tbuckley/cabot-search huggingface dataset:
Associations of calcium and vitamin D with E-cadherin and β-catenin expression in normal-appearing rectal tissue; markers of adenomatous polyps II (MAP II) case-control study
Authors: Ahearn Thomas, Chiranjeev Dash, Roberd Bostick
Journal: Cancer Research (2008)

565   Colorectal cancer is the second leading cause of cancer deaths in the United States. Despite advances in screening methods and treatments, mortality attributed to the disease has declined minimally over the last 30 years. There are no accepted biomarkers of risk for colorectal cancer even though the molecular basis of the disease is becoming clearer. E-cadherin, a calcium-dependent cell-cell adhesion transmembrane glycoprotein, is essential for maintaining cellular organization, morphology, and migration. β-catenin, an important component of the Wnt pathway that serves as a transcriptional coactivator of cellular proliferation, dimerizes with α-catenin which then binds to E-cadherin. There is mounting evidence for antiproliferative, pro-differentiating, and pro-apoptotic effects of calcium and vitamin D on the gastrointestinal epithelium. Calcium and vitamin D stimulate E-cadherin expression and β-catenin translocation from the nucleus to the cell membrane where it binds with E-cadherin. An influx of intracellular calcium has also been associated with triggering proteolytic cleaving of E-cadherin. In a colonoscopy-based, pilot case-control study of incident, sporadic colorectal adenoma (n = 49 cases, 154 controls) to investigate E-cadherin and β-catenin expression as possible biomarkers of risk for colorectal cancer, biopsies from normal-appearing rectal mucosa from a random selection of cases and controls (E-cadherin: 40 cases, 45 controls; β-catenin: 37 cases, 41 controls) were immunohistochemically processed for E-cadherin and β-catenin. E-cadherin and β-catenin expression was assessed by quantifying their staining intensities with a novel image analysis program. Plots of E-cadherin and β-catenin expression from the base of rectal crypts to the apex revealed nearly identical shapes and intensities for E-cadherin and β-catenin, suggesting a tight association between the two markers. Although mean overall expression of neither E-cadherin nor β-catenin differed significantly between cases and controls (0.5%, [p = 0.96], and 6.9% [p = 0.17], respectively), expression plots stratified by total calcium and vitamin D consumption suggested that expression of both β-catenin and E-cadherin (especially E-cadherin) in persons who were consuming high amounts of calcium and vitamin D were substantially different from those in persons who were consuming low amounts of both nutrients together or high amounts of only one nutrient or the other alone. These preliminary data suggest that E-cadherin and β-catenin expression may be modified by calcium and vitamin D intakes. Further investigation into the potential of E-cadherin and β-catenin as modifiable biomarkers of risk for colorectal cancer is warranted.
No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)
Authors: D.C. Muller, A.M. Hodge, A. Fanidi, D. Albanes, X.M. Mai, X.O. Shu, S.J. Weinstein, T.L. Larose, X. Zhang, J. Han, M.J. Stampfer, S.A. Smith-Warner, J. Ma, J.M. Gaziano, H.D. Sesso, V.L. Stevens, M.L. McCullough, T.M. Layne, R. Prentice, M. Pettinger, C.A. Thomson, W. Zheng, Y.T. Gao, N. Rothman, Y.B. Xiang, H. Cai, R. Wang, J.M. Yuan, W.P. Koh, L.M. Butler, Q. Cai, W.J. Blot, J. Wu, P.M. Ueland, Ø. Midttun, A. Langhammer, K. Hveem, M. Johansson, J. Hultdin, K. Grankvist, A.A. Arslan, L. Le Marchand, G. Severi, M. Johansson, P. Brennan
Journal: Annals of Oncology (2018)

There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3).
Abstract 14221: Angiogenic Adipokine Neuregulin 4 Ameliorates Obesity Associated With Adipocyte Dysfunction by Regulating Adipose Tissue Angiogenesis
Authors: Dhite B Nugroho, Koji Ikeda, Agian J Barinda, Donytra A Wardhana, Ken-Ichi Hirata, Noriaki Emoto
Journal: Circulation (2016)

