tbuckley/cabot-search huggingface dataset:
Prospective study of the incidence, aetiology and outcome of adult lower respiratory tract illness in the community
Authors: J Macfarlane
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Acute lower respiratory tract illness in previously well adults is usually labelled as acute bronchitis and treated with antibiotics without establishing the aetiology. Viral infection is thought to be the cause in most cases. We have investigated the incidence, aetiology, and outcome of this condition. <h3>METHODS</h3> Previously well adults from a stable suburban population consulting over one year with a lower respiratory tract illness were studied. For the first six months detailed investigations identified predetermined direct and indirect markers of infection. Evidence of infection was assessed in relation to presenting clinical features, indirect markers of infection, antibiotic use, and outcome. <h3>RESULTS</h3> Consultations were very common, particularly in younger women (70/1000 per year in previously well women aged 16–39 years), mainly in the winter months; 638 patients consulted, of whom 316 were investigated. Pathogens were identified in 173 (55%) cases: bacteria in 82 (<i>Streptococcus pneumoniae</i> 54,<i>Haemophilus influenzae</i> 31,<i>Moraxella catarrhalis</i> 7), atypical organisms in 75 (<i>Chlamydia pneumoniae</i> 55,<i>Mycoplasma pneumoniae</i> 23), and viruses in 61 (influenza 23). Seventy nine (24%) had indirect evidence of infection. Bacterial and atypical infection correlated with changes in the chest radiograph and high levels of C reactive protein but not with (a) the GP9s clinical assessment of whether infection was present, (b) clinical features other than focal chest signs, and (c) outcome, whether or not appropriate antibiotics were prescribed. <h3>CONCLUSIONS</h3> Over 50% of patients have direct and/or indirect evidence of infection, most commonly bacterial and atypical pathogens, but the outcome is unrelated to the identified pathogens. Many patients improve without antibiotics and investigations do not help in the management of these patients. GPs can reassure patients of the causes and usual outcome of this self-limiting condition.
Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium
Authors: Richard Aplenc, Susan M. Blaney, Lewis C. Strauss, Frank M. Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, John J. Wright, Peter C. Adamson
Journal: Journal of Clinical Oncology (2011)

Purpose Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. Patients and Methods A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome–positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m 2 /dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. Results A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m 2 dose levels. At 110 mg/m 2 , two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m 2 ), grade 3 diarrhea (85 mg/m 2 ), and grade 2 creatinine elevation (50 mg/m 2 ) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. Conclusion Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.
Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Suppressor of Intestinal Tumorigenesis
Authors: Shinri Hoshiko, Makiko Kawaguchi, Tsuyoshi Fukushima, Yukihiro Haruyama, Kenji Yorita, Hiroyuki Tanaka, Motoharu Seiki, Haruhiko Inatsu, Kazuo Kitamura, Hiroaki Kataoka
Journal: Cancer Research (2013)

Abstract Hepatocyte growth factor activator inhibitor type 1 (HAI-1/SPINT1) is a membrane-bound serine protease inhibitor expressed on the surface of epithelial cells. Although HAI-1/SPINT1 is abundantly expressed in the intestinal epithelium, its role in intestinal tumorigenesis is not known. In this study, we investigated the role of Hai-1/Spint1 in intestinal tumorigenesis using mouse models. The membranous Hai-1/Spint1 immunoreactivity was decreased in murine ApcMin/+ tumors and also in carcinogen (azoxymethane treatment followed by dextran sodium sulfate administration)-induced colon tumors compared with the adjacent non-neoplastic epithelium. The decreased immunoreactivity appeared to be due to sheddase activity of membrane-type 1 matrix metalloprotease. Then, we examined the effect of intestine-specific deletion of Spint1 gene on ApcMin/+ mice. The loss of Hai-1/Spint1 significantly accelerated tumor formation in ApcMin/+ mice and shortened their survival periods. Activation of HGF was enhanced in Hai-1/Spint1–deficient ApcMin/+ intestine. Gene expression profiling revealed upregulation of the Wnt/β-catenin signaling circuit, claudin-2 expression, and angiogenesis not only in tumor tissue but also in the background mucosa without macroscopic tumors in Hai-1/Spint1–deficient ApcMin/+ intestine. Intestinal deletion of Spint1 also enhanced the susceptibility to carcinogen-induced colon tumorigenicity of wild-type Apc mice. Our findings suggest that HAI-1/SPINT1 has a crucial role in suppressing intestinal tumorigenesis, which implies a novel link between epithelial cell surface serine protease inhibitors and protection from carcinogenic stimuli. Cancer Res; 73(8); 2659–70. ©2013 AACR.
Primary plasma cell leukemia: a retrospective multicenter study of 73 patients
Authors: L. Pagano, C.G. Valentini, V. De Stefano, A. Venditti, G. Visani, M.T. Petrucci, A. Candoni, G. Specchia, C. Visco, E.M. Pogliani, F. Ferrara, P. Galieni, A. Gozzetti, L. Fianchi, M. De Muro, G. Leone, P. Musto, A. Pulsoni
Journal: Annals of Oncology (2011)
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease
Authors: Brinda Ravikumar, Coralie Vacher, Zdenek Berger, Janet E Davies, Shouqing Luo, Lourdes G Oroz, Francesco Scaravilli, Douglas F Easton, Rainer Duden, Cahir J O'Kane, David C Rubinsztein
Journal: Nature Genetics (2004)
Capillary C4d Deposition as a Marker of Humoral Immunity in Renal Allograft Rejection
Authors: Bruno Watschinger, Manuel Pascual
Journal: Journal of the American Society of Nephrology (2002)

