tbuckley/cabot-search huggingface dataset:
P08.69 A lentiviral-based system for targeting the regulatory subunit R2A of protein kinase A in human glioblastoma
Authors: M. Zorzan, C. Del Vecchio
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM) is the most frequent and lethal primary brain tumor, associated with a median survival of 12-15 months after first diagnosis. The identification of new therapeutic approaches is required for the development of effective treatments. The cAMP-activated protein kinase (PKA) pathway is dysregulated in many pathological conditions, including cancer, and could potentially provide new therapeutic targets for GBM treatment. In rodent and human GBM cells the regulatory subunit R2A of PKA presents a specific localization on Golgi apparatus, that is not detectable in the healthy brain parenchyma. Moreover, downregulation of PKA R2A expression induces a reduction of GBM cell viability. In order to deeply investigate the effects of stable PKA R2A downregulation, a lentiviral-based system was developed for delivery of short hairpin RNA (shRNA) targeting PKA R2A gene to human GBM cells. The 3rd generation lentiviral vector cPPT.hCMV.EGFP was first tested for transduction of U87 human GBM cell line and primary GBM cell cultures. Then, recombinant lentiviral vectors were generated for expression of shRNA targeting PKA R2A gene. This lentiviral system represents an efficient strategy for shRNA delivery and downregulation of PKA R2A expression. Material and method: U87 human GBM cell line and primary GBM cell cultures were grown respectively as adherent cells in serum-supplemented medium and as spheres in serum-free medium. 293T cells were used for production and titration of lentiviral vectors. EGFP expression was monitored at epifluorescence microscope and western blot analysis was performed to evaluate R2A expression. Results and discussion: The lentiviral cPPT.hCMV.EGFP vector is able to efficiently transduce U87 cells and primary GBM spheres. Transduced U87 cells maintain the expression of the EGFP reporter gene for more than two weeks and no apparent influence on cell growth was observed. Expression of EGFP is detected from most, but not all, cells forming the transduced primary GBM spheres. Moreover, transduced primary GBM cells are able to form spheres and maintain the expression of the reporter gene after dissociation. Recombinant lentiviral cPPT.hCMV.EGFP-based vectors were generated for expression of shRNA.Temp1 or shRNA.Temp2, targeting different exons of PKA R2A gene, and for their co-expression with EGFP. Western blot analysis demonstrated an efficient reduction of R2A expression in cells transfected with the cis-elements of recombinant vectors and in cells transduced with the recombinant lentiviral particles. Conclusion: The 3rd generation lentiviral cPPT.hCMV.EGFP vector proved to efficiently transduce human GBM cells and primary GBM spheres. This lentiviral system allows efficient delivery of shRNA for downregulation of PKA R2A expression, thus representing a new strategy for targeting protein kinase A in human GBM cells.
Genomic and protein alterations in 126 triple-negative (TN) metaplastic breast cancers.
Authors: Sherri Z. Millis, Rebecca A. Feldman, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2014)

1029 Background: Metaplastic breast cancer (MpBC) is a rare subtype (less than 1% of all breast cancers), is generally ER, PR and HER2-negative (TN), demonstrates a claudin-low gene expression profile, and is poorly responsive to cytotoxic therapy. Little is known about the genomic alterations (GA) in MpBC nor about overexpressed proteins that may be amenable to targeted therapy. Methods: Of 2000 TN breast cancers (TNBC) referred to Caris Life Sciences since 2009 from 50 states and 59 countries, 126 cases were TN MpBCs based on local pathology evaluation. Specific testing was performed per physician request and included sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]), and/or gene amplification (CISH or FISH). Results: The Table shows the percent gene mutations, amplifications, and IHC findings for biomarkers that were different between TNBC and MpBCs, as a percentage of total patients tested. Conclusions: Comparison of the genomic and protein expression profiles highlights some differences between the two cancers.Multiplatform profiling shows that most MpBCs have gene alterations in the PI3K pathway. The low RRM1 expression rate suggests possible gemcitabine effectiveness. Other potential therapeutically targetable gene alterations are present at low incidence in this large series of MpBCs. Gene mutation ISH EGFR IHC Gene TP53 PIK3CA PTEN HRAS cMET cMET EGFR PTEN loss AR cMET RRM1 TOPO1 TNBC 60 14 3 0 0 0 22 31 17 13 34 70 Metaplastic 33 45 7 10 7 7 17 41 9 4 28 50
Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life
Authors: Daniel H. Leung, Sonya L. Heltshe, Drucy Borowitz, Daniel Gelfond, Margaret Kloster, James E. Heubi, Michael Stalvey, Bonnie W. Ramsey
Journal: JAMA Pediatrics (2017)

