tbuckley/cabot-search huggingface dataset:
Induction of apoptosis and growth inhibition by cooperative effects of inhibitors for proteasome and fatty acid synthase in endocrine resistant breast cancer
Authors: Hong Liu, Binghui Li, Ruth Lupu
Journal: Cancer Research (2008)

1339   Endocrine resistance has been a great drawback of endocrine therapy in breast cancer. Designing treatments for endocrine resistance is one of the big challenges for breast cancer scientists and clinicians. Inhibition of the proteasome using proteasome inhibitors shows anti-tumor activity in a variety of malignancy, including breast cancer. Fatty Acid Synthase (FASN) is an important multifunctional metabolic complex synthesizing palmitate. Pharmacological inhibition of FASN activity as well as RNA interference of FASN gene expression result in apoptosis of cancer cells and elongate survival time of cancer xenograft animals. To develop a novel therapy for endocrine resistant breast cancer, we tested combinative antitumor action of blocking both proteasome and FASN. In this study, we determined the effects of MG132, a commonly used proteasome inhibitor for preclinical study, and C75 or cerulenin, FASN inhibitors, as single agents or in combination on cell viability/growth and cell death in endocrine sensitive MCF-7, acquired endocrine resistant MCF-7/F, and “de novo” endocrine resistant MDA-MB-231 cells. Our results show that treatment with MG132, C75 or cerulenin as single agents causes significant decrease in viability measured by MTT assays and increase in cell cycle arrest determined by propidium iodine staining in concentration-dependent manners in these cells. In addition, MG132 induces apparent apoptosis determined by Annexin V staining at higher concentrations in endocrine resistant MCF-7/F and MDA-MB-231 cells. C75 or cerulenin synergistically enhances the effect of MG132 on cell viability/growth measured by MTT in the three cell lines tested. However, C75 or cerulenin augments MG132-induced apoptosis more significantly in endocrine resistant MCF-7/F and MDA-MB-231 cells. These data indicate that inhibiting FASN potentiates antitumoric activity of proteasome inhibitors and that FASN blockers would potentially enhance the effectiveness of proteasome inhibitors in endocrine resistant breast cancer. Although the mechanism for the synergistic effects of MG132 and C75/cerulenin is yet unclear, our results suggest that combination therapy of blocking both proteasome and FASN could be an effective treatment for advanced endocrine resistant breast cancer.
Do Sugar-Sweetened Beverages Cause Obesity and Diabetes?
Authors: Joanne Slavin
Journal: Annals of Internal Medicine (2017)

Letters4 July 2017Do Sugar-Sweetened Beverages Cause Obesity and Diabetes?Joanne Slavin, PhD, RDJoanne Slavin, PhD, RDFrom University of Minnesota, St. Paul, Minnesota.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0189 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I was contacted by a reporter who wanted to know more about my sugar-sweetened beverage (SSB) "industry sponsorship/conflicts of interest" that were listed in the Supplement of Schillinger and colleagues' observation (1). I assume that observations are not peer-reviewed, because all the information listed for my work is incorrect.I served on the 2010 Dietary Guidelines Advisory Committee (DGAC) and was chair of the Carbohydrate Subcommittee. We were charged with updating the questions that the 2005 DGAC had reviewed. The DGAC uses an evidence-based review process to conduct original systematic scientific reviews, dietary data analyses, and food ...References1. Schillinger D, Tran J, Mangurian C, Kearns C. Do sugar-sweetened beverages cause obesity and diabetes? Industry and the manufacture of scientific controversy [Letter]. Ann Intern Med. 2016;165:895-7. [PMID: 27802504]. doi:10.7326/L16-0534 LinkGoogle Scholar2. Slavin J. Beverages and body weight: challenges in the evidence-based review process of the Carbohydrate Subcommittee from the 2010 Dietary Guidelines Advisory Committee. Nutr Rev. 2012;70 Suppl 2:S111-20. [PMID: 23121345] doi:10.1111/j.1753-4887.2012.00537.x CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From University of Minnesota, St. Paul, Minnesota.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0189. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoDo Sugar-Sweetened Beverages Cause Obesity and Diabetes? Industry and the Manufacture of Scientific Controversy Dean Schillinger , Jessica Tran , Christina Mangurian , and Cristin Kearns Do Sugar-Sweetened Beverages Cause Obesity and Diabetes? Maia M. Jack Do Sugar-Sweetened Beverages Cause Obesity and Diabetes? Dean Schillinger and Cristin Kearns Metrics Cited bySugar Beverage Habitation Relieves Chronic Stress-Induced Anxiety-like Behavior but Elicits Compulsive Eating Phenotype via vLSGAD2 NeuronsPublic Meets Private: Conversations Between Coca‐Cola and the CDC 4 July 2017Volume 167, Issue 1Page: 71-72KeywordsBeveragesBody weightConflicts of interestMetabolic processesNutritionObesityProteinsResearch fundingSystematic reviewsWeight gain ePublished: 4 July 2017 Issue Published: 4 July 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
A third of junior doctors say rota gaps have worsened their training, GMC finds
Authors: Abi Rimmer
Journal: BMJ (2017)