Although the detrimental effect of preformed donor-specific antibodies (DSA) became apparent in the 1960s, the possible pathogenic role of de novo DSA production against allografts after renal transplantation remained controversial for many years ([1][1]). An interesting initial observation, however
Fibroblast surface antigen produced but not retained by virus-transformed human cells.
Authors: A Vaheri, E Ruoslahti
Journal: The Journal of Experimental Medicine (1975)

Normal human fibroblasts contain a cell type-specific glycoprotein antigen (SF) that is known to be slowly shed into the medium and to be present also in human serum. Immunofluorescence with anti-SF antibodies showed that SF antigen has a highly nonrandom fibrillar distribution in surface of normal fibroblasts. Simian virus 40-transformed fibroblasts also produced the SF antigen, as shown by radioimmunoassay or immunodiffusion tests, but it was not retained by the surface of these cells. This creates a major difference between the surfaces of normal and malignant cells.
A 50-Gene Intrinsic Subtype Classifier for Prognosis and Prediction of Benefit from Adjuvant Tamoxifen
Authors: Stephen K. Chia, Vivien H. Bramwell, Dongsheng Tu, Lois E. Shepherd, Shan Jiang, Tammi Vickery, Elaine Mardis, Samuel Leung, Karen Ung, Kathleen I. Pritchard, Joel S. Parker, Philip S. Bernard, Charles M. Perou, Matthew J. Ellis, Torsten O. Nielsen
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry. Experimental Design: Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2–enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes. Results: Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit [DFS: HR, 0.52; 95% confidence interval (CI), 0.32–0.86 vs. HR, 0.80; 95% CI, 0.50–1.29 for nonluminal subtypes], although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease. Conclusions: In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen. Clin Cancer Res; 18(16); 4465–72. ©2012 AACR.
Extent of perilesional edema differentiates radionecrosis from tumor recurrence following stereotactic radiosurgery for brain metastases
Authors: J. E. Leeman, D. A. Clump, J. C. Flickinger, A. H. Mintz, S. A. Burton, D. E. Heron
Journal: Neuro-Oncology (2013)

Differentiation of tumor recurrence from radionecrosis is a critical step in the follow-up management of patients treated with stereotactic radiosurgery (SRS) for brain metastases. A method that can reliably differentiate tumor recurrence from radiation necrosis using standard MR sequences would be of significant value. We analyzed the records of 49 patients with 52 brain metastases treated with SRS who subsequently underwent surgical resection of the same lesion. Forty-seven of the lesions had preoperative MRI available for review (90%), including T1 postcontrast, T2, and fluid attenuated inversion recovery sequences. Pre-SRS and preoperative lesion and edema volumes were manually contoured and measured in a blinded fashion using radiation treatment planning software. A neuropathologist analyzed samples for the presence of tumor and/or radiation necrosis. Longer time between SRS and resection (P < .001) and a larger edema/lesion volume ratio (high T2/T1c, P = .002) were found to be predictive of radionecrosis as opposed to tumor recurrence. Using a cutoff value of 10 for the edema/lesion volume ratio, we were able to predict the presence of tumor with a positive predictive value of 92%, which increased to 100% when looking only at patients who underwent resection <18 months following SRS. On follow-up imaging, lesions with a high edema/lesion volume ratio and lesions that progress later after SRS are more likely to contain radionecrosis. These indices may help guide clinical decision making in the context of evolving lesions after SRS for brain metastases and thereby avoid unnecessary interventions.
In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits
Authors: Xiao-Ke Liu, Alexander Katchman, Bernard H Whitfield, Grace Wan, Einsley M Janowski, Raymond L Woosley, Steven N Ebert
Journal: Cardiovascular Research (2002)

