tbuckley/cabot-search huggingface dataset:
Association Between Maternal Fluoride Exposure During Pregnancy and IQ Scores in Offspring in Canada
Authors: Rivka Green, Bruce Lanphear, Richard Hornung, David Flora, E. Angeles Martinez-Mier, Raichel Neufeld, Pierre Ayotte, Gina Muckle, Christine Till
Journal: JAMA Pediatrics (2019)

The potential neurotoxicity associated with exposure to fluoride, which has generated controversy about community water fluoridation, remains unclear.To examine the association between fluoride exposure during pregnancy and IQ scores in a prospective birth cohort.This prospective, multicenter birth cohort study used information from the Maternal-Infant Research on Environmental Chemicals cohort. Children were born between 2008 and 2012; 41% lived in communities supplied with fluoridated municipal water. The study sample included 601 mother-child pairs recruited from 6 major cities in Canada; children were between ages 3 and 4 years at testing. Data were analyzed between March 2017 and January 2019.Maternal urinary fluoride (MUFSG), adjusted for specific gravity and averaged across 3 trimesters available for 512 pregnant women, as well as self-reported maternal daily fluoride intake from water and beverage consumption available for 400 pregnant women.Children's IQ was assessed at ages 3 to 4 years using the Wechsler Primary and Preschool Scale of Intelligence-III. Multiple linear regression analyses were used to examine covariate-adjusted associations between each fluoride exposure measure and IQ score.Of 512 mother-child pairs, the mean (SD) age for enrollment for mothers was 32.3 (5.1) years, 463 (90%) were white, and 264 children (52%) were female. Data on MUFSG concentrations, IQ scores, and complete covariates were available for 512 mother-child pairs; data on maternal fluoride intake and children's IQ were available for 400 of 601 mother-child pairs. Women living in areas with fluoridated tap water (n = 141) compared with nonfluoridated water (n = 228) had significantly higher mean (SD) MUFSG concentrations (0.69 [0.42] mg/L vs 0.40 [0.27] mg/L; P = .001; to convert to millimoles per liter, multiply by 0.05263) and fluoride intake levels (0.93 [0.43] vs 0.30 [0.26] mg of fluoride per day; P = .001). Children had mean (SD) Full Scale IQ scores of 107.16 (13.26), range 52-143, with girls showing significantly higher mean (SD) scores than boys: 109.56 (11.96) vs 104.61 (14.09); P = .001. There was a significant interaction (P = .02) between child sex and MUFSG (6.89; 95% CI, 0.96-12.82) indicating a differential association between boys and girls. A 1-mg/L increase in MUFSG was associated with a 4.49-point lower IQ score (95% CI, -8.38 to -0.60) in boys, but there was no statistically significant association with IQ scores in girls (B = 2.40; 95% CI, -2.53 to 7.33). A 1-mg higher daily intake of fluoride among pregnant women was associated with a 3.66 lower IQ score (95% CI, -7.16 to -0.14) in boys and girls.In this study, maternal exposure to higher levels of fluoride during pregnancy was associated with lower IQ scores in children aged 3 to 4 years. These findings indicate the possible need to reduce fluoride intake during pregnancy.
Abstract #LB-110: RASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf-MEK-ERK pathway and inhibition of Akt in vitro and in a double-conditional xenograft model
Authors: Sonja Thaler, Arno Schad, Reinhard Dammann
Journal: Cancer Research (2009)