<h3>Importance</h3> Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described. <h3>Objective</h3> To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS. <h3>Design, Setting, and Participants</h3> The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation–accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up. <h3>Exposure</h3> Cystic fibrosis. <h3>Main Outcome and Measures</h3> Attained weight and length for age and World Health Organization normative<i>z</i>scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori). <h3>Results</h3> Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean<i>z</i>score, −0.15; 95% CI, −0.27 to −0.04) and higher birth lengths (mean<i>z</i>score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean<i>z</i>score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean<i>z</i>score, −0.56; 95% CI, −0.70 to −0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory<i>Pseudomonas aeruginosa</i>infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length<i>z</i>scores were negatively correlated with caloric intake. <h3>Conclusions and Relevance</h3> Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.
Cardiac Morphometry on Computed Tomography and Exacerbation Reduction with β-Blocker Therapy in Chronic Obstructive Pulmonary Disease
Authors: Surya P. Bhatt, Gonzalo Vegas-Sánchez-Ferrero, Farbod N. Rahaghi, Erick S. MacLean, German Gonzalez-Serrano, Carolyn E. Come, Gregory L. Kinney, John E. Hokanson, Matthew J. Budoff, Michael J. Cuttica, J. Michael Wells, Raúl San José Estépar, George R. Washko
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
TTI-281, an Orally Bioavailable Bromodomain and Extraterminal Domain (BET) Inhibitor, Is a Promising Candidate for the Treatment of Multiple Myeloma
Authors: Zezhou Wang, Jaehyun Choi, Peter Dove, Chunlei Wang, Aaron D. Schimmer, Penka S. Petrova, Robert A. Uger, Malik Slassi
Journal: Blood (2016)
Injuries impair the chance of successful performance by sportspeople: a systematic review
Authors: Michael K Drew, Ben P Raysmith, Paula C Charlton
Journal: British Journal of Sports Medicine (2017)

Cost-benefit analyses have been proposed for determining acceptable risk of injury regarding training and competition participation. Currently, there is no best evidence synthesis of the literature evaluating the relationship between injury/illness and chance of success or failure.To evaluate the relationship between injury and/or illness and success and/or failure in athletic populations (individual and team sports).This review was prospectively registered (PROSPERO CRD42016036729) and a systematic electronic search was conducted in May 2016. Inclusion criterion was any study design describing the association between injury and/or illness and success or failure in athletic performance. Two independent authors screened search results, performed data extraction and assessed methodological quality and strength of evidence using a modified Downs and Black appraisal tool and a modified van Tulder method, respectively.Of 10 546 titles identified, 14 satisfied the inclusion criteria and 7 had low risk of bias. Outcome measures associated with success and/or failure included: (1) availability of team members, (2) injury incidence, (3) injury burden, (4) squad utilisation and (5, 6) precompetition and in-competition injury. There was strong evidence that (1) increased availability of team members/athletes decreased the risk of failure and (2) precompetition and in-competition injuries were associated with increased risk of failure.Injuries have a detrimental impact on team and individual athletic success. Increased player availability improves chances of success. Conversely, injuries sustained both prior to and during competition may increase risk of failure. Injury prevention should therefore be a priority for maximising athletic performance.
The RET Receptor Tyrosine Kinase Promotes Acute Myeloid Leukemia through Protection of FLT3-ITD Mutants from Autophagic Degradation
Authors: Saskia Rudat, Anja Pfaus, Claudia Bühler, Sophie Rabe, Lars Bullinger, Stefan Gröschel, Stephen M. Sykes, Michael D. Milsom, Jana M. Ellegast, Stefan Fröhling, Claudia Scholl
Journal: Blood (2016)
Calcific Constrictive Pericarditis
Journal: Annals of Internal Medicine (2000)

