tbuckley/cabot-search huggingface dataset:
miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer
Authors: Claire Corcoran, Sweta Rani, Susan Breslin, Martina Gogarty, Irene M Ghobrial, John Crown, Lorraine O’Driscoll
Journal: Molecular Cancer (2014)

While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630's regulation of mRNA, proteins and their phosphorylated forms. We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630's regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients' response to HER-targeting drugs.
Clinical Relevance of Circulating Immune Complexes in Human Leukemia
Authors: Nicole A. Carpentier, Ghislaine T. Lange, Denis M. Fiere, Gilbert J. Fournie, Paul-Henri Lambert, Peter A. Miescher
Journal: Journal of Clinical Investigation (1977)

The occurrence of circulating immune complexes was investigated in 467 serum samples from 230 leukemia patients using the [(125)I]Clq-binding test. There was an increased serum [(125)I]Clq-binding activity in 40% of patients with acute myeloid leukemia, 23% with acute lymphatic leukemia, 46% in blastic crisis of chronic myeloid leukemia, 12% with chronic lymphatic leukemia, and 13% with chronic myeloid leukemia. In 48 patients, serum was also tested for soluble immune complexes by the Raji cell radioassay; the correlation between results of the two tests was significant. The Clq-binding material had properties identical with those of immune complexes. It sedimented as 14-28s material on sucrose density gradient. It contained IgG which could be dissociated at acid pH. Its Clq-binding properties could be removed after passage through anti-IgG immuno-absorbant or after a mild reduction-alkylation treatment, but were not sensitive to deoxyribonuclease treatment. Circulating immune complexes were found most commonly during the blastic stage of leukemia.Remission took place in 75.4% of patients with no detectable circulating immune complexes at the onset of acute leukemia, but in only 32.7% of those with detected complexes during this period. Median survival times of the former group of patients were more than 18 mo in acute myeloid leukemia and acute lymphatic leukemia and more than 8(1/2) mo in blastic crisis of chronic myeloid leukemia. The corresponding median survival times in the latter patient group were 64, 135, and 90 days. These findings were unrelated to prognostic features already known.
Polysomnographic parameters associated with morning headache
Authors: Paul Hamor, David Barnes, Brendon Yee, Keith Wong
Journal: European Respiratory Journal (2013)

Introduction: Patients visiting sleep physicians commonly report recurrent morning headaches upon awakening. Published rates of morning headache range from 11 to 60%. Our aim was to look at the prevalence of morning headache in patients undertaking diagnostic sleep studies at 2 sleep study centres in Sydney; and then look at sleep study parameters that are associated with morning headache.  Methods: Patients attending for polysomnography volunteered to complete a 2 page questionnaire, asking about the frequency and quality of headaches. These questions included the Headache Impact Test (HIT-6), the International Headache Society (IHS) criteria for sleep apnoea headache, as well as screening for depression, anxiety and chronic pain disorders.  Results: Between January and October 2012, 352 patients participated. After excluding 163 patients from analysis due to incomplete surveys, or undergoing polysomnography with CPAP, 109 (57.7% of the remaining 189 patients) reported a history of morning headaches, and 50 patients (26%) had severe headaches as assessed by HIT-6.  Those without obstructive sleep apnoea (AHI  Conclusion: In contrast to previous studies, we found that morning headaches were less likely in patients with sleep apnoea, but more likely in those patients with increased arousals, reduced sleep efficiency and reduced total sleep time.
The impact of docetaxel, estramustine, and low dose hydrocortisone on the quality of life of men with hormone refractory prostate cancer and their partners: A feasibility study
Authors: A.B. Kornblith, J.E. Herndon, E. Zuckerman, P.A. Godley, D. Savarese, N.J. Vogelzang, J.C. Holland
Journal: Annals of Oncology (2001)
Consistent probabilistic outputs for protein function prediction
Authors: Guillaume Obozinski, Gert Lanckriet, Charles Grant, Michael I Jordan, William Noble
Journal: Genome biology (2008)

