tbuckley/cabot-search huggingface dataset:
The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer
Authors: Angela DeMichele, Douglas Yee, Donald A. Berry, Kathy S. Albain, Christopher C. Benz, Judy Boughey, Meredith Buxton, Stephen K. Chia, Amy J. Chien, Stephen Y. Chui, Amy Clark, Kirsten Edmiston, Anthony D. Elias, Andres Forero-Torres, Tufia C. Haddad, Barbara Haley, Paul Haluska, Nola M. Hylton, Claudine Isaacs, Henry Kaplan, Larissa Korde, Brian Leyland-Jones, Minetta C. Liu, Michelle Melisko, Susan E. Minton, Stacy L. Moulder, Rita Nanda, Olufunmilayo I. Olopade, Melissa Paoloni, John W. Park, Barbara A. Parker, Jane Perlmutter, Emanuel F. Petricoin, Hope Rugo, Fraser Symmans, Debasish Tripathy, Laura J. van‘t Veer, Rebecca K. Viscusi, Anne Wallace, Denise Wolf, Christina Yau, Laura J. Esserman
Journal: Clinical Cancer Research (2015)

Abstract The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.
Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors
Authors: Joannes F.M. Jacobs, Albert J. Idema, Kalijn F. Bol, Stefan Nierkens, Oliver M. Grauer, Pieter Wesseling, J. André Grotenhuis, Peter M. Hoogerbrugge, I. Jolanda M. de Vries, Gosse J. Adema
Journal: Neuro-Oncology (2008)

The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex vivo analysis is often limited because large parts of many brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4+FoxP3+CD25high CD127low regulatory T cells (Tregs) in glioblastomas (n = 29) and metastatic brain tumors (n = 20). No Treg accumulation was observed in benign tumors such as meningiomas (n = 10) and pituitary adenomas (n = 5). A significant Treg increase in blood was seen only in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor-derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor-infiltrating Tregs were localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4+ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors.
Treatment of active Crohn's disease by exclusion diet: East Anglian Multicentre Controlled Trial
Authors: A.M. Riordan, J.O. Hunter, J.R. Crampton, G. Neale, R.E. Cowan, A.R. Davidson, R.J. Dickinson, M.W. Dronfield, I.W. Fellows, H.J. Kennedy, S. Hishon, G.N.W. Kerrigan, R.C.M. McGouran, J.H.B. Saunders
Journal: The Lancet (1993)
Carbon monoxide diffusing capacity in polycythaemia rubra vera.
Authors: A P Greening, K Patel, A W Goolden, A J Munro, J M Hughes
Journal: Thorax (1982)

The diffusing capacity of the lung, or transfer factor, for carbon monoxide (TLCO) was measured in 12 patients with polycythaemia rubra vera. This was significantly raised (mean 152% predicted, SEM +/- 14%) and remained so even after correction to a standard haemoglobin concentration of 14 . 6 g/dl (mean 139% predicted, SEM +/- 13%). Serial measurements of TLCO on two patients after treatment of polycythaemia rubra vera showed a greater fall in relation to haemoglobin concentration than would have been predicted on theoretical grounds if the increases in TLCO had been due entirely to the increased haemoglobin concentration. The pulmonary capillary blood volume (estimated from TLCO) also fell in these two patients after treatment. There was a strong correlation between TLCO and the technetium-99m-labelled red cell volume for the seven men (r = 0 . 92; p less than 0 . 01) and five women (r = 0 . 99; p less than 0 . 001) when studies were performed on the same day. In patients with polycythaemia rubra vera who have no evidence of coexistent pulmonary disease the pulmonary capillary bed appears to share in the expansion of the body blood volume. The single-breath TLCO test may act as a convenient and simple monitor for the response of the disease to treatment.
Bone Turnover Markers as Predictors of Skeletal Complications in Prostate Cancer, Lung Cancer, and Other Solid Tumors
Authors: J. E. Brown, R. J. Cook, P. Major, A. Lipton, F. Saad, M. Smith, K.-A. Lee, M. Zheng, Y.-J. Hei, R. E. Coleman
Journal: JNCI Journal of the National Cancer Institute (2005)

Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid.Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided.In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels.Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.
A NOTE ON THE USE OF THE GALVANOMETER AS AN AID TO THE DIAGNOSIS OF NERVE LESIONS
Authors: C. N. Longridge
Journal: BMJ (1916)

t 0 7sndefined limits formed over the sacrum.This was incised later.Suction was applie(d to the uterus on two successive days, after which the temperature did not rise above 990, and the patient made a good recovery.CASE i.
Prevalence of Skin Test Reactivity to Tomato Peel and Pulp Extracts in the Mediterranean Coast of Spain
Authors: A. Ferrer, C. Larramendi, J. Huertas, J. García-Abujeta, C. Andreu, R. Tella, M. Cerdà, J. Lavin, J. Pagán, J. Bartra, J. Carnés, E. Fernández-Caldas
Journal: Journal of Allergy and Clinical Immunology (2006)
From theory to practice: molecular strain typing for the clinical and public health setting
Authors: R V Goering, R Köck, H Grundmann, G Werner, A W Friedrich, None on behalf of the ESCMID Study Group
Journal: Eurosurveillance (2013)

The persistence and transmission of infectious disease is one of the most enduring and daunting concerns in healthcare. Over the years, epidemiological analysis especially of bacterial etiological agents has undergone a remarkable evolutionary metamorphosis. While initially relying on purely phenotypic characterisation, advances in molecular biology have found translational application in a number of approaches to strain typing which commonly centre either on 'epityping' (molecular epidemiology) to characterise outbreaks, perform surveillance, and trace evolutionary pathways, or 'pathotyping' to compare strains based on the presence or absence of specific virulence or resistance genes. A perspective overview of strain typing is presented here considering the issues surrounding analyses which are employed in the localised clinical setting as well as at a more regional/national public health level. The discussion especially considers the shortcomings inherent in epidemiological analysis: less than full isolate characterisation by the typing method and limitations imposed by the available data, context, and time constraints of the epidemiological investigation (i.e. the available epidemiological window). However, the promises outweigh the pitfalls as one considers the potential for advances in genomic characterisation and information technology to provide an unprecedented aggregate of epidemiological information and analysis. .
Use of the ΔAG/ΔHCO3 − Ratio in the Diagnosis of Mixed Acid-Base Disorders
Authors: Asghar Rastegar
Journal: Journal of the American Society of Nephrology (2007)

When a strong acid is added to plasma, one expects a quantitative relationship between excess anion gap (ΔAG) and bicarbonate deficit (ΔHCO3−) with the ΔAG/ΔHCO3− ratio close to unity. If true, then this ratio could be used to diagnose mixed acid-base disorders in patients with metabolic acidosis. Although the mean ratio in selected patients is close to unity, this ratio also has a wide range, making its use in individual patients problematic. The ratio should therefore be used cautiously in making a diagnosis of mixed acid-base disorders.
Enhanced Antitumor Effect of Combined Triptolide and Ionizing Radiation
Authors: Wei Wang, Shanmin Yang, Ying Su, Zhenyu Xiao, Chunyou Wang, Xinfeng Li, Ling Lin, Bruce M. Fenton, Scott F. Paoni, Ivan Ding, Peter Keng, Paul Okunieff, Lurong Zhang
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The lack of effective treatment for pancreatic cancer results in a very low survival rate. This study explores the enhancement of the therapeutic effect on human pancreatic cancer via the combination of triptolide and ionizing radiation (IR). Experimental Design: In vitro AsPC-1 human pancreatic cancer cells were treated with triptolide alone, IR alone, or triptolide plus IR. Cell proliferation was analyzed with sulforhodamine B (SRB) method and clonogenic survival; comparison of apoptosis induced by the above treatment was analyzed by annexin V–propidium iodide (PI) staining. Furthermore, the expression of apoptotic pathway intermediates was measured by the assay of caspase activity and Western blot. Mitochondrial transmembrane potential was determined by JC-1 assay. In vivo, AsPC-1 xenografts were treated with 0.25 mg/kg triptolide, 10 Gy IR, or triptolide plus IR. The tumors were measured for volume and weight at the end of the experiment. Tumor tissues were tested for terminal nucleotidyl transferase–mediated nick end labeling (TUNEL) and immunohistochemistry. Results: The combination of triptolide plus IR reduced cell survival to 21% and enhanced apoptosis, compared with single treatment. In vivo, tumor growth of AsPC-1 xenografts was reduced further in the group treated with triptolide plus IR compared with single treatment. TUNEL and immunohistochemistry of caspase-3 cleavage in tumor tissues indicated that the combination of triptolide plus IR resulted in significantly enhanced apoptosis compared with single treatments. Conclusions: Triptolide in combination with ionizing radiation produced synergistic antitumor effects on pancreatic cancer both in vitro and in vivo and seems promising in the combined modality therapy of pancreatic cancer.
The V delta 1 T cell receptor repertoire in human small intestine and colon.
Authors: Y Chowers, W Holtmeier, J Harwood, E Morzycka-Wroblewska, M F Kagnoff
Journal: The Journal of Experimental Medicine (1994)

