tbuckley/cabot-search huggingface dataset:
Borderline resectable (BRPC) and locally advanced unresectable (LAPC) pancreas cancer treatment: A single Institution experience.
Authors: Walid Labib Shaib, James Qu, Chao Zhang, Andrew Ip, Zhengjia Chen, Bassel F. El-Rayes, Olatunji Alese
Journal: Journal of Clinical Oncology (2015)

e15260 Background: There is growing interest in preoperative combination chemotherapy (CC) regimens [Fluorouracil, Irinotecan, Oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel] in BRPC and LAPC treatment on the basis of their activity in metastatic pancreas cancer (PC). Progress in treating local PC is limited by inadequate systemic control and poor response rates. Our experience in BRPC and LAPC treatment is evaluated here. Methods: Retrospective clinicopathologic data was collected for local PC patients (pts) treated at Emory University between January 2009 and December 2013. Staging was based on the Alliance-A021101 criteria. Statistical analysis assessing progression free survival (PFS) and overall survival (OS) using univariate and multivariate analysis for local PC preoperative treatment with gemcitabine (Gem) compared to CC was evaluated. Results: Resectable PC (72), BRPC (89) and LAPC (42) pts were identified (N = 203). Median age was 67 (30–86), 50.7% males, 61.7% white (35.5% black) and 54 BRPC underwent resection (10 positive surgical margin and 34 lymph node positive). PFS was significantly different between resectable, BRPC, and LAPC (P= 0.0015). The median OS for resectable, BRPC, and LAPC was 22, 13, and 10 months (mos), respectively (P= 0.0006). There was a statistically significant OS difference between BRPC and LAPC (P= 0.028). Resected BRPC pts who received CC had a higher OS compared to Gem alone (26 vs. 15 mos; P= 0.11). There was no OS difference for LAPC treated with CC vs. Gem alone (14 vs 12 months; P= 0.43). Radiation (RT) did not have a significant OS difference (1-year survival: 73% for no RT vs. 67% RT, P= 0.51). No significant OS difference was observed for resected vs. non-resected BRPC (15 vs. 12 mos, P= 0.31); 1-year survival was 54.8% vs. 44.9%, respectively. In the multivariate analysis, and after adjusting for age, gender, and race, CC vs. Gem alone (HR: 3.01; 95% CI: 1.16-7.76, P= 0.023), and BRPC vs. LAPC (HR: 0.34; 95% CI: 0.15-0.81; P= 0.014) were independent predictors of OS. Conclusions: Surgery for BRPC did not have a significant impact on OS in our series. CC proved a significant trend in OS for local PC pts compared to Gem alone.
Abstract 12533: First Noninvasive Visualization of Sinoatrial Node Fibrosis via High-Resolution 3D Gadolinium Enhanced MRI of Intact Human Hearts
Authors: Thomas A Csepe, Jichao Zhao, Brian J Hansen, Ning Li, Yufeng Wang, Anna Bratasz, Kimerly A Powell, Robert D Higgins, Ahmet Kilic, Subha V Raman, Orlando P Simonetti, Peter J Mohler, Paul M Janssen, Vadim V Fedorov
Journal: Circulation (2015)

Introduction: The normal adult human sinoatrial node (SAN) structure consists of 35-55% fibrotic tissue, which provides mechanical and electrical protection for the primary pacemaker of the heart. The level of fibrosis and its spatial density can significantly increase in disease conditions, leading to SAN dysfunction. We hypothesize that gadolinium enhanced MRI (GE MRI) can be used to identify and locate 3D SAN structure in the human heart. Methods: Explanted human hearts (n=5, 19-65 y.o., 507±135 g) were coronary-perfused and the SAN was functionally identified with an intramural optical mapping approach. After mapping, the preparations were formalin fixed and incubated in 0.2% gadolinium based contrast agent to perform GE MRI (9.4T Bruker BioSpin Spectrometer) with a spatial resolution of 78-175μm3. The entire SAN pacemaker structure was then sectioned at 5μm thickness and stained with Masson’s trichrome. Results: Percent fibrosis vs total tissue area was measured from 2D GE MRI sections by applying a fibrosis enhancement mask, which was based on signal intensity threshold differences of connective and muscular tissue and validated with 2D histology sections from the same locations (Figure). GE MRI vs histology percent fibrosis measurements of SAN (60±6% vs 63±1%), CT (16±6% vs 18±4%), RAFW (13±6% vs 14±2%) and septum (29±22% vs 28±7%) were strongly correlated (r = 0.87, p &lt; 0.01). GE MRI allowed for the complete delineation of the 3D SAN structure (averaged SAN size 16.6±2.8 x 3.9±0.7 x 2.2±0.6 mm3) by distinguishing significant increased fibrosis in SAN compared to surrounding atrial tissue. Conclusions: Our integrative study for the first time demonstrated the application of GE MRI to resolve the intact 3D structure of the human SAN and estimate its fibrotic spatial density and distribution. Analysis of SAN fibrosis content with GE MRI supports further work to develop in vivo SAN fibrosis imaging in patients and help predict the need for pacemaker implantation.
CCL2 in the Circulation Predicts Long‐Term Progression of Interstitial Lung Disease in Patients With Early Systemic Sclerosis: Data From Two Independent Cohorts
Authors: Minghua Wu, Murray Baron, Claudia Pedroza, Gloria A. Salazar, Jun Ying, Julio Charles, Sandeep K. Agarwal, Marie Hudson, Janet Pope, Xiaodong Zhou, John D. Reveille, Marvin J. Fritzler, Maureen D. Mayes, Shervin Assassi
Journal: Arthritis & Rheumatology (2017)

