tbuckley/cabot-search huggingface dataset:
Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia
Authors: Ihsan Ekin Demir, Elke Tieftrunk, Stephan Schorn, Ömer Cemil Saricaoglu, Paulo L Pfitzinger, Steffen Teller, Kun Wang, Christine Waldbaur, Magdalena U Kurkowski, Sonja Maria Wörmann, Victoria E Shaw, Timo Kehl, Melanie Laschinger, Eithne Costello, Hana Algül, Helmut Friess, Güralp O Ceyhan
Journal: Gut (2016)

<h3>Objective</h3> The impact of <i>glia</i> cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. <h3>Design</h3> Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras<sup>G12D</sup>/KC interbred with IL6<sup>−/−</sup> or sgp130<sup>tg</sup> mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. <h3>Results</h3> Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6<sup>−/−</sup> (32.06%±5.25% of PanINs) and KC;sgp130<sup>tg</sup> (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6<sup>−/−</sup> mice: 5.9±0.9; and KC;sgp130<sup>tg</sup>: 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. <h3>Conclusions</h3> Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC–central glia interplay during cancer progression.
Bahraini doctor detained for Tweets needs legal and medical support, says BMA
Authors: Clare Dyer
Journal: BMJ (2016)

A Bahraini ophthalmologist and activist who was detained in Bahrain after protesting on Twitter about Saudi Arabia’s execution of the prominent Saudi Shi’a cleric Sheikh Nimr al-Nimr must be granted access to legal and medical support, the BMA has urged.

Saeed al-Samahiji was arrested on 3 January at his home near the Bahraini capital, Manama, and is being held at the Dry Dock prison in Manama. Amnesty International said that he told his family he was being held for interrogation over his comments about the cleric’s execution and for …
A phase I safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with erlotinib in patients (pts) with advanced solid tumors.
Authors: C. Moldovan, J. Soria, P. LoRusso, T. Guthrie, C. Song, L. T. Nguyen, J. Martini, J. R. Infante, H. A. Burris
Journal: Journal of Clinical Oncology (2010)

3070 Background: The PI3K pathway is frequently dysregulated in cancer cells and has been implicated as a mechanism of resistance to EGFR inhibitors. In preclinical xenograft models, the oral, selective Class I PI3K inhibitor XL147 augments the anti-tumor efficacy of EGFR inhibitors including erlotinib (E). Methods: A standard 3 + 3 design was used with a maximum tolerated dose (MTD) cohort expansion in NSCLC pts. E is dosed qd, and XL147 is dosed qd on days 1-21 of each 28-day cycle. Dose limiting toxicities are determined using cycle 1 safety data. Tumor response is evaluated every 8 weeks. Results: 23 pts with diverse advanced solid tumors have been enrolled including 8 NSCLC and 5 CRC. Pts have been treated at 7 dose levels up to 600 mg XL147/150 mg E. The most frequently reported related AEs were rash (45%), nausea (30%), diarrhea, fatigue and vomiting (each 20%). One pt (status post pneumonectomy) treated with XL147 600 mg and E 150 mg had a treatment-related SAE of DRESS (drug rash with eosinophilia and systemic symptoms) syndrome and died from progressive disease and DRESS. No major PK interaction between XL147 and E was evident across cohorts based on comparison with single agent data. In tissue biopsies, robust inhibition of the PI3K and MAPK/EGFR signaling pathways was evident. For example, in serial tumor biopsies from a pt with an ethmoid tumor, maximum reductions in pAKT- T308 (61%), pERK (68%), and pEGFR (68%) were evident at day 43 post-dose, with a corresponding reduction in Ki67 (45%) and induction of apoptosis (2.6-fold). One EGFR inhibitor-naïve NSCLC pt had a confirmed PR (59% reduction in the sum of target lesions). One pt with adenoid cystic carcinoma had a decrease in FDG uptake by PET and a decrease in size of a lung nodule by CT. One pt with HNSCC (left maxillary alveolar ridge) had a decrease in FDG uptake by PET and a shrinkage of the primary tumor bulk by CT. Eight pts continued on treatment ≥ 16 weeks, including 5 pts on treatment ≥ 24 weeks. Conclusions: The combination of XL147 and E is generally well tolerated at doses up to 400 mg XL147/150 mg E with no major PK interaction and results in clinical activity and robust simultaneous inhibition of PI3K and EGFR signaling. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Exelixis Exelixis
Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles
Authors: Meghna Talekar, Malav Trivedi, Parin Shah, Qijun Ouyang, Adwait Oka, Srujan Gandham, Mansoor M Amiji
Journal: Molecular Therapy (2015)

