tbuckley/cabot-search huggingface dataset:
Burosumab Therapy in Children with X-Linked Hypophosphatemia
Authors: Thomas O Carpenter, Michael P Whyte, Erik A Imel, Annemieke M Boot, Wolfgang Högler, Agnès Linglart, Raja Padidela, William Van't Hoff, Meng Mao, Chao-Yin Chen, Alison Skrinar, Emil Kakkis, Javier San Martin, Anthony A Portale
Journal: New England Journal of Medicine (2018)

X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia.
Abstract B04: Activating K-RasA146T mutations induce Mapk-dependent hyperproliferation in the intestinal epithelium
Authors: Emily Poulin, Jessica Gierut, Kevin Haigis
Journal: Cancer Research (2018)

Abstract Ras is the most commonly mutated oncogene in human cancer, and is highly mutated in pancreatic, lung, and colorectal cancer. The most commonly reported canonical activating point mutations occur in codons 12, 13, and 61. Colorectal cancer, in particular, harbors a number of noncanonical K-Ras mutations, including mutations at codon 146, which occur in ~4% of patients. To understand the biologic effects of K-RasA146T expression in the intestinal epithelium and other tissues, we engineered a conditional Cre recombinase-dependent mutant allele (K-RasLSL-A146T), expressed from the endogenous KRas locus. We crossed K-RasLSL-A146T mice to Fabpl-Cre mice, which express Cre recombinase in the colonic and distal small intestinal epithelium, and compared the phenotype of Fabpl-Cre; K-RasLSL-A146T/+ mice to that of Fabpl-Cre; K-RasLSL-G12D/+ mice. Compared to K-RasG12D, expression of K-RasA146T results in a mild hyperplastic and hyperproliferative phenotype, while expression of K-RasG12D causes drastic hyperplasia and hyperproliferation. Additionally, we found that K-RasA146T expression activates Mapk signaling and that K-RasA146T-induced hyperproliferation is Mapk-dependent. Interestingly, unlike Fabpl-Cre; K-RasLSL-G12D mice, which lack Paneth cells in the small intestine, Fabpl-Cre; K-RasLSL-A146T/+ mice have intact Paneth cells. Finally, we found that although K-RasG12D expression in the pancreas causes neoplastic transformation, K-RasA146T expression has no detectable effect on pancreatic homeostasis, even after one year. Together, our results suggest that compared to the canonical K-RasG12D mutation, activating K-RasA146T mutations have a similar but milder effect on colonic homeostasis. Additionally, consistent with human data, we found that K-RasA146T mutations have tissue-specific effects on neoplastic transformation. Citation Format: Emily Poulin, Jessica Gierut, Kevin Haigis. Activating K-RasA146T mutations induce Mapk-dependent hyperproliferation in the intestinal epithelium [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B04.
Consumption of Sugars, Sugary Foods, and Sugary Beverages in Relation to Cancer Risk: A Systematic Review of Longitudinal Studies
Authors: Nour Makarem, Elisa V. Bandera, Joseph M. Nicholson, Niyati Parekh
Journal: Annual Review of Nutrition (2018)

High sugar intake may increase cancer risk by promoting insulin-glucose dysregulation, oxidative stress, inflammation, and body adiposity, but epidemiologic evidence is unclear. Associations between dietary sugars and lifestyle-related cancer risk from longitudinal studies were evaluated. We systematically searched PubMed, Embase, and CINAHL and identified 37 prospective cohort studies (1990-2017) reporting multivariable adjusted risk estimates for dietary sugars in relation to cancer. Of 15 and 14 studies on total sugar and sucrose respectively, 11 reported a null association in relation to cancer. Of 14 studies on fructose, 8 reported null associations, and 2 reported protective and 4 reported detrimental associations. In two of five studies on added sugars, a 60-95% increased cancer risk was observed with higher intakes. In 8 of 15 studies on sugary foods and beverages, a 23-200% higher cancer risk was observed with higher sugary beverage consumption. In conclusion, most studies were indicative of a null association, but suggestive detrimental associations were reported for added sugars and sugary beverages.
Anti-apoptotic Protein BIRC5 Maintains Survival of HIV-1-Infected CD4+ T Cells
Authors: Hsiao-Hsuan Kuo, Rushdy Ahmad, Guinevere Q. Lee, Ce Gao, Hsiao-Rong Chen, Zhengyu Ouyang, Matthew J. Szucs, Dhohyung Kim, Athe Tsibris, Tae-Wook Chun, Emilie Battivelli, Eric Verdin, Eric S. Rosenberg, Steven A. Carr, Xu G. Yu, Mathias Lichterfeld
Journal: Immunity (2018)
Response to: ’To DAPSA or not to DAPSA? That is not the question' by Schoels<i>et al</i>
Authors: Leonieke J J van Mens, Marleen G H van de Sande, Arno W R van Kuijk, Dominique L P Baeten, Laura C Coates
Journal: Annals of the Rheumatic Diseases (2018)

