tbuckley/cabot-search huggingface dataset:
Adaptive Treatment Strategies in Chronic Disease
Authors: Philip W. Lavori, Ree Dawson
Journal: Annual Review of Medicine (2007)

An adaptive treatment strategy (ATS) is a rule for adapting a treatment plan to a patient's history of previous treatments and the response to those treatments. The ongoing management of chronic disease defines an ATS, which may be implicit and hidden or explicit and well-specified. The ATS is characterized by the use of intermediate, early markers of response to dynamically alter treatment decisions, in order to achieve a favorable ultimate outcome. We illustrate the ATS concept and describe how the effect of initial treatment decisions depends on the performance of subsequent decisions at later stages. We show how to compare two or more ATSs, or to determine an optimal ATS, using a sequential multiple assignment randomized (SMAR) trial. Designers of clinical trials might find the ATS concept useful in improving the efficiency and ecological relevance of clinical trials.
Enhanced Therapeutic Effect of HSV-tk+GCV Gene Therapy and Ionizing Radiation for Prostate Cancer
Authors: Madhu Chhikara, Hanxian Huang, Maria T. Vlachaki, Xiaohong Zhu, Bin Teh, Kam J. Chiu, Shiao Woo, Barry Berner, E.O'Brian Smith, Kerby C. Oberg, Laura K. Aguilar, Timothy C. Thompson, E.Brian Butler, Estuardo Aguilar-Cordova
Journal: Molecular Therapy (2001)

Standard therapies for prostate cancer including radiation, prostatectomy, and hormone ablation have significant toxicities and recurrence risk. HSV-tk gene therapy may be effective in combination with radiation therapy due to complementary mechanisms and distinct toxicity profiles. Mouse prostate tumors transplanted subcutaneously were treated by either gene therapy involving intratumoral injection of AdV-tk followed by systemic ganciclovir or local radiation therapy or the combination of gene and radiation therapy. Both single-therapy modalities showed a 38% decrease in tumor growth compared to controls. The combined treatment resulted in a decrease of 61%. In addition the combined-therapy group had a mean survival of 22 days versus 16.6 days for single therapy and 13.8 days for nontreated controls. To analyze systemic anti-tumor activity, lung metastases were generated by tail vein injection of RM-1 prostate cancer cells on the same day that they were injected subcutaneously. The primary tumors were treated as before with AdV-tk followed by ganciclovir, radiation, or the combination. The number of lung nodules was reduced by 37% following treatment with AdV-tk, whereas radiotherapy alone had no effect on metastatic growth. The combination led to an additional 50% reduction in lung colonization. Primary tumors that received the combination therapy had a marked increase in CD4 T cell infiltrate. This is the first report showing a dramatic systemic effect following the local combination treatment of radiation and AdV-tk. A clinical study using this strategy has been initiated and patient accrual is ongoing.
Viscoelastic properties of the rectal wall in Hirschsprung's disease.
Authors: P Arhan, G Devroede, K Danis, C Dornic, C Faverdin, B Persoz, D Pellerin
Journal: Journal of Clinical Investigation (1978)

Viscoelastic properties of the rectal wall were compared with Hirschsprung's disease. The elasticity of the rectal wall after accomodation to distension was found to be significantly greater (P less than 0.001) in patients, and the time taken by the rectum to accomodate was also found to be longer (P less than 0.001). The increased elasticity correlated well with severity of the illness, but none of the parameters correlated with length of aganglionic segment. Measuring elastic properties of the rectal wall may help to assess the severity of illness in patients with Hirschsprung's disease.
Switching to statins: a challenge for primary care
Authors: N G Fisher, A J Marshall, J Went
Journal: Journal of the Royal Society of Medicine (1999)