V delta 1 bearing T cells comprise the major population of gamma/delta T cells in the human intestinal tract. To gain insight into mechanisms involved in the generation of these cells and the diversity of their repertoire, we have characterized the junctional sequences of V delta 1 T cell receptor transcripts in the human small intestine and colon. Mucosal biopsies obtained from defined regions along the length of the small intestine or colon contained a high frequency of either one or a few identical in frame V delta 1 sequences. Less abundant sequences were also detected repeatedly throughout the length of small intestine or colon. Moreover, the intestinal V delta 1 repertoire in the small intestine and colon appeared compartmentalized and showed no overlap with the V delta 1 repertoire in peripheral blood. Dominant V delta 1 transcripts in each subject differed between the small intestine and colon, and the dominant transcripts within these sites differed among individuals. Analysis of small intestinal transcripts obtained at a 1-yr interval revealed that the V delta 1 repertoire was stable over time. The fact that the majority of V delta 1 transcripts, both dominant and rare, are distributed throughout a several meter length of the adult intestinal tract and are stable over time suggests they are not generated by an ongoing process of in situ VDJ gene rearrangement. Our results favor a model in which the repertoire of V delta 1 T cells in the intestinal tract is shaped by positive selection in response to a limited array of ligands before the migration of V delta 1 cells throughout the small intestine or colon.
Impact of anti-TNF treatment on growth in severe juvenile idiopathic arthritis
Authors: P Tynjala
Journal: Annals of the Rheumatic Diseases (2006)

To evaluate the impact of anti-tumour necrosis factor (TNF) treatment on growth and to identify the predictors for the change in growth in severe juvenile idiopathic arthritis (JIA).Data from 71 JIA patients (43 on etanercept, 28 on infliximab) were reviewed two years before and two years on the anti-TNF treatment. The patients had polyarticular disease course (48 polyarthritis, 19 extended oligoarthritis, two systemic arthritis, and two enthesitis related arthritis). At the initiation of the anti-TNF treatment, their mean age was 9.6 years and the mean duration of JIA, 5.7 years.In the patients with delayed growth before anti-TNF treatment (n = 53), the growth velocity, measured as the change in height standard deviation score, accelerated +0.45 (95% confidence interval, 0.33 to 0.56) (p<0.001) during the anti-TNF treatment. In the patients with normal or accelerated growth before anti-TNF treatment (n = 18), the change in growth velocity was +0.05 (0.07 to 0.16) (p = 0.39). At two years on anti-TNF treatment, the growth velocity between these two groups was similar. No difference was found between the patients treated with etanercept or infliximab. A decelerating growth rate before the anti-TNF treatment was the strongest predictor for the observed increase in the growth velocity. The change in the inflammatory activity remained a significant predictor of the growth velocity even after the decrease in glucocorticoid dose was taken into account.In the treatment of polyarticular JIA, the anti-TNF treatment not only suppresses inflammation but also restores growth velocity.
Incidence and prevalence of paediatric home parenteral nutrition (HPN): a nationwide study from the Scottish HPN managed clinical network
Authors: A. R. Barclay, J. Baxter, D. C. Wilson
Journal: Gut (2011)

