tbuckley/cabot-search huggingface dataset:
Effects of Cycloheximide on the Response of Intestinal Mucosa to Cholera Enterotoxin
Authors: Daniel V. Kimberg, Michael Field, Elaine Gershon, Robert T. Schooley, Antonia Henderson
Journal: Journal of Clinical Investigation (1973)

Prior studies have indicated that effects of cholera enterotoxin (CT) on the small intestine are delayed in onset and involve an interaction with adenyl cyclase in the mucosa. It has also been shown that the administration of cycloheximide to rabbits in doses which inhibit crypt cell mitoses (20 mg/kg), diminishes CT-induced fluid production in jejunal loops. These latter studies have been interpreted as indications that CT-related intestinal secretion is a crypt cell function and that it is mediated by a CT-induced protein. The present study was undertaken to delineate more precisely the nature of the interaction in the intestine between cycloheximide and cholera toxin. Pretreatment of rabbits with cycloheximide reduced by 60% the secretory response to CT in isolated ileal loops with intact blood supply. Sodium and chloride flux measurements on mucosa isolated from these and control loops indicated that this antisecretory effect of cycloheximide persists in vitro. Measurements of radioactive leucine incorporation into mucosal protein indicated that the dose of cycloheximide employed inhibited protein synthesis by 90%. This inhibitory effect was shown to be independent of any effect of cycloheximide on amino acid uptake across the brush border. Measurements of adenyl cyclase activity and cyclic AMP levels in ileal mucosa of cycloheximide pretreated and control animals indicated that cycloheximide did not diminish the CT-induced increases in these parameters. These observations demonstrate that cycloheximide reduces CT-induced intestinal fluid production without interfering with the CT-induced augmentation of adenyl cyclase activity or the consequent rise in cyclic. AMP concentration. Since the antisecretory effect of cycloheximide persists in vitro, it probably involves a direct interaction of the antibiotic with mucosal cell ion transport mechanisms rather than an indirect effect mediated by other humoral or neurogenic factors. The present observations also suggest that the secretory response of the intestine to CT involves neither the synthesis of new adenyl cyclase nor that of a protein modifying its activity.
HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas
Authors: Efterpi Kostareli, Dana Holzinger, Olga Bogatyrova, Thomas Hielscher, Gunnar Wichmann, Michaela Keck, Bernd Lahrmann, Niels Grabe, Christa Flechtenmacher, Christopher R. Schmidt, Tanguy Seiwert, Gerhard Dyckhoff, Andreas Dietz, Daniela Höfler, Michael Pawlita, Axel Benner, Franz X. Bosch, Peter Plinkert, Christoph Plass, Dieter Weichenhan, Jochen Hess
Journal: Journal of Clinical Investigation (2013)

High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.
Novel DNA Damage Checkpoints Mediating Cell Death Induced by the NEDD8-Activating Enzyme Inhibitor MLN4924
Authors: Jonathan L. Blank, Xiaozhen J. Liu, Katherine Cosmopoulos, David C. Bouck, Khristofer Garcia, Hugues Bernard, Olga Tayber, Greg Hather, Ray Liu, Usha Narayanan, Michael A. Milhollen, Eric S. Lightcap
Journal: Cancer Research (2012)

MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic machinery, ubiquitin system, and DNA damage response pathways. In particular, genes involved in DNA replication, p53, BRCA1/BRCA2, transcription-coupled repair, and base excision repair seemed to be important for MLN4924 lethality. In contrast, genes within the G(2)-M checkpoint affected sensitivity to MLN4924 in colon cancer cells. Cell-cycle analysis in melanoma cells by flow cytometry following RNAi-mediated silencing showed that MLN4924 prevented the transition of cells from S-G(2) phase after induction of rereplication stress. Our analysis suggested an important role for the p21-dependent intra-S-phase checkpoint and extensive rereplication, whereas the ATR-dependent intra-S-phase checkpoint seemed to play a less dominant role. Unexpectedly, induction of the p21-dependent intra-S-phase checkpoint seemed to be independent of both Cdt1 stabilization and ATR signaling. Collectively, these data enhance our understanding of the mechanisms by which inhibition of NEDD8-dependent ubiquitination causes cell death, informing clinical development of MLN4924.
Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study
Authors: Renee Heffron, Deborah Donnell, Helen Rees, Connie Celum, Nelly Mugo, Edwin Were, Guy de Bruyn, Edith Nakku-Joloba, Kenneth Ngure, James Kiarie, Robert W Coombs, Jared M Baeten
Journal: The Lancet Infectious Diseases (2011)
Effect of treatment on erythrocyte phosphoribosyl pyrophosphate synthetase and glutathione reductase activity in patients with primary gout.
Authors: J Braven, T R Hardwell, P Hickling, M Whittaker
Journal: Annals of the Rheumatic Diseases (1986)