In 1997, doctors in England received official guidelines on the use of statins (3-hydroxy-3-methylglutaryl coenzyme A inhibitors) for primary and secondary prevention of coronary heart disease (CHD). Six months later we determined the status of patients who had been discharged from a specialist lipid clinic in 1989. 195 patients received questionnaires, with the consent of their general practitioners, regarding morbidity in, the subsequent decade and present medication, and were asked to have their cholesterol checked. Analysis was confined to the 86 with a current cholesterol measurement. Of 61 patients who had been discharged on a regimen of dietary advice and/or medication for primary prevention of CHD, 8 had been changed to a statin and 6 had been started on one. According to the new guidelines, none of these qualified for treatment. Of 25 patients who had been discharged on drugs for secondary prevention, all qualified for a statin but only 14 were receiving one--in 6 cases without achieving the recommended reductions in cholesterol. In many of the patients reviewed, treatment had not been altered to conform with the new guidelines. If hyperlipidaemic patients are to benefit promptly from advances in treatment, one solution might be a central registry that arranged regular tests and reported back to general practitioners. However, since many patients at risk do not have very high cholesterol levels, a coordinated approach to CHD risk factors would be preferable.
Anakinra effects on T cells in patients with refractory idiopathic inflammatory myopathies
Authors: M. Zong, V. Malmstrom, I. E. Lundberg
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Interleukin 1 (IL-1) is overexpressed in muscle tissue of inflammatory myopathies. A clinical response to IL-1 blockade with anakinra was seen in 7/15 patients with refractory myositis, but the biological explanation for improvement has not been clarified nor has predictors of response been identified (Dorph <i>et al</i>, Abstract ACR 2009). IL-1 is a multifunctional cytokine, and anakinra therapy could affect many cell types. The authors have here focused on its role in mediating T cell differentiation into Th17-like cells. The authors have here explored possible predictive biomarkers for anakinra therapy response, and investigated changes in effector T cell function and phenotype. <h3>Materials and methods</h3> 15 refractory myositis patients were included in a 12-month open-label study (100 mg anakinra per day). Serum creatine kinase (s-CK) was measured as a surrogate marker for clinical response. Peripheral blood samples were collected before and after 6 months. Serum levels of IL-1 receptor antagonist (IL-1Ra) were detected by a commercial ELISA, and T cells were studied by flow cytometry. To assess systemic immune activation, the proportions of naïve versus memory T cells were determined. The effector function of in vivo primed T cells was assessed by re-stimulating cells with anti-CD3 for 6 h and performing intracellular cytokine staining for interferon γ (IFNγ), tumour necrosis factor α and IL-17A. <h3>Results</h3> Before treatment the patients demonstrated elevated levels of serum IL-1Ra (n=14, mean=2559 pg/ml, range 467–6937 pg/ml) compared to healthy controls (mean=354 pg/ml, range 11–839 pg/ml, Son <i>et al</i>, <i>Intern Med</i>, 2000). 10/14 patients were still on anakinra therapy at 6 months and thus displayed significantly elevated IL-1Ra (mean=19 571 pg/ml, range 19 572–18 844 pg/ml, p=0.005). Viable cells from peripheral blood were available at baseline for eight patients and following 6 months of therapy for six subjects (three responders and three non-responders). When dissecting the pool of naïve versus activated/memory T cells, a strong negative correlation was seen between baseline level of CD4 CD45RO T cells and changes in CK levels after 6 months (R=−0.9, p=0.001). The levels of IFNγ-secreting CD4 T cells (mean=1.1%, range 0.08–4.96%) increased after 6 months, while IL-17 producing T cells (mean=0.16%, range 0.03–0.4%) decreased in 2/3 responders. <h3>Conclusions</h3> Patients with myositis may respond to anakinra treatment. This functional assay indicates that anakinra might favour T cell differentiation into Th1 rather than Th17 as indicated by more IFNγ and less IL-17A secretion. Furthermore, a high level of CD4 activated memory T cells might indicate a worse clinical outcome as demonstrated by less decreased CK levels.
Thermally Induced Asthma and Airway Drying
Authors: E. R. McFADDEN, JO ANN NELSON, M. E. SKOWRONSKI, K. A. LENNER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The purpose of this study was to determine whether mucosal dehydration causes thermally induced asthma. To provide data on this point, we studied the effects on lung function of progressive water loss (WL) from the respiratory tract by having eight subjects perform isocapnic hyperventilation for 1, 2, 4, and 8 min at a constant level (V E = 57.5 +/- 6.3 L/min [mean +/- SEM]) while they breathed dry air at frigid (TI = -12.5 +/- 2.7 degrees C) (cold trial) and ambient (24.3 +/- 0.7 degrees C) (warm trial) temperatures. Expired temperatures (TE) were continuously monitored, and WL from the intrathoracic airways was calculated from published relationships. FEV1 was measured before and after each challenge. Each inspirate produced stimulus-response decrements in FEV1, but the effect of cold air was greater (% Delta cold8min = 30.0 +/- 4.7%, warm = 16.0 +/- 4.4%; p = 0.01). Water loss, however, was significantly less in the cold experiment because TE was lower (WL cold8min = 4.8 +/- 0.4 g, warm = 7.1 +/- 0.7 g; p = 0.001; TE cold8min = 22.8 +/- 2.3 degrees C, warm 30.9 +/- 1.5 degrees C; p = 0.003). The FEV1 decreased as WL rose, but the largest intrathoracic losses were associated with the smallest obstructive response (% DeltaFEV1 cold8min = 30%, WL = 4.7 mg; % DeltaFEV1 warm8min = 16%, WL = 7.1 mg; p = 0.002). These data show that removal of water from the lower respiratory tract, and by inference the development of a hyperosmolar periciliary fluid, do not appear to be the primary causes of thermally induced asthma.
Localized fibrous pleural tumour of the interlobular pleura
Authors: CM Sanguinetti, F Marchesani, R Ranaldi, R Pela, L Cecarini
Journal: European Respiratory Journal (1996)

