tbuckley/cabot-search huggingface dataset:
Entecavir resistance is rare in nucleoside naïve patients with hepatitis B
Authors: Richard J. Colonno, Ronald Rose, Carl J. Baldick, Steven Levine, Kevin Pokornowski, Cheng F. Yu, Ann Walsh, Jie Fang, Mayla Hsu, Charles Mazzucco, Betsy Eggers, Sharon Zhang, Mary Plym, Kenneth Klesczewski, Daniel J. Tenney
Journal: Hepatology (2006)

Comprehensive monitoring of genotypic and phenotypic antiviral resistance was performed on 673 entecavir (ETV)-treated nucleoside naïve hepatitis B virus (HBV) patients. ETV reduced HBV DNA levels to undetectable by PCR (<300 copies/mL, <57 IU/mL) in 91% of hepatitis B e antigen (HBeAg)-positive and -negative patients by Week 96. Thirteen percent (n = 88) of the comparator lamivudine (LVD)-treated patients experienced a virologic rebound (> or =1 log increase from nadir by PCR) in the first year, with 74% of these having LVD resistance (LVDr) substitutions evident. In contrast, only 3% (n = 22) of ETV-treated patients exhibited virologic rebound by Week 96. Three ETV rebounds were attributable to LVDr virus present at baseline, with one having a S202G ETV resistance (ETVr) substitution emerge at Week 48. None of the other rebounding patients had emerging genotypic resistance or loss of ETV susceptibility. Genotyping all additional ETV patients with PCR-detectable HBV DNA at Weeks 48, 96, or end of dosing identified seven additional patients with LVDr substitutions, including one with simultaneous emergence of LVDr/ETVr. Generally, ETV patients with LVDr were detectable at baseline (8/10) and most subsequently achieved undetectable HBV DNA levels on ETV therapy (7/10). No other emerging substitutions identified decreased ETV susceptibility. In conclusion, ETVr emergence in ETV-treated nucleoside naïve patients over a 2-year period is rare, occurring in two patients with LVDr variants. These findings suggest that the rapid, sustained suppression of HBV replication, combined with a requirement for multiple substitutions, creates a high genetic barrier to ETVr in nucleoside naïve patients.
Impaired type I and III interferon response to rhinovirus infection during pregnancy and asthma
Authors: Rebecca Louise Forbes, Peter G Gibson, Vanessa E Murphy, Peter A B Wark
Journal: Thorax (2011)

Acute respiratory tract infections are common ailments to all individuals and the human rhinoviruses (HRVs) cause most of these infections. Pregnant women have increased susceptibility and disease severity to viral infections like influenza and HRVs, as do asthmatics. Successful pregnancy requires immunological modulation to permit fetal tolerance.To determine whether pregnant women have reduced innate antiviral interferon (IFN) responses to HRV infection compared with non-pregnant women.An in vitro culture system was used, where peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 54 women, including 10 stable asthmatics who were pregnant and 10 who were not pregnant, 10 non-asthmatic women who were pregnant, 10 who were ≥6 months post partum and 10 who were not pregnant. Samples were also collected from four exacerbating pregnant asthmatics. PBMCs were cultured with HRV43 and HRV1B. The antiviral proteins IFNα and IFNλ were measured from culture supernatants by ELISA.Compared with healthy non-pregnant women, pregnant women had significantly reduced innate IFN responses to HRV infection (p<0.02), persisting ≥6 months post partum (p≤0.02). Pregnant asthmatics had significantly reduced IFNλ responses compared with healthy non-pregnant women (p≤0.034), while during current asthma exacerbations a decrease in IFNα (p≤0.023) and IFNλ (p=0.007) was observed. Induction by a TLR7 agonist induced a similar pattern of decreased innate IFNs during pregnancy as observed when HRV was the inducing agent.Reduced antiviral IFNs during pregnancy and asthma provide an important mechanism for increased susceptibility, morbidity and mortality in pregnant women with respiratory viral infection.
Effective Incorporation of Biomarkers into Phase II Trials
Authors: Lisa M. McShane, Sally Hunsberger, Alex A. Adjei
Journal: Clinical Cancer Research (2009)