The activities of erythrocyte phosphoribosyl pyrophosphate (PRPP) synthetase and glutathione reductase (GTR) were studied in 26 patients with primary gout who were receiving no treatment or treatment with either allopurinol or azapropazone, and compared with the activity in a group of healthy controls. The activity of PRPP synthetase was significantly higher in the gout group and was not influenced by either drug. No significant difference in the activity of GTR was observed. The failure of either drug to suppress the increased activity of PRPP synthetase associated with gout is discussed.
Sigma receptors and their ligands in cancer biology: overview and new perspectives for cancer therapy
Authors: Véronique Megalizzi, Marie Le Mercier, Christine Decaestecker
Journal: Medicinal Research Reviews (2010)

A large number of drugs are known to bind with high affinity to sigma receptors (sigma-Rs) and have been used in the clinic to treat mental disorders for many years. However, recent publications highlighting sigma-R overexpression in many cancer tissues suggest potential applications for sigma-R ligands in cancer diagnosis and therapy. The present review focuses on the involvement of sigma-Rs in cancer biology and the potential therapeutic contributions of their pharmacologic ligands in oncology. After summarizing the current and general knowledge regarding sigma-Rs, we detail data reported in the particular context of oncology. We then investigate the potential and specific signal transduction pathways and mechanisms involved in the actions of sigma-R ligands in cancer biology. These processes include modulations of (1) the plasma membrane and lipid raft components, (2) intracellular calcium levels, (3) cytoskeletal protein functions, and (4) endoplasmic reticulum stress. Finally, we conclude by speculating on the roles of sigma-R overexpression and sigma-R ligands in cancer biology and offer perspectives on cancer therapy.
Genesis and evolution of the Evx and Moxgenes and the extended Hox and ParaHox gene clusters
Authors: Carolina Minguillón, Jordi Garcia-Fernàndez
Journal: Genome biology (2003)

Hox and ParaHox gene clusters are thought to have resulted from the duplication of a ProtoHox gene cluster early in metazoan evolution. However, the origin and evolution of the other genes belonging to the extended Hox group of homeobox-containing genes, that is, Mox and Evx, remains obscure. We constructed phylogenetic trees with mouse, amphioxus and Drosophila extended Hox and other related Antennapedia-type homeobox gene sequences and analyzed the linkage data available for such genes.We claim that neither Mox nor Evx is a Hox or ParaHox gene. We propose a scenario that reconciles phylogeny with linkage data, in which an Evx/Mox ancestor gene linked to a ProtoHox cluster was involved in a segmental tandem duplication event that generated an array of all Hox-like genes, referred to as the 'coupled' cluster. A chromosomal breakage within this cluster explains the current composition of the extended Hox cluster (with Evx, Hox and Mox genes) and the ParaHox cluster.Most studies dealing with the origin and evolution of Hox and ParaHox clusters have not included the Hox-related genes Mox and Evx. Our phylogenetic analyses and the available linkage data in mammalian genomes support an evolutionary scenario in which an ancestor of Evx and Mox was linked to the ProtoHox cluster, and that a tandem duplication of a large genomic region early in metazoan evolution generated the Hox and ParaHox clusters, plus the cluster-neighbors Evx and Mox. The large 'coupled' Hox-like cluster EvxHox/MoxParaHox was subsequently broken, thus grouping the Mox and Evx genes to the Hox clusters, and isolating the ParaHox cluster.
P269 CPAP Therapy Does Not Reduce Serum Uric Acid Levels in Obstructive Sleep Apnoea
Authors: B Prudon, E Roddy, JR Stradling, SD West
Journal: Thorax (2012)