Localized fibrous tumours of the pleura (LFTP) are rare, generally benign and asymptomatic neoplasms, which originate from the pleural layers. We report on the case of a 67 year old woman who had a 1.5 cm diameter pulmonary nodule in the right upper lobe, which had been found by chance. Video-assisted thoracoscopy (VAT) was used to excise the nodule. The diagnosis of localized fibrous tumour of the interlobar pleura was made on microscopic evaluation. After 17 months, the patient is well and her chest radiographic image is normal.
Induction of Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) <u>Restricts</u> Clonal Expansion of Helper T Cells
Authors: Alden M. Doyle, Alan C. Mullen, Alejandro V. Villarino, Anne S. Hutchins, Frances A. High, Hubert W. Lee, Craig B. Thompson, Steven L. Reiner
Journal: The Journal of Experimental Medicine (2001)

Cytotoxic T lymphocyte antigen (CTLA)-4 plays an essential role in immunologic homeostasis. How this negative regulator of T cell activation executes its functions has remained controversial. We now provide evidence that CTLA-4 mediates a cell-intrinsic counterbalance to restrict the clonal expansion of proliferating CD4+ T cells. The regulation of CTLA-4 expression and function ensures that, after ∼3 cell divisions of expansion, most progeny will succumb to either proliferative arrest or death over the ensuing three cell divisions. The quantitative precision of the counterbalance hinges on the graded, time-independent induction of CTLA-4 expression during the first three cell divisions. In contrast to the limits imposed on unpolarized cells, T helper type 1 (Th1) and Th2 effector progeny may be rescued from proliferative arrest by interleukin (IL)-12 and IL-4 signaling, respectively, allowing appropriately stimulated progeny to proceed to the stage of tissue homing. These results suggest that the cell-autonomous regulation of CTLA-4 induction may be a central checkpoint of clonal expansion of CD4+ T cells, allowing temporally and spatially restricted growth of progeny to be dictated by the nature of the threat posed to the host.
Nonsterile Glove Use in Addition to Hand Hygiene to Prevent Late-Onset Infection in Preterm Infants
Authors: David A. Kaufman, Amy Blackman, Mark R. Conaway, Robert A. Sinkin
Journal: JAMA Pediatrics (2014)

IMPORTANCE Late-onset infections commonly occur in extremely preterm infants and are associated with high rates of mortality and neurodevelopmental impairment.Hand hygiene alone does not always achieve the desired clean hands, as microorganisms are still present more than 50% of the time.We hypothesize that glove use after hand hygiene may further decrease these infections.OBJECTIVE To determine if nonsterile glove use after hand hygiene before all patient and intravenous catheter contact, compared with hand hygiene alone, prevents late-onset infections in preterm infants. DESIGN, SETTINGS, AND PARTICIPANTSA prospective, single-center, clinical, randomized trial was conducted in infants admitted to the neonatal intensive care unit who weighed less than 1000 g and/or had a gestational age of less than 29 weeks and were less than 8 days old.There were 175 eligible infants, of which 120 were enrolled during a 30-month period from December 8, 2008, to June 20, 2011.INTERVENTIONS Infants were randomly assigned to receive care with nonsterile gloves after hand hygiene (group A) or care after hand hygiene alone (group B) before all patient and intravenous line (central and peripheral) contact.Study intervention was continued while patients had central or peripheral venous access. MAIN OUTCOMES AND MEASURESOne or more episodes of late-onset (>72 hours of age) infection in the bloodstream, urinary tract, or cerebrospinal fluid or necrotizing enterocolitis. RESULTSThe 2 groups were similar in baseline demographic characteristics.Late-onset invasive infection or necrotizing enterocolitis occurred in 32% of infants (19 of 60) in group A compared with 45% of infants (27 of 60) in group B (difference, -12%; 95% CI, -28% to 6%; P = .13).In group A compared with group B, there were 53% fewer gram-positive bloodstream infections (15% [9 of 60] vs 32% [19 of 60]; difference, -17%; 95% CI, -31% to -1%; P = .03)and 64% fewer central line-associated bloodstream infections (3.4 vs 9.4 per 1000 central line days; ratio, 0.36; 95% CI, 0.16 to 0.81; P = .01).CONCLUSIONS AND RELEVANCE Glove use after hand hygiene prior to patient and line contact is associated with fewer gram-positive bloodstream infections and possible central line-associated bloodstream infections in preterm infants.This readily implementable infection control measure may result in decreased infections in high-risk preterm infants.
It Is Not Always Necessary to Do Axillary Dissection for T1 and T2 Breast Cancer—Point
Authors: Monica Morrow
Journal: Cancer Research (2013)