A third of junior doctors think that they have lost opportunities for learning because of gaps in rotas, a survey by the UK General Medical Council has found.1

On Tuesday 4 July the GMC published the initial findings from its 2017 national training survey. The survey received 53 335 responses from UK doctors in training (a 98% response rate) and was conducted between 21 March and 10 May 2017.

Responding to the survey, 32% of trainees disagreed or strongly disagreed with the statement, “In my current post, educational/training opportunities are rarely lost to gaps in the rota.”

The survey also received responses from 24 577 trainers (a …
ARTemis: A randomised trial of bevacizumab with neoadjuvant chemotherapy (NACT) for patients with HER2-negative early breast cancer—Primary endpoint, pathological complete response (pCR).
Authors: Helena Margaret Earl, Louise Hiller, Clare Blenkinsop, Louise Grybowicz, Anne-Laure Vallier, Jean Abraham, Jeremy Thomas, Elena Provenzano, Luke Hughes-Davies, Karen McAdam, Steve Chan, Rizvana Ahmad, Tamas Hickish, Stephen Houston, Daniel Rea, John M. S. Bartlett, Carlos Caldas, David A. Cameron, Janet Dunn, Richard L Hayward
Journal: Journal of Clinical Oncology (2014)

1014 Background: Bevacizumab (bev) has been used with NACT in breast cancer trials. Geparquinto reported benefit for bev in triple negative (neg) patients (pts) (pCR 36.4% v 27.8% p=0.02), as did CALGB 40603 (pCR 52% v 44%, p=0.057), although the NSABP-B40 study showed benefit in ER-positive (pos) pts (pCR 23.3% v 15.2%, p=0.008). Methods: ARTemis is a randomised phase 3 trial adding bev to NACT (docetaxel (D)-FEC). Pts with HER2-neg invasive breast cancer were eligible. Stratification was by age, ER status (neg: weak pos: strong pos), tumour size (T2:T3/4), clinical involvement of axillary nodes and inflammatory/locally advanced disease. Pts were randomised (1:1) to bev+D-FEC or D-FEC. The primary endpoint was pCR, defined as no residual invasive cancer in the breast or axillary lymph nodes after NACT. 800 pts were required to detect 10% differences in pCR rates, at the 5% (2-sided) level of significance with 85% power. Results: 800 pts were randomised from 66 UK centres (May’09 to Jan’13). 68% were <50 years old, 19% had inflammatory and/or locally advanced disease, 79% of tumours <50mm, 52% clinical node pos and 33% ER-neg. A 2-reader independent review of pathology reports was carried out. Significantly more pts on bev+D-FEC had a pCR (22% (18-27%) vs 17% (13-21%) with D-FEC; p=0.03 [adjusted for stratification factors]). pCR rates differed significantly across ER groups (neg 38%, weak pos 39%, strong pos 7%; p<0.0001). Treatment effect of bev remained significant after adjustment for ER (p=0.03). Conclusions: ARTemis showed a significant improvement in pCR with the addition of bev to D-FEC. ER-neg and ER-weak pos / HER2-neg breast cancer pts appeared to benefit most from bev, whilst pCR rates in ER-strong pos pts were lower and did not appear to show improvement from the addition of bev. Our results are similar to those reported in Geparquinto and CALGB 40603. Clinical trial information: 68502941. Factor D-FEC pCR (95% CI) bev+D-FEC pCR (95% CI) p* ER-neg (Allred 0-2) (n=253) 32% (24-41) 44% (36-54) 0.03 ER-weak pos (Allred 3-5) (n=67) 26% (13-44) 52% (34-69) ER-strong pos (Allred 6-8) (n=461) 7% (4-11) 6% (3-10) * p-value across treatment groups, after adjusting for ER.
Acute appendicitis
Authors: Daniel L H Baird, Constantinos Simillis, Christos Kontovounisios, Shahnawaz Rasheed, Paris P Tekkis
Journal: BMJ (2017)