Obstructive Sleep Apnoea (OSA) is associated with a high prevalence of hyperuricaemia, which occurs in up to 57% of men with severe OSA, most likely due to increased oxidative stress. Previous work has shown that treatment of OSA with Continuous Positive Airway Pressure (CPAP) reduces serum and urinary uric acid levels, but these studies have been conducted without appropriate control groups. We aimed to assess this effect in a randomised controlled trial. Stored serum samples from a previously described trial group were analysed (1). This consisted of samples taken from 38 men with known type 2 diabetes and newly diagnosed OSA (&gt;10 dips/h &gt;4% in oxygen saturation (ODI)), randomised to receive either therapeutic (n=19) or placebo CPAP (n=19) for 3 months. Serum Uric Acid (SUA) levels were measured from samples taken at baseline and after 3 months CPAP. <h3>Results</h3> are expressed as mean (SD). Both groups were well matched at baseline, with no significant difference between age 58.1 years (10.6) therapeutic CPAP group vs. 55.6 (6.9) placebo CPAP group, BMI 36.4 kg/m2 (5.0) vs. 35.6 (3.6), HbA1c 8.5% (1.8) vs. 8.1% (1.6), or ODI 33.9/hour (21.9) vs. 35.7/hour (21.1). There was also no significant difference in therapeutic or placebo CPAP usage 3.7h/night (3.2) vs. 3.7 (2.6) p=0.8. There was no significant difference in SUA levels at baseline 362 µmol/l (96) vs. 413 µmol/l (91), or at 3 months 354 µmol/l (83) vs. 406 µmol/l (101). Baseline SUA did not correlate with Apnoea-Hypopnoea Index (r=–0.2, p=0.5), ODI (r=0.1, p=0.6), BMI (r=0.1, p=0.4), or HbA1c (r=–0.3, p=0.9). The mean change in SUA at 3 months did not differ significantly between treatment groups (–7.6 µmol/l (35.9) vs. –6.2 µmol/l (46.2); p=0.9, 95% CI –28.7 to 25.9). This RCT using therapeutic and placebo CPAP has shown no evidence of a significant reduction in serum uric acid following three months treatment. This is in contrast to previously published uncontrolled data. This study was not however powered to detect a difference in SUA levels and may be therefore underpowered. Further RCTs are needed to explore this effect further. West SD, et al. Thorax. 2007; 62:969–974.
Incidence and causes of non-invasive mechanical ventilation failure after initial success
Authors: M. Moretti
Journal: Thorax (2000)

<h3>BACKGROUND</h3> The rate of failure of non-invasive mechanical ventilation (NIMV) in patients with chronic obstructive pulmonary disease (COPD) with acute respiratory insufficiency ranges from 5% to 40%. Most of the studies report an incidence of "late failure" (after &gt;48 hours of NIMV) of about 10–20%. The recognition of this subset of patients is critical because prolonged application of NIMV may unduly delay the time of intubation. <h3>METHODS</h3> In this multicentre study the primary aims were to assess the rate of "late NIMV failure" and possible associated predictive factors; secondary aims of the study were evaluation of the best ventilatory strategy in this subset of patients and their outcomes in and out of hospital. The study was performed in two respiratory intensive care units (ICUs) on patients with COPD admitted with an episode of hypercapnic respiratory failure (mean (SD) pH 7.23 (0.07), Paco<sub>2</sub> 85.3 (15.8) mm Hg). <h3>RESULTS</h3> One hundred and thirty seven patients initially responded to NIMV in terms of objective (arterial blood gas tensions) and subjective improvement. After 8.4 (2.8) days of NIMV 31 patients (23%; 95% confidence interval (CI) 18 to 33) experienced a new episode of acute respiratory failure while still ventilated. The occurrence of "late NIMV failure" was significantly associated with functional limitations (ADL scale) before admission to the respiratory ICU, the presence of medical complications (particularly hyperglycaemia), and a lower pH on admission. Depending on their willingness or not to be intubated, the patients received invasive ventilation (n=19) or "more aggressive" (more hours/day) NIMV (n=12). Eleven (92%) of those in this latter subgroup died while in the respiratory ICU compared with 10 (53%) of the patients receiving invasive ventilation. The overall 90 day mortality was 21% and, after discharge from hospital, was similar in the "late NIMV failure" group and in patients who did not experience a second episode of acute respiratory failure. <h3>CONCLUSIONS</h3> The chance of COPD patients with acute respiratory failure having a second episode of acute respiratory failure after an initial (first 48 hours) successful response to NIMV is about 20%. This event is more likely to occur in patients with more severe functional and clinical disease who have more complications at the time of admission to the ICU. These patients have a very poor in-hospital prognosis, especially if NIMV is continued rather than prompt initiation of invasive ventilation.
Does DeCIDE Give a Decisive Answer Against Induction Chemotherapy in Head and Neck Cancers?
Authors: Santam Chakraborty, Vijay Maruti Patil
Journal: Journal of Clinical Oncology (2015)