The incorporation of biomarkers into the drug development process will improve understanding of how new therapeutics work and allow for more accurate identification of patients who will benefit from those therapies. Strategically planned biomarker evaluations in phase II studies may allow for the design of more efficient phase III trials and better screening of therapeutics for entry into phase III development, hopefully leading to increased chances of positive phase III trial results. Some examples of roles that a biomarker can play in a phase II trial include predictor of response or resistance to specific therapies, patient enrichment, correlative endpoint, or surrogate endpoint. Considerations for using biomarkers most effectively in these roles are discussed in the context of several examples. The substantial technical, logistic, and ethical challenges that can be faced when trying to incorporate biomarkers into phase II trials are also addressed. A rational and coordinated approach to the inclusion of biomarker studies throughout the drug development process will be the key to attaining the goal of personalized medicine.
Agonist-induced calcium regulation in freshly isolated renal microvascular smooth muscle cells.
Authors: E W Inscho, M J Mason, A C Schroeder, P C Deichmann, K D Stiegler, J D Imig
Journal: Journal of the American Society of Nephrology (1997)

The studies presented here were performed to determine the effect of agonist stimulation on the cytosolic free Ca2+ concentration ([Ca2+]i) in single smooth muscle cells, freshly isolated from afferent arterioles and interlobular arteries averaging between 10 to 40 microns in diameter. Microvessels were obtained from male Sprague-Dawley rats using an iron oxide collection technique followed by collagenase digestion. Freshly isolated microvascular smooth muscle cells (MVSMC) were loaded with fura 2 and studied using fluorescence photometry techniques. The resting [Ca2+]i averaged 67 +/- 3 nM (N = 82 cells). Increasing the extracellular K+ concentration significantly increased [Ca2+]i dose-dependently (P < 0.05). Involvement of extracellular Ca2+ in the response to KCl-induced depolarization was also evaluated. Resting [Ca2+]i increased approximately 132% from 40 +/- 5 nM to 93 +/- 26 nM in response to 90 mM extracellular KCl. This change was abolished in nominally Ca(2+)-free conditions and markedly attenuated by diltiazem. Inhibition of K+ channels with charybdotoxin or tetraethylammonium chloride produced a modest transient increase in [Ca2+]i during the response to 30 mM K+ and had no detectable effect on responses to 90 mM K+. Studies were also performed to establish whether freshly isolated renal MVSMC exhibit appropriate responses to receptor-dependent physiological agonists. Angiotensin II (100 nM) increased cell Ca2+ from 97 +/- 10 nM to 265 +/- 47 nM (N = 12 cells). Similarly, 100 microM ATP increased MVSMC [Ca2+]i from a control level of 71 +/- 14 nM to 251 +/- 47 nM (N = 11 cells). Norepinephrine administration caused [Ca2+]i to increase from 63 +/- 4 nM to 212 +/- 47 nM (N = six cells), and vasopressin increased [Ca2+]i from 86 +/- 10 nM to 352 +/- 79 nM (N = five cells). These data demonstrate that receptor-dependent and -independent vasoconstrictor agonists increase [Ca2+]i in MVSMC, freshly isolated from rat preglomerular vessels. Furthermore, the ability to measure [Ca2+]i in responses to physiological stimuli in these single cells permits investigation of signal transduction mechanisms involved in regulating renal microvascular resistance.
Patients with cystic fibrosis should be intubated and ventilated
Authors: Ian Ketchell
Journal: Journal of the Royal Society of Medicine (2010)

Although chronic respiratory failure remains the primary cause of mortality in cystic fibrosis (CF), the natural history of the disease remains unpredictable. Patients are surviving longer, with an increased incidence of CF-related complications such that the CF team is not infrequently faced acutely with a critically-ill patient.
Changes in elastic fibres in the small airways and alveoli in COPD
Authors: P. N. Black, P. S. T. Ching, B. Beaumont, S. Ranasinghe, G. Taylor, M. J. Merrilees
Journal: European Respiratory Journal (2008)