We thank the authors for the interest in our paper and are grateful for the opportunity to respond to the points raised.1 We agree that there is a clear distinction between composite measures of psoriatic arthritis such as disease activity in PsA (DAPSA) and composite measures of psoriatic disease such as minimal or very low disease activity (MDA/VLDA) and the PsA disease activity score (PASDAS). As the Vienna group rightly point out, these measures differ in terms of the components included, but not due to disagreement within the outcome measure community as suggested in the letter. The choice of components for each composite measure was decided using different methodology in the development of each one, thus resulting in different measures. We believe that this variation in scores is one reason for the need to compare such scores in different populations to establish the optimal measure or measures for psoriatic arthritis (PsA). Indeed when the DAPSA was originally suggested, it was because the same components used in the disease activity in reactive arthritis (DAREA) were identified in a principal component analysis (PCA) in PsA. Interestingly in this analysis, the variables tested were taken from the Outcome mesaures in Rheumatology (OMERACT) PsA domains and therefore DAPSA was not, a priori, designed specifically to be a unidimensional composite measure. The fourth component identified in the PCA was the psoriasis area and severity index (PASI) highlighting the importance of skin in PsA despite the fact that patients had a low baseline mean PASI of only 3.3. While PASI was not included in the DAPSA as the eigenvalue was 0.949 and therefore just under the threshold of 1,2 it is interesting to imagine how the results may have differed if …
Sirolimus Gel Treatment vs Placebo for Facial Angiofibromas in Patients With Tuberous Sclerosis Complex
Authors: Mari Wataya-Kaneda, Yuuki Ohno, Yasuyuki Fujita, Hiroo Yokozeki, Hironori Niizeki, Masaaki Ogai, Kazuyoshi Fukai, Hiroshi Nagai, Yuichi Yoshida, Izumi Hamada, Taihei Hio, Kenji Shimizu, Hiroyuki Murota
Journal: JAMA Dermatology (2018)

<h3>Importance</h3> Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment. <h3>Objective</h3> To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions. <h3>Design, Setting, and Patients</h3> Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC. <h3>Interventions</h3> Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks. <h3>Main Outcomes and Measures</h3> The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated." <h3>Results</h3> Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%;<i>P</i> = .01), 43% (95% CI, 26%-63%;<i>P</i> &lt; .001), and 60% (95% CI, 41%-77%;<i>P</i> &lt; .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment. <h3>Conclusions and Relevance</h3> Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02635789
Serum lipid levels are associated with allergic rhinitis, nasal symptoms, peripheral olfactory function, and nasal airway patency in children
Authors: D. K. Yon, S. W. Lee, E. K. Ha, K. S. Lee, Y.‐H. Jung, H. M. Jee, M. A. Kim, J.‐C. Ahn, Y. H. Sheen, M. Y. Han
Journal: Allergy (2018)
RISK-ADAPTED CRANIOSPINAL RADIOTHERAPY FOLLOWED BY HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL RESCUE IN CHILDREN WITH LARGE CELL/ANAPLASTIC MEDULLOBLASTOMA: RESULTS FROM ST. JUDE MEDULLOBLASTOMA 96 (SJMB96) AND ST. JUDE MEDULLOBLASTOMA 03 (SJMB03)
Authors: KD Wright, M Chintagumpala, T Hassall, David Ashley, E Bouffet, SJ Kellie, S Gururangan, R Cohn, M Fisher, A Broniscer, I Qaddoumi, EB Morris, G Armstrong, TE Merchant, AP Panandiker, DW Ellison, S Lesh, D Wallace, A Gajjar
Journal: Neuro-Oncology (2010)
Abstract A36: Characterizing the role of Egfr signaling in mediating the exacerbative effect of acute inflammation on tumor development in a mouse model for familial adenomatous polyposis
Authors: Wei Li, Yu-Ping Yang, Robert J. Coffey
Journal: Cancer Research (2018)