In predicting hierarchical protein function annotations, such as terms in the Gene Ontology (GO), the simplest approach makes predictions for each term independently. However, this approach has the unfortunate consequence that the predictor may assign to a single protein a set of terms that are inconsistent with one another; for example, the predictor may assign a specific GO term to a given protein ('purine nucleotide binding') but not assign the parent term ('nucleotide binding'). Such predictions are difficult to interpret. In this work, we focus on methods for calibrating and combining independent predictions to obtain a set of probabilistic predictions that are consistent with the topology of the ontology. We call this procedure 'reconciliation'. We begin with a baseline method for predicting GO terms from a collection of data types using an ensemble of discriminative classifiers. We apply the method to a previously described benchmark data set, and we demonstrate that the resulting predictions are frequently inconsistent with the topology of the GO. We then consider 11 distinct reconciliation methods: three heuristic methods; four variants of a Bayesian network; an extension of logistic regression to the structured case; and three novel projection methods - isotonic regression and two variants of a Kullback-Leibler projection method. We evaluate each method in three different modes - per term, per protein and joint - corresponding to three types of prediction tasks. Although the principal goal of reconciliation is interpretability, it is important to assess whether interpretability comes at a cost in terms of precision and recall. Indeed, we find that many apparently reasonable reconciliation methods yield reconciled probabilities with significantly lower precision than the original, unreconciled estimates. On the other hand, we find that isotonic regression usually performs better than the underlying, unreconciled method, and almost never performs worse; isotonic regression appears to be able to use the constraints from the GO network to its advantage. An exception to this rule is the high precision regime for joint evaluation, where Kullback-Leibler projection yields the best performance.
Molecular Mechanisms Deployed by Virally Encoded G Protein–Coupled Receptors in Human Diseases
Authors: Silvia Montaner, Irina Kufareva, Ruben Abagyan, J. Silvio Gutkind
Journal: The Annual Review of Pharmacology and Toxicology (2011)

G protein-coupled receptors (GPCRs) represent the largest family of cell surface molecules involved in signal transduction. Surprisingly, open reading frames for multiple GPCRs were hijacked in the process of coevolution between Herpesviridae family viruses and their human and mammalian hosts. Virally encoded GPCRs (vGPCRs) evolved as parts of viral genomes, and this evolution allowed the power of host GPCR signaling circuitries to be harnessed in order to ensure viral replicative success. Phylogenetically, vGPCRs are distantly related to human chemokine receptors, although they feature several unique characteristics. Here, we describe the molecular mechanisms underlying vGPCR-mediated viral pathogenesis. These mechanisms include constitutive activity, aberrant coupling to human G proteins and β-arrestins, binding and activation by human chemokines, and dimerization with other GPCRs expressed in infected cells. The likely structural basis for these molecular events is described for the two closest viral homologs of human GPCRs. This information may aid in the development of novel targeted therapeutic strategies against viral diseases.
Effect of off-road competitive motocross race on plasma oxidative stress and damage markers
Authors: António Ascensão, Rita Ferreira, Franklim Marques, Eduardo Oliveira, Victor Azevedo, José Soares, José Magalhães
Journal: British Journal of Sports Medicine (2006)

Aim: To analyse the effect of an off-road motocross heat on plasma levels of oxidative stress and damage, blood leucocyte counts and urine catecholamine concentration. Methods: Plasma contents of total, reduced and oxidised (GSSG) glutathione, %GSSG, malondialdehyde (MDA), protein carbonyl and sulphydryl groups, total antioxidant status (TAS), uric acid, and blood neutrophil and lymphocyte counts were evaluated in 10 male top-level riders before, immediately after (0 h) and 1 h after a simulated competitive motocross race. 24-h urine adrenaline, noradrenaline and dopamine concentrations were also measured. Results: The motocross heat resulted in an increase in plasma oxidative stress and damage (p&lt;0.05). This was shown by a significant increase in %GSSG, TAS, MDA and carbonyls, and by a decrease in sulphydryl groups after the race. There was a significant increase in both plasma uric acid and urine catecholamine concentration after the race (p&lt;0.05). Blood neutrophil counts increased at 0 and 1 h after exercise (p&lt;0.05). Lymphocyte count increased from baseline to 0 h, although it decreased from baseline and 0 to 1 h after exercise (p&lt;0.05). Conclusion: The data reinforce the marked metabolic and hormonal demands imposed by motocross, resulting in a condition of enhanced plasma oxidative stress and damage.
Role of Carbonic Anhydrase IX in Human Tumor Cell Growth, Survival, and Invasion
Authors: Naomi Robertson, Christian Potter, Adrian L. Harris
Journal: Cancer Research (2004)