conductingavitalstudythatanswerssomeimportantquestionsinthe managementoflocallyadvancedheadandneckcancers.Thenegative resultsoftheDeCIDE(DocetaxelBasedChemotherapyPlusorMinus InductionChemotherapytoDecreaseEventsinHeadandNeckCancer) and the PARADIGM (Induction Chemotherapy Followed by Concurrent Chemoradiotherapy [sequential chemoradiotherapy] Versus Concurrent Chemoradiotherapy Alone in Locally Advanced Head and Neck Cancer) studies have undoubtedly tempered the initial enthusiasm for induction chemotherapy that was generated after the results of the TAX studies (which showed improved outcomes with triplet induction chemotherapy over the traditional cisplatinflurouracil doublet) were published. 2-4 Although the negative results of the Cohen et al 1 study may be related to the potential confounding influence of human papillomavirus‐positive oropharyngeal cancer, some further methodologic issues may also explain the results. The study was performed on the premise that induction chemotherapy before concurrent chemoradiotherapy (CRT) may improve survival by reducing the distant metastasis rate in a subgroup of patients felt to be at a higher risk of distant metastasis. However, the risk ofmetastasismaynotbethesameinallpatientswithN2nodaldisease. AmajorityofthepatientsintheCohenetal 1 studyhadN2bandstage IVA disease. The patient population with the greatest risk of distant metastasis (ie, those with N3 disease) was under-represented and accounted for just over 10% of the patient population. In an interesting study, Garden et al 5 demonstrated that in patientswithearlyT-stageoropharyngealcancerswhoareconsideredto have advanced disease because of the presence of lymphadenopathy, little is gained from adding chemotherapy to radiation alone in terms of locoregional control. In that study, approximately 50% of the patients had T1 and T2 primaries. This is probably not the population that should be subjected to more intensified treatment in the form of induction chemotherapy followed by CRT. Another reason for the lack of effect as seen in this study may havebeenpoorcompliancewithtreatment.Approximately94%of the patients randomly assigned to the CRT arm completed their treatment as compared with only 85% of the patients randomly assigned to the induction chemotherapy arm. This difference of nearly 9% was probably enough to eliminate any gains made by induction chemotherapy. Furthermore, the manuscript provides no data regarding the delay in starting CRT in patients receiving neoadjuvant chemotherapy (NACT). Only 79% of patients received the intended two doses of NACT. The dual factors of delay
Editorial in response to the systematic review by de Vos<i>et al</i>: ‘Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review’
Authors: Taco Gosens, Allan K Mishra
Journal: British Journal of Sports Medicine (2014)

We would like to compliment the authors on their recent efforts to construct a review article concerning the use of platelet-rich plasma (PRP) in the treatment of lateral epicondylar tendinopathy.1 As the authors of two of the studies evaluated in the paper, we would like to comment about the interpretation of our investigations and provide suggestions about the conclusions that may be drawn from the published data.

First, we would like to discuss the terminology used to describe the effect of a steroid injection in the published studies by Peerbooms et al 2 and Gosens et al 3 In these investigations, the group treated with steroids returned to baseline pain and function levels after 1 and 2 years (see figure 2 in ref 3). A steroid injection may have the negative effect implied by de Vos et al ,1 but in this study we were able to show that the condition of patients did not worsen. It is therefore incorrect to use these papers2 ,3 as evidence to suggest that steroid injections are detrimental.

