tbuckley/cabot-search huggingface dataset:
There is more to some EGF receptor inhibitors - PD153035 reveals triple action: EGF receptor inhibition, DNA-intercalation, RAR-beta induction
Authors: Thomas Grunt, Renate Wagner, Katharina Tomek, Klaudia Puckmair, Christoph Zielinski
Journal: Cancer Research (2007)

4017  We have previously shown that the epidermal growth factor-receptor (EGFR) tyrosine kinase inhibitor PD153035 induces retinoic acid receptor(RAR)-beta expression in breast and ovarian cancer cells by mechanisms that are independent of its blocking activity on EGFR (ErbB1) or on any other ErbB receptor (ErbB2, ErbB3, ErbB4). RAR-beta2, one of three human RAR-beta isoforms (RAR-beta1, RAR-beta2, RAR-beta4), is silenced in many tumors and acts as a tumor suppressor. Forced expression of RAR-beta2 reverts the malignant phenotype of RAR-beta2-negative breast cancer cells and reconstitutes retinoid sensitivity in these cells. Here we demonstrate that the EGFR inhibitor PD153035 specifically induces RAR-beta2, but not the other two isoforms (RAR-beta1, RAR-beta4) in human breast (MDA-MB-468, MDA-MB-453) cancer cells. Induction was seen at the mRNA (RT-PCR) and protein level (Western analysis). PD153035-mediated induction of RAR-beta2 was associated with synergistic growth inhibition in cells co-treated with PD153035 and all-trans retinoic acid (tRA). Most importantly, PD153035 restored retinoid sensitivity in retinoid resistant cells. Our previous work also revealed that PD153035 directly intercalates into the DNA double helix suggesting that changes in the chromatin structure contribute to the RAR-beta inducing effect of PD153035. This prompted us to examine the effect of classical DNA intercalating chemotherapeutic drugs such as doxorubicin, amsacrine and mitoxantrone on the expression of RAR-beta. Vincristine was used for comparative reasons, since this cytotoxic drug does not target the DNA. All four compounds caused dose-dependent growth inhibition in MDA-MB-468 and MDA-MB-453 cells. Interestingly, compounds that directly interact with the DNA double helix (doxorubicin, amsacrine, mitoxantrone) caused a time-dependent upregulation of the RAR-beta expression in all cell lines examined, whereas the negative control drug vincristine, which causes disassembly of microtubule structures, did not stimulate RAR-beta expression. This data further supports the notion that induction of the RAR-beta tumor suppressor gene in cancer cells by PD153035 is mediated at least in part by its DNA intercalating activity.
Caffeine induces the splicing factor SC35 and regulates alternative splicing of a subset of cancer-associated genes: The KLF6 story
Authors: Jia Shi, Zhen Hu, Kirk Pabon, Kathleen Scotto
Journal: Cancer Research (2007)

2575  Alternative pre-mRNA splicing adds to the complexity of gene expression by producing multiple splice variants from one single gene. Importantly, splice variants involved in differentiation, apoptosis, invasion, and metastasis often exist in a delicate equilibrium that is perturbed during tumorigenesis; indeed, efforts to use these splice variants as either biomarkers or drug targets are currently underway. Interestingly, many of the factors that control splicing are also overexpressed in tumors, strongly suggesting that aberrant splicing plays a major role in tumorigenesis and/or progression. To date, however, there is relatively little known about the regulation of alternative splicing either in normal or malignant cells, largely due to a lack of tools to recapitulate alternative splicing in a global system. In the present study, we report that caffeine, a highly consumed stimulant in the American diet and a widely used therapeutic agent, can induce expression of a subset of cancer-related splice variants. Using the tumor suppressor gene KLF6 as a prototype for this cancer gene subclass, we show that caffeine induces the expression of SpKLF6, a novel splice variant of KLF6 in a number of different cell lines. The induction of SpKLF6 (which involves aberrant inclusion of a cryptic exon designated exon 1a) is concentration-, time-dependent, and reversible. Importantly, caffeine induction is due to a direct affect on splice site selection, since other possibilities, such as SpKLF6 RNA stabilization by inhibition of nonsense-mediated decay, have been ruled out . Using a combination of KLF6 minigene deletion/mutation analyses and RNAi assays we have now identified two cis-acting RNA regulatory elements and the cognate splicing factors involved in SpKLF6 exon 1a alternative splicing. We show that the splicing factor SC35 is required for the caffeine-mediated induction of SpKLF6; importantly, SC35 itself is markedly induced by caffeine, implicating this factor in general caffeine-mediated splicing regulation. We hypothesize that caffeine mimics an endogenous and perhaps normal pathway that is activated in certain tumor cells. This novel effect of caffeine provides a valuable tool for dissecting alternative splicing regulation of a cancer-related gene subset, providing insight into the etiology of these tumor-specific variants. Current studies will determine whether caffeine can also regulate alternative splicing in vivo, an effect that could impact the use of cancer-specific splice variants as biomarkers and druggable targets.
Year-to-year impact budget analysis of biologic therapies for first-line metastatic colorectal cancer (mCRC) therapy in Spain.
Authors: Brezo Martinez-Amores, Laura Mezquita, Inmaculada Ibañez de Cáceres, Angel Ayuso Sacido, Jose Maria Peña, Rosario Perona, Cristobal Belda-Iniesta
Journal: Journal of Clinical Oncology (2012)

