tbuckley/cabot-search huggingface dataset:
Intranuclear Inclusions and Neoplasms in the Kidneys of Wild Rats&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: L. Kilham, R. J. Low, S. F. Conti, F. D. Dallenbach
Journal: JNCI Journal of the National Cancer Institute (1962)

Nuclear inclusions have been found in kidneys of nearly 100 percent of seemingly healthy, adult wild rats (Rattus norvegicus) captured on refuse dumps in the vicinity of Hanover, New Hampshire. In spite of the viral-like appearance of the inclusions, repeated attempts at isolation of virus were unsuccessful. A number of other investigations indicated that lead was the probable etiologic agent. To test this hypothesis, intranuclear inclusions were induced in the kidneys of albino rats by lead acetate and these inclusions had the same peculiarities, both histochemically and electron microscopically, as those in the wild rats. Assays of wildrat tissues revealed abnormal content of lead and suggested that these animals had chronic lead poisoning. The nuclear inclusions appeared to be associated with development of renal neoplasms ranging from circumscribed tumors to invasive, metastasizing carcinomas. The source of the lead inducing these changes has not been determined. Field observations have suggested that rat populations living and feeding on burning refuse dumps have a fairly constant exposure to leadcontaining fumes.
Budesonide reverses IL-13-induced airway hyper-responsiveness but has little effect on β2 agonist response in human small airways
Authors: Cynthia Koziol-White, Philip Cooper, Jie Zhang, Ian Dainty, Reynold Panettieri
Journal: European Respiratory Journal (2012)

IL-13 modulates airway smooth muscle sensitivity to contractile stimulus. Steroids and β2 adrenoceptor (AR) agonists decrease inflammation and inhibit airway hyper-responsiveness (AHR) in asthma. We postulate that steroids decrease AHR after IL-13 stimulation, and IL-13 alters bronchodilation of small airways.  Precision cut lung slices (PCLS) from disease-free donors were incubated with 100 ng/mL IL-13 (18 h) and examined for carbachol (Cch)-induced bronchoconstriction, and formoterol- (Form) or forskolin (Fsk)-induced bronchodilation. To assess the effect of steroids, slices were preincubated with budesonide (Bud) for 1 h prior to IL-13. Data shown are mean % change of baseline luminal area ± sem.  IL-13 significantly increased bronchoconstriction to a maximal effective concentration (100 μM) of Cch (Control (C): -80 ± 4, IL-13: -89 ± 3, p=0.02) and decreased the bronchodilation to 0.3 nM Form (C: 54 ± 8, IL-13: 20 ± 4, p  These data suggest that pretreatment with budesonide completely prevents the effects of IL-13 on both airway contractility and adenylyl cyclase-mediated bronchodilation but does not prevent the IL-13-induced impairment of β2AR agonist-mediated bronchodilation. Further studies will define the underlying mechanisms by which IL-13 attenuates β2AR-mediated bronchodilation.
Marked activity of bortezomib, rituximab, and dexamethasone (BORID) in heavily pretreated patients with mantle cell lymphoma
Authors: J. Drach, H. Kaufmann, O. Pichelmayer, V. Sagaster, S. Seidl, A. Chott, C. Zielinski, M. Raderer
Journal: Journal of Clinical Oncology (2006)

17522 Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. Methods: We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m 2 administered on days 1, 4, 8, and 11, R at 375 mg/m 2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. Results: Up to now, we have enrolled 10 pts (median age, 69 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 8 pts, high-dose therapy in 3 pts, and thalidomide in 5 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (&gt; grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (&lt; 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 8 pts evaluable for efficacy, 7 have achieved a response (3 CR, 4 PR), and 1 pt experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. 6 of 6 pts are still progression-free at 6 months after treatment initiation. Recruitment of patients is ongoing, and updated results will be presented. Conclusions: Data obtained thus far indicate that BORID has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable response. [Table: see text]
Abstract 2749: SRPK1 inhibition and modulation of VEGF alternative splicing as a potential therapeutic strategy in prostate cancer
Authors: Athina Mavrou, Dave Bates, Sebastian Oltean
Journal: Cancer Research (2014)