Abstract Over the past decade a number of inducible mouse models of intestinal tumor formation have been developed to study the genetic and cellular changes that contribute to colorectal cancer (CRC) development. Among them, the Lrig1-Cre/+;Apcfl/+ mice serve as a good model to study familial adenomatous polyposis (FAP), as the targeted elimination of one copy of the Apc gene in the Lrig1-expressing (Lrig1+) intestinal progenitor cells leads to loss of heterozygosity of the remaining wild-type Apc allele in the intestinal epithelium and eventually the formation of multiple histologically advanced adenomas in the distal colon. However, adenomas formed in the Lrig1-Cre/+;Apcfl/+ mice do not progress to adenocarcinomas. In order to develop a mouse model that recapitulates the process of CRC development in its entirety, we treated the Lrig1-Cre/+;Apcfl/+ mice with the proinflammatory reagent dextran sodium sulfate (DSS) and found that a single cycle of DSS right after tamoxifen-induced initial loss of one Apc allele significantly exacerbated tumor formation in the distal colon. Interestingly, DSS-treated Lrig1-Cre/+;Apcfl/+ mice also developed highly dysplastic tumors in the proximal colon, which is normally spared from tumor formation in the untreated Lrig1-Cre/+;Apcfl/+ mice. Using a newly developed chimeric Egfr protein reporter mouse, we are interrogating the roles of dysregulated epithelial and stromal Egfr signaling in promoting tumor development in the DSS-treated Lrig1-Cre/+;Apcfl/+;EgfrEmGFP/+ mice. Citation Format: Wei Li, Yu-Ping Yang, Robert J. Coffey, Jr. Characterizing the role of Egfr signaling in mediating the exacerbative effect of acute inflammation on tumor development in a mouse model for familial adenomatous polyposis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A36.
Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety
Authors: Nina Dedic, Claudia Kühne, Mira Jakovcevski, Jakob Hartmann, Andreas J. Genewsky, Karina S. Gomes, Elmira Anderzhanova, Max L. Pöhlmann, Simon Chang, Adam Kolarz, Annette M. Vogl, Julien Dine, Michael W. Metzger, Bianca Schmid, Rafael C. Almada, Kerry J. Ressler, Carsten T. Wotjak, Valery Grinevich, Alon Chen, Mathias V. Schmidt, Wolfgang Wurst, Damian Refojo, Jan M. Deussing
Journal: Nature Neuroscience (2018)
Infographic: Exercise to prevent falls in older adults
Authors: Bruno Paula Caraça Smirmaul, Anne Tiedemann, Catherine Sherrington
Journal: British Journal of Sports Medicine (2018)

![Figure][1]</img> 1. 1. 2. Sherrington C , 3. Michaleff ZA , 4. Fairhall N , et al . Exercise to prevent falls in older adults: an updated systematic review and meta-analysis. Br J Sports Med 2017;51:1750–8.[doi:10.1136/bjsports-2016-096547][2] [OpenUrl
Mineralocorticoid Receptor Antagonists in ST-Segment Elevation Myocardial Infarction
Authors: Bertram Pitt, Faiez Zannad
Journal: JAMA Internal Medicine (2018)

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Antiplatelet Therapy after Ischemic Stroke or TIA
Authors: James C. Grotta
Journal: New England Journal of Medicine (2018)

Antiplatelet therapy is the mainstay for the prevention of primary stroke in patients with risk factors and for the prevention of recurrent stroke after transient ischemic attack (TIA) or ischemic stroke. An outstanding question concerns appropriate antiplatelet regimens under various clinical scenarios. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, the results of which have now been published in the Journal,1 investigated antiplatelet regimens for the prevention of recurrent stroke in patients after TIA or minor stroke, with the latter being defined according to a National Institutes of Health Stroke Scale score of 3 or less . . .
International Task Force on Benzodiazepines
Authors: Richard Balon, Guy Chouinard, Fiammetta Cosci, Steven L. Dubovsky, Giovanni A. Fava, Rafael C. Freire, David J. Greenblatt, John H.  Krystal, Antonio E. Nardi, Karl Rickels, Thomas Roth, Carl Salzman, Richard Shader, Edward K. Silberman, Nicoletta Sonino, Vladan Starcevic, Steven J. Weintraub
Journal: Psychotherapy and Psychosomatics (2018)
Abstract 11993: Intracellular Renin Preserves Mitochondrial Function and Protects Cardiomyocytes From Ischemic Injury in Diabetic Heart
Authors: Daishi Nonaka, Hideki Katoh, Azumi Kumazawa, Masao Saotome, Tsuyoshi Urushida, Hiroshi Satoh, Hideharu Hayashi
Journal: Circulation (2013)