<h3>Introduction</h3> The four tertiary centres in Scotland providing paediatric (&lt;16 years of age) HPN are formalised within the Scottish HPN MCN; only these centres have facilities and expertise to give prolonged PN beyond term. Scotland comprises 8.6% (5.2 million/61 million × 100) of the paediatric population of the UK. Our aim was to demonstrate nationwide incidence and prevalence of need for paediatric HPN in Scotland, as a representative part of the UK. <h3>Methods</h3> The prospective cohort of HPN cases managed in all 4 tertiary paediatric HPN centres in Scotland (Aberdeen, Dundee, Edinburgh and Glasgow) has been ongoing from 01/2003. We reviewed prevalence and incidence of paediatric HPN for each year from 2003 to 2010 (10 months only for 2010), with point prevalence on the 31<sup>st</sup> of each October. Outcomes of interest included fate - continuing HPN or leaving paediatric network, and reason why. <h3>Results</h3> There were 39 HPN cases in this period, with 6 prevalent cases on 01.01.03. There were 33 incident HPN, and 28 of 39 stopped HPN (14 adapted, 2 withdrew, 1 transitioned, 1 left Scotland, and 10 died). Prevalence and incidence data are shown in table 1. * 01.01.03-31.10.10 only. <h3>Conclusion</h3> We report nationwide data on the incidence and prevalence of paediatric HPN in Scotland, managed in the 4 HPN centres. Extrapolation of our Scottish nationwide data (collected within a national MCN) to the UK ((nx100/8.6)/12 years) suggests that there are annual minimum paediatric incidences and period prevalences of 48 and 126 cases respectively needing HPN in the UK, with an increasing trend in the last 8 years. These data are important for counselling families and for planning regional and national paediatric HPN specialist services in the UK.
PROmiRNA: a new miRNA promoter recognition method uncovers the complex regulation of intronic miRNAs
Authors: Annalisa Marsico, Matthew R Huska, Julia Lasserre, Haiyang Hu, Dubravka Vucicevic, Anne Musahl, Ulf Andersson Orom, Martin Vingron
Journal: Genome biology (2013)

The regulation of intragenic miRNAs by their own intronic promoters is one of the open problems of miRNA biogenesis. Here, we describe PROmiRNA, a new approach for miRNA promoter annotation based on a semi-supervised statistical model trained on deepCAGE data and sequence features. We validate our results with existing annotation, PolII occupancy data and read coverage from RNA-seq data. Compared to previous methods PROmiRNA increases the detection rate of intronic promoters by 30%, allowing us to perform a large-scale analysis of their genomic features, as well as elucidate their contribution to tissue-specific regulation. PROmiRNA can be downloaded from http://promirna.molgen.mpg.de.
Preferential Duplication in the Sparse Part of Yeast Protein Interaction Network
Authors: L. Li, Y. Huang, X. Xia, Z. Sun
Journal: Molecular Biology and Evolution (2006)

Gene duplication is an important mechanism driving the evolution of biomolecular network. Thus, it is expected that there should be a strong relationship between a gene's duplicability and the interactions of its protein product with other proteins in the network. We studied this question in the context of the protein interaction network (PIN) of Saccharomyces cerevisiae. We found that duplicates have, on average, significantly lower clustering coefficient (CC) than singletons, and the proportion of duplicates (PD) decreases steadily with CC. Furthermore, using functional annotation data, we observed a strong negative correlation between PD and the mean CC for functional categories. By partitioning the network into modules and assigning each protein a modularity measure Qn, we found that CC of a protein is a reflection of its modularity. Moreover, the core components of complexes identified in a recent high-throughput experiment, characterized by high CC, have lower PD than that of the attachments. Subsequently, 2 types of hub were identified by their degree, CC and Qn. Although PD of intramodular hubs is much less than the network average, PD of intermodular hubs is comparable to, or even higher than, the network average. Our results suggest that high CC, and thus high modularity, pose strong evolutionary constraints on gene duplicability, and gene duplication prefers to happen in the sparse part of PINs.
Orbitofrontal Cortex and Its Contribution to Decision-Making
Authors: Jonathan D. Wallis
Journal: Annual Review of Neuroscience (2007)

Damage to orbitofrontal cortex (OFC) produces an unusual pattern of deficits. Patients have intact cognitive abilities but are impaired in making everyday decisions. Here we review anatomical, neuropsychological, and neurophysiological evidence to determine the neuronal mechanisms that might underlie these impairments. We suggest that OFC plays a key role in processing reward: It integrates multiple sources of information regarding the reward outcome to derive a value signal. In effect, OFC calculates how rewarding a reward is. This value signal can then be held in working memory where it can be used by lateral prefrontal cortex to plan and organize behavior toward obtaining the outcome, and by medial prefrontal cortex to evaluate the overall action in terms of its success and the effort that was required. Thus, acting together, these prefrontal areas can ensure that our behavior is most efficiently directed towards satisfying our needs.