Abstract Angiogenesis is required for tumor growth and is induced principally by VEGF-A. VEGF-A pre-mRNA is alternatively spliced at the terminal exon to produce two families of isoforms, pro- and anti-angiogenic, only the former of which is upregulated in prostate cancer. In renal epithelial cells and colon cancer cells, the choice of VEGF splice isoforms is controlled by the splicing factor SRSF1, phosphorylated by SRPK1. Immunohistochemistry staining of human samples revealed a significant increase in SRPK1 expression both in prostate intra-epithelial neoplasia lesions as well as malignant adenocarcinoma compared to benign prostate tissue. We therefore tested the hypothesis that the selective upregulation of pro-angiogenic VEGF in prostate cancer may be under control of SRPK1 activity. SRPK1 levels were up-regulated in several prostate cancer cell lines in comparison with normal prostate epithelial cells. A switch in the expression of VEGF165 towards the anti-angiogenic isoform, VEGF165b, was seen in PC-3 cells with SRPK1 knock-down (KD). PC-3 -SRPK1 KD cells resulted in tumors that grew more slowly in xenografts, with decreased microvessel density. No effect was seen as a result of SRPK1 KD on growth, proliferation, migration and invasion capabilities of PC-3 cells in vitro. Moreover, VEGF over-expression from a splicing-insensitive construct in PC-3/SRPK1 KD cells rescued tumor growth. Small molecule inhibitors of SRPK1 are able to switch splicing towards the anti-angiogenic isoform, VEGF165b in PC3 cells in vitro and decrease tumor growth when administered intraperitoneally in vivo in a mouse model of orthotopic prostate cancer. Our study suggests that modulation of SRPK1 and subsequent inhibition of tumor angiogenesis by regulation of VEGF splicing can alter prostate tumor growth and supports further studies into the use of SRPK1 inhibition as a potential anti-angiogenic therapy in prostate cancer. Note: This abstract was not presented at the meeting. Citation Format: Athina Mavrou, Dave Bates, Sebastian Oltean. SRPK1 inhibition and modulation of VEGF alternative splicing as a potential therapeutic strategy in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2749. doi:10.1158/1538-7445.AM2014-2749
APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells
Authors: Antonia Cagnetta, Irene Caffa, Chirag Acharya, Debora Soncini, Prakrati Acharya, Sophia Adamia, Ivana Pierri, Micaela Bergamaschi, Anna Garuti, Giulio Fraternali, Luca Mastracci, Alessandro Provenzani, Chiara Zucal, Gianluca Damonte, Annalisa Salis, Fabrizio Montecucco, Franco Patrone, Alberto Ballestrero, Santina Bruzzone, Marco Gobbi, Alessio Nencioni, Michele Cea
Journal: Clinical Cancer Research (2015)

The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, APO866, has been previously shown to have antileukemic activity in preclinical models, but its cytotoxicity in primary leukemia cells is frequently limited. The success of current antileukemic treatments is reduced by the occurrence of multidrug resistance, which, in turn, is mediated by membrane transport proteins, such as P-glycoprotein-1 (Pgp). Here, we evaluated the antileukemic effects of APO866 in combination with Pgp inhibitors and studied the mechanisms underlying the interaction between these two types of agents.The effects of APO866 with or without Pgp inhibitors were tested on the viability of leukemia cell lines, primary leukemia cells (AML, n = 6; B-CLL, n = 19), and healthy leukocytes. Intracellular nicotinamide adenine dinucleotide (NAD(+)) and ATP levels, mitochondrial transmembrane potential (ΔΨ(m)), markers of apoptosis and of endoplasmic reticulum (ER) stress were evaluated.The combination of APO866 with Pgp inhibitors resulted in a synergistic cytotoxic effect in leukemia cells, while sparing normal CD34(+) progenitor cells and peripheral blood mononuclear cells. Combining Pgp inhibitors with APO866 led to increased intracellular APO866 levels, compounded NAD(+) and ATP shortage, and induced ΔΨ(m) dissipation. Notably, APO866, Pgp inhibitors and, to a much higher extent, their combination induced ER stress and ER stress inhibition strongly reduced the activity of these treatments.APO866 and Pgp inhibitors show a strong synergistic cooperation in leukemia cells, including acute myelogenous leukemia (AML) and B-cell chronic lymphocytic leukemia (B-CLL) samples. Further evaluations of the combination of these agents in clinical setting should be considered.
Newly Recognized Syndrome in the Neck: Horner's Syndrome with Ipsilateral Vocal Cord and Phrenic Nerve Palsies<sup>1</sup>
Authors: C M E Rowland Payne
Journal: Journal of the Royal Society of Medicine (1981)