Objective There are few clinical predictors of the progression of systemic sclerosis (SSc)–related interstitial lung disease (ILD). The purpose of this study was to examine the predictive significance of key cytokines for long‐term progression of ILD and survival in 2 independent cohorts of patients with early SSc. Methods Plasma levels of 11 Th1/Th2 cytokines (interleukin‐1β [IL‐1β], IL‐5, IL‐6, IL‐8, IL‐10, IL‐12, IL‐13, tumor necrosis factor, CCL2, interferon‐inducible T cell α chemoattractant, and interferon‐γ–inducible 10‐kd protein) were measured in 266 patients with early SSc in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) discovery cohort. Levels of CCL2, IL‐10, and IL‐6 were measured in 171 patients with early SSc in the Canadian Scleroderma Research Group (CSRG) replication cohort. The primary outcome measure was a decline in the forced vital capacity percent predicted (FVC%) value over time. A joint analysis of longitudinal FVC% values and survival was performed. Results After adjustment for age, sex, and ethnicity, CCL2 and IL‐10 were found to be significant predictors of ILD progression in the discovery cohort. Higher CCL2 levels predicted a faster decline in FVC% values (b = −0.57, P = 0.032), while higher IL‐10 levels predicted a slower decline (b = 0.26, P = 0.01). A higher CCL2 value was also predictive of poorer survival (hazard ratio 1.76, P = 0.030). In the CSRG replication cohort, higher CCL2 levels predicted a faster decline in FVC% values (b = −0.58, P = 0.038), but neither IL‐10 nor IL‐6 had predictive significance. A higher CCL2 level also predicted poorer survival (hazard ratio 3.89, P = 0.037). Conclusion Higher CCL2 levels in the circulation were predictive of ILD progression and poorer survival in patients with early SSc, findings that support the notion that CCL2 has a role as a biomarker and potential therapeutic target.
Management of Multifocal Lung Cancer: Results of a Survey
Authors: Konstantinos Leventakos, Tobias Peikert, David E. Midthun, Julian R. Molina, Shanda Blackmon, Francis C. Nichols, Yolanda I. Garces, Christopher L. Hallemeier, Stephen J. Murphy, George Vasmatzis, Sarah L. Kratz, William P. Holland, Charles F. Thomas, John J. Mullon, K. Robert Shen, Stephen D. Cassivi, Randolph S. Marks, Marie Christine Aubry, Alex A. Adjei, Ping Yang, Mark S. Allen, Eric S. Edell, Dennis Wigle, Aaron S. Mansfield
Journal: Journal of Thoracic Oncology (2017)
Possible Treatment Approach to an Extravasation of 177Lu-PSMA-617
Authors: Carl Diedrich Schlenkhoff, Markus Essler, Hojjat Ahmadzadehfar
Journal: Clinical Nuclear Medicine (2017)

A rare accident of a subcutaneous extravasation in the elbow with 4280 MBq Lu-PSMA-617 occurred in our clinic. We tried to reduce the damage by warming the elbow for 12 hours, then cooling it, and recommended the patient avoid exercises with the elbow for the next 3 days. We recognized a good resorption of the radionuclide in the scintigraphic imaging in the first 2 days. No pain, burning, or necrosis occurred. The administered therapy afterward showed an adequate decrease in the tumor marker level.
Efficacy of Stereotactic Conformal Radiotherapy vs Conventional Radiotherapy on Benign and Low-Grade Brain Tumors
Authors: Rakesh Jalali, Tejpal Gupta, Jayant S. Goda, Savita Goswami, Nalini Shah, Debnarayan Dutta, Uday Krishna, Jayita Deodhar, Padmavati Menon, Sadhna Kannan, Rajiv Sarin
Journal: JAMA Oncology (2017)