Adipose tissue angiogenesis plays an important role in the maintenance of adipocyte function, impairment of which causes systemic metabolic disorders. Although adipocytes produce various angiogenic factors, the interactive communications between endothelial cells (EC) and mature adipocytes in the regulation of adipose tissue homeostasis remain to be elucidated. We searched for genes that is highly expressed in adipose tissue, and the expression of which is regulated by EC. Microarray analysis using RNAs prepared from mature adipocytes treated with EC conditioned medium revealed several genes with unknown functions; one of which encodes neuregulin 4 (Nrg4), a latest member of neuregulin family that belong to the EGF family proteins. Here, we demonstrate that Nrg4 is a paracrine-acting adipokine that regulates adipose tissue angiogenesis through a signaling crosstalk between EC and mature adipocytes. Nrg4 is highly and preferentially expressed in mature adipocytes, while its receptor is expressed in EC but not in adipocyte. Nrg4 enhanced endothelial angiogenic functions and angiogenesis but its expression in adipocytes was negatively regulated by EC and/or blood vessels, constituting a negative-feedback loop for adipose Nrg4. Genetic loss of Nrg4 caused overweight and impaired metabolic homeostasis even while consuming normal chow, whereas targeted activation of Nrg4 (aP2 Nrg4 Tg) in adipocytes enhanced insulin sensitivity and protected mice from obesity-related metabolic disorders. Mechanistically, Nrg4 modulated energy expenditure, adipose tissue inflammation and adipokine expression by regulating adipose tissue angiogenesis. These data provide new insights in the interactive communication between EC and mature adipocytes in the regulation of adipose tissue angiogenesis, and shed light on Nrg4 as a therapeutic target for the treatment of metabolic disorders associated with obesity.
Gavin Cranston Arneil
Authors: Alan Craft, Heather Maxwell
Journal: BMJ (2018)

Gavin Cranston Arneil, who has died aged 93, was a pioneer in the treatment of children with kidney disease. He established the first specialist children’s kidney unit in the UK and went on to found national, European, and international paediatric nephrology societies. In the 1950s there was little that could be done to help children who had kidney failure, and most kidney disease was untreatable. Today it is very rare for children to die from kidney failure, and transplantation is very successful leading to virtually normal lives.

Gavin Arneil was born in Glasgow. His father was a university senior lecturer and his mother an infant teacher. He was educated at Jordanhill College School and Glasgow University from 1940 to 1945, where he was a member of the Home Guard. He then did national service, including 18 months in charge of research at the War Office. He trained in paediatrics in Glasgow under the formidable James Hutchison. He was appointed as consultant to the city’s …
Tips for Analyzing Large Data Sets From the <i>JAMA Surgery</i> Statistical Editors
Authors: Amy H. Kaji, Alfred W. Rademaker, Terry Hyslop
Journal: JAMA Surgery (2018)

With the advent of administrative databases and patient registries, big data is increasingly accessible to researchers.The large sample size of these data sets make the study of rare outcomes easier and provide the potential to determine national estimates and regional variations.As such, the JAMA Surgery editors and reviewers have seen more submissions using big data to answer clinical and policy-related questions.However, no database is completely free of bias and measurement error.With bigger data, random signals may denote statistical significance, and precision may be incorrectly inferred because of narrow confidence intervals.While many principles apply to all studies, the importance of these methodological issues is amplified in large, complex data sets.
A ritual by any other name
Authors: Rohan Kapitány, Christopher Kavanagh
Journal: Behavioral and Brain Sciences (2018)

Abstract We question the privileged role of trance within the framework presented. The features that Singh suggests make it unique are not well demarcated from those of rituals more generally, and we challenge the depth of explanation presented for the mechanisms of trance. We outline the form of a solution, which may facilitate increased operational utility for the presented framework.
EA5, novel EphA2-targeted monoclonal antibody, inhibits growth and metastasis in human breast cancer xenografts
Authors: Kathy D. Miller, Yesim Gokmen-Polar, Kerry Sanders, Elizabeth Bruckheimer, Michael Kinch
Journal: Cancer Research (2005)