Abstract Carbonic anhydrase IX (CAIX) is a membrane-associated carbonic anhydrase (CA), strongly induced by hypoxia. CAIX is overexpressed in a variety of tumor types and associated with increased metastasis and poor prognosis. An inhibitor of CAs, acetazolamide has been reported to inhibit invasion. We used RNA interference (RNAi) to examine the function of CAIX in MDA468 and MDA231 breast carcinoma cells, which express high levels of CAIX under hypoxia. Hypoxia-induced CA activity was completely blocked by specific RNAi (P &amp;lt; 0.01). RNAi-treated cells showed growth delay in dense monolayer culture and a 50% reduction in clonogenic survival under hypoxia. In the MDA468 cells, there was no effect of RNAi treatment on invasion. In a cell line that did not induce CAIX under hypoxia, RT112, we found no effect on the ability of cells transfected with CAIX to invade or migrate. Thus, CAIX plays an important role in the growth and survival of tumor cells under normoxia and hypoxia, making it a potential target for cancer therapy, but is not involved in invasion.
Discontinuation of thioridazine in patients with learning disabilities: balancing cardiovascular toxicity with adverse consequences of changing drugs
Authors: S. J C Davies
Journal: BMJ (2002)

When evidence emerges on rare but potentially dangerous drug effects, the Committee on Safety of Medicines needs to act to protect the public. On the basis of clinical experience after guidelines relating to thioridazine were revised, Davies and colleagues argue that directives should take greater account of the risks associated with changing successfully established drug regimens, especially in vulnerable populations such as people with learning disabilities

When new evidence is unearthed of rare but dangerous side effects of drugs used in current practice, agencies such as the Committee on Safety of Medicines need to review and rewrite prescription guidelines. When new guidelines restrict the use of a commonly prescribed agent to a limited range of circumstances, doctors may be left in a dilemma. Patients who do not meet the criteria for continuing with a drug under revised guidelines, but who benefit from using it, may have to be exposed to the adverse consequences of changing their drugs. Influenced by the current culture of defensive medical practice, clinicians may be reluctant to continue prescribing drugs when guidelines state that the balance of risks and benefits is unfavourable in circumstances that apply to their patient. We present examples from our practice of the consequences of discontinuing established drugs in line with the Committee on Safety of Medicines' advice.

#### Summary points

The Committee on Safety of Medicines restricted the licensed indications for thioridazine after this antipsychotic drug was associated with prolonged QTc intervals

Patients with learning disabilities and psychiatric illness have been placed at higher risk by stopping or substituting antipsychotic drugs than had the drug been continued

Many people with learning disabilities lack the capacity to give their own consent to medical interventions, and psychiatrists may be reluctant to over-ride guidelines when responsibility for making decisions cannot be shared with the patient

Directives should …
THE EFFECT OF SECONDARY INFECTIONS ON EXPERIMENTAL TRACHOMA
Authors: P. K. Olitsky, R. E. Knutti, J. R. Tyler
Journal: The Journal of Experimental Medicine (1931)

The possibility suggested itself, in view of the theories already advanced with regard to the rô1e of secondary infections in the later manifestations of trachoma (1), that the implantation of common bacteria on the conjunctivae of monkeys already having well marked characteristic granulosis lesions might give rise to a condition showing less predominance of the follicular reaction and more of the hyperemic granulopapillary effect. We believe we have succeeded, by a suitable technique, in doing this and in producing thereby in the experimental animals a condition closely resembling the florid type of human trachoma (Type IIb and c of MacCallan). The organisms used were some of those which are found in the conjunctival sac of monkey and man with different types of granular conjunctivitis. Of themselves, they produced only a transient reaction or none, as Noguchi had already shown and as we ourselves had observed in control animals. When inoculated together with material containing Bacterium granulosis, they did not affect the usual action of this organism, but when introduced into a conjunctiva in which granulosis lesions were already well developed, they induced more of the characteristics of the florid stage of trachoma than have been hitherto observed in animals, notably increased hyperemia, edema and thickening, papillary hypertrophy, obscurity of blood vessels, and masking of the follicles. Microscopically these changes were accompanied by increased scar tissue formation, lymphoid infiltration, and papillary hyperplasia.
STUDIES OF TWO KINDS OF VIRUS PARTICLES WHICH COMPRISE INFLUENZA A2 VIRUS STRAINS
Authors: Purnell W. Choppin, Igor Tamm
Journal: The Journal of Experimental Medicine (1960)

