictable hemodynamic progression in childhood and high reoperation rate; however, data about adulthood are scarce.Adult patients who previously underwent surgery for discrete subaortic stenosis were included in this retrospective multicenter cohort study. Mixed-effects and joint models were used to assess the postoperative progression of discrete subaortic stenosis and aortic regurgitation, as well as reoperation. A total of 313 patients at 4 centers were included (age at baseline, 20.2 years [25th-75th percentile, 18.4-31.0 years]; 52% male). Median follow-up duration was 12.9 years (25th-75th percentile, 6.2-20.1 years), yielding 5617 patient-years. The peak instantaneous left ventricular outflow tract gradient decreased from 75.7±28.0 mm Hg preoperatively to 15.1±14.1 mm Hg postoperatively (P<0.001) and thereafter increased over time at a rate of 1.31±0.16 mm Hg/y (P=0.001). Mild aortic regurgitation was present in 68% but generally did not progress over time (P=0.76). A preoperative left ventricular outflow tract gradient ≥80 mm Hg was a predictor for progression to moderate aortic regurgitation postoperatively. Eighty patients required at least 1 reoperation (1.8% per patient-year). Predictors for reoperation included female sex (hazard ratio, 1.53; 95% confidence interval, 1.02-2.30) and left ventricular outflow tract gradient progression (hazard ratio, 1.45; 95% confidence interval, 1.31-1.62). Additional myectomy did not reduce the risk for reoperation (P=0.92) but significantly increased the risk of a complete heart block requiring pacemaker implantation (8.1% versus 1.7%; P=0.005).Survival is excellent after surgery for discrete subaortic stenosis; however, reoperation for recurrent discrete subaortic stenosis is not uncommon. Over time, the left ventricular outflow tract gradient slowly increases and mild aortic regurgitation is common, although generally nonprogressive over time. Myectomy does not show additional advantages, and because it is associated with an increased risk of complete heart block, it should not be performed routinely.
Breastfeeding is associated with increased lung function at 18 years of age: a cohort study
Authors: N. Soto-Ramírez, M. Alexander, W. Karmaus, M. Yousefi, H. Zhang, R.J. Kurukulaaratchy, A. Raza, F. Mitchell, S. Ewart, S.H. Arshad
Journal: European Respiratory Journal (2011)

Breastfeeding has been linked with increased forced vital capacity (FVC) in children but not in older adolescents. Our aim was to investigate the effects of breastfeeding duration and infant weight gain on FVC in both developmental periods. In a birth cohort, information on breastfeeding duration was collected at 1 and 2 yrs; spirometric tests were conducted at 10 and 18 yrs. To estimate the effect of breastfeeding duration on FVC at 18 yrs of age, we used linear models; to analyse repeated FVC measurements at 10 and 18 yrs of age, we used linear mixed models. Links between breastfeeding, infant weight gain and FVC at 10 and 18 yrs of age were analysed through path analyses. Among 808 breastfed children, 49% were breastfed for ≥4 months. At 18 yrs of age the augmenting effect of breastfeeding on FVC was reduced with increased height. Linear mixed models identified that breastfeeding duration was associated with increased FVC. Path analysis suggested a direct effect of breastfeeding on FVC at 10 yrs of age, but an indirect effect at 18 yrs of age via FVC at 10 yrs of age. Although inversely related to breastfeeding, a higher weight gain in infants led to taller adolescents and, in turn, resulted in increased FVC. In conclusion, a longer duration of breastfeeding contributes to lung health in childhood and adolescence.
Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial
Authors: Lars Wallentin, Salim Yusuf, Michael D Ezekowitz, Marco Alings, Marcus Flather, Maria Grazia Franzosi, Prem Pais, Antonio Dans, John Eikelboom, Jonas Oldgren, Janice Pogue, Paul A Reilly, Sean Yang, Stuart J Connolly
Journal: The Lancet (2010)