561   Rationale: Overexpression and altered function of EphA2 receptor tyrosine kinase are critical in the progression of breast cancer and may provide a novel target for breast cancer therapy. EA5, a novel monoclonal EphA2 antibody, mimics binding of the natural ligand and induces EphA2 phosphorylation and degradation. We have previously demonstrated that EA5 decreases breast cancer cell growth and restores tamoxifen sensitivity in EphA2-transfected MCF-7 cells  in vitro . In this study, we evaluated the  in vivo  anti-tumor efficacy of the EA5 antibody using both transfected MCF-7 EphA2  and naturally EphA2-overexpressing MDA-MB-231 xenografts in athymic mice. Methods: 1x10 6  MCF7 EphA2 or MDA-MB-231 cells were implanted into mammary fat pad (20 mice per group) of athymic mice treated with supplemental estrogen. The EphA2 antibody EA5 (2 mg/kg twice weekly to 14 mg/kg daily) or vehicle (PBS) control were administered as an intraperitoneal injection once tumors reached an average volume of 100 mm 3  (∼day 18 post-implantation). To determine the impact of EA5 on spontaneous metastases, MDA-MB-231 tumors were allowed to reach a volume of ∼500 mm 3 , then resected. Treatment with EA5, 2 mg/kg/d or PBS was initiated two days following resection. Lung metastases were assayed by Bouins solution after 6 weeks of therapy. Results: Daily administration provided superior control of primary tumor growth in both models. Maximum inhibition of the MCF-7 EphA2  xenografts was achieved at 2 mg/kg (67% inhibition, p≤ 0.05). In contrast, 7 mg/kg was required to provide maximal inhibition in the MDA-MB-231 xenografts (66% inhibition, p=0.05); increasing the dose to 14 mg/kg did not alter results. As predicted by our  in vitro  studies, EphA2 expression was decreased in EA5 treated tumors  in vivo  in both models. Additional analysis of resected tumors, including proliferation (Ki-67) and microvessel density (CD31) is ongoing. EA5 treated mice had fewer lung metastasis (mean 6 vs. 10.18; p=0.02). EA5 treated mice remained active and displayed no obvious toxicity or weight loss. Conclusion: Our results suggest that EA5 has inhibits primary tumor growth and metastasis of EphA2-overexpressing breast cancers.
Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial
Authors: Thierry André, Dewi Vernerey, Laurent Mineur, Jaafar Bennouna, Jérôme Desrame, Roger Faroux, Serge Fratte, Marine Hug de Larauze, Sophie Paget-Bailly, Benoist Chibaudel, Jeremie Bez, Jérôme Dauba, Christophe Louvet, Céline Lepere, Olivier Dupuis, Yves Becouarn, May Mabro, Joëlle Egreteau, Olivier Bouche, Gaël Deplanque, Marc Ychou, Marie Pierre Galais, François Ghiringhelli, Louis Marie Dourthe, Jean-Baptiste Bachet, Ahmed Khalil, Franck Bonnetain, Aimery de Gramont, Julien Taieb
Journal: Journal of Clinical Oncology (2018)

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.
Obstetrician who altered notes of patient who had stillbirth is struck off
Authors: Clare Dyer
Journal: BMJ (2018)

A specialty doctor in obstetrics and gynaecology who altered a patient’s notes to deflect blame after a stillbirth has been struck off by a medical practitioners tribunal.

Aamir Iqbal Malik’s retrospective alteration of the notes, to make it seem that he had told midwives to restart monitoring the fetal heartbeat sooner than he had, might have gone unnoticed had not one of the midwives photocopied the original, the tribunal heard.

Malik was not accused of causing the death of the fetus or any harm to the mother, a 23 year old woman in her first pregnancy who was admitted by ambulance to Pinderfields General Hospital, Wakefield, in December 2015. …
Safety of trifluridine/tipiracil (TAS-102) in combination with temozolomide for metastatic neuroendocrine tumors.
Authors: Nataliya Volodymyrivna Uboha, Dustin A. Deming, Sam Joseph Lubner, Daniel Mulkerin, Jens C. Eickhoff, Noelle K. LoConte
Journal: Journal of Clinical Oncology (2018)

TPS549 Background: Low and intermediate grade neuroendocrine tumors (NETs) are incurable once they metastasize. Cytoreductive surgery and locoregional therapies play an important role in their management, but ultimately most patients are treated with systemic therapies. In clinical studies, combination of temozolomide (TMZ) and capecitabine (CAP) demonstrated significant response rates (&gt; 50%) in patients with advanced pancreatic NETs. Trifluridine/tipiracil (FTD/TPI), also known as TAS-102, is a new anti-metabolite agent that is non-cross resistant with 5-fluorouracil (5-FU) and CAP and that has a different toxicity profile from CAP. In clinical trials, FTD/TPI has been associated with limited toxicities in patients with chemotherapy refractory (including 5-FU and CAP) metastatic colorectal cancer. Given that CAP has demonstrated activity in metastatic NETs, we hypothesize that FTD/TPI in combination with TMZ will be well tolerated and will be efficacious in metastatic NETs. Methods: This is a two-part investigator-initiated phase IB clinical trial (NCT02943733). Part 1 is a dose escalation portion of the study that will determine maximum tolerated doses of FTD/TPI administered in combination with TMZ in patients with advanced NETs. Patients with low and intermediate grade NETs of any origin are eligible for part 1. This part follows a classical “3+3” design to establish the phase 2 doses. Both drugs are oral agents that are administered on a 28 day cycle. FTD/TPI is taken twice a day on days 1-5 and days 8-12. TMZ is taken daily on days 8-12. This schedule was selected based on the pre-clinical data demonstrating schedule-dependent synergism between 5-FU and TMZ. Because of concern for overlapping bone marrow toxicities between the two agents, TMZ is started at the dose of 100 mg/m2 and escalated to a goal dose of 200mg/m2 daily if no dose limiting toxicities are observed. FTD/TPI is started at a goal dose of 35 mg/m2. Part 2 of the study will enroll estimated 15 patients with metastatic pancreatic NETs. Primary endpoint of part 2 is overall response rate, and secondary endpoints are progression free survival, disease control rate and overall survival. Part 1 of the trial is currently open to enrollment. Clinical trial information: NCT02943733.
Safety of Estradiol Treatment in Perimenopausal Asymptomatic Women—Reply
Authors: David R. Rubinow, Jennifer L. Gordon, Susan S. Girdler
Journal: JAMA Psychiatry (2018)