Acute appendicitis is the most common abdominal surgical emergency in the world, with around 50 000 and 300 000 acute appendicectomies performed annually in the UK and in the US respectively. 1 2However, its incidence is falling for unknown reasons. 3 4 This clinical update provides information on how patients may present and what investigations and treatments are available. Who is affected?Acute appendicitis can affect people of any age but is most common between the ages of 10 and 20 years. 4 5It is more common in males, although females are twice as likely to undergo an appendicectomy. 6 7The lifetime risk of acute appendicitis is 8.6% in males and 6.9% in females; the lifetime appendicectomy rate is 12% in males and 23% in females. 6 7Perforation is found in 13-20% of patients with acute appendicitis. 8 9 What causes appendicitis?The aetiology remains uncertain, 7-10 but possible causes include luminal obstruction blocking the escape of mucosal secretions and leading to an increase in pressure, causing engorgement and stasis that can lead to necrosis and eventually perforation. 7 90][11][12] There is no known genetic cause of acute appendicitis, but increased risk has been observed in twin studies and in those with a positive family history. 13 14 How do patients present with acute appendicitis?0][21] The differential diagnoses are broadest in pre-menopausal women, as symptoms of acute appendicitis can be similar to the pain some women experience during normal menstruation, dysmenorrhoea, or ovulation and pathology such as ovarian torsion, ectopic pregnancy, and pelvic inflammatory disease. 15Diagnosis is harder if communication is limited-for example, where there is a language barrier or in patients who are very young, have dementia, a mental health diagnosis or a learning difficulty. 20In these patients, a collateral history of becoming withdrawn, less active, or having a reduced oral intake will raise the index of suspicion.
Psychosocial Problems of the Patients Suffering from Gastrointestinal Cancer
Authors: P Heras, A Hatzopoulos
Journal: Endoscopy (2006)

Aim: The gastrointestinal tract tumors are commonest in patients over 50 years of age. The patient suffering from gastrointestinal tract cancer is usually submitted to radical or palliative surgical procedure. Its symptoms are related to basic functions such as: nutrition, digestion and defecation. All of the above functions are disturbed in various degrees in the different stages of the disease. The patient suffering from cancer passes through different psychosocial stages that are distinguished from organic disturbances and cancer's psychology in a way difficult to be perceived. In our study we evaluate the quality of life of patients suffering from gastrointestinal tract tumor.
Vitrification using dimethyl sulfoxide free cryoprotectant as a cryopreservation method for fertility preservation of immature mouse testicular tissue.
Authors: Takeshi Shin, Mai Fukushima, Ryo Sato, Kojiro Nishio, Hiroshi Yagi, Gaku Arai, Shigehiro Soh, Hiroshi Okada
Journal: Journal of Clinical Oncology (2015)

e20672 Background: Loss of fertility is a major problem for childhood cancer survivors treated with gonadotoxic therapy. Cryopreservation of testicular tissue is a promising approach to preserve fertility for prepubertal boys, as sperm banking cannot be considered for these patients. Slow freezing (SF) and vitrification are cryopreservation techniques that were successfully applied in several animal models but need further exploration for clinical application. Methods: Fragments of imamature testicular tissue from 6-day-old mice were assigned to one of the following cryopreservation procedures: SF using dimethyl sulfoxide (DMSO) as cryoprotectants, SF using DMSO free cryoprotectant, vitrification using DMSO, vitrification using DMSO free cryoprotectant. Histological and immunohistochemical analyses were performed to evaluate cell viability, intratubular proliferation (Ki-67), apoptosis (caspase-3) after freezing and thawing. Thawed testicular tissue were cultured for in vitro production of mature sperm using previously described organ culture method. The fertility of induced spermatozoa was tested by intracytoplasmic sperm injection (ICSI). Results: Seminiferous tubules showed good integrity after cryopreservation and thawing in SF with DMSO group and vitrification with DMSO free cryoprotectant group. In these groups, cell viability and their ability to proliferate were observed by immunohistochemistry, and mature spermatozoa were induced after 35 days of organ culture. ICSI showed fertility of induced spermatozoa only in vitrification using DMSO free cryoprotectant group. Conclusions: An optimal cryopreservation protocol enhances the chances for successful fertility restoration.The findings of the present study have potential implications for cryobanking of immature testicular tissue and fertility preservation. Vitrification using DMSO free cryoprotectant would be a preferable cryopreservation method for later induction of functional spermatozoa.
Abstract P298: Probucol Inhibits Oxidized Low-Density Lipoprotein--Induced Immune Maturation of Dendritic Cells via Heme Oxygenase 1
Authors: Aijun Sun, Xueting Jin, Keqiang Wang, Yunzeng Zou, Junbo Ge
Journal: Circulation Research (2011)