Three patients are reported who exhibited a previously undescribed syndrome resulting from disruption of the sympathetic chain, the phrenic nerve and the innervation of the ipsilateral vocal cord. Each patient had pain in the ipsilateral shoulder and metastatic carcinoma of the breast. It is likely that this syndrome exists in association with other diseases such as carcinoma of the lung. The presence of this syndrome in patients with malignant disease has sinister significance and appears to carry a very grave prognosis.
Advancing our grasp of constrained variation in a crucial cognitive domain
Authors: Stephen C. Levinson
Journal: Behavioral and Brain Sciences (2010)

Abstract Jones's system of constraints promises interesting insights into the typology of kin term systems. Three problems arise: (1) the conflation of categories with algorithms that assign them threatens to weaken the typological predictions; (2) OT-type constraints have little psychological plausibility; (3) the conflation of kin-term systems and kinship systems may underplay the “utility function” character of real kinship in action.
Lucentis excluded from WHO list of essential medicines
Authors: D. Cohen
Journal: BMJ (2015)

The World Health Organization has rejected an application by Novartis to include ranibizumab (Lucentis) for neovascular eye diseases in the most recent update of its essential medicines list.1 The agency has, however, included “groundbreaking” new treatments for hepatitis C, a variety of cancers (including breast cancer and leukaemia), and multidrug resistant tuberculosis, among others.

Every two years a WHO expert committee meets to decide what should be included on the list, to provide guidance to countries about the “prioritization of medicines from a clinical and public health perspective.” The list was set up in 1977, and anyone can make an application for the inclusion of a drug.

In November last year Novartis wrote to WHO to …
Abstract 4230: Comparison of Dobutamine-atropine Stress Echocardiography and Magnetic Resonance for Detection of Obstructive Coronary Artery Disease by Assessing Wall Motion and Myocardial Perfusion Abnormalities
Authors: Sandra N Falcao, Jeane Tsutsui, Carlos E Rochitte, Luis Silva, Pedro A Lemos, Wilson Mathias
Journal: Circulation (2008)

Background: The analysis of wall motion abnormalities (WMA) with dobutamine stress echocardiography or magnetic resonance is an established method for the detection of myocardial ischemia. Contrast echocardiography has been demonstrated a useful technique for evaluating myocardial perfusion (MP). We test the hypothesis that combination of MP and WMA would improve the diagnosis of coronary artery diseasen (CAD). Objective: To compare the diagnostic accuracy of dobutamine stress real-time myocardial contrast echocardiography (RTMCE) and gadolinium-enhanced magnetic resonance imaging (G-MRI) for detecting CAD by analyzing left ventricular WMA and MP. Methods: We prospectively studied 46 patients (23 males, mean age 58±8 years) referred for coronary angiography, RTMCE and MRI within a maximum interval of two weeks. Protocol used in RTMCE and G-MRI was four-stage dobutamine protocol (10 – 40 mcg/kg/min), with injection of atropine as required to reach 85% of age-adjusted target heart rate. Patients underwent first dobutamine stress RTMCE and then G-MRI using the same doses of dobutamine and atropine. RTMCE was performed using low-mechanical index imaging combined with intravenous commercially available contrast agent (Definity, Bristol-Myers Squibb). Positivity for the stress test was defined as new or worsening WMA or reversible perfusion defects in &gt;2 contiguous segments. Quantitative coronary angiography (QCA) was performed in all patients. CAD was defined as the presence of lesion &gt;50 % in at least one coronary artery territory. Results: All patients tolerated well dobutamine stress. In five patients G-MRI was not performed (2 because of claustrofobia, 1 because patient did not fit in MRI, 2 because of extensive ischemia by dobutamine RTMCE). A total of 41 patients underwent dobutamine RTMCE, G-MRI and QCA. The sensitivity, specificity, and accuracy to detect CAD by dobutamine RTMCE were 74%, 89% and 80% for the analysis of wall motion, 83%, 89% and 85% for the analysis of MP and 65%, 83% and 73% for dobutamine stress G-MRI. C onclusion: RTMCE seems to have better performance for detecting angiographically significant CAD than G-MRI using dobutamine stress. The analysis of MP increases sensitivity to RTMCE without changing specificity.
Analysis of expression of Eph/Ephrin tyrosine kinases in advanced ovarian cancer
Authors: S. S. Sabesan, D. Wyld, N. Herath, A. Boyd
Journal: Journal of Clinical Oncology (2005)