e14144 Background: Pharmacoeconomic studies deal with populations of patients as if they were admitted at the division of medical oncology in the same date. Real patients are treated along the entire year so that budget simulations should be adjusted to chronological patterns of oncological assistance. Deferred budget impact analysis is undergone in order to assess long-run economic implications of clinical decisions on first-line mCRC therapies in Spain. Methods: As metastatic colorectal cancer diagnosis is not affected by seasonal influences, we have created a mathematical model assuming that a single patient is diagnosed every month and this patient has a 53% possibility to harbor a native K-Ras sequence. Calculi were arranged based on median duration of therapy. For bevacizumab-based therapy, budget impact for year t+1 begins at month 5 and beyond. For patients that receive cetuximab-based therapy, budget impact for year t+1 begins at month 7. The same approach was performed for doublets without any monoclonal antibody. Prices for all drugs in Spain were assumed to represent the best-value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by randomized trials was used to calculate the final budget. 70kg and 1.7 m were used as reference for patient dose calculations. Results: When K-Ras status is not tested and bevacizumab-based schedules are administered to every patient, annual growth of budget increases by 55- 60%. If K-Ras status is analyzed and wild-type patients are treated with cetuximab combinations and mutated patients receive bevacizumab, yearly budget growth amounts to 39-41%. Annual budget growth is minimized (25%) when K-Ras wt patients are treated with cetuximab combinations whereas K-Ras mutated tumours received chemotherapy alone. Conclusions: Duration of therapy plays a key role on budget impact estimations from both overall and year to year perspectives. K-Ras based clinical decisions not only optimize outcomes as measured by response rates but also minimize economic implications on annual budget growths.
Spliceosome Mutations Are Associated with Frailty in Older Patients with Myeloid Malignancies
Authors: Marlise R. Luskin, Angel M. Cronin, Kevin Copson, Wooram Jung, Martha Wadleigh, Daniel J. DeAngelo, David P. Steensma, Jane Driver, Andrew A. Lane, R. Coleman Lindsley, Gregory A. Abel
Journal: Blood (2017)
Response to: ‘On using machine learning algorithms to define clinically meaningful patient subgroups’ by Knevel and Huizinga
Authors: Alain Meyer, Lionel Spielmann, François Séverac
Journal: Annals of the Rheumatic Diseases (2019)

We thank Knevel and Huizinga for their good comments 1 on our work in which we used hierarchical clustering on principal components to define clinically meaningful subgroups of patients with anti-Ku antibodies 2 and, to a lesser extent, on the work of Mariampillai et al 3 in which the authors used a similar method to reveal subgroups of myositis and propose a classification of these diseases.Knevel and Huizinga nicely explain how this statistical tool is a useful alternative to detailed insight in pathogenesis to improve taxonomy and personalise medicine.In this regards, myositis, which is rare and heterogeneous condition, is perfectly fitted for this method.Knevel and Huizinga also challenge the concern about these techniques raised by Pinal-Fernandez and Mammen through a statistical sophistry. 4In this regards, the initiative started by the European League Against Rheumatism (EULAR) to guide the use of big data techniques for rheumatic and musculoskeletal diseases will help to promote the development and the standardisation of these tools. 5inally, Knevel and Huizinga point out the importance of the validation of the findings.Given the extreme rarity of anti-Ku patients, we used k-fold cross-validation method as detailed by the authors. 1 2 Furthermore, Mariampillai et al 3 have used the independent cohort of 50 patients to confirm 4 groups of myositis they highlighted through hierarchical clustering on principal components analysis.As a conclusion, myositis and related conditions are examples of musculoskeletal diseases that are well fitted for big data techniques such as hierarchical clustering on principal components.We welcome the initiative of EULAR to further improve the development and the standardisation of these techniques.
When “B” becomes “A”: the emerging threat of influenza B virus
Authors: Lokesh Sharma, Andre Rebaza, Charles S. Dela Cruz
Journal: European Respiratory Journal (2019)