Two kinds of virus particles have been found in varying proportions in influenza A2 strains isolated during the 1957 pandemic. Pure populations of the different particles were obtained, and these substrains were genetically stable on serial passage in the chick embryo. The two virus particles differ markedly in several biological properties though they are antigenically similar. One kind of particle, designated "+," is relatively sensitive to specific antibody, is highly sensitive to inhibition by serum inhibitors and urinary mucoprotein, fails to elute or elutes very slowly from human erythrocytes, and is capable of agglutinating erythrocytes treated extensively with V. cholerae filtrate. The other particle, designated "-," is relatively insensitive to antibodies and urinary mucoprotein, completely insensitive to serum inhibitors, elutes rapidly from erythrocytes, and can agglutinate erythrocytes treated extensively with V. cholerae filtrate. Both "+" and "-" particles destroy virus receptors on urinary mucoprotein. The relative proportions of these two particles determine the characteristics of parent strains in reactions with specific antibody, mucoprotein inhibitors, and erythrocytes. The "+" and "-" particles with several easily identifiable markers are well suited for genetic studies.
Multicopy Suppression Underpins Metabolic Evolvability
Authors: W. M. Patrick, E. M. Quandt, D. B. Swartzlander, I. Matsumura
Journal: Molecular Biology and Evolution (2007)

Our understanding of the origins of new metabolic functions is based upon anecdotal genetic and biochemical evidence. Some auxotrophies can be suppressed by overexpressing substrate-ambiguous enzymes (i.e., those that catalyze the same chemical transformation on different substrates). Other enzymes exhibit weak but detectable catalytic promiscuity in vitro (i.e., they catalyze different transformations on similar substrates). Cells adapt to novel environments through the evolution of these secondary activities, but neither their chemical natures nor their frequencies of occurrence have been characterized en bloc. Here, we systematically identified multifunctional genes within the Escherichia coli genome. We screened 104 single-gene knockout strains and discovered that many (20%) of these auxotrophs were rescued by the overexpression of at least one noncognate E. coli gene. The deleted gene and its suppressor were generally unrelated, suggesting that promiscuity is a product of contingency. This genome-wide survey demonstrates that multifunctional genes are common and illustrates the mechanistic diversity by which their products enhance metabolic robustness and evolvability.
Cost-effectiveness of isoniazid chemoprevention in close contacts
Authors: R. Diel, A. Nienhaus, T. Schaberg
Journal: European Respiratory Journal (2005)

The aim of the present study was to perform a cost-effectiveness analysis in young and middle-aged adults with latent tuberculosis (TB) infection in Germany. A Markov model simulated the progression of 20- and 40-yr-old close contacts of active TB cases over 20 yrs. Health and economic outcomes of isoniazid (INH) chemoprevention versus no intervention were compared. The analysis determined the incremental cost-effectiveness ratio in terms of cost per quality-adjusted life year and the difference between numbers of TB cases and of TB-related deaths. INH chemoprevention prevented 79% of expected TB cases in both age groups, and saved €9,482 and €9,142 in the lower and higher age groups, respectively, per case prevented. Quality-adjusted life expectancy was slightly extended by 8 days in the lower age group and 7 days in the higher age group, at a cost saving of €417 and €375, respectively, per person. Annual savings were €20,862 and €18,742 per 1,000 contacts, respectively. The number needed to be treated to prevent one TB case in the lower age group was 23 and 25 in the higher age group. The programme also prevented three TB-related deaths in the younger and two in the older cohort. The results are highly sensitive to treatment-cost assumptions. In conclusion, isoniazid chemoprevention in Germany is a highly cost-effective approach for reducing the burden of tuberculosis in recently converted young and middle-aged adults.
A Synopsis of Rheumatic Diseases
Authors: R K Jacoby
Journal: Annals of the Rheumatic Diseases (1990)

<h3>Abstract</h3> In both vertebrates and invertebrates, generating a functional appendage requires interactions between ectoderm-derived epithelia and mesoderm-derived cells. To investigate such interactions, we used single-cell transcriptomics to generate a cell atlas of the <i>Drosophila</i> wing disc at two time points during development. Using these data, we investigate gene expression using a multi-layered model of the wing disc and catalogued ligand-receptor pairs that could mediate signaling between epithelial cells and adult muscle precursors (AMPs). We found that localized expression of the FGF ligands, Thisbe and Pyramus, in the disc epithelium regulates the number and location of the AMPs. In addition, Hedgehog ligand from the epithelium activates a specific transcriptional program within adjacent AMP cells, which is critical for proper formation of a subset of the direct flight muscles. More generally, our annotated atlas provides a global view of potential cell-cell interactions between subpopulations of epithelial and myogenic cells.