tbuckley/cabot-search huggingface dataset:
Apoptosis During Cardiovascular Development
Authors: Steven A. Fisher, B. Lowell Langille, Deepak Srivastava
Journal: Circulation Research (2000)

Abstract —Morphogenesis and developmental remodeling of cardiovascular tissues involve coordinated regulation of cell proliferation and apoptosis. In the heart, clear evidence points toward focal apoptosis as a contributor to development of the embryonic outflow tract, cardiac valves, conducting system, and the developing coronary vasculature. Apoptosis in the heart is likely regulated by survival and death signals that are also present in many other tissues. Cell type–specific regulation may be superimposed on general cell death/survival machinery through tissue-specific transcriptional pathways. In the vasculature, apoptosis almost certainly contributes to developmental vessel regression, and it is of proven importance in remodeling of arterial structure in response to local changes in hemodynamics. Physical forces, growth factors, and extracellular matrix drive vascular cell survival pathways, and considerable evidence points to local nitric oxide production as an important but complex regulator of vascular cell death. In both the heart and vasculature, progress has been impeded by inadequate information concerning the incidence of apoptosis, its relative importance compared with the diverse cell behaviors that remodel developing tissues, and by our primitive knowledge concerning regulation of cell death in these tissues. However, tools are now available to better understand apoptosis in normal and abnormal development of cardiovascular structures, and a framework has been established that should lead to considerable progress in the coming years.
Measurement and Clinical Monitoring of Human Lymphocyte Clonality by Massively Parallel V-D-J Pyrosequencing
Authors: Scott D. Boyd, Eleanor L. Marshall, Jason D. Merker, Jay M. Maniar, Lyndon N. Zhang, Bita Sahaf, Carol D. Jones, Birgitte B. Simen, Bozena Hanczaruk, Khoa D. Nguyen, Kari C. Nadeau, Michael Egholm, David B. Miklos, James L. Zehnder, Andrew Z. Fire
Journal: Science Translational Medicine (2009)

Massively parallel sequencing of rearranged immune receptor genes permits detection and tracking of specific immune cell populations in normal and pathological contexts.
Is it possible to increase the reliability of estimated incidence and prevalence rates by disease modelling?
Authors: Hendriek C Boshuizen, Nancy Hoeymans
Journal: The Lancet (2013)

BackgroundIn order to monitor the impact of health policy, morbidity estimates must be timely and reliable. Registries in general practice (GP) are key sources for morbidity estimates, as the general practitioner is the gatekeeper of health care. However, morbidity estimates between different GP registration networks vary considerably, and these differences could not be explained by characteristics of the patient population. The aim of this research is to see whether these differences can be explained by variation between networks in the accuracy of distinguishing new (incident) cases from existing (prevalent) cases, and if so, whether modelling this enables more reliable estimates.MethodsWe used 2010 data from five Dutch GP registration networks and data on four chronic diseases (chronic obstructive pulmonary disease, diabetes, heart failure, and osteoarthritis). We fitted a joint model (DisMod) using all information on morbidity (incidence and prevalence) in each network as well as mortality rates in those with and without the disease. The model assumed stable incidence and survival probabilities over time and included a misclassification factor that allows for misclassification of a percentage of prevalent cases as incident cases. We fitted this model by maximum likelihood and compared the prevalence and incidence estimates for each network with the observed prevalence and incidence estimates.FindingsOsteoarthritis of the knee showed large misclassifications (between 2 and 24%), especially in episode-based registrations. Before taking this misclassification into account, prevalence rate estimates from different networks were 1·0–2·8%, while they were 1·3–3·9% afterwards. Incidence rates changed from 2·4–4·5 per 1000 person-years before taking misclassification into account, to 0·8–3·0 per 1000 person-years afterwards. Also, for the other diseases, including a misclassification term mostly affected incidence estimates (lowering them) but did not systematically decrease the variation between prevalence and incidence estimates from different networks.InterpretationEpisode-based registers cannot reliably deliver first incidence rates for chronic diseases requiring low levels of professional health care. For the other diseases, modelling misclassification rates does not systematically decrease the variation between registration networks, and only modestly influences estimates. However, such a modelling exercise gives qualitative insight into the reliability of estimates.FundingNational Institute of Public Health and the Environment.
Regulation of B-lymphocyte clonal proliferation by stimulatory and inhibitory macrophage-derived factors
Authors: JI Kurland, PW Kincade, MAS Moore
Journal: The Journal of Experimental Medicine (1977)