Promoter hypermethylation preventing expression of the RAS association domain family 1 isoform A (RASSF1A) gene product is among the most abundant epigenetic deregulations in human cancer. Restoration of RASSF1A inhibits tumor cell growth in vitro and in murine xenograft models. RASSF1A-deficient mice feature increased spontaneous and carcinogen-induced tumor formation. Mechanistically, RASSF1A impacts on several cellular functions, such as microtubule dynamics, migration, proliferation and apoptosis; however, its tumor-suppressive mechanism is incompletely understood. To study the functional consequences of RASSF1A expression in human cancer cells, we made use of a tetracycline-inducible expression system and a RASSF1A-deficient lung cancer cell line. We observed that RASSF1A induces cell cycle arrest in G1 phase and senescence. RASSF1A-mediated growth inhibition was accompanied by upregulation of the Cyclin-dependent kinase (CDK) inhibitor p21Cip1/Waf1 and proceeded independently of p53, p14Arf and p16Ink4a. Loss of p21Cip1/Waf1 or co-expression of the human papilloma virus (HPV) 16 oncoprotein E7 was found to override RASSF1A-induced cell cycle arrest and senescence. Conditional RASSF1A impacted on mitogen-activated protein kinase (MAPK) and protein kinase B/Akt (Akt) signaling to upregulate p21Cip1/Waf1 and to facilitate its nuclear localization. To further investigate the inhibitory effect RASSF1A on Akt-signaling, we generated double-conditional A549 cells co-expressing tetracycline-inducible RASSF1A and tamoxifen-activatible membrane-targeted Akt (myr-Akt-ERtam). Using this cellular model we observed that RASSF1A leads to inhibition of tumor cell growth even in the presence of activated myr-Akt-ERtam. To further investigate this effect in vivo, A549 cells double-conditional for RASSF1A and myr-Akt-ERtam were injected intravenously into NOD/SCID mice. We observed that tumors of double-conditional A549 cells formed in the lungs of mice treated with doxycycline and tamoxifen display less Ser473-phosphorylated Akt than tumors in the lungs from mice only treated with tamoxifen. Furthermore double-immunofluorescence staining of paraffin-sections for detection of RASSF1A and phospho-AktSer473 in xenografts tumors from doxycycline and tamoxifen treated mice reveal reciprocal staining patterns of RASSF1A and phospho-AktSer473 confirming a function of RASSF1A as Akt inhibitor. In summary, RASSF1A can mediate cell cycle arrest and senescence in human cancer cells by p53-independent regulation of p21Cip1/Waf1 caused by modulation of the Raf-MEK-ERK pathway and inhibition of Akt.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-110.
Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis
Authors: Yinglian Xiao, Shutian Zhang, Ning Dai, Guijun Fei, Khean-Lee Goh, Hoon Jai Chun, Bor-Shyang Sheu, Chui Fung Chong, Nobuo Funao, Wen Zhou, Minhu Chen
Journal: Gut (2019)

Objective To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). Design In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). Results In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI –3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI –1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI –4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI –5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI –8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI –9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. Conclusion Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. Trial registration number NCT02388724 .
Metabolic health in the Middle East and north Africa
Authors: Fereidoun Azizi, Farzad Hadaegh, Farhad Hosseinpanah, Parvin Mirmiran, Atieh Amouzegar, Hengameh Abdi, Golaleh Asghari, Donna Parizadeh, Seyed Ali Montazeri, Mojtaba Lotfaliany, Farzin Takyar, Davood Khalili
Journal: The Lancet Diabetes & Endocrinology (2019)
The functional role of hMLH1 splice variants in childhood acute lymphoblastic leukemia (ALL)
Authors: Amy Peasland, Elizabeth C. Matheson, Andrew G. Hall, Julie A. Irving
Journal: Cancer Research (2005)