Women have longer rate-corrected QT intervals (QTc) and are at higher risk for developing life-threatening torsades de pointes ventricular arrhythmias than men, especially after taking medications that block cardiac human ether-a-go-go-related gene (HERG)-encoded K(+) channels. The purpose of the present study was to determine if the male sex steroid hormone, dihydrotestosterone (DHT), influences QT intervals in orchiectomized (Orch) male rabbits.ECG and whole-cell patch-clamp analyses were employed to evaluate cardiac repolarization and K(+) currents in hearts isolated from orchiectomized (Orch) male New Zealand White rabbits receiving subcutaneous sustained release pellets for either dihydrotestosterone (DHT) or placebo. The efficacy of the treatment paradigm was monitored by measuring plasma DHT concentrations before and after the treatment period (10-14 days).The results show that rate- and drug-induced QT-lengthening is attenuated in hearts from DHT-treated rabbits relative to placebo-treated controls. No significant changes in QRS were observed in response to DHT, thereby indicating that DHT influences QT primarily through an effect on ventricular repolarization. In addition, hearts from DHT-treated rabbits displayed significantly less QT lengthening in response to quinidine challenge compared to placebo controls. Current densities for two important cardiac repolarizing K(+) currents, I(K1) and I(Kr), were found to be significantly increased in ventricular myocardium of DHT-treated rabbits. Further, the half-maximal voltage of activation (V(1/2)) for I(Kr) was significantly shifted to more negative potentials in myocytes from DHT vs. placebo hearts (21.2+/-1.2 vs. 30.2+/-1.4 mV, respectively, n=12, P<0.001). Corresponding changes in rabbit ether-a-go-go-related gene (RERG) mRNA were not found when examined by Northern blot hybridization.These results suggest that the presence of male sex steroid hormones in male rabbits helps to suppress rate- and drug-induced delays in cardiac repolarization. DHT action produces increased current densities for I(K1) and I(Kr) and a left-shift in the V(1/2) for I(Kr) that could account, at least in part, for the observed QTc differences between males and females. Since little change was seen in ventricular RERG gene expression, DHT action in the heart may influence I(Kr) via post-transcriptional and/or post-translational mechanisms.
Isolated Subsegmental Pulmonary Embolus Diagnosed by Multidetector-Row Computed Tomography
Authors: U. Joseph Schoepf, Philip Costello
Journal: Circulation (2004)

A 45-year-old man presented with increasing pain and swelling in his left calf after a long-distance flight.Ultrasound of the lower extremities revealed deep venous thrombosis in the left popliteal, posterior tibial, and peroneal veins.A regimen of low-molecular-weight heparin and warfarin was initiated.During a blood draw, the patient had a syncopal episode.The patient's vital signs were remarkable for a PO 2 of 94% on room air.Contrast-enhanced 16-slice multidetector-row CT pulmonary angiography with 0.75-mm
Medically assisted reproduction in the presence of chronic viral diseases
Authors: Y. Englert
Journal: Human Reproduction Update (2004)