Purpose:  Cardiac myocytes express intracellular renin, which is different from circulating renin, and this type of renin increased after myocardial infarction. However, the role of intracellular renin is unknown. We investigated the distribution and expression of intracellular renin after ischemia and the effects of intracellular renin on ischemic cell injury in diabetic heart.   Methods:  In Goto-Kakizaki (DM) and Wistar (non-DM) rats, Langendorff-perfused heart was subjected to ischemia by coronary artery ligation for 90 min. Direct renin inhibitor, aliskiren (DRI; 1μM), and angiotensin II type 1 receptor antagonist, valsartan (ARB; 0.1μM), were perfused before ischemia. Infarct size (IS) and expression of RAS components (Western blot analysis (WB) and immunohistochemistry (IHC)) were examined. For the assessment of mitochondrial function, we measured expression of uncoupling protein-2 (UCP-2), NAD+/NADH ratio and ATP concentration. Mitochondrial membrane potential (ΔΨm) was measured in isolated mitochondria or myocytes.   Results:  (1) In DM, reduction of left ventricular developed pressure (LVDP) and elevation of end diastolic pressure (EDP) during ischemia were prevented, and IS was significantly smaller than non-DM (41% vs 54%, p≤0.05). (2) DRI but not ARB deteriorated cardiac function (LVDP and EDP) and increased IS in DM. (3) WB and IHC showed that renin expression in the ischemic area was significantly increased in DM. Angiotensin II was slightly increased in DM. The expression of (pro)renin receptor was not different between two groups. Electron microscope analysis showed that renin was predominantly localized within mitochondria. (4) Ischemia-induced UCP-2 expression was reduced in DM compared to non-DM. (5) Exposure of renin to permeabilized myocytes or isolated mitochondria hyperpolarized ΔΨm, and accelerated NAD+/NADH ratio in mitochondria and increased ATP concentration in myocytes. The effect of renin on ΔΨm was inhibited by DRI but not by ARB.   Conclusions:  During ischemia, expression of intracellular renin, which localizes within mitochondria, was induced in DM. Intracellular renin could afford protective effect against ischemic injury by preventing depolarization of ΔΨm and increasing ATP in diabetic heart.
Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes
Authors: Seh-Hoon Oh, Marzena Swiderska-Syn, Mark L. Jewell, Richard T. Premont, Anna Mae Diehl
Journal: Journal of Hepatology (2018)

Highlights•During liver regeneration, hepatocytes transiently proliferate despite active TGFβ signaling.•Regenerating hepatocytes reduce epithelial markers and increase mesenchymal markers.•Hepatocyte knockout of Yap1 reduces this transient epithelial-mesenchymal transition.•TGFβ and Yap1 cooperate to reprogram regenerating hepatocytes to a more primitive state.Graphical abstractAbstractBackground & AimsChronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFβ, since TGFβ signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis.MethodsWild-type mice underwent 70% partial hepatectomy (PH); TGFβ expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24–72 h after PH. To determine the role of Yap1 in regulating TGFβ signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice.ResultsTGFβ expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1α1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation.ConclusionInteractions between the TGFβ and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFβ-enriched microenvironment and regenerate injured livers.Lay summaryThe adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.
Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy
Authors: Lu Wang, Zibo Zhao, Patrick A. Ozark, Damiano Fantini, Stacy A. Marshall, Emily J. Rendleman, Kira A. Cozzolino, Nundia Louis, Xingyao He, Marc A. Morgan, Yoh-hei Takahashi, Clayton K. Collings, Edwin R. Smith, Panagiotis Ntziachristos, Jeffrey N. Savas, Lihua Zou, Rintaro Hashizume, Joshua J. Meeks, Ali Shilatifard
Journal: Nature Medicine (2018)
Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery
Authors: Ting Li, Hu-Lin Jiang, Yun-Guang Tong, Jin-Jian Lu
Journal: Journal of Hematology & Oncology (2018)

Heat shock protein 90 (Hsp90) is a critical molecular chaperone protein that regulates the folding, maturation, and stability of a wide variety of proteins. In recent years, the development of Hsp90-directed inhibitors has grown rapidly, and many of these inhibitors have entered clinical trials. In parallel, the functional dissection of the Hsp90 chaperone machinery has highlighted the activity disruption of Hsp90 co-chaperone as a potential target. With the roles of Hsp90 co-chaperones being elucidated, cell division cycle 37 (Cdc37), a ubiquitous co-chaperone of Hsp90 that directs the selective client proteins into the Hsp90 chaperone cycle, shows great promise. Moreover, the Hsp90-Cdc37-client interaction contributes to the regulation of cellular response and cellular growth and is more essential to tumor tissues than normal tissues. Herein, we discuss the current understanding of the clients of Hsp90-Cdc37, the interaction of Hsp90-Cdc37-client protein, and the therapeutic possibilities of targeting Hsp90-Cdc37-client protein interaction as a strategy to inhibit Hsp90 chaperone machinery to present new insights on alternative ways of inhibiting Hsp90 chaperone machinery.