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Phase II study of copanlisib (BAY 80-6946) in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma.
Authors: Rutika Jitesh Mehta, Dae Won Kim, Heloisa P. Soares, Jongphil Kim, Richard D. Kim
Journal: Journal of Clinical Oncology (2018)

TPS525 Background: The current standard of treatment for cholangiocarcinoma (CCA) is gemcitabine and cisplatin that favored both overall survival (OS) and progression free survival (PFS) when compared to gemcitabine alone. The survival however remains less than than 1 year. Predominant activation of PI3K/AKT signaling pathway is seen in cell line and human tumors of CCA promoting tumorigenesis and increased resistance to radiation and chemotherapy. Inhibition of this pathway sensitizes CCA cells to therapies. Copanlisib is a selective and reversible pan-class I PI3K inhibitor. In preclinical studies, copanlisib demonstrated anti-tumor activity in PIK3CA mutated cells particularly in BC. In a Phase I study, 4 treatment naïve patients with CCA showed response, including 1 complete response. The maximum tolerated dose of copanlisib was determined to be 0.8 mg/kg in this study. We hypothesize that the addition of copanlisib to gemcitabine + cisplatin will enhance the efficacy of the current standard regimen in advanced CCA. Tumor tissue will be collected on every patient for PTEN immunohistochemical staining and NGS analysis using a 26-genes panel. Methods: This is a single institution phase II single arm two-stage design trial using copanlisib in combination with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients include those diagnosed with advanced, unresectable CCA that are treatment naïve or should have received adjuvant treatment more than 6 months prior to initiating the trial. Patients will be treated with Cisplatin (25 mg/m 2 ) plus Gemcitabine (1000 mg/m 2 ) and Copanlisib (60 mg) on days 1 and 8 on a 21 days cycle. Primary objective of the study is PFS at 6 months with secondary objectives being response rate, median PFS, OS, safety and tolerability. Accrual began on June 28, 2016, with planned enrollment for 25 patients. 14 eligible patients will be enrolled in the first stage. If 8 or more patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be enrolled in the second stage. 11 patients have been enrolled until now. After 3 cycles, response and progression will be evaluated using RECIST v1.1. Clinical trial information: NCT02631590.
Reply to: “May sarcopenia and/or hepatic encephalopathy improve the predictivity of model for end-stage liver disease?” and “Has the time come for using MELD-Sarcopenia score?”
Authors: Jeroen L.A. van Vugt, Louise J.M. Alferink, S. Buettner, Herold J. Metselaar, Jan N.M. IJzermans
Journal: Journal of Hepatology (2018)
Images in cardiovascular medicine. Detection of luminal-intimal border and coronary wall enhancement in intravascular ultrasound imaging after injection of microbubbles ans simultaneous sonication with transthoracic echocardiography
Authors: M Vavuranakis, Ia Kakadiaris, Sm O'malley, C Stafanadis, S Vaina, M Drakopoulou, I Mitropoulos, Stéphane Carlier, M Naghavi
Journal: Circulation (2005)
Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells
Authors: A. Le Moignic, V. Malard, T. Benvegnu, L. Lemiègre, M. Berchel, P.-A. Jaffrès, C. Baillou, M. Delost, R. Macedo, J. Rochefort, G. Lescaille, C. Pichon, F.M. Lemoine, P. Midoux, V. Mateo
Journal: Journal of Controlled Release (2018)