Teams practising medically assisted reproduction techniques try to avoid viruses as much as possible. Attitudes towards chronic carriers of viruses are rapidly changing, especially for human immunodeficiency virus (HIV) patients. We focus our attention on the legitimacy of systematic screening before assisted reproductive techniques and the need for specialized approaches including an adapted laboratory for viral hazards as well as the need for a multidisciplinary team. Specificities of HIV, hepatitis C virus (HCV), hepatitis B virus (HBV) carriers and the hypothesis of a reduced fertility potential are discussed. Are male HIV carriers a new indication for assisted reproductive techniques in order to prevent virus transmission? It is largely proven that sperm gradient preparation techniques efficiently decrease viral loads and therefore have a protective effect on contamination risk during assisted reproductive techniques. Although a few thousand assisted reproductive technique cycles were performed in the world for this indication without contamination, it is still too early to demonstrate that this technology is fully safe. Two examples of contaminations during insemination are examined. Many questions remain unresolved, such as the lack of standardized techniques for semen preparation or virus detection or the relative merits of intrauterine insemination or ICSI to prevent HIV contamination during assisted reproductive techniques. The authors plead for well‐structured, separate programmes of care linked to research objectives.
Reply
Authors: Christine E. McLaren, James C. Barton, Pradyumna D. Phatak, Mary J. Emond, V. Nathan Subramaniam, Lyle C. Gurrin, Paul C. Adams, Lawrie W. Powell, Grant A. Ramm, Gregory J. Anderson, Gordon D. McLaren
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We appreciate the responses of Besson‐Fournier et al. and Ryan et al. to our report that the allele frequency of GNPAT p.D519G (rs11558492) in HFE C282Y homozygotes with low alcohol consumption (<20 g daily) is significantly higher in men with severe iron phenotypes (>10 g iron removed to achieve iron depletion and/or hepatic iron concentration >236 μmol/g dry weight) than in men with mild iron phenotypes.1 Besson‐Fournier et al. studied 174 unrelated men with C282Y homozygosity who resided in southern France and came to medical attention with abnormal iron indices or clinical symptoms. They compared the allele frequency of rs11558492 in 81 men with severe iron phenotypes (serum ferritin [SF] >1000 μg/L, no current or past alcohol consumption >20 g/day, and >5 g Fe removed by phlebotomy) with that of 93 other men with iron phenotypes of lesser severity. Their analyses confirmed that the allele frequency of rs11558492 is enriched in the subset of men with severe iron phenotypes. In HFE C282Y homozygotes, SF is a surrogate for hepatic iron concentration or body iron stores determined using iron removed by phlebotomy to achieve iron depletion. Ryan et al. studied 264 men with C282Y homozygosity in the Irish hereditary hemochromatosis cohort and observed that the allele frequency of rs11558492 was not greater in men with SF ≥1000 μg/L than in men with SF <1000 μg/L. A comparison of men with SF <1000 μg/L versus those with SF ≥1000 μg/L, not characterized further using phlebotomy or liver iron measures, will include some with intermediate levels of iron stores. Thus, it is not surprising that the results of Ryan et al. did not replicate ours because there were differences in the definitions of the comparison groups and the way in which the data were analyzed. Their methods and results cannot be compared with ours. The results of Ryan et al. are consistent with the initial observation of Besson‐Fournier et al. that the additive effect of rs11558492 on the logarithm of SF, assessed in a linear regression controlling for sex, age, and alcohol consumption, was not significant. Likewise, Beutler et al. compared iron removed by phlebotomy to achieve iron depletion with SF levels at diagnosis in 54 HFE C282Y homozygotes and concluded that "the serum ferritin level does provide some information regarding total iron burden but even in the case of C282Y homozygotes, the correlation is not very strong."2 Because SF reflects not only storage iron in C282Y homozygotes but also the concomitant occurrence of diverse noniron conditions, it is plausible that SF phenotyping and iron phenotyping of C282Y homozygotes would yield disparate results in some study designs. We agree that, "Further studies are warranted in order to clarify the role of the GNPAT p.D519G variant as a modifier of the hemochromatosis phenotype."
Antibiotic or symptomatic therapy in URTI-related pediatric acute cough?
Authors: Alessandro Zanasi, Luigi Lanata, Francesco De Blasio, Federico Saibene, Giovanni Fontana, Rossella Balsamo, Peter Dicpinigaitis
Journal: European Respiratory Journal (2013)

Acute cough is a widespread symptom in children, the disproportionate use of antibiotic prescription increases parental satisfaction, although URTI are generally self-limiting.  We analyzed treatment effect of antibiotics and symptomatic drugs (antitussives and mucolitics) in two trials on URTI-related cough.  The first retrospective study involved 59 children with acute moist cough, treated with antibiotics or inhaled mucoactive drugs. Cough was measured, by means of a verbal category descriptive (VCD) score.  The second prospective study included 305 children with acute cough. Severity, frequency and type of cough were assessed after 6 days of treatment using a standardized questionnaire.  In the retrospective series, patients treated with inhaled mucoactive drugs (sobrerol or N-acetylcysteine) showed a significant improvement after 7 days compared with the group receiving antimicrobial therapy (p  In the prospective study children treated with antibiotics alone showed lower percentage of cough resolution after 6 days than patient treated with antitussive only, no difference was detected between children treated with antitussive alone vs patients receiving antibiotics and antitussives. The use of levodropropizine demonstrated a statistically significant effect in terms of cough resolution as compared to centrally acting antitussive drugs (codeine or cloperastine) (47% vs. 28%, p = 0.0012).  Our analysis of the studies showed that the effect of antibiotics on acute cough caused by URTI is inferior to symptomatic therapy. Antibiotics are not generally useful for treating cough, both alone and in association with antitussives. Mostly antibiotics is of little benefit and is outweighed by the adverse effects.
Platinum‐based anticancer agents: Innovative design strategies and biological perspectives
Authors: Yee‐Ping Ho, Steve C.F. Au‐Yeung, Kenneth K.W. To
Journal: Medicinal Research Reviews (2003)

Abstract The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum‐based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA–Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2‐diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA–Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt‐based anticancer agents will materialize in the near future. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 5, 633–655, 2003