Evidence for application of stereotactic and other conformal radiotherapy techniques in treating brain tumors is largely based on data derived from dosimetric, retrospective, or small prospective studies. Therefore, we conducted a randomized clinical trial of stereotactic conformal radiotherapy (SCRT) compared with conventional radiotherapy (ConvRT) evaluating clinically meaningful end points.To compare neurocognitive and endocrine functional outcomes and survival at 5 years in young patients with residual and/or progressive benign or low-grade brain tumors treated with SCRT and ConvRT techniques.This phase 3 randomized clinical trial enrolled 200 young patients (ages 3-25 years) with residual or progressive benign or low-grade brain tumors at a single center between April 2001 to March 2012. Patients were randomly allocated (1:1) to either SCRT (n = 104) or ConvRT (n = 96) arms.Patients were randomly assigned to either high-precision SCRT or ConvRT to a dose of 54 Gy in 30 fractions over 6 weeks.Detailed neuropsychological and neuroendocrine assessments were performed at preradiotherapy baseline, at 6 months, and annually thereafter until 5 years on longitudinal follow-up. Change in these functional parameters was compared between the 2 arms as the primary end point and overall survival (OS) as the secondary end point.In total, 200 young patients (median [interquartile range] age, 13 [9-17] years; 133 males and 67 females) were enrolled. Mean full-scale or global intelligence quotient (IQ) and performance IQ scores over a period of 5 years were significantly superior in patients treated with SCRT compared with those treated with ConvRT (difference in slope = 1.48; P = .04 vs difference in slope = 1.64; P = .046, respectively). Cumulative incidence of developing new neuroendocrine dysfunction at 5 years was significantly lower in patients treated with SCRT compared with ConvRT (31% vs 51%; P = .01) while developing a new neuroendocrine axis dysfunction in patients with preexisting dysfunction in at least 1 axis at baseline was also significantly lower in the SCRT arm compared with the ConvRT arm (29% vs 52%; P = .02). Five-year OS in SCRT and ConvRT arms was 86% and 91%, respectively (P = .54).In young patients with residual and/or progressive benign or low-grade brain tumors requiring radiotherapy for long-term tumor control, SCRT compared with ConvRT achieves superior neurocognitive and neuroendocrine functional outcomes over 5 years without compromising survival.clinicaltrials.gov Identifier: NCT00517959.
Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients
Authors: Matthew Loxham, Donna E. Davies
Journal: Journal of Allergy and Clinical Immunology (2017)

The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.
Abstract 087: Reversal of Aging-Induced Contrast Changes of Cardiac SERCA 2a and Inducible Nitric Oxide Synthase in Mice Deficient in Beta3-Adrenoreceptor: Insights into the Molecular Mechanism of Cardiac Aging
Authors: Che Ping Cheng, Heng-Jie Cheng, Peng Zhou, Tian-Kai Li, Dalane W Kitzman, Stephen B Kritchevsky, William C Little
Journal: Circulation Research (2013)

