tbuckley/cabot-search huggingface dataset:
Mild traumatic brain injury is associated with increased levels of axonal injury biomarkers in blood
Authors: Pashtun Shahim, Kaj Blennow, Henrik Zetterberg, Yelverton Tegner
Journal: British Journal of Sports Medicine (2017)

Objective To investigate whether sports-related concussion is associated with elevated blood biomarkers reflecting axonal injury (total-tau [T-tau], [tau-A] and [tau-C]) and astroglial injury (S100B), as well as neurons-specific enolase (NSE). Design and setting A multicenter prospective cohort study involving all 12 teams of the top professional ice hockey league in Sweden. Participants A total of 288 players consented to participate in the study. Thirty-five players sustained concussions, of whom 28 underwent repeated blood samplings at 1, 12, 36, and 144 hours after the trauma, or when the player returned to play (7-&gt;90 days). Outcome measures Concentrations of T-tau was, tau-A, tau-C, S100B and NSE in blood. Results Players with sports-related concussion had increased levels of the axonal injury biomarker T-tau compared to preseason values. The highest biomarker concentrations of T-tau were measured immediately after a concussion and decreased during rehabilitation. There was no significant increase in the levels of tau-A in post-concussion samples compared with preseason values. However, serum levels of tau-C were significantly higher in post-concussion samples compared with preseason. The levels of the astroglial injury biomarker S100B were also increased in players with sports-related concussion compared to preseason values. No significant changes were measured in the levels of NSE. Conclusions Sports-related concussion in professional ice hockey players is associated with acute axonal and injury. Plasma T-tau may be used both in the diagnosis and clinical decision-making when an athlete is declared fit to return to play. Competing interests None.
Correction: AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy
Authors: Christina Ising, Gilbert Gallardo, Cheryl E.G. Leyns, Connie H. Wong, Hong Jiang, Floy Stewart, Lauren J. Koscal, Joseph Roh, Grace O. Robinson, Javier Remolina Serrano, David M. Holtzman
Journal: The Journal of Experimental Medicine (2017)
DIPG-10. MULTIMODAL IMMUNOTHERAPY AS PART OF MULTIMODAL TREATMENT FOR DIPG
Authors: Stefaan Van Gool, Maria Lulei, Volker Schirrmacher, Wilfried Stuecker
Journal: Neuro-Oncology (2017)

The prognosis of DIPG remains poor, and there are no chances for cure. The immune system might provide long-term tumor control via memory T cell activity against tumor antigens. Our concept consists of induction of intratumoral immunogenic cell death through infusion of Newcastle Disease Virus (NDV) together with local application of modulated electrohyperthermia (mEHT) and injections of autologous mature monocyte-derived dendritic cells (DCs) loaded with NDV/mEHT-induced serum-derived antigenic microparticles + NDV. Treatment is provided on individual basis. Data were retrospectively collected. 28 DIPG children with median age 6.9y (range 3-19y) were treated with immunotherapy, 18 of them as part of primary treatment (DIPGprim) and 10 at time of progressive disease after first line treatment (DIPGprog). 14/18 DIPGprim children had a Lansky score >70. At start of immunotherapy, 36% of patients had deficient IFN-g expression in the CD4+ T cells. Diminished NK function was observed in 64%. The treatment was feasible without major toxicity. We detected the increase of GBM antigen cross-reacting IFN-g-producing T cells in those patients that could be immunomonitored. Median PFS was 8.26m. Rescue after progression was mainly re-irradiation. Median OS is still undefined with a median follow up of 10.26m (range 4.3-19m). 18m OS is estimated as 55% (asymmetrical 95%CI: +27.39, -39.9). Median OS of the 10 DIPGprog children calculated from last event prior to immunotherapy was 5.55m. These clinical experiences support the concept that immunotherapy can be considered as part of multimodal treatment for patients with DIPG at an early stage of their disease. Its effect is primarily located at an improvement of long-term OS. This read-out, together with the individualized treatment approach, makes the scientific steps towards evidence-based efficacy demonstration very challenging.
Abstract 302: Four-and-a-half Lim Domain Protein-1 Upregulation via an Alternate Start Site Prepares the Left Atrium for Birth
Authors: Ilton M Cubero Salazar, Anna Axelsson, Hiroko Wakimoto, Daniel DeLaughter, Danos Christodoulou, Jianming Jiang, Michael Burke, Craig Benson, Joshua Gorham, Steve Depalma, Ju Chen, Srinivasan Mukundan, Michael Jerosch-Herold, Christine E Seidman, Jonathan G Seidman
Journal: Circulation Research (2015)