Small airways are the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD). This is attributed to loss of elastin in alveoli and fibrosis in small airways. In the present study, it was hypothesised that changes to elastic fibres in alveoli might be paralleled by a similar reduction in elastic fibres in small airways. Tissue blocks from patients who had lobectomy for bronchial carcinoma were studied. Patients were classified as COPD (forced expiratory volume in one second (FEV 1 ) &lt;80% predicted, FEV 1 /forced vital capacity (FVC) &lt;0.7) or controls (FEV 1 ≥80% pred, FEV 1 /FVC ≥0.7). Elastic fibres were visualised using Elastic van Gieson staining and the volume fraction (v/f) of elastic fibres was determined as a percentage of tissue volume using point counting. Elastic fibre networks were also visualised by confocal microscopy. The v/f for elastic fibres in alveoli was 18.6% for COPD and 32.8% in controls. In the airways the v/f was 14.6% for COPD and 25.5% in controls. FEV 1 % predicted was correlated with v/f in both alveoli and small airways. The volume fraction of elastic fibres was reduced to a similar extent in small airways and alveoli in chronic obstructive pulmonary disease and both were correlated with the extent of airflow obstruction. Loss of elastic fibres in small airways may contribute to the development of airflow obstruction in chronic obstructive pulmonary disease.
Gene transfer of cytidine deaminase protects myelopoiesis from cytidine analogs in an in vivo murine transplant model
Authors: Ina Rattmann, Veronika Kleff, Ursula R. Sorg, Walter Bardenheuer, Annette Brueckner, Ralf A. Hilger, Bertram Opalka, Siegfried Seeber, Michael Flasshove, Thomas Moritz
Journal: Blood (2006)
Lung Mechanics and Dyspnea during Exacerbations of Chronic Obstructive Pulmonary Disease
Authors: Nicola J. Stevenson, Paul P. Walker, Richard W. Costello, Peter M. A. Calverley
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Exacerbation of chronic obstructive pulmonary disease commonly causes hospitalization. The change in lung mechanics during exacerbation and its relationship to symptoms in spontaneously breathing individuals has not been described.Objective: We hypothesized that changes in both airflow and lung volumes would occur during an exacerbation, but that only volume change would relate to symptomatic improvement.Methods: Lung mechanics and resting dyspnea were recorded in 22 hospitalized patients during recovery from exacerbation.Measurements: Spirometry, inspiratory capacity, respiratory system resistance and reactance, tidal breathing patterns, and expiratory flow limitation were recorded after nebulized bronchodilator therapy on the first 3 d after admission, at discharge, and 6 wk postadmission (Day 42). Prebronchodilator measurements were taken on Day 2, at discharge, and on Day 42.Main Results: Postbronchodilator inspiratory capacity increased 0.23 ± 0.07 L by discharge and 0.42 ± 0.1 L by Day 42, FEV1 rose 0.09 ± 0.04 and 0.2 ± 0.05 L at discharge and Day 42, respectively, and FVC increased 0.21 ± 0.08 and 0.47 ± 0.09 L at discharge and Day 42 (all p < 0.05). Consistent reduction in dyspnea was seen as the exacerbation resolved. Respiratory system resistance, FEV1/FVC, and expiratory flow limitation were unchanged throughout, indicating that changes in lung volume rather than airflow resistance predominated.Conclusions: Improvement in operating lung volumes is the principal change seen as a chronic obstructive pulmonary disease exacerbation resolves and increase in inspiratory capacity is a useful guide to a reduction in dyspnea.
Radiofrequency lesioning of dorsal root ganglia for chronic lumbosacral radicular pain: a randomised, double-lind, controlled trial
Authors: Jos WM Geurts, Roelof MAW van Wijk, Herman J Wynne, Edwin Hammink, Erik Buskens, Richel Lousberg, Johannes TA Knape, Gerbrand J Groen
Journal: The Lancet (2003)
Identification of Matrix Metalloproteinase 11 as a Predictive Tumor Marker in Serum Based on Gene Expression Profiling
Authors: Yan-Hong Yang, Hua Deng, Wen-Mei Li, Qing-Yun Zhang, Xiao-Ting Hu, Bai Xiao, Hai-Hong Zhu, Pai-Li Geng, You-Yong Lu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Prognostic markers discovery is a strategy for early diagnosis and individualization therapy for human cancer. In this study, we focus to integrate different methods to identify specific biomarker and elucidate its clinical significance. Experimental Design: A powerful tool named Digital Gene Expression Display online was applied to isolate differentially expressed genes correlated with gastric cancer. Matrix metalloproteinase 11 (MMP11) was selected and confirmed at both mRNA and protein level in 10 cell lines, 123 cases of tumor tissues, and 305 cases of gastric cancer serum specimen by semiquantitative PCR, immunohistochemistry staining, and ELISA techniques, respectively. Results: Our data showed that overexpression of MMP11 at mRNA and protein level was consistently detected in cell lines and primary tumors compared with matched normal tissues. Importantly, serum MMP11 levels were also significantly elevated in gastric cancer patients compared with those of the control subjects (P &amp;lt; 0.001), and the positive expression was well correlated with metastasis in gastric cancer patients (P = 0.009). Furthermore, we have shown that overexpression of MMP11 was associated with the malignant proliferation of AGS cells. Conclusions: Combination of gene expression profiling and specific clinical resource is a promising approach to validate gene expression patterns associated with malignant phenotype. As a secreted protein, MMP11 may play an important role in carcinogenesis and has potential implication as a biomarker for the diagnosis and prognosis of human cancers including gastric cancer.
Hepatocellular Carcinoma: Reasons for Phase III Failure and Novel Perspectives on Trial Design
Authors: Josep M. Llovet, Virginia Hernandez-Gea
Journal: Clinical Cancer Research (2014)