Background: We have shown previously that aging-induced cardiac dysfunction and β-adrenergic desensitization were prevented in β 3 -adrenergic receptor (AR) knockout (β 3 KO) aged mice. However, the molecular mechanism is unclear. We hypothesize that reversal of aging-induced alterations of cardiomyocyte SR Ca 2+ -ATPase (SERCA 2a) and inducible nitric oxide (NO) synthase by β 3 -AR deficiency may play a key role for the protective effect. Methods: We compared SERCA 2a, iNOS, β 1 - and β 3 -AR protein expression, myocyte contractile, and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to isoproterenol (ISO, 10 -8 M) in cardiomyocytes obtained from 2 young (Y) (~6 mo) and 2 aged (A) (~26-30 mo) groups (5/group) of wild-type (WT) and β 3 KO mice, respectively. Results: Compared with YWT, AWT myocytes had significantly decreased protein levels of SERCA 2a (AWT: 0.22 vs YWT: 0.61) and β 1 -AR (0.34 vs 0.56), but increased iNOS (0.49 vs 0.24) and β 3 -AR (0.29 vs 0.14). These changes were associated with reduced basal cell contraction (dL/dt max ) (84.3 vs 124.8 μm/s), relaxation (dR/dt max ) (-66.1 vs -98.8 μm/s), and [Ca 2+ ] iT (0.19 vs 0.23). This was accompanied by diminished ISO-stimulated inotropic response. In AWT myocytes, ISO caused significantly less increases in dL/dt max (34% vs 82%), dR/dt max (22% vs 60%), and [Ca 2+ ] iT (15% vs 35%). Compared with YWT, Yβ 3 KO did not alter basal myocyte contraction and relaxation and response to ISO stimulation, but had significantly increased protein levels of SERCA 2a (Yβ 3 KO: 1.3 vs YWT: 0.61) and reduced iNOS (0.17 vs 0.24) with relatively unchanged β 1 -AR (0.63 vs 0.60). Aβ 3 KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ 3 KO myocytes, the increased SERCA 2a (1.1) and reduced iNOS (0.19) correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated inotropic response. ISO caused similar increases in dL/dt max (82% vs 84%) and [Ca 2+ ] iT (31% vs 33%) compared to Yβ 3 KO mice. Conclusions: β 3 -AR deficiency prevents aging-caused downregulation of cardiac β 1 -ARs and reverses increased iNOS and decreased SERCA 2a, leading to the preservation of myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve in aged hearts. Thus, blocking β 3 -AR may provide a new strategy for myocardial aging.
Dendritic cells conditioned by activin A–induced regulatory T cells exhibit enhanced tolerogenic properties and protect against experimental asthma
Authors: Maria Semitekolou, Ioannis Morianos, Aggelos Banos, Dimitris Konstantopoulos, Marina Adamou-Tzani, Tim Sparwasser, Georgina Xanthou
Journal: Journal of Allergy and Clinical Immunology (2017)
Identifying Cellular and Molecular Mechanisms for Magnetosensation
Authors: Benjamin L. Clites, Jonathan T. Pierce
Journal: Annual Review of Neuroscience (2017)

Diverse animals ranging from worms and insects to birds and turtles perform impressive journeys using the magnetic field of the earth as a cue. Although major cellular and molecular mechanisms for sensing mechanical and chemical cues have been elucidated over the past three decades, the mechanisms that animals use to sense magnetic fields remain largely mysterious. Here we survey progress on the search for magnetosensory neurons and magnetosensitive molecules important for animal behaviors. Emphasis is placed on magnetosensation in insects and birds, as well as on the magnetosensitive neuron pair AFD in the nematode Caenorhabditis elegans. We also review conventional criteria used to define animal magnetoreceptors and suggest how approaches used to identify receptors for other sensory modalities may be adapted for magnetoreceptors. Finally, we discuss prospects for underutilized and novel approaches to identify the elusive magnetoreceptors in animals.
Clonal Evolution Underlying the Progression from Myelodysplastic Syndromes to Ph-Positive Acute Lymphoblastic Leukemia
Authors: Masataka Taguchi, Tomoko Kohno, Hiroyuki Mishima, Hiroaki Taniguchi, Takeharu Kato, Hidehiro Itonaga, Shinya Sato, Akira Kinoshita, Tomoko Hata, Yukiyoshi Moriuchi, Koh-ichiro Yoshiura, Yasushi Miyazaki
Journal: Blood (2016)
Abstract 283: Chaer Lncrna Negatively Regulates Polycomb Repressive Complex 2 During Cardiac Hypertrophy
Authors: Zhihua Wang, Xinghua Wang, Iris Chen, Chen Gao, Tomohiro Yokota, He Wang, Shuxun Ren, Ashley Cass, Xinshu G Xiao, Guangping Li, Yibin Wang
Journal: Circulation Research (2015)