5105 Background: Eph-receptor protein tyrosine kinases and their ligands (Ephrins) play important roles in embryological development including axonal migration and angiogenesis. They are over expressed in many cancers. Aim of our study was to examine the patterns of expression of this receptor family and their impact on outcome in advanced ovarian cancer. Methods: Eph A1, Eph A2, Ephrin A1, Ephrin A5, Eph B2, Eph B3, Eph B6 and Ephrin B1 mRNA expression was examined by real time quantitative PCR on 25 ovarian cancer specimens, two normal ovarian tissue, two benign ovarian tumours, two cancer cell lines and one normal ovarian epithelial cell line. Progression free survival (PFS) was calculated by retrospective review of medical records. Results: 25 specimens were obtained after debulking surgery for stage III /IV ovarian cancer. Adjuvant platinum based chemotherapy was given to all patients. Median PFS was 14 months (3–33 months). All receptors and ligands studied except Ephrin B1 were minimally expressed in normal and benign specimens whereas their expression was more than five fold in one third of the cancer specimens. Eph A1 and Eph A2 expression was significantly correlated with the expression of their ligand Ephrin A1 (r=0.506; p= 0.007 and r=0.466; p=0.014 respectively). Similar correlation was found between expression of Eph B2 and Eph B3 and their ligand Ephrin B1(r=0.452; p=0.018 and r=0.577; p= 0.002 respectively). Expression of Ephrin A5 was associated with shorter PFS (r= - 0.465; p = 0.022). Conclusions: Ephs and Ephrins are over expressed in ovarian carcinoma and Ephrin A5 predicted shorter PFS. Co-expression of receptors and their ligands in the same specimen suggests that this is an active system and may have a role in tumour progression or metastasis. If these results are confirmed, they could be used as targets for biological therapies. No significant financial relationships to disclose.
Intra-Operative Monitoring of the Common Peroneal Nerve during Total Knee Replacement
Authors: A J Unwin, M Thomas
Journal: Journal of the Royal Society of Medicine (1994)

We present a method allowing intra-operative monitoring of the common peroneal nerve during total knee arthroplasty using a magnetic stimulator. Previous reports have shown no pre-operative method successful in selecting those patients prone to develop a post-operative palsy. The device, placed beneath the lumbar spine, stimulates the cauda equina; common peroneal nerve function is assessed via the response in extensor digitorum brevis. There is a loss of signal from the nerve with the use of a tourniquet 25 min following its application. The protocol therefore requires that a tourniquet is used at least only for fixation of the prosthetic components. The method is quick, safe, non-invasive and reproducible, and is of use both in at-risk patients and in research work.
Primary, secondary, and quality-of-life endpoint results from PREVAIL, a phase 3 study of enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Andrew J. Armstrong, Bertrand Tombal, Cora N. Sternberg, Celestia S. Higano, Dana E. Rathkopf, Yohann Loriot, Fred Saad, Anthony M. Joshua, Johann Sebastian De Bono, Peter M. Venner, Joan Carles, Paul N. Mainwaring, Christopher P. Evans, Sarah B. Noonberg, Harry H. Mansbach, Suman Bhattacharya, Frank Perabo, De Phung, Tomasz M. Beer
Journal: Journal of Clinical Oncology (2014)