Influenza virus (flu) caused the worst disease mediated devastation in recorded human history in 1918, when global death was estimated to be between 50 and 100 million people [1]. Flu continues to kill more people every year with no apparent decrease in its pathogenicity despite advancement in our understanding of the disease and with the availability of vaccines and antiviral agents. Last year, the death toll of influenza was estimated to be 80 000 in the USA alone, making it the most lethal infectious disease [2]. One apparent change that occurred in the influenza virus is the emergence of influenza B strain as a significant contributor to the annual disease over the years. The origin of influenza B is unclear but was first isolated around 1940 and later separated into two clear lineages by 1983, the Yamagata-like and Victoria-like strains [3]. The scientific and healthcare community has been underplaying this important event and influenza B has been labelled as the "B" team compared to influenza A. Influenza B is believed to be a milder virus compared to some strains of influenza A, such as H3N2, but more potent than the influenza A strains like H1N1 [4]. In fact, multiple studies have suggested increased potency of influenza B virus in causing severe disease and mortality. Influenza B is the most prominent circulating strain of influenza every four to five years. Furthermore, influenza B infections carried higher risks of hospitalisations compared to influenza A infections in HIV patients [5]. Similarly, influenza B has been described to have significantly higher mortality rates compared to influenza A strains. For example, during the flu season in 2010–2011, influenza B was responsible for 38% of deaths in the paediatric population. National Respiratory and Enteric Virus Surveillance System collaborating laboratories indicated that only 26% of circulating strains of flu were influenza B viruses during this period [6]. Similarly, a Canadian study from 2004 to 2013 found significantly higher mortality rates due to influenza B compared to influenza A in children younger than 16 years of age [7]. These data strongly refute the claims that influenza B is the milder version of the flu. In this issue of the European Respiratory Journal , the study by Bui et al. [8] sheds light on influenza B interactions within the human respiratory tract and lung to demonstrate its pathogenicity and its potential to spread and cause severe lung infections. Influenza B virus can be as virulent as influenza A <http://bit.ly/2SnBZ72>
Effect of interventions using physical activity trackers on physical activity in people aged 60 years and over: a systematic review and meta-analysis
Authors: Juliana S Oliveira, Cathie Sherrington, Elizabeth R Y Zheng, Marcia Rodrigues Franco, Anne Tiedemann
Journal: British Journal of Sports Medicine (2019)

Older people are at high risk of physical inactivity. Activity trackers can facilitate physical activity. We aimed to investigate the effect of interventions using activity trackers on physical activity, mobility, quality of life and mental health among people aged 60+ years.For this systematic review, we searched eight databases, including MEDLINE, Embase and CENTRAL from inception to April 2018. Randomised controlled trials of interventions that used activity trackers to promote physical activity among people aged 60+ years were included in the analyses. The study protocol was registered with PROSPERO, number CRD42017065250.We identified 23 eligible trials. Interventions using activity trackers had a moderate effect on physical activity (23 studies; standardised mean difference (SMD)=0.55; 95% CI 0.40 to 0.70; I2=86%) and increased steps/day by 1558 (95% CI 1099 to 2018 steps/day; I2=92%) compared with usual care, no intervention and wait-list control. Longer duration activity tracker-based interventions were more effective than short duration interventions (18 studies, SMD=0.70; 95% CI 0.47 to 0.93 vs 5 studies, SMD=0.14; 95% CI -0.26 to 0.54, p for comparison=0.02). Interventions that used activity trackers improved mobility (three studies; SMD=0.61; 95% CI 0.31 to 0.90; I2=10%), but not quality of life (nine studies; SMD=0.09; 95% CI -0.07 to 0.25; I2=45%). Only one trial included mental health outcomes and it reported similar effects of the activity tracker intervention compared with control.Interventions using activity trackers improve physical activity levels and mobility among older people compared with control. However, the impact of activity tracker interventions on quality of life, and mental health is unknown.
Time-course of upper respiratory tract viral infection and COPD exacerbation
Authors: Daiana Stolz, Eleni Papakonstantinou, Leticia Grize, Daniel Schilter, Werner Strobel, Renaud Louis, Christian Schindler, Hans H. Hirsch, Michael Tamm
Journal: European Respiratory Journal (2019)