Long non-coding RNAs (lncRNAs) emerge to be critical regulators of cellular processes, but only a few out of thousands have been functionally characterized. We identified a novel heart-specific lncRNA, named cardiac hypertrophy associated epigenetics regulator (Chaer), which was both necessary and sufficient for hypertrophy of neonatal rat ventricular cardiomyocytes. RNA deep-sequencing revealed that Chaer contributed to the global transcriptome reprogramming during phenylephrine (50 μM)-induced hypertrophy, and regulated imprinted gene H19 expression independent of DNA methylation but dependent on histone tri-methylation at H3K27 (H3K27me3). RNA immunoprecipitation assay found that Chaer directly interacting with and negatively regulating PRC2 function on H3K27me3. Tagged RNA pull-dwon and RNA EMSA assays confirmed that Chaer directly bound to the catalytic subunit Ezh2 with a conserved 66-mer motif near its 5’ end in competition with and functionally interrupting other PRC2-binding lncRNAs. Interestingly, Chaer-PRC2 interaction was transiently enhanced at the onset of hypertrophy and responsible for hypertrophy fetal gene induction which was sensitive to Ezh2 inhibitor GSK126 (1 μM). Moreover, mTOR inhibitor rapamycin (20 nM) completely blocked the enhanced Chaer-PRC2 interaction, reversed the decrease of global H3K27me3, and abolished phenylephrine-induced expression of hypertrophy fetal genes. Finally, Chaer silence in vivo using chemically modified siRNA and nanoparticle transfection reagents significantly reversed the development of cardiac hypertrophy, pathological remodeling and H3K27m3-modification-mediated fetal gene induction under transaortic-constriction-induced pressure overload. The findings unveil Chaer as an epigenetic determinant of cardiac hypertrophy, and shed a light into the early molecular events under cardiac stress.
Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML
Authors: Akihide Yoshimi, Maria E. Balasis, Alexis Vedder, Kira Feldman, Yan Ma, Hailing Zhang, Stanley Chun-Wei Lee, Christopher Letson, Sandrine Niyongere, Sydney X. Lu, Markus Ball, Justin Taylor, Qing Zhang, Yulong Zhao, Salma Youssef, Young Rock Chung, Xiao Jing Zhang, Benjamin H. Durham, Wendy Yang, Alan F. List, Mignon L. Loh, Virginia Klimek, Michael F. Berger, Elliot Stieglitz, Eric Padron, Omar Abdel-Wahab
Journal: Blood (2017)
Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors
Authors: L. A. Howard, K. E. Bullock, J. C. Bendell, H. E. Uronis, G. Vlahovic, G. C. Blobe, R. F. Riedel, A. B. Nixon, J. P. Gockerman, H. I. Hurwitz
Journal: Journal of Clinical Oncology (2009)

3551 Background: In preclinical models, VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects as monotherapies and in combination. B inhibits VEGF; E inhibits mTOR; P inhibits EGFR. There is also potential for interaction between the pathways. Previously BE and BE + erlotinib were evaluated and showed signs of clinical activity. Methods: Patients (pts) with refractory advanced solid tumors were accrued in a phase I dose escalation of B + E + P on a 28d cycle. Dose levels are shown in the table below. DLT was defined as any treatment-related grade 4 heme, grade 3/4 non-heme adverse event (AE), or receiving &lt;85% any study drug in Cycle 1. Blood, skin, and tumor biopsies pre- and on-treatment were collected for correlative biomarkers of angiogenesis. Results: At this time, 12 pts (3M: 9F) are evaluable for toxicity; 9 for efficacy. Median age: 54 years (range 23–72). 9 of 12 pts had prior B exposure. Dose level 1 was expanded due to 1/3 DLT, with total of 3/6 DLT (Grade (Gr) 3 mucositis (n=2), Gr3 hypokalemia (n=1)). Dose level -1 had 3/3 DLT (Gr3, Gr4 mucositis (n=2), Gr3 non-acneform rash (n=1)). Dose level -2 had 0/3 pts DLT. Gr 3–4 related toxicities in cycle 2+: hypokalemia (n=4); hypophosphatemia (n = 1); hypomagnesemia (n = 1); diarrhea (n=1); hoarseness (n=1). Other events of interest were: Gr1–2 mucositis (n=7); Gr1 hyperlipidemia (n=5); Gr1–2 hyperglycemia (n=4); Gr2 hypertension (n=2); Gr1–2 neutropenia (n=5); Gr1–2 thrombocytopenia (n=5). 8/9 evaluable pts had SD as best response (median 26 wks, range 8+ to 32+ wks): 1 pt with pancreatic cancer and progression on 2 prior EGFR inhibitors had prolonged 32+ wk SD. There was 1 minor response (23.3%) in a pt with bevacizumab-refractory ovarian cancer (32+ wks). No CR or PR were seen. Conclusions: B + E + P at full doses has dose limiting toxicities of rash and mucositis. B 10 mg/kg q2wks + E 5 mg q48h + P 4.8 mg/kg q2wks is the maximum tolerated dose. This dose is currently being expanded in 20 patients with extensive pre- and on-treatment biomarker analyses. Updated clinical and biomarker data will be presented. [Table: see text] [Table: see text]