Summaries for Patients21 March 2000Calcific Constrictive PericarditisSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-132-6-200003210-00029 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail What is the problem and what is known about it so far?Calcium deposits in the sac around the heart (pericardium) can sometimes be seen on x-rays. When these calcium deposits occur in patients with heart failure, they suggest a condition known as constrictive pericarditis. In this condition, stiff scar tissue in the pericardium squeezes the heart and prevents it from beating normally. Tuberculosis used to be a common cause of constrictive pericarditis; now, as tuberculosis has become less frequent in the United States, more common causes are previous heart operation, pericarditis, and radiation treatment.Why did the researchers do ... Author, Article, and Disclosure InformationThe summary below is from the full report titled “Calcific Constrictive Pericarditis: Is It Still with Us?” It is in the 21 March 2000 issue of Annals of Internal Medicine (volume 132, pages 444-450). The authors are L.H. Ling, J.K. Oh, J.F. Breen, H.V. Schaff, G.K. Danielson, D.W. Mahoney, J.B. Seward, and A.J. Tajik.Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoCalcific Constrictive Pericarditis: Is It Still with Us? Lieng H. Ling , Jae K. Oh , Jerome F. Breen , Hartzell V. Schaff , Gordon K. Danielson , Douglas W. Mahoney , James B. Seward , and A. Jamil Tajik Metrics Cited byConstrictive PericarditisCalcific constrictive pericarditis 21 March 2000Volume 132, Issue 6 Page: 444 Keywords Calcium Computed axial tomography Geographic areas Heart Heart failure Pericardium Scars Surgery Thorax ePublished: 15 August 2000 Issue Published: 21 March 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.Loading ...
Alitretinoin therapy for palmoplantar pustulosis
Authors: A.M.G. Brunasso, C. Massone
Journal: British Journal of Dermatology (2017)

We read with interest the RCT by Reich et al., and we found that the conclusion given: “this study provided no evidence to support further exploration of alitretinoin in the treatment of severe palmoplantar pustulosis (PPP)” should be carefully interpreted.1 The authors found no significant difference in the percentage change in PPPASI between the alitretinoin (45.2% ±32.8 of improvement) and placebo (44.6%, ±45.9), 95% CI rate difference -31% to 32%.1

This article is protected by copyright. All rights reserved.
P17.13 Dosimetric comparison and feasibility of simultaneous integrated boost (SIB) in treatment of malignant gliomas using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT)
Authors: P. Rapole, G. Karunanidhi
Journal: Neuro-Oncology (2017)

OBJECTIVE: Simultaneous integrated boost(SIB) is a hypo-fractionation technique wherein the tumor receives different doses to different areas in a single fraction. In our study, we have evaluated the dosimetric feasibility of SIB in the treatment of malignant gliomas and compared the SIB plans of VMAT and IMRT. METHODOLOGY: The patient's MRI (taken four weeks after surgery) and planning CT were used for generating SIB plans with VMAT and IMRT. GPTV is defined as the tumor edema in FLAIR plus a margin of 5 mm. CPTV is defined as the GPTV plus a margin of 2 cm. A dose of 2Gy per fraction was prescribed to the CPTV and 2.4Gy to the GPTV for a total of 25 fractions. The plans were accepted only if they met the set of planning objectives defined in the protocol. The feasibility of SIB planning was evaluated, and the dosimetric data of VMAT and IMRT for SIB planning was compared. Results: The GPTV coverage was significantly better in VMAT than in IMRT (98.67% vs 98.19%;p=0.024). The conformity index for GPTV in IMRT was higher than that of VMAT (0.83 vs 0.76; p=0.001). In contrast to what observed in GPTV, the percentage coverage of CPTV was better in IMRT (97.88% vs 96.87%; p=0.021). But the conformity index of CPTVannulus was higher in VMAT (0.72 vs 0.67; p=0.01). There was no difference in homogeneity index of GPTV and CPTV annulus between the plans. The mean dose received by Normal brain was higher in IMRT than in VMAT (28Gy vs 24.2Gy; p<0.001). Ipsilateral optic nerve has received lesser Dmax in IMRT (44.2Gy vs 46.95Gy; p=0.02). The Dmax of PRV brainstem was higher in VMAT (58Gy vs 57.3Gy; p=0.003). No difference was seen in Dmax of brainstem OAR, optic chiasm PRV and OAR, contralateral optic nerve, ipsilateral lens and cochleae. The treatment times and monitor units were significantly less in VMAT than in IMRT. CONCLUSION: SIB is dosimetrically feasible for hypofractionation in malignant gliomas using IMRT and VMAT. IMRT plans had better boost conformity, lower ipsilateral optic nerve and brainstem maximum doses compared to VMAT. Whereas, VMAT had better coverage, better overall PTV conformity, lower normal brain mean dose, lower monitor units and lesser treatment times. By giving dose constraints to the PRV rather than for OAR itself, the OAR doses can be further reduced while maintaining the PTV coverage. Although planning of VMAT is cumbersome and time consuming, the advantage of reducing treatment time is beneficial to the patients' comfort and better managing of patient load in high volume centers.
Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity
Authors: Pankaj Seth, Eva Csizmadia, Andreas Hedblom, Marta Vuerich, Han Xie, Mailin Li, Maria Serena Longhi, Barbara Wegiel
Journal: Cancer Research (2017)

Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis, diminished numbers of PD-L1+ cancer cells, increased numbers of CD3+ T cells, and activation status of CD8+ T cells. Furthermore, it was associated with more pronounced antitumor T-cell immunity via induction of IL17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expressions of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T-cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape. Cancer Res; 77(13); 3632-43. ©2017 AACR.
Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study
Authors: John R. Teerlink, Adriaan A. Voors, Piotr Ponikowski, Peter S. Pang, Barry H. Greenberg, Gerasimos Filippatos, G. Michael Felker, Beth A. Davison, Gad Cotter, Claudio Gimpelewicz, Leandro Boer‐Martins, Margaret Wernsing, Tsushung A. Hua, Thomas Severin, Marco Metra
Journal: European Journal of Heart Failure (2017)

Abstract Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.
P17.11 The fesibility of reirradiation using intensity modulated radiation in selected patients with recurrent gliomas
Authors: E. Nowicka, M. Gawkowska
Journal: Neuro-Oncology (2017)

BACKGROUND: Brain gliomas often recur after initial treatment and for high grade tumours recurrences are inevitable. While there is no standard treatment for recurrent gliomas, reirradiation is an option. The aim of this study is to determine the feasibility and early results of reirradiation in selected patients with recurrent gliomas. METHODS: Between 2011 and 2016, 26 adult patients with recurrent gliomas were reirradiated with IMRT at the time of tumor recurrence. There were 10 women and 16 men. The primary histological diagnosis included: low grade gliomas in 19 pts, high grade gliomas in 7 pts: oligostrocytoma anaplasticum in 2 pts, GBM WHO IV in 4 pts and ganglioglioma WHO III in 1 pt. Median age at primary diagnosis was 35y (range, 18,3-70,1 y).The median time between primary radiotherapy and reirradiation for the whole group was 60,3 months (range, 10,3 -178,6 months) and for LGG was 72,8 months (range, 10,3-178 months) and for HGG 31,6 months (range, 15,9-108 months). Primary radiotherapy was performed with 3DCRT in 11 pts and IMRT in 15 pts. Mean dose was 57Gy/g (range, 50-60 Gy/g). Tumour progression and/or transformation to HGG was confirmed in gadolinium-enhanced magnetic resonance imaging in all patients. 13 pts were re-operated and one re-biopsied. In nine pts HGG was confirmed. All tumours recurred in filed. In all but one pts IMRT technique of reirradiation was used. Mean dose for reirradiation was 38,2Gy/g (range, 12-45Gy/g). In 8 pts the stereotactic boost to recurrent tumor was used with mean dose of 12,7Gy (6-18 Gy) in one to three fractions. In 15 pts chemotherapy was administered with temozolomid concurrently or PCV/ CCNU after radiotherapy. Results: Median follow-up time from primary diagnosis was 85 months (range, 22-203 months) and 6,5 months (range, 0-54 months) from reirradiation. Median time to recurrence was 57,7 months (range, 6,4-170 months), for LGG- 69,8 months (range, 64-170 months) and HGG 28,2 months (range 9,0-102 months). All but one patient completed the planned course of radiotherapy. The response was assessed in MRI three months after completion of radiotherapy: twelve patients achieved complete or partial response, stable disease was observed in 8 patients and two patients progressed. While analysis four patients have just completed the irradiation. Median survival for LGG and HGG were: 86,2 months (range, 38- 203 months) and 40,5 months (range, 22-133 months) respectively. Median survival after reirradiation for whole group of pts was 6,5 months (range, 0,1-54,1 months). Median PFS was 4,8 months (range, 0,1-49,4 months). There were no difference in PFS and OS according to PS at reirradiation, gender, age, and primary histology. Conclusions: Reirradiation with IMRT is a feasible treatment options for recurrent gliomas and it may provide a benefit in disease control. Further follow up is essential especially with respect to toxicity of reirradiation.