Viral respiratory tract infections have been implicated as the predominant risk factor for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We aimed to evaluate, longitudinally, the association between upper respiratory tract infections (URTI) caused by viruses and AECOPD. Detection of 18 viruses was performed in naso- and orοpharyngeal swabs from 450 COPD patients (Global Initiative for Chronic Obstructive Lung Disease stages 2–4) who were followed for a mean of 27 months. Swabs were taken during stable periods (n=1909), at URTI onset (n=391), 10 days after the URTI (n=356) and during an AECOPD (n=177) and tested using a multiplex nucleic acid amplification test. Evidence of at least one respiratory virus was significantly higher at URTI onset (52.7%), 10 days after the URTI (15.2%) and during an AECOPD (38.4%), compared with the stable period (5.3%, p&lt;0.001). During stable visits, rhinovirus accounted for 54.2% of all viral infections, followed by coronavirus (20.5%). None of the viruses were identified in two consecutive stable visits. Patients with a viral infection at URTI onset did not have a higher incidence of exacerbation than patients without viral infection (p=0.993). Τhe incidence of any viral infection during an AECOPD was similar between URTI-related AECOPD and non-URTI-related AECOPD (p=0.359). Only 24% of the patients that had a URTI-related AECOPD had the same virus at URTI onset and during an AECOPD. Detection of parainfluenza 3 at URTI onset was associated with a higher risk of an AECOPD (p=0.003). Rhinovirus and coronavirus were the most frequently detected viruses during AECOPD visits, accounting for 35.7% and 25.9% of all viral infections, respectively. The prevalence of viral infection during the stable period of COPD was low. The risk of exacerbation following the onset of URTI symptoms depends on the particular virus associated with the event and was significant only for parainfluenza 3.
β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes
Authors: Laura I. Hudish, Jane E.B. Reusch, Lori Sussel
Journal: Journal of Clinical Investigation (2019)

In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.
The Desire for Life and Motherhood Despite Metastatic Lung Cancer
Authors: Chiara Catania, Ester Del Signore, Gianluca Spitaleri
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Matching pennies games as asymmetric models of conflict
Authors: Michał Wiktor Krawczyk
Journal: Behavioral and Brain Sciences (2019)

Abstract De Dreu and Gross (D&amp;G) seem to have disregarded some relevant experimental literature on games of conflict, most notably variations on “matching pennies” games. While in such games, “attacker” and “defender” are typically not explicitly labelled, players’ differentiated roles yield naturally to such notions. These studies partly validate some of D&amp;G's findings and interpretations.
Association of SULT1A1 and UGT1A1 polymorphisms with breast cancer phenotypes and the age of onset
Authors: Ekaterina G. Shatalova, Andre Rogatko, Rebecca L. Blanchard, Timothy R. Rebbeck
Journal: Cancer Research (2004)

4492  Estrogens have been shown to play a significant role in breast cancer development. SULT1A1 and UGT1A1 proteins participate in estrogen metabolism and thus influence the risk of breast cancer. Both SULT1A1 and UGT1A1 genes are known to be polymorphic. A transition in SULT1A1 of G to A at codon 213 causes Arg to His amino acid substitution (SULT1A1*2 allele) and results in an enzyme with low activity. This allele is common with a frequency of about 30% in Caucasian Americans, Caucasian Europeans, African Americans and Africans. The most common UGT1A1 polymorphism lies within the promoter TATA-box. 6 TA repeats (UGT1A1*1 allele) is the most common allelic variant. It was demonstrated that transcript level is inversely proportional to the number of TA repeats within the UGT1A1 promoter TATA box. We hypothesized that individuals with variant capacity to metabolize estrogens will exhibit different tumor phenotypes and age of breast cancer onset. This hypothesis was investigated in a case-series study performed in a cohort of 190 Caucasian and 25 African-American women of 49-80 years old with breast cancer. SULT1A1 and UGT1A1 genotypes were determined using Pyrosequencing and Genescan techniques, respectively, and genotype-phenotype associations were analyzed with the Odds Ratio test. We found that the SULT1A1*1 homozygous genotype was associated with a tumor size
Antibiotic prophylaxis in the surgical management of miscarriage in low-income countries: a cost-effectiveness analysis of the AIMS trial
Authors: Ilias Goranitis, David M Lissauer, Arri Coomarasamy, Amie Wilson, Jane Daniels, Lee Middleton, Jonathan Bishop, Catherine A Hewitt, Andrew D Weeks, Chisale Mhango, Ronald Mataya, Iffat Ahmed, Olufemi T Oladapo, Javier Zamora, Tracy E Roberts
Journal: The Lancet Global Health (2019)

There is ongoing debate on the clinical benefits of antibiotic prophylaxis for reducing pelvic infection after miscarriage surgery. We aimed to study the cost-effectiveness of antibiotic prophylaxis in the surgical management of miscarriage in low-income countries.