4445  The mismatch repair (MMR) system plays an important role in the maintenance of genomic integrity by eliminating errors from the newly synthesized strand during DNA replication. The 85KDa hMLH1 protein forms part of the MutL complex with hPMS2, which is recruited to the repair pathway by the MutSα or MutSβ mismatch recognition complex. Abnormalities in MMR proteins have been detected in a variety of hematological malignancies and may cause resistance to drugs used in their treatment. As well as base-base mismatches and insertion-deletion loops, MMR recognizes chemotherapeutic lesions introduced by some drugs used to treat ALL (e.g. mercaptopurines, thioguanines). Therefore, loss of MMR leads to resistance to these agents. Alternatively spliced forms of hMLH1 have been investigated in a variety of normal and tumour tissues, particularly lymphocytes, and are tissue-specific. Their effect on MMR and drug sensitivity is undetermined. Bone marrow samples from children with ALL at presentation and relapse have been screened, along with peripheral blood mononuclear cells (PBMNC) from normal controls and a range of leukemic cell lines. Splice variants of hMLH1 have been characterized using RT-PCR, with overlapping primer pairs spanning all 19 exons. Transcripts lacking exons 6, 9, 9-10, 10-11, 9-11, 12, 16 and 17 were identified in all patient samples and PBMNC, although levels varied amongst patients. Some patients expressed greater proportions of variant transcripts than of full-length transcript. This was reflected in the varying levels of full-length protein in patient samples, as visualized by western blotting. The transcripts identified are predicted to encode truncated or internally deleted proteins of uncertain functional role. The most abundant alternatively spliced form, hMLH1Δ9/10, has been translated in vitro and shown to be expressed in patient cells by western blotting. Alternatively spliced isoforms of DNA repair proteins have been reported to exert a dominant-negative modulatory effect in the nucleotide excision repair pathway 1. MMR-proficient HeLa cells have been transfected with variant hMLH1 and an in vitro MMR assay 2 has been carried out to assess the effects of variant protein expression on repair activity. Results indicate that expression of the hMLH1Δ9/10 transcript in MMR-proficient cells has a dominant negative effect, significantly reducing repair activity from 61.22% to 13.46% for G/T-5’ repair (P=0.006; two-tailed students t-test), and from 71.18% to 7.94% for G/T-3’ repair (P=0.007). Expression of this variant transcript may have marked effects on thioguanine sensitivity in lymphoblasts of children with ALL. References Khan, S.G. et al. (2002) Nucleic Acids Res., vol. 30, no. 16, pp.3624-3631. Thomas, D.C. et al. (1991) J Biol Chem., vol. 266, no. 6, pp.3744-51.
Oxaliplatin given by hepatic arterial infusion (HAI) or systemic (SYS) with capecitabine in patients (pts) with unresectable liverlimited metastasis (Ur-LLM) from colorectal cancer (CRC).
Authors: Benny Vittrup Jensen, Henrik Noergaard, Magnus Bergenfeldt, Ole Larsen, Estrid Vilma Solyom Hoegdall, Jakob Johansen, Kirstine Hermann, Dorte Nielsen
Journal: Journal of Clinical Oncology (2013)

e14593 Background: Whether therapy of Ur-LLM from CRC by HAI is superior to SYS is unknown. Methods: First line phase II study of pts. with Ur-LLM from CRC. Included were 88 pts. HAI oxaliplatin (100 mg/m 2 ) was given to 66 pts. every 2nd week (wk) for a median of 11 series (1-12) and capecitabine 3500 mg/m 2 day 1-7 every 2nd wk for a median of 12 (2-14) series. Vessel variation made HAI unsuitable for 22 pts. They had systemic oxaliplatin (130 mg/m 2 ) for a median of 8 (1-10) series with capecitabine 2000 mg/m 2 day 1-14 every 3rd wk for a median of 8 series (1-45) with bevacizumab 7½ mg/kg day 1 in 14 pts. Primary endpoints were response, secondary median overall and therapy free survival (mOS) and toxicity. KRAS mutation status was determined in all pts. with the DxS kit. Survival was evaluated by the Kaplan Meier method and differences with the log rank test. 95% confidence interval are given in brackets. Results: Pts. treated with HAI and SYS were comparable. HAI yielded higher response rates than SYS (table 1). Pts. with KRAS-WT tumors treated with HAI had a mOS of 61 (43-80) mths, with KRAS-MT tumors 28 (21-35) mths (p&lt; 0.0001). SYS in KRAS-WT and MT types yielded equal mOS 36 (27-45) mths and 27 (12-44) mths. Pts. with KRAS-WT tumors treated with HAI lived longer than when treated with SYS (p=0.05). Pts. with HAI with KRAS-WT tumors lived without any kind of therapy for a median of 27 (16-37) mths with 42% living more than 40 mths. with KRAS-MT tumors 8 (3-13) mths (p&lt;0.0001) with 12% living more than 40 mths. Therapy free mOS with SYS in patients with KRAS-WT and KRAS-MT tumors was19 (0-39) mths.for pts. and 12 (4-20) mths respectively with 17% and 22% living more than 2 years.The findings were independent of cetuximab-based therapy in later lines. The toxicity was comparable. Conclusions: Effect of HAI oxaliplatin combined with capecitabine on response and survival is restricted to pts. with KRAS-WT tumors. [Table: see text]
Ending Surprise Medical Bills
Authors: Robert Steinbrook
Journal: JAMA Internal Medicine (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 Internal Medicine 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 Internal Medicine journal
Influence of tumor-conditioned medium on hypoxia-mediated inhibition of growth and survival of endothelial cells
Authors: Rave Sanker Ezhilarasan, Kathiravan Govindarajan, Indra Mohanam, Jasti S. Rao, G. Yancey Gillespie, Sanjeeva Mohanam
Journal: Cancer Research (2006)