Hepatocellular carcinoma (HCC) is a major health problem. Most patients with HCC experience a recurrence after resection/ablation or are diagnosed at advanced stages. Sorafenib remains the only approved systemic drug for these patients. Molecular therapies targeting signaling cascades involved in hepatocarcinogenesis have been explored in phase III clinical trials. However, none of the drugs tested have shown positive results in the first-line (brivanib, sunitinib, erlotinib, and linifanib) or second-line (brivanib, everolimus) setting after sorafenib progression. Reasons for failure are heterogeneous and include lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design, or marginal antitumoral potency. These trials are also challenging time to progression as a surrogate endpoint of survival. Trials ongoing testing drugs head-to-head versus sorafenib in "all comers" might have difficulties in achieving superior results in the first line. Novel trials are also designed testing drugs in biomarker-based subpopulations of patients with HCC. Most common mutations, however, are undruggable, such as p53 and CTNNB1. Two types of studies are proposed: (i) phase II pivotal proof-of-concept studies testing drugs blocking potential oncogenic addiction loops, such as the one testing MEK inhibitors in RAS(+) patients or amplification of FGF19 as a target; and (ii) phase II to III studies using biomarker-based trial enrichment for defining HCC subpopulations, such as the case of enriching for MET-positive tumors. These strategies have been deemed successful in breast, melanoma, and lung cancers, and are expected to change the landscape of trial design of HCC.
Elafin is induced in epidermis in skin disorders with dermal neutrophilic infiltration: interleukin-1β and tumour necrosis factor-α stimulate its secretion in vitro
Authors: N. Tanaka, A. Fujioka, S. Tajima, A. Ishibashi, S. Hirose
Journal: British Journal of Dermatology (2000)

Elafin, an elastase inhibitor produced by keratinocytes, is overexpressed in the subcorneal region of skin affected by psoriasis, a major feature of which is epidermal infiltration by neutrophil leucocytes.We studied the expression of elafin in the epidermis in other skin disorders characterized by dermal neutrophil infiltration and in skin disorders with dermal lymphocyte infiltration.We examined biopsies from the lesional skin of patients with Behçet's syndrome, Sweet's syndrome, pyoderma gangrenosum, cutaneous allergic vasculitis and acute bacterial infection (cellulitis), and from the skin of patients with chronic prurigo, discoid lupus erythematosus and psoriasis. We performed in vitro experiments using cultured keratinocytes treated with mediators such as interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha, IL-6, neutrophil elastase and interferon (IFN)-gamma.Anti-elafin antibody showed a strong reaction with the subcorneal region of the epidermis in patients with Behçet's syndrome, Sweet's syndrome, pyoderma gangrenosum, cutaneous allergic vasculitis and acute bacterial infection (cellulitis), but showed no reaction in skin from patients with dermal lymphocyte infiltration such as is seen in chronic prurigo and discoid lupus erythematosus. The in vitro experiments demonstrated that treatment with IL-1 beta and TNF-alpha resulted in 2.6-fold and 4-fold stimulation of elafin secretion, respectively, whereas IL-6, neutrophil elastase and IFN-gamma caused no significant changes in elafin release.These results suggest that inflammatory mediators such as IL-1 beta or TNF-alpha secreted by dermal neutrophils may be involved in overexpression of elafin in keratinocytes; this could protect the epidermis from degradation by dermal neutrophil infiltration.
Treatment Selection and Outcomes in Early-Stage Classical Hodgkin Lymphoma: Analysis of the National Cancer Data Base
Authors: Adam J. Olszewski, Rajesh Shrestha, Jorge J. Castillo
Journal: Journal of Clinical Oncology (2015)