Second, the title of the article “Strong evidence against platelet-rich plasma injections for chronic lateral …
Responsiveness of the shoulder function assessment scale in patients with rheumatoid arthritis
Authors: H M Vermeulen
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> To investigate the responsiveness of the Shoulder Function Assessment scale (SFA) in patients with rheumatoid arthritis (RA). <b>Methods:</b> In 35 patients with RA receiving a (peri-)articular injection because of local shoulder complaints the SFA, impact of shoulder function on activities of daily living, active shoulder range of motion (ROM), the 28 joint count Disease Activity Score (DAS28), and the Health Assessment Questionnaire (HAQ) were measured before and 4–6 weeks after treatment. Responsiveness was determined using the standardised response mean (SRM), effect size (ES), and responsiveness ratio (RR). <b>Results:</b> Overall, significant improvement was seen according to the SFA (mean change 10.9 (95% confidence interval 6.5 to 15.3)), active shoulder ROM (except external rotation), and the impact of shoulder function on daily activities. In addition, the DAS28 and HAQ scores improved significantly. The responsiveness of the SFA was excellent, with the SRM, ES, and RR being −0.86, −1.16, and 1.28, respectively. <b>Conclusions:</b> In addition to its good validity and reliability, the SFA proved to have a high sensitivity to clinical changes in patients with RA who received local treatment for shoulder complaints.
Curcumin Modulates Tamoxifen Response in Resistant Breast Cancer Cells.
Authors: M. De Gasperi, D. Cavazos, L. deGraffenried
Journal: Cancer Research (2009)

Abstract Despite significant improvement in both detection and treatment, breast cancer remains the second leading cause of cancer deaths for women in the United States. Tamoxifen is the most commonly used treatment for estrogen receptor positive (ER+) breast carcinoma, yet up to 50% of patients with metastatic disease present with de novo resistance to tamoxifen, and almost all patients will eventually become resistant to tamoxifen treatment. The mechanism(s) for this resistance appear to be largely dependent upon activation of growth factor signaling pathways. Aberrant activation of the PI3K/Akt and MAPK pathways and their cross talk with both the genomic and nongenomic activity of the ER is implicated in tamoxifen resistance. Breast cancer cell lines with constitutively activated Akt are characterized by high levels of the pro-survival transcription factor Nuclear Factor kappa B (NF-kB), estrogen-independent growth, and resistance to tamoxifen treatment. Studies have shown that curcumin, a polyphenol derived from the rhizome of the perennial herb Curcuma longa, is able to inhibit the activation of NF-kB, which is implicated as one mechanism by which breast cancer cells become resistant to tamoxifen treatment. Previous studies in our laboratory have demonstrated that inhibition of NF-kB is sufficient to sensitize MCF-7 cells that have constitutively activated Akt and elevated NF-kB levels to tamoxifen treatment. However, clinical NF-kB inhibitors such as Velcade generally involve suppression of the proteosome, leading to severe toxicities. Therefore, identification of alternative approaches for suppressing NF-kB activity in the absence of toxicity could prove beneficial for enhancing response to tamoxifen. In the present study, we assessed the efficacy of curcumin at inhibiting breast cancer cell proliferation and survival both as a single agent and in combination with tamoxifen in MCF-7 cells that expressed both “normal” levels of Akt (Control) activity as well as those that expressed the constitutively active form of Akt (myrAkt). As has been previously reported, curcumin treatment inhibited survival and proliferation in the Control MCF-7 cells, but importantly curcumin was also able to suppress survival and proliferation in the myrAKT MCF-7 cells. Curcumin and tamoxifen co-treatment was found to synergistically inhibit survival in myrAKT MCF-7 cells. These findings demonstrate that curcumin can sensitize myrAKT MCF-7 cells to tamoxifen treatment. This preliminary data suggests that the combination of natural NF-kB inhibitors such as curcumin with tamoxifen may be a viable strategy to either prevent tamoxifen resistant disease or to re-sensitize refractory disease to tamoxifen treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3098.