Four-and-a-half-LIM-domain protein-1 (FHL1) participates in the heart’s response to biomechanical stress during pathological states. Normally, the basal isoform, bFhl1 , predominates in non-stressed states. In pathology, a change in start site leads to expression of the induced isoform, iFhl1 , which is 16 amino acid residues longer than bFHL1. We have studied the expression and role of Fhl1 during normal cardiac development. The shift from fetal to neonatal circulation signifies new stress for the heart, and provides a unique opportunity to study the role FHL1 in the setting of physiological stress. We hypothesize that selective iFhl1 upregulation during this transitional period prepares the heart for the stress involved. Using 5’ RNA-seq, we demonstrate that iFhl1 was selectively upregulated by 10-fold in the left atrium by embryonic gestation day 17.5 (E17.5; p=2 x 10 -5 ) but remained unchanged in the other cardiac chambers (see B). The preferential increase in expression in the left atrium was confirmed with X-gal staining of Fhl1 Lacz mice hearts (see D, blue stain), and the selective expression of the induced isoform at the protein level was confirmed by Western blot (see C). Assessment of left atrial volume by magnetic resonance imaging in mice at 2 weeks of age showed that Fhl1-null mice have significantly larger left atria than wild-type littermates (0.63±0.10 μl vs. 0.45±0.04 μl, p=0.004). The demonstrated selective upregulation of iFhl1 prior to birth and the increase in left atrial volume that follows genetic ablation of Fhl1 suggests that Fhl1 is central in the heart’s ability to respond to physiological stress as represented by normal birth.
Corrigendum re: “Urinary Incontinence and Erectile Dysfunction After Robotic Versus Open Radical Prostatectomy: A Prospective, Controlled, Nonrandomised Trial” [Eur Urol 2015;68:216–25]
Authors: Eva Haglind, Stefan Carlsson, Johan Stranne, Anna Wallerstedt, Ulrica Wilderäng, Thordis Thorsteinsdottir, Mikael Lagerkvist, Jan-Erik Damber, Anders Bjartell, Jonas Hugosson, Peter Wiklund, Gunnar Steineck
Journal: European Urology (2017)
MEDU-21. TREATMENT OF PNETS WITH THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD RESULTS IN ANTITUMOR EFFECT
Authors: Marc Garcia-Moure, Naiara Martínez-Vélez, Marisol Gonzalez-Húarriz, Montserrat Puigdelloses, Ana Patiño-Garcia, Miguel Angel Idoate, Ricardo Díez-Valle, Sonia Tejada, Cande Gomez-Manzano, Juan Fueyo, Marta M Alonso
Journal: Neuro-Oncology (2017)

Primitive Neuroectodermal Tumors (PNETs) are very rare aggressive pediatric tumors characterized by the presence of poorly differentiated tumor cells. Despite formidable advances in targeted therapies and in the knowledge of the molecular make-up of these tumors, the development of curative therapies is still lagging. Therefore, the outcome for children affected with PNETs still remains dismal. Thus, it is critical to propel alternative therapeutic approaches to improve the survival and quality of life of these children. Delta-24-RGD is an oncolytic adenovirus engineered to have a tumor restricted replication and an expanded tropism to cancer cells. Altogether, these modifications result in a potent antitumor and lack of toxicity as shown by preclinical and clinical studies. In this work we describe the antitumor effect mediated by Delta-24-RGD in PNETs (PFSK-1 and SK-PN-DW cells), as well as a in a new unpublished cell line (PBT-25) that we have generated from a tumor biopsy. First, we demonstrated in vitro that Delta-24-RGD transduces efficiently PNET cells leading to an effective replication yielding high titers of new infectious particles when compared with other type of brain tumors such as glioma. Treatment with the virus in vitro resulted in an effective cell killing effect, obtaining IC50 values ranging from 7 to 18 MOIs. In vivo, Delta-24-RGD showed a safety profile since no signs of toxicity were observed upon its administration. Finally, the antitumor effect of Delta-24-RGD was assessed in vivo in two orthotopic models of sPNET. Delta-24-RGD treatment resulted in a significant increase in overall survival of the animals (19 and 21 days for PFSK-1 and SK-PN-DW, respectively) compared to vehicle treated animals (14 days) and led to long-term survivors free of disease. In vivo antitumor effect in PBT-25 is on-going. In summary, these results demonstrate the potential therapeutic benefit of Delta-24-RGD for the treatment of PNETs.
Abstract 190: Serum HDL-C Decreases in MicroRNA-33b Knock-in Mice for an Intron of Sterol Regulatory Element-binding Factor 1 (Srebf1)
Authors: Takahiro Horie, Tomohiro Nishino, Yasuhide Kuwabara, Osamu Baba, Takeshi Kimura, Koh Ono
Journal: Circulation Research (2015)