The choice between combined-modality therapy (CMT) and chemotherapy alone for early-stage Hodgkin lymphoma (HL) remains controversial. Our objective was to define factors affecting treatment selection and resulting survival outcomes in the United States.We identified 20,600 patients treated with CMT or chemotherapy between 2003 and 2011 from the National Cancer Data Base. Factors affecting treatment selection were studied in a mixed-effects logistic model. Survival outcomes were compared using a propensity score analysis to account for indication bias.Only 49.5% of patients received CMT, and this proportion steadily declined between 2003 (59.4%) and 2011 (45.2%), particularly in younger patients. Apart from classical prognostic factors (age, stage, tumor location, histology, comorbidities), treatment selection was significantly influenced by sex, black race, distance to facility, and type of insurance. Uninsured patients had the lowest odds of receiving CMT. A significant random effect related to facility-specific treatment preference was also evident. Estimated 5-year overall survival (OS) was 89.6%, and relative survival (RS) was 94.3%. After adjustment for guarantee-time and indication biases, CMT was associated with better OS (hazard ratio [HR], 0.61; 95% CI, 0.53 to 0.70) and RS (excess HR, 0.42; 95% CI, 0.33 to 0.54) than chemotherapy alone. This effect was without significant heterogeneity in subset analysis and was not sensitive to unobserved confounding.Socioeconomic factors affect selection of curative treatments in HL. Widespread abandonment of CMT beyond circumstances sanctioned by guidelines may affect survival. Further research should focus on developing strategies that minimize toxicity and access disparities without compromising survival.
Association of Actual and Preferred Decision Roles With Patient-Reported Quality of Care
Authors: Kenneth L. Kehl, Mary Beth Landrum, Neeraj K. Arora, Patricia A. Ganz, Michelle van Ryn, Jennifer W. Mack, Nancy L. Keating
Journal: JAMA Oncology (2015)

Shared decision making is associated with improved patient-reported outcomes of cancer treatment, but not all patients prefer to participate in medical decisions. Results from studies of the effect of matching between actual and preferred medical decision roles on patients' perceptions of care quality have been conflicting.To determine whether shared decision making was associated with patient ratings of care quality and physician communication and whether patients' preferred decision roles modified those associations.We performed a population- and health system-based survey of participants in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study diagnosed with lung and/or colorectal cancer between 2003 and 2005 (56% with colorectal cancer, 40% with non-small-cell lung cancer, and 5% with small-cell lung cancer). The CanCORS study included 9737 patients (cooperation rate among patients contacted, 59.9%) treated in integrated care delivery systems, academic institutions, private offices, and Veterans Affairs hospitals. The medical records were abstracted between October 11, 2005, and April 30, 2009; all analyses were conducted between 2013 and 2014.We surveyed patients specifically about their preferred roles in cancer treatment decisions and their actual roles in decisions about surgery, chemotherapy, and radiation therapy. We analyzed the responses of 5315 patients who completed baseline surveys and reported decision roles for a total of 10 817 treatment decisions and assessed associations of patients' decision roles with patient-reported quality of care and physician communication.The outcomes (identified before data collection) included patient-reported excellent quality of care and top ratings (highest score) on a physician communication scale.After adjustment, patients describing physician-controlled (vs shared) decisions were less likely to report excellent quality of care (odds ratio [OR], 0.64; 95% CI, 0.54-0.75; P < .001). Patients' preferred decision roles did not modify this effect (P = .29 for the interaction). Patients describing either actual or preferred physician-controlled (vs shared) roles were less likely to provide a top rating of physician communication (OR, 0.55; 95% CI, 0.45-0.66; P < .001, and OR, 0.67; 95% CI, 0.51-0.87; P = .002, respectively). The preferred role did not modify the effect of the actual role (P = .76 for interaction).Physician-controlled decisions regarding lung or colorectal cancer treatment were associated with lower ratings of care quality and physician communication. These effects were independent of patients' preferred decision roles, underscoring the importance of seeking to involve all patients in decision making about their treatment.