2797  The hypoxic microenvironment of solid tumors is associated with malignant progression and it renders tumors more resistant to cancer therapies. Endothelial cell damage may occur following hypoxic conditions and lead to dysfunction; however, endothelial cells in tumors survive hypoxic conditions providing nutrients and oxygen to facilitate tumor growth. In this study, we investigated the effects of tumor-conditioned medium on hypoxia-induced changes in endothelial cell growth, migration and survival. Tumor conditioned medium collected from hypoxic or normoxic human glioblastoma tumor cells were applied to endothelial cultures in normoxia and hypoxia conditions. Cell survival and viability were assessed by the colony formation assay. Cell cycle distribution was analyzed by flow cytometry and migration was measured by spheroid and wound-induced migration assays. Endothelial cells were stained for nucleus morphology with Hoechst 33342 dye and for intracellular active caspase-3 with western blotting. Changes in gene expression were determined by RT-PCR and quantified by real-time PCR for VEGF, VEGFR2, uPA, and uPAR gene transcripts. MMP-1, MMP-2 and MMP-9 secretion was evaluated by zymography. In capillary-like structure formation studies, endothelial cells were seeded into matrigel and then exposed to hypoxia. Hypoxia caused a reduction in clonogenic cell survival response and growth arrest at the G0-G1 phases of the cell cycle in endothelial cells. Hypoxia compared with normoxia significantly reduced the number of migrating endothelial cells. Nuclear staining with dye and caspase-3 activation in endothelial cells showed that hypoxia-induced apoptosis involves caspase-dependent mechanisms. Exposure to hypoxia caused a decrease in gene expression of VEGF, VEGFR2, uPA, and uPAR in endothelial cells. Furthermore, hypoxia showed a strong inhibition of capillary tube formation on Matrigel, and a decrease in MMP-1, MMP-2 and MMP-9 secretion by endothelial cells. Tumor conditioned medium enhanced survival and rescued endothelial cells from apoptosis induced by hypoxia. These molecular changes in endothelial cells could, in part, contribute to the angiogenic response that occurs in the development of hypoxic neovascularization in solid tumors.
Beyond the One Gene–One Disease Paradigm
Authors: Marina Cerrone, Carol Ann Remme, Rafik Tadros, Connie R. Bezzina, Mario Delmar
Journal: Circulation (2019)

Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.
Efficacy and safety of lower versus higher CO<sub>2</sub> extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study
Authors: Alain Combes, Tommaso Tonetti, Vito Fanelli, Tai Pham, Antonio Pesenti, Jordi Mancebo, Daniel Brodie, V Marco Ranieri
Journal: Thorax (2019)