Background: MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33 (miR-33a) located within the intron of sterol regulatory element-binding factor (SREBF) 2 controls cholesterol homeostasis. Primates, but not rodents, express a second miR-33 gene (miR-33b) from an intron of SREBF1. To address miR-33b function in vivo, we developed humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron. Methods: The human miR-33b sequence was introduced into intron 16 of mouse Srebf1 because miR-33b is located in intron 16 of human SREBF1 and there are high homologies in exons 16 and 17 between human and mouse. The expression of serum miRNA was normalized with cel-miR-39 as a spike-in control. Results: We successfully established miR-33b knock-in (KI) mice with C57BL/6 background and this miR-33b KI strategy did not alter Srebf1 intron 16 splicing, which was confirmed by RT-PCR and sequencing. An LXR agonist T0901317, which induces Srebf1 expression, enhanced miR-33b expression in primary hepatocytes and the liver of miR-33 KI mice. The protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. Peritoneal macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Serum HDL-C levels were reduced by almost 35% in miR-33b KI mice. HPLC elution analysis showed that the decreased HDL-C levels were mainly composed of very large-, large-, medium sized HDL-C, which was compatible with the previous results of miR-33a deficient mice. Next, we measured miR-33b levels in serum of human. The expressions of miR-33b-3p were inversely correlated with serum HDL-C levels (P=0.025, R=0.336). Conclusions: miR-33b KI mice for an intron of Srebf1 showed reduced HDL-C level and serum miR-33b-3p levels were inversely correlated with HDL-C levels in human. These results indicate that miR-33b can be a potential target for raising HDL-C and may account for lower HDL-C levels in humans than those in mice. These mice will aid in elucidating the roles of miR-33s and screening of the drugs that can alter miR-33s levels and activities.
Eye movement and white matter integrity in patients with post-concussion syndrome
Authors: Foad Taghdiri, Samantha Irwin, Namita Multani, Apameh Tarazi, Ahmed Ebraheem, Jonathan Chung, Mozghan Khodadadi, Ruma Goswami, Richard Wennberg, Robin Green, Dave Mikulis, Charles Tator, Moshe Eizenman, Maria Carmela Tartaglia
Journal: British Journal of Sports Medicine (2017)

Objective To assess eye movements in patients with post-concussion syndrome (PCS) and use diffusion tensor imaging (DTI) to determine relationship between eye movements and white matter integrity. Design cross-sectional study. Intervention Attention and executive function were tested using Visual Attention Scanning Technology (VAST) [EL-MAR Inc., Toronto, Ontario, Canada]. In a matching task, the normalised number of transitions (NNT) to a master image before making the first selection was used as a surrogate of working memory. During this task, subjects view a set of slides, each slide includes a master image and six variants, and they have to select a variant that is similar to the master (only one variant is an exact replica of the master). Outcome measures We related performance on VAST to white matter integrity using Tract-Based Spatial Statistics of DTI metrics such as fractional anisotropy (FA) for whole brain analyses as well as seed-based probabilistic tractography analysis of the superior longitudinal fasciculus (SLF), Cingulum tract, and Uncinate fasciculus (UF). Main results 60 participants (mean age 34.3 years, SD 13.8) had a mean of 4 concussions. There were negative correlations between whole brain FA and NNT (r=−0.501, p&lt;0.001). In addition, when we performed probabilistic tractography analyses, we found a negative correlation between the FA of right SLF and NNT (r=−0.332, p=0.009). Conclusions Impaired performance on eye tracking measures of attention and executive function may reflect alterations in white matter tracts. Competing interests None. Moshe Eizenman is a director in EL-MAR Inc.
Treatment of <i>PIK3CA</i> and <i>APC</i> mutant colorectal cancers with dual PI3K/mTOR inhibition.
Authors: Foley Tyler, Susan Payne, Alexander Yeuh, Dana Van DeHey, Cheri Pasch, Linda Clipson, Kristina Matkowskyj, Dustin A. Deming
Journal: Journal of Clinical Oncology (2015)