5007 Background: Enzalutamide (ENZ), an androgen receptor inhibitor, improved overall survival (OS) in men with mCRPC who had received prior docetaxel therapy (Scher, N Engl J Med 2012;367:13). The PREVAIL study examined whether ENZ could prolong OS and radiographic progression-free survival (rPFS) in men with mCRPC who had progressed on androgen deprivation therapy (ADT). Methods: In this randomized double-blind, placebo-controlled, multinational study (NCT01212991), asymptomatic or mildly symptomatic patients were randomized 1:1 to ENZ 160 mg/day or placebo (PBO). OS and rPFS were co-primary endpoints and analyzed for the intent-to-treat population. Key prespecified secondary and exploratory endpoints are noted in the table below. Results: 872 men were randomized to ENZ and 845 to PBO, with respective median treatment durations of 16.6 and 4.6 months. Based on a planned interim analysis at 540 deaths the Data Monitoring Committee recommended stopping the study and crossing PBO patients to ENZ. Efficacy results are shown in the Table. The most common adverse events with a higher incidence in the ENZ arm than PBO were fatigue (35.6% vs 25.8%), back pain (27.0% vs 22.2%), constipation (22.2% vs 17.2%), and arthralgia (20.3% vs 16.0%). Seizure was reported in 1 patient in each treatment arm (0.1%). Conclusions: In men with mCRPC who progress on ADT, treatment with enzalutamide has a favorable safety profile and significantly improves OS, rPFS, and secondary measures of disease response and progression. Clinical trial information: NCT01212991. Co-primary endpoints Est. median (95% CI) months HR (95% CI) P value ENZ PBO OS 32.4 (31.5, NYR) 30.2 (28, NYR) 0.71 (0.60, 0.84) < 0.0001 rPFS NYR (13.8, NYR) 3.9 (3.7, 5.4) 0.19 (0.15, 0.23) < 0.0001 Other efficacy endpoints Time to cytotoxic chemotherapy 0.35 (0.30, 0.40) < 0.0001 Time to antineoplastic treatmenta 0.27 (0.24, 0.31) < 0.0001 Time to first SRE 0.72 (0.61, 0.84) < 0.0001 Time to PSA progression 0.17 (0.15, 0.20) < 0.0001 Time to FACT-P degradation 0.63 (0.54, 0.72) < 0.0001 Best objective response (CR+PR) ENZ = 58.8% PBO = 5.0% < 0.0001 PSA decline from baseline ENZ PBO ≥ 50% 78.0% 3.5% < 0.0001 ≥ 90% 46.8% 1.2% < 0.0001 a Cytotoxic, hormonal, or investigational therapy.
Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease and Risk of Death and Hospitalization
Authors: Vincent S. Fan, Chris L. Bryson, J. Randall Curtis, Stephan D. Fihn, Pierre-Olivier Bridevaux, Mary B. McDonell, David H. Au
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Observational studies of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD) have shown improved survival whereas randomized trials have not. It has been suggested that this difference may be due to immortal time bias. To investigate this further, we performed a prospective cohort study of patients with COPD, using time-dependent methods to determine whether use of inhaled corticosteroids more than 80% of the time reduced the risk of all-cause mortality and COPD exacerbations. Of 8,033 patients, 2,686 (33%) received inhaled corticosteroids. We did not find a significant reduction in mortality for average inhaled steroid use at either low (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.69-1.33) or medium/high dose (HR, 0.86; 95% CI, 0.67-1.10). Similarly, recent inhaled corticosteroid use was not associated with a reduction in mortality at low (HR, 0.80; 95% CI, 0.60-1.07) or medium/high doses (HR, 0.88; 95% CI, 0.71-1.09). There was no association between inhaled corticosteroid use and hospitalizations or exacerbations due to COPD. Patients using medium/high-dose inhaled corticosteroids did not have a significantly lower risk of COPD hospitalizations (HR, 0.85; 95% CI, 0.64-1.13) or COPD exacerbations (HR, 1.13; 95% CI, 0.94-1.36). In a time-dependent study of outpatients with COPD, adherence to inhaled corticosteroid use was not associated with a decreased risk of mortality or exacerbations.