The anti-atherosclerotic mechanism of Probucol remains to be elucidated. Studies confirmed the key role of Dendritic Cells (DCs) and cytoprotective role of heme oxygenase 1(HO1) in the development of atherosclerosis. Here, we tested the hypothesis that probucol exerts is anti-atherosclerotic effect by inhibiting maturation of DCs via HO1. [Method]Immature DCs were derived from purified human monocytes; HO1 siRNA, probucol ,ox-LDL or LDL was added to different groups of medium. The maturation markers of DCs were analyzed by Flow cytometric analysis, including CD1a, CD40, CD86, HLA-DR, endocytosis function and the cytokines secretions of culture supernatants (IL-4,TNF-α) by ELISA. The expression of HO1, STAT1 (signal transducers and activators of transcription 1) and STAT1(Tyr 701) phosphorylation were analyzed by Westernblot and the expression of CIITA(MHC II transactivator) by Real Time PCR. [Results] Ox-LDL promoted immune maturation of DCs : MIF of CD86,CD 40, CD1a and HLA-DR was significantly increased after ox-LDL stimulation (7697±672 vs 2120±662, 7844±754 vs 843±109 ,323±31 vs 272±14,2636±173 vs 1443±45,respectively); decreased endocytosis function (26256±354 vs 34511±3078); increased TNF-α(43±5 vs 30±0.3 pg/ml), suppressed IL-4 (852±9 vs 793±11 pg/ml)2. Probucol inhibited immune maturation of DCs ,which was most obviously in ox-LDL treated group : MIF of CD 86 CD 40, CD1a and HLA-DR was significantly decreased after probucol treatment (7697±672 vs 3202±660,7844±754 vs 843±109,323±31 vs 56±31, 2636±173 vs 304±60), endocytosis (26256±1689 vs 109568±4195), TNF-α(43±5 vs 14±0.6 pg/ml), IL-4(793±11 vs 1037±17 pg/ml) (P&lt;0.05). 3. After silencing of the expression of HO-1 by siRNA, immune maturation markers of DCs were increased than respective non-silencing group ,such as CD86, CD 40, HLA-DR (549±19 vs 353±23, 2645±307vs 524±119,1179±66 vs 766±23,respectivly), endocytosis function were suppressed (7408±229 vs 10860±706), TNF-αwas increased (22±0.2 vs 14±0.6 pg/ml), IL-4 was decreased (926±2 vs 1037±17 pg/ml) (P&lt;0.05), STAT1(701) phosphorylation and CIITA expression level were increased. [Conclusion]Probucol significantly inhibited immune maturation of DCs and is associated with HO1, STAT1/CIITA signaling pathway.
Metabolomics-based test accurately detects and differentiates adenomatous polyps from human sera
Authors: Kristi Kruusmaa, Paola Hurtado, Rosa Argamasilla, Ángela Peralbo Molina, Rosa Delgado Sánchez, Patricia Rodríguez, Antonio Adsuar, Marko Bitenc, Mireia Díaz, Lorena Moreno
Journal: Annals of Oncology (2017)
Abstract 21: Stiffness-Dependent Notch1 Activation Regulates Cardiogenic Differentiation of Cardiac Progenitor Cells
Authors: Archana V Boopathy, Khalid Salaita, Michael E Davis
Journal: Circulation Research (2012)