Abstract Axillary lymph node dissection (ALND) has been a part of breast cancer management since the 1900s. The idea that axillary metastases do not require surgical removal is a repudiation of the Halstedian concept of breast cancer biology, yet multiple prospective randomized studies show that the incidence of nodal recurrence in patients not having ALND is substantially lower than expected, based on the incidence of axillary metastases in patients having ALND, and survival does not differ based on axillary treatment. Avoidance of axillary dissection significantly reduces the morbidity of breast cancer surgery. As the use of systemic therapy has increased and targeted therapies have become available, the incidence of axillary recurrence in patients not having dissection has decreased to approximately 1% at 5 years, making routine axillary dissection difficult to justify. ALND is no longer standard management for patients with T1 and T2, clinically node-negative cancers undergoing breast-conserving therapy and found to have a positive sentinel node, and can also be avoided in patients with these tumor features having mastectomy if the need for postmastectomy radiotherapy is clear with the finding of a positive sentinel node. Cancer Res; 73(24); 7151–4. ©2013 AACR.
Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development
Authors: Maren Luchtefeld, Christina Grothusen, Andreas Gagalick, Kumaravelu Jagavelu, Harald Schuett, Uwe J.F. Tietge, Oliver Pabst, Karsten Grote, Helmut Drexler, Reinhold Förster, Bernhard Schieffer
Journal: Circulation (2010)

Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice.CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7(-/-) T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7(-/-)-derived T cells primed with oxidized low-density lipoprotein-pulsed dendritic cells resulted in a reconstitution of atherogenesis in ccr7(-/-)/ldlr(-/-) mice.These results demonstrate that both CCR7-dependent T-cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue are crucially involved in atherosclerotic plaque development.
Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer
Authors: Alan Sandler, Robert Gray, Michael C. Perry, Julie Brahmer, Joan H. Schiller, Afshin Dowlati, Rogerio Lilenbaum, David H. Johnson
Journal: New England Journal of Medicine (2006)

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers.Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non-small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival.The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage.The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)
A gene required for class II-restricted antigen presentation maps to the major histocompatibility complex.
Authors: E Mellins, S Kempin, L Smith, T Monji, D Pious
Journal: The Journal of Experimental Medicine (1991)

We have previously described a set of mutants (16.23-selected mutants) of a B lymphoblastoid cell line that are defective in the presentation of intact proteins to class II-restricted T cells, but effectively present immunogenic peptides. The mutations in these mutants are recessive in somatic cell hybrids and are not in Class II structural genes. Here, we report on a unique mutant, 5.2.4, in which a similar defect in class II-restricted antigen presentation has occurred in association with a one-megabase homozygous deletion in the class II region of the major histocompatibility complex (MHC). The defects in class II presentation among three of the 16.23-selected mutants, and between these mutants and 5.2.4, are noncomplementary in somatic cell hybrids. This suggests that the class II presentation-defective phenotype in all four mutants results from lesions in a single MHC-linked gene, a conclusion strengthened by the finding that in a hybrid made with a second, unrelated MHC deletion mutant, T2, the class II presentation defect in a 16.23-selected mutant is also not complemented. Mutant 5.2.4, in addition to its class II presentation defect, is also defective in surface expression of MHC class I molecules, most likely because its deletion encompasses the peptide supply factor 1 gene, whose function is known to be required for normal abundance of cell surface class I molecules. However, the surface abundance of class I molecules is normal in the 16.23-selected mutants, suggesting that the lesions affecting class I surface abundance and class II presentation result from mutations in different genes.
Skin prick test responses and allergen-specific IgE levels as predictors of peanut, egg, and sesame allergy in infants
Authors: Rachel L. Peters, Katrina J. Allen, Shyamali C. Dharmage, Mimi L.K. Tang, Jennifer J. Koplin, Anne-Louise Ponsonby, Adrian J. Lowe, David Hill, Lyle C. Gurrin
Journal: Journal of Allergy and Clinical Immunology (2013)
Platelet activity in mitral valve prolapse: A study of platelet aggregation, malondialdehyde production, and plasma β-thromboglobulin
Authors: Francisco Arocha, Maria Diez‐Ewald, Ana I. Durango, Tulio Sulbarán
Journal: American Journal of Hematology (1985)

Abstract Platelet aggregation, malondialdehyde (MDA) production, and recovery after aspirin (ASA) administration and plasma levels of beta‐thromboglobulin (BTG) were determined in 40 asymptomatic patients with mitral valve prolapse (MVP) and 17 normal subjects. Platelet aggregation was similar in patients and controls, although two patients presented spontaneous aggregation. Production of MDA and plasma levels of BTG were higher in MVP than in controls; however, recovery after ASA was similar in both groups. The results further indicate that platelet hyperactivity is present in a significant number of asymptomatic patients with MVP.