e14632 Background: Colorectal cancer (CRC) remains a leading cause of mortality and morbidity, despite developments in the understanding of tumor biology. The diverse nature of these cancers calls for the development of therapeutic options aimed towards individual subtypes of CRC. Mutations in PIK3CA, which result in a constitutively active phosphoinositide-3-kinase protein (PI3K), are present in 20-30% of CRCs. Aberrations in the Adenomatous Polyposis Coli (APC) gene are found in 86% of PIK3CA mutant CRCs. While the mechanism of interaction between APC and PI3K has not been fully elucidated, the potential for treatment of tumors with this specific profile is of great interest. Methods: Mice expressing a constitutively active PI3K and loss of APC were generated and spheroid cultures were derived from the resulting cancers. PIK3CA and APC mutant spheroids were treated with NVP-BYL719 (BYL), a PI3K alpha inhibitor, or NVP-BEZ235 (BEZ), a dual mTOR/PI3K inhibitor. Proliferation was measured by changes in spheroid diameter over time. BEZ treatment of mice with PIK3CA and APC mutant CRCs was performed over 14 days. Tumor response was measured with serial murine colonoscopy and dual hybrid 18F-FDG PET/CT imaging. Results: BEZ treatment resulted in a reduction in size of PIK3CA and APC mutant CRC spheroids, whereas BYL did not. This correlated with significant suppression of phosphorylated AKT and phosphorylated RPS6 in BEZ-treated spheroids and incomplete PI3K pathway inhibition following BYL treatment. BEZ treatment was then investigated in mice with PIK3CA and APC mutant CRCs. BEZ elicited a dramatic treatment response in these cancers on endoscopy, with a 45% decrease in median lumen occlusion compared to a 70% increase in controls over the 14 day treatment period. BEZ resulted in inhibition of the PI3K pathway in these tumors. Reactivation of PI3K signaling was observed upon withdrawal of BEZ. BEZ was well tolerated and associated with a decrease in anemia compared to controls. Conclusions: These results identify PIK3CA and APC mutant CRCs as a targetable subtype. A significant treatment response was seen in this subtype with dual PI3K/mTOR inhibition. These results warrant further investigation in clinical studies.
Retrospective analysis of octagenarian breast cancer patients: Multicenter retrospective study.
Authors: Omer Dizdar, Cagatay Arslan, Tulay Eren, Selim Yalcin, Nadire Kucukoztas, Sercan Aksoy, Samed Rahatli, Didem Sener Dede, Ozden Altundag, Nurullah Zengin, Ozgur Ozyilkan, Mustafa Kadri Altundag
Journal: Journal of Clinical Oncology (2012)

e11011 Background: As life expectancy has steadily increased, more patients &gt;80 yo are diagnosed with breast cancer. Data on the tumor biology, treatment choices, and outcomes are limited in this “oldest old” patient population. We herein present a multicenter retrospective analysis of octogenarian breast cancer patients including patient and tumor characteristics, treatment outcomes and survival. Methods: Patients &gt;80 years of age who were diagnosed with breast cancer were retrospectively evaluated in 4 different cancer centers. Demographic features, tumor characteristics, treatment regimens and patient outcomes in terms of DFS and OS were analyzed. Results: A total of 83 patients were identified. Results were summarized in the table. Median age was 82. 69 (83%) had at least one co-morbid disease. Chemotherapy and radiotherapy were utilized in 15 (18%) and 21 (25%) of the patients, respectively, while endocrine treatment was given in 89% of the HR(+) patients. Median follow up was 22 months (range 1-181 months). Ten patients relapsed on follow up and 20 patients died. One of the relapses was locoregional and 9 were distant relapses. Median DFS was 68 months. Five-year OS was 61.9%. Conclusions: Breast cancer in octogenarian patients more likely seems to be low grade and hormone receptor positive. Adjuvant chemotherapy and radiotherapy were utilized infrequently. However, overall survival is fairly well with more than half of the patients alive for &gt;5 years. [Table: see text]
Risk of hematologic malignancies following radiation treatment for well-differentiated thyroid cancer in the United States over 37 years.
Authors: Surbhi Sidana, Xuefei Jia, Aaron Thomas Gerds, Betty Ky Hamilton, Ramon Velasquez Tiu, Yogen Saunthararajah, Jaroslaw P. Maciejewski, Frederic J. Reu, Hetty Carraway, Brian Thomas Hill, Mitchell Reed Smith, Matt E. Kalaycio, John H. Suh, Mikkael A. Sekeres, Sudipto Mukherjee
Journal: Journal of Clinical Oncology (2014)