A functional subpopulation of murine B lymphocytes proliferate in semisolid agar culture in the presence of 2-mercaptoethanol to form colonies. The effects of diffusible macrophage-derived factors on this focal proliferation was investigated using a two-layer culture system which prevented macrophage-lymphocyte contact and permitted B-cell activation to be critically assessed under conditions of extremely low cell densities. Adherent peritoneal macrophages incorporated within underlayers of spleen or lymph node cell cultures potentiated both the number and size of developing B-cell colonies. These effects were most striking when low numbers of spleen or lymph node cells, or macrophage- depleted lymphoid cell suspensions were used. Thus, macrophage-depleted lymph node ceils gave rise to virtually no colonies, but colony-forming ability was restored by the presence of an optimal number of macrophages. When the number of macrophages exceeded that required for optimal stimulation, colony formation was suppressed; an effect which was largely prevented by indomethacin, an inhibitor of prostaglandin synthesis. Under these conditions, stimulation and inhibition of B-cell activation by macrophages could be dissociated, indicating that each signal is selectively controlled by individual molecules elaborated by the macrophage. With an appropriate number of macrophages required for B-cell activation, and sufficient indomethacin to inhibit the accumulation of macrophage-derived prostaglandin, B-lymphocyte clonal proliferation was a linear function of the number of B cells placed in culture. In the absence of macrophages, B-cell colony formation was potentiated by both lipopolysaccharide and intact sheep erythrocytes through a mechanism different from that of the macrophage-derived stimulatory factor. In addition to their direct stimulatory effect on B-cell proliferation, lipopolysaccharide and sheep erythrocytes were each capable of modulating the production and/or release of B-cell stimulatory and inhibitory factors by the macrophage. Parallel studies of conventional mitogen- stimulated lymphocyte cultures did not show a requirement for macrophages and confirm that the semisolid assay is uniquely suited to studies on the regulatory role of the macrophage in B-cell activation.
Experimental Evolution of Pseudogenization and Gene Loss in a Plant RNA Virus
Authors: Mark P. Zwart, Anouk Willemsen, José-Antonio Daròs, Santiago F. Elena
Journal: Molecular Biology and Evolution (2013)

Viruses have evolved highly streamlined genomes and a variety of mechanisms to compress them, suggesting that genome size is under strong selection. Horizontal gene transfer has, on the other hand, played an important role in virus evolution. However, evolution cannot integrate initially nonfunctional sequences into the viral genome if they are rapidly purged by selection. Here we report on the experimental evolution of pseudogenization in virus genomes using a plant RNA virus expressing a heterologous gene. When long 9-week passages were performed, the added gene was lost in all lineages, whereas viruses with large genomic deletions were fixed in only two out of ten 3-week lineages and none in 1-week lineages. Illumina next-generation sequencing revealed considerable convergent evolution in the 9- and 3-week lineages with genomic deletions. Genome size was correlated to within-host competitive fitness, although there was no correlation with virus accumulation or virulence. Within-host competitive fitness of the 3-week virus lineages without genomic deletions was higher than for the 1-week lineages. Our results show that the strength of selection for a reduced genome size and the rate of pseudogenization depend on demographic conditions. Moreover, for the 3-week passage condition, we observed increases in within-host fitness, whereas selection was not strong enough to quickly remove the nonfunctional heterologous gene. These results suggest a demographically determined "sweet spot" might exist, where heterologous insertions are not immediately lost while evolution can act to integrate them into the viral genome.
IL-2–dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells
Authors: Georg Gasteiger, Saskia Hemmers, Matthew A. Firth, Audrey Le Floc’h, Morgan Huse, Joseph C. Sun, Alexander Y. Rudensky
Journal: The Journal of Experimental Medicine (2013)

The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non-self–ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2–dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2.
Translating Clinical Trials into Meaningful Outcomes
Authors: Patricia M. LoRusso, Lowell E. Schnipper, David J. Stewart, Scott A. Boerner, Steven D. Averbuch, Walter Wolf
Journal: Clinical Cancer Research (2010)