Cardiac progenitor cells (CPCs) are multipotent, self-renewing cells that can regenerate the myocardium and improve cardiac function in animal models of MI by cardiogenic differentiation. However, limited survival of stem/progenitor cells, myocardial scarring and fibrosis inhibit cardiac regeneration. Notch signaling promotes early cardiac development, cardiomyocyte survival and cardiac gene expression in circulating endothelial progenitor cells, mesenchymal stem cells and CPCs. As misregulation of Notch signaling during development is lethal due to cardiovascular defects, activating this critical pathway during cell transplantation could improve the efficacy of stem cell therapy. We investigated whether self-assembling peptide nanofiber hydrogels can be used to activate Notch1 signaling. The 16 amino acid self-assembling scaffold (RAD) was modified with a 20 amino acid peptide mimicking the active site of Notch1 ligand, Jagged1 (RJAG) or with the corresponding scrambled peptide (RSCR). To determine whether scaffold stiffness regulates Notch1 activation, CHO cells with Notch1 responsive YFP expression were cultured in scaffolds of 1-3% w/v in presence of RSCR or RJAG at a 1:10 ligand: scaffold ratio in 3D. Presence of the RJAG peptide (p&lt;0.01) and % concentration of the scaffold (p&lt;0.01) increased Notch1 activation significantly (n=5) indicating that RJAG mediated Notch1 activation in 3D is scaffold stiffness-dependent. Therefore, CPCs were cultured within 3D scaffolds (1-3% w/v; empty, scaffold +RJAG or RSCR) and cardiogenic gene expression was determined by qPCR. An increase in expression of early endothelial (Flk1, Flt1, vWF) and smooth muscle (sm22α, sm αactin) genes was observed in CPCs cultured in 3D scaffolds containing RJAG but not when cultured in 2D. These data show that Notch1 activation is dependent on ligand density and scaffold stiffness. Delivery of CPCs in JAG1 containing self-assembling scaffolds could be used to enhance therapeutic angiogenesis and improve cardiac function following myocardial infarction.
Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance
Authors: Noelia Martínez-Sánchez, Patricia Seoane-Collazo, Cristina Contreras, Luis Varela, Joan Villarroya, Eva Rial-Pensado, Xabier Buqué, Igor Aurrekoetxea, Teresa C. Delgado, Rafael Vázquez-Martínez, Ismael González-García, Juan Roa, Andrew J. Whittle, Beatriz Gomez-Santos, Vidya Velagapudi, Y.C. Loraine Tung, Donald A. Morgan, Peter J. Voshol, Pablo B. Martínez de Morentin, Tania López-González, Laura Liñares-Pose, Francisco Gonzalez, Krishna Chatterjee, Tomás Sobrino, Gema Medina-Gómez, Roger J. Davis, Núria Casals, Matej Orešič, Anthony P. Coll, Antonio Vidal-Puig, Jens Mittag, Manuel Tena-Sempere, María M. Malagón, Carlos Diéguez, María Luz Martínez-Chantar, Patricia Aspichueta, Kamal Rahmouni, Rubén Nogueiras, Guadalupe Sabio, Francesc Villarroya, Miguel López
Journal: Cell Metabolism (2017)

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.
American Heart Association Newly Elected Fellows, Spring 2008
Journal: Circulation (2008)

Fifty Premium Professional Members were elected Fellows and International Fellows of the American Heart Association (AHA) in spring 2008. Fellows are elected on the basis of their outstanding credentials, achievements, and community contributions to cardiovascular disease and stroke. Persons elected to fellowship are entitled to use FAHA, Fellow of the American Heart Association, as a professional designation. Fellows who reside outside the United States and Canada are designated International Fellows. For more information on the AHA Fellowship program, please visit our Web site at http://www.americanheart.org/presenter.jhtml?identifier=3033104

S. Helena Kuivaniemi, MD, PhD, FAHA 

Wayne State University School of Medicine

Detroit, Mich

Rene J. Alvarez, Jr, MD, FAHA 

University of Pittsburgh Medical Center

Wexford, Pa

Mark A. Fogel, MD, FAHA 

University of Pennsylvania School of Medicine

Philadelphia, Pa

Joel T. Hardin, MD, FAHA 

UMDNJ-New Jersey Medical …