6633 Background: Radiation therapy (XRT) including radioisotopes (RI), radioactive implants (RAI) and external beam radiation (EBRT) are commonly used for treatment of well differentiated thyroid malignancies (WDTMs) – papillary and follicular. We investigated the risk of all secondary hematologic malignancies (SHMs) in a population-based cohort of patients (pts) with WDTMs treated with XRT. Methods: Surveillance, Epidemiology, and End Results (SEER) 17 registries were queried to identify a cohort of 52,121 adult pts with WDTM as the first primary cancer between 1/1973 and 12/2010 who had adequate follow up. To determine the risk of development of SHM at least one year after the diagnosis of WDTM, pts who received XRT were compared to those who did not. SHMs included leukemias, lymphomas and Multiple Myeloma (MM). Fine and Gray competing risk regression analysis was performed with SHM as a time-dependent endpoint and death from any cause, development of non-hematologic malignancy as the competing events. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Results: The median age at WDTM diagnosis was 45 (range 18 - 100) years (yrs); most pts were Caucasian (82.4%); female (77%). 45% of patients were treated with XRT; of them 85% received RI or RAI, 4.9% received EBRT, 16.9% both and in 9.3% details were not specified. In total, 371 pts developed SHM after a median interval of 7.6 yrs (range 1- 37.2) from WDTM diagnosis: 178 pts developed lymphoma [Non-Hodgkin’s Lymphoma (n=163); Hodgkin’s Disease (n=15)]; 124 pts developed leukemia [Acute Myeloid Leukemia (n=44); Chronic Lymphocytic Leukemia (n=34); Chronic Myeloid Leukemia (n=23)] and 68 developed MM. In multivariate analysis, XRT was associated with an increased risk of developing SHM vs. no XRT (HR=1.27; CI, 1.01 – 1.60, p=0.038). Among the XRT modalities, RAI or RI were associated with 32% increased risk (HR=1.32; CI, 1.02 – 1.71, p=0.037) vs. no XRT. Age (HR=1.39, p<0.0001), male gender (HR=1.39, p=0.004) and papillary histology (HR=1.43, p=0.044) were additional risk factors. Conclusions: XRT increases the risk for developing SHM by 27% in pts with WDTM, which is mainly attributable to 32% increased risk with RAI/RI.
Pazopanib in advanced germ cell tumors after chemotherapy failure: results of the open-label, single-arm, phase 2 Pazotest trial
Authors: A. Necchi, S. Lo Vullo, P. Giannatempo, D. Raggi, G. Calareso, E. Togliardi, F. Crippa, M. Pennati, N. Zaffaroni, F. Perrone, A. Busico, M. Colecchia, N. Nicolai, L. Mariani, R. Salvioni
Journal: Annals of Oncology (2017)

Therapeutic options for patients with chemoresistant germ cell tumors (GCTs) are limited. Pazopanib is a selective tyrosine kinase inhibitor with distinct antiangiogenic activity. We aimed to evaluate pazopanib activity in patients with refractory GCT.In the open-label, single-arm, phase 2 Pazotest study (NCT01743482), patient eligibility included failure of ≥2 platinum-based regimens, and allowed prior high-dose chemotherapy administration. Patients were given pazopanib 800 mg/day until disease progression (PD) or onset of unacceptable toxicity. Measurements of serum tumor markers (STM), computed tomography and FDG-PET were carried out at baseline, after 4 weeks of pazopanib treatment, and every 8 weeks thereafter. PD was defined as increasing levels of STM, increasing size of non-teratomatous masses, or appearance of new lesions. The study primary endpoint was progression-free survival (PFS, H0: 3-month PFS ≤ 10%, H1: ≥25%, α = 5%, β = 20%).Forty-three patients were enrolled from May 2013 to July 2016. The number of prior chemotherapy regimens was: 2 (11.6%), 3 (51.2%), >3 (37.2%). Grade 3 adverse events were observed in six patients (13.9%). Overall, 70.3% of patients had reduced levels of STM after 4 weeks. There were 2 partial responses (4.7%), 19 cases of stable disease, and 16 cases of PD (6 not evaluable by RECIST). The median follow-up duration was 29.6 months. The 3-month PFS probability was 12.8% [95% confidence interval (CI): 5.7%-28.9%]. The 24-month OS probability was 14.2% (95% CI: 6.0%-33.7%). In patients with a >50% decline in STM, the 24-month OS probability was 24.1% (95% CI: 8.3%-69.6%). The small sample size was the major limitation.Despite pazopanib showed potent but short-lived activity in refractory GCT, long-term survival was obtained in a proportion of treated patients. According to the kinetics of pazopanib activity, this drug may be investigated in less pre-treated patients as an optimal bridging therapy preceding and/or combined with salvage chemotherapy.
Beware of Nocebo-Paternalism: Pitfalls of Tailored Nondisclosure
Authors: Bettina Schoene-Seifert
Journal: The American Journal of Bioethics (2017)

Nocebo effects in the context of clinical care have recently received increased attention, not the least in medical ethics (e.g., Wells and Kaptchuk 2012; Cohen 2014; Annoni and Miller 2016). In th...