Abstract Efforts to unravel the complex biology that is necessary to develop new therapies best suited for an individual with cancer are at a crossroads with a strained health care system and an insufficient clinical trial apparatus. The resulting failures have been described as the “valley of death.” Progress into the future will require new considerations and the engagement of a broad band of stakeholders. To identify novel therapeutics that are likely to succeed in late development and to be meaningful for clinical practice, investigators will need to make a paradigm shift in designing clinical trials and endpoints while adhering to scientific rigor when interpreting results and making informed decisions. Large phase III trials that show a modest incremental benefit will continue to diminish in value for patients, clinicians, payers, and industry. Outcomes that are robust in both magnitude and application to the real world will take on increasing importance. Ensuring active participation by patients, lowering barriers to health care access, and protecting patients through health care reform are requirements for the future success of the cancer clinical research enterprise. The challenge today is to develop new approaches to translate scientific discovery into cost-effective and meaningful improvements in cancer outcomes. Clin Cancer Res; 16(24); 5951–5. ©2010 AACR.
Oxygen and Renal Hemodynamics in the Conscious Rat
Authors: Bert Flemming, Erdmann Seeliger, Thomas Wronski, Katharina Steer, Nicole Arenz, Pontus B. Persson
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Previous studies have suggested a link between renal metabolism and local kidney hemodynamics to prevent potential hypoxic injury of particularly vulnerable nephron segments, such as the outer medullary region. The present study used three different inspiratory oxygen concentrations to modify renal metabolic state in the conscious rat (hypoxia 10% O 2 , normoxia 20% O 2 , and hyperoxia 100% O 2 ). Renal blood flow (RBF) was assessed by ultrasound transit time; renal perfusion pressure (RPP) was controlled by a hydroelectric servo-control device. Local RBF was estimated by laser-Doppler flux for the cortical and outer medullary region (2 and 4 mm below renal surface, respectively). Hypoxia led to a generalized significant increase in RBF, whereas hyperoxia-induced changes did not (hypoxia 6.6 ± 0.6 ml/min versus normoxia 5.7 ± 0.7 ml/min, P &lt; 0.05). Moreover, regional and total RBF autoregulation was markedly attenuated by hypoxia. Conversely, hyperoxia enhanced RBF autoregulation. Under normoxic and hyperoxic conditions, medullary RBF was very well maintained, even at low RPP (medullary RBF: approximately 70% of control at 50 mmHg). The hypoxic challenge, however, significantly diminished the capacity to maintain medullary blood flow at low RPP (medullary RBF: approximately 30% of control at 50 mmHg, P &lt; 0.05). These data suggest that renal metabolism and renal hemodynamics are closely intertwined. In response to acute hypoperfusion, the kidney succeeds in maintaining remarkably high medullary blood flow. This is not accomplished, however, when a concomitant hypoxic challenge is superimposed on RPP reduction.
The origin and development of nonlymphoid tissue CD103+ DCs
Authors: Florent Ginhoux, Kang Liu, Julie Helft, Milena Bogunovic, Melanie Greter, Daigo Hashimoto, Jeremy Price, Na Yin, Jonathan Bromberg, Sergio A. Lira, E. Richard Stanley, Michel Nussenzweig, Miriam Merad
Journal: The Journal of Experimental Medicine (2009)

CD103+ dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c+MHCII+ cells separated on the basis of CD103 and CD11b expression coexist in most nonlymphoid tissues with the exception of the lamina propria. CD103+ DCs are related to lymphoid organ CD8+ DCs in that they are derived exclusively from pre-DCs under the control of fms-like tyrosine kinase 3 (Flt3) ligand, inhibitor of DNA protein 2 (Id2), and IFN regulatory protein 8 (IRF8). In contrast, lamina propria CD103+ DCs express CD11b and develop independently of Id2 and IRF8. The other population of CD11c+MHCII+ cells in tissues, which is CD103−CD11b+, is heterogenous and depends on both Flt3 and MCSF-R. Our results reveal that nonlymphoid tissue CD103+ DCs and lymphoid organ CD8+ DCs derive from the same precursor and follow a related differentiation program.
Diagnostic impact of signs and symptoms in acute infectious conjunctivitis: systematic literature search
Authors: Remco P Rietveld, Henk C P M van Weert, Gerben ter Riet, Patrick J E Bindels
Journal: BMJ (2003)

In acute infectious conjunctivitis the general practitioner has to distinguish a bacterial cause from a viral one to select the patients who are most likely to benefit from antibiotic treatment. The doctor makes this distinction on the basis of the presenting signs and symptoms. Additional diagnostic investigations, such as a culture of the conjunctiva, are seldom done, mainly because the result is delayed a few days.

Most treatment trials show that a bacterial pathogen can be isolated from the conjunctiva in only half of patients with clinically diagnosed acute bacterial conjunctivitis. However, general practitioners prescribe antibiotics in most cases of acute infectious conjunctivitis. Although the subject has never been investigated in a primary care setting, studies on suspected acute bacterial conjunctivitis show that topical antibiotics improve the five day remission rate by only …
The Influence of Intern Home Call on Objectively Measured Perioperative Outcomes
Authors: Zachary J. Kastenberg, Kim F. Rhoads, Marc L. Melcher, Sherry M. Wren
Journal: JAMA Surgery (2012)