Retrospective analysis of the SUPERNOVA trial exploring the hypothesis that efficacy and safety of extracorporeal carbon dioxide removal (ECCO 2 R) to facilitate reduction of tidal volume (V T ) to 4 mL/kg in patients with acute respiratory distress syndrome (ARDS) may differ between systems with lower (area of membrane length 0.59 m 2 ; blood flow 300–500 mL/min) and higher (membrane area 1.30 m 2 ; blood flow between 800 and 1000 mL/min) CO 2 extraction capacity. Ninety-five patients with moderate ARDS were included (33 patients treated with lower and 62 patients treated with higher CO 2 extraction devices). We found that (1) V T of 4 mL/kg was reached by 55% and 64% of patients with the lower extraction versus 90% and 92% of patients with higher extraction devices at 8 and 24 hours from baseline, respectively (p&lt;0.001), and (2) percentage of patients experiencing episodes of ECCO 2 R-related haemolysis and bleeding was higher with lower than with higher extraction devices (21% vs 6%, p=0.045% and 27% vs 6%, p=0.010, respectively). Although V T of 4 mL/kg could have been obtained with all devices, this was achieved frequently and with a lower rate of adverse events by devices with higher CO 2 extraction capacity.
Opioids: GPs suspended after prescribing online without verifying patients’ histories
Authors: Clare Dyer
Journal: BMJ (2019)

Two GPs who prescribed opioids online without verifying patients’ self reported medical histories have been suspended from the UK medical register.

Edward Pooley and Dharson Dharmasena prescribed dihydrocodeine and other powerful pain treatments even though some of their patients refused to consent to their GPs being contacted and informed, a medical practitioners tribunal heard.

Both doctors worked for the White Pharmacy, a private online prescription medication service. Dharmasena was its clinical director from May 2017 until he left in August …
Awareness about EGFR testing and use of TKIs in advanced lung cancer: A questionnaire-based survey of medical oncologists from India.
Authors: Purvish M. Parikh
Journal: Journal of Clinical Oncology (2013)

e19116 Background: EGFR is an important driver mutation in lung cancer. The pattern of usage of EGFR mutation testing is not well defined in the Indian population. Methods: A total of 70 medical oncologists from India were interviewed to identify current practices in the management of advanced lung cancer. They were in clinical practice for 2 to 35 (median 9) years. Their affiliation included medical college (21), regional cancer center (6), corporate hospitals (29) and private practice (14). Their collective experience in conducting international clinical trials in lung cancer was significant (range 0 to 35 trials). Results: The number of new patients with lung cancer seen by them in a month was a median of 8 (range 1 to 20). EGFR testing on the lung cancer tissue was recommended in a median of 60 % (range 10 to 100 %) of paients and was actually carried out in a median of 30 % (range 0 to 90 %). Tissue samples were inadequate for EGFR testing in 30 % of cases (range 2 to 95 %). Method of EGFR testing used included IHC by 06, molecular by 52 and both by 12 of the oncologists. The time to obtain a report was 10 days (range 5 to 21 days). EGFR testing showed mutation/ overexpression in approximately 25 % of cases (range 0 to 70 %. In a large national tertiary cancer center with inhouse laboratory that did testing by PCR and sequencing, EGFR mutations were seen in 30 % of 481 samples. The EGFR mutations considered clinically important included del 19 by 56, L858R by 41 and T790M by 31 of the responding oncologists. The first line therapy used in EGFR mutation positive Lung cancer patients was platinum doublet chemotherapy by 7, gefitinib by 55 and erlotinib by 8 oncologists. The side effects of TKIs considered important were diarrhea by 64, mucositis by 47, rash by all 70, paronychea by 50, nausea vomiting by 52, fatigue by 51 and myelosuppression by 6. The common methods of managing these side effects included dose reduction by 22, drug interruption by 50, symptomatic treatment by 49 and counseling by 22. Conclusions: The awareness about EGFR mutation and use of TKIs among medical oncologist is increasing in India. However availability of sufficient tissue for molecular testing remains a problem.