In July 2011, surgical interns were prohibited from being on call from home by the new residency review committee guidelines on work hours. In support of the new Accreditation Council for Graduate Medical Education work-hour restrictions, we expected that a period of intern home call would correlate with increased rates of postoperative morbidity and mortality.Prospective cohort.University-affiliated tertiary Veterans Affairs Medical Center.All patients identified in the Veterans Affairs National Surgical Quality Improvement Program database who underwent an operation performed by general, vascular, urologic, or cardiac surgery services between fiscal years (FYs) 1999 and 2010 were included.During FYs 1999-2003, the first call for all patients went to an in-hospital intern. In the subsequent period (FYs 2004-2010), the first call went to an intern on home call. Thirty-day unadjusted morbidity and mortality rates and risk-adjusted observed to expected ratios were analyzed by univariate analysis and joinpoint regression, respectively.Unadjusted overall morbidity rates decreased between 1999-2003 and 2004-2010 (12.14% to 10.19%, P = .003). The risk-adjusted morbidity observed to expected ratios decreased at a uniform annual percentage change of -6.03% (P < .001). Unadjusted overall mortality rates also decreased between the 2 periods (1.76% to 1.26%; P = .05). There was no significant change in the risk-adjusted mortality observed to expected ratios during the study.The institution of an intern home call schedule was not associated with increased rates of postoperative morbidity or mortality.
Prognostic Significance of Baseline Reverse Transcriptase-PCR for Prostate-Specific Antigen in Men with Hormone-Refractory Prostate Cancer Treated with Chemotherapy
Authors: Robert W. Ross, Judith Manola, Kristen Hennessy, Matthew Galsky, Howard Scher, Eric Small, W. Kevin Kelly, Philip W. Kantoff
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Methods accurately categorizing the diverse biology of prostate cancer are needed. A positive baseline reverse transcriptase-PCR for prostate-specific antigen (RT-PCR PSA) in the androgen-independent setting is an independent prognostic marker of survival. The objectives of the current study were to examine the prognostic implication of baseline RT-PCR PSA positivity during treatment with an active chemotherapeutic agent and explore whether an RT-PCR PSA “response” provides prognostic information. Materials and Methods: In a combined analysis of a phase I and a randomized phase II trial of BMS-247550 (an epothilone B analogue), 104 patients with hormone-refractory prostate cancer had whole blood samples collected at baseline, then with each cycle of therapy. RT-PCR PSA was assessed and related to time to progression (TTP). Results: From 100 evaluable patients, 368 samples were received, of which 90.8% were evaluable for RT-PCR PSA status. Baseline RT-PCR PSA status was significantly associated with TTP (hazard ratio, 2.22; 95% confidence interval, 1.40-3.52). Twenty-six of 38 patients positive at first assessment had at least one follow-up RT-PCR PSA that was negative (“response”). In univariate analysis, RT-PCR PSA response was not significantly associated with TTP, but in multivariate analysis, RT-PCR PSA response was of borderline statistical significance in predicting TTP (hazard ratio, 0.41; 95% confidence interval, 0.16-1.01). Conclusion: These results provide further confirmation that baseline RT-PCR PSA is a statistically significant predictor of TTP in hormone-refractory prostate cancer. Moreover, this is the first report to suggest that RT-PCR PSA response during chemotherapy treatment may predict TTP.
Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria
Authors: C. Iking-Konert, M. Aringer, J. Wollenhaupt, T. Mosch, S. Tuerk, E. Feist, G. R. Burmester
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Remission is the established goal in rheumatoid arthritis (RA) treatment. Although originally defined by a disease activity score in 28 joints (DAS28) &lt;2.6, more stringent criteria may imply the absence of disease activity. The 2011 ACR/EULAR remission criteria provide the newest and most stringent definition of remission. <h3>Objectives</h3> To evaluate post hoc the remission by ACR/EULAR criteria and compare the criteria with the conventional DAS28 in TAMARA, an open-label phase IIIb tocilizumab (TCZ) trial including patients with active RA receiving inadequate disease-modifying antirheumatic drugs (DMARDs) or tumour necrosis factor α (TNFα) inhibitor treatment. <h3>Results</h3> 286 patients were enrolled, 99.7% of patients were receiving a conventional DMARD and 41.6% had TNFα inhibitor pretreatment. Baseline mean DAS28 of 6.0 ± 1.0 fell to 2.6 ± 1.5 at week 24. DAS28 &lt;2.6 was achieved by 47.6% at week 24. Remission rates with the new ACR/EULAR Boolean-based criteria for clinical studies were 15.0% after 12 weeks and 20.3% after 24 weeks. Of note, 13.5% of patients with previous TNFα blocker inadequate response still achieved remission according to the new ACR/EULAR criteria after 24 weeks. Clinical Disease Activity Index and Simplified Disease Activity Index remission rates were 24.1% and 25.2%, respectively. <h3>Conclusions</h3> Under the definition of the new stringent 2011 ACR/EULAR remission criteria, patients with active RA despite DMARD treatment and even after inadequate response to TNFα inhibitors, receiving TCZ showed significant rates of remission. Similar remission rates were achieved, when clinical practice criteria, not inclusive of acute phase reactants, were used.