Mutations in KRAS and p53 signaling pathways contribute to loss of responsiveness to current therapies and a decreased survival in lung cancer. In this study, we have investigated the delivery and transfection of wild-type (wt-) p53 and microRNA-125b (miR-125b) expressing plasmid DNA, in SK-LU-1 human lung adenocarcinoma cells as well as in KrasG12D/p53fl/fl (KP) genetically engineered mouse model of lung cancer. Systemic plasmid DNA delivery with dual CD44/EGFR-targeted hyaluronic acid (HA)-based nanoparticles (NPs) resulted in a 2- to 20-fold increase in wt-p53 and miR-125b gene expression in SK-LU-1 cells. This resulted in enhanced apoptotic activity as seen with increased APAF-1 and caspase-3 gene expression. Similarly, in vivo evaluations in KP mouse model indicated successful CD44/EGFR-targeted delivery. Tumor growth inhibition and apoptotic induction were also observed with (wt-p53+miR125b) combination therapy in KP tumor model. Lastly, J774.A1 murine macrophages co-cultured with transfected SK-LU-1 cells showed a 14- to 35-fold increase in the iNOS-Arg-1 ratio, supportive of previous results demonstrating a role of miR-125b in macrophage repolarization. Overall, these results show tremendous promise of wt-p53 and miR-125b gene therapy using dual CD44/EGFR-targeting HA NP vector for effective treatment of lung cancer. Mutations in KRAS and p53 signaling pathways contribute to loss of responsiveness to current therapies and a decreased survival in lung cancer. In this study, we have investigated the delivery and transfection of wild-type (wt-) p53 and microRNA-125b (miR-125b) expressing plasmid DNA, in SK-LU-1 human lung adenocarcinoma cells as well as in KrasG12D/p53fl/fl (KP) genetically engineered mouse model of lung cancer. Systemic plasmid DNA delivery with dual CD44/EGFR-targeted hyaluronic acid (HA)-based nanoparticles (NPs) resulted in a 2- to 20-fold increase in wt-p53 and miR-125b gene expression in SK-LU-1 cells. This resulted in enhanced apoptotic activity as seen with increased APAF-1 and caspase-3 gene expression. Similarly, in vivo evaluations in KP mouse model indicated successful CD44/EGFR-targeted delivery. Tumor growth inhibition and apoptotic induction were also observed with (wt-p53+miR125b) combination therapy in KP tumor model. Lastly, J774.A1 murine macrophages co-cultured with transfected SK-LU-1 cells showed a 14- to 35-fold increase in the iNOS-Arg-1 ratio, supportive of previous results demonstrating a role of miR-125b in macrophage repolarization. Overall, these results show tremendous promise of wt-p53 and miR-125b gene therapy using dual CD44/EGFR-targeting HA NP vector for effective treatment of lung cancer.
Expression of p21Cip1/Waf1/Sdi1 and p27Kip1Cyclin-Dependent Kinase Inhibitors During Human Hematopoiesis
Authors: Toshiyasu Taniguchi, Hisako Endo, Norio Chikatsu, Kaoru Uchimaru, Shigetaka Asano, Toshiro Fujita, Tatsutoshi Nakahata, Toru Motokura
Journal: Blood (1999)
Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients
Authors: Sarah Berhane, Hidenori Toyoda, Toshifumi Tada, Takashi Kumada, Chiaki Kagebayashi, Shinji Satomura, Nora Schweitzer, Arndt Vogel, Michael P. Manns, Julia Benckert, Thomas Berg, Maria Ebker, Jan Best, Alexander Dechêne, Guido Gerken, Joerg F. Schlaak, Arndt Weinmann, Marcus A. Wörns, Peter Galle, Winnie Yeo, Frankie Mo, Stephen L. Chan, Helen Reeves, Trevor Cox, Philip Johnson
Journal: Clinical Gastroenterology and Hepatology (2016)
Miniautologous transplantation of lymphokine-activated killers (LAK) in cytokine-pretreated patients with metastatic renal cell carcinoma (RCC): A Slovak phase II study
Authors: J. Mardiak, J. Lakota, Z. Sycova-Mila, J. Obertova, M. Reckova, M. Mego, M. Ladicka, T. Salek, K. Brozmanova, Z. Risnyovszka, I. Koza
Journal: Journal of Clinical Oncology (2006)

14593 Background: Prognosis of patients with metastatic renal carcinoma remains poor. We evaluated the efficacy and toxicity of miniautologous transplantation of LAK in cytokine pretreated patients (pts) with metastatic RCC. Methods: Between May 1998 and July 2005, 29 pts (23M/6F) with metastatic RCC were included. All patients were pretreated with cytokine-based therapy (9 pts with interferon alfa, 9 pts with interferon alfa+5FU+IL-2, 10 pts with interferon alfa+5-FU and 1 patient with IL-2). Median age was 58 years (range 49–71). Patients were assigned into three prognostic groups according to MSKCC prognostic criteria for 2nd line treatment (Motzer et al., 2004). Six, seventeen and six pts had 0, 1 and 2–3 risk factors, respectively. Median number of metastatic sites was 2 (range 1–6). 9 pts had liver, 12 bone and 2 patients had cerebral metastases. Median time from cytokine treatment to LAK therapy was 9 months (range 0–41). Periferal blood stem cells (PBSC) were isolated. Part of the PBSC was used to isolate mononuclear cells (MNC). The MNC were incubated in the presence of IL-1, IL-3, IL-6, GM-CSF and SCF. After the conditioning regimen with cyclophosphamide (2g/m 2 ), the PBSC and MNC were pooled and reinfused. Results: Minor response was achieved in 2 pts (7%), 95% CI (0–16%). Overall survival was 8.0 months (5.0–9.8). Median survival 10.0, 8.0 and 9.7 months was achieved in patient’s group with 0, 1 and 2–3 MSKCC risk factors, respectively. Treatment was well tolerated. Four pts (14%) experienced febrile neutropenia after the conditioning regimen. There was no Grade 3–4 non-hematological toxicity and no treatment related death. Conclusions: Despite good tolerability and feasibile administration, the results of our trial do not warrant further study of herein presented experimental treatment. However, new treatment aproaches are needed. No significant financial relationships to disclose.
Tinzaparin vs Warfarin for Acute Venous Thromboembolism
Authors: Anna Maruyama, Aaron M. Tejani, Thomas L. Perry
Journal: JAMA (2016)

To the Editor Primary results from the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) trial1 were reported as negative, but the authors found an association between tinzaparin use compared with warfarin and reduction in the secondary outcome of clinically relevant nonmajor bleeding. Analysis of serious adverse events and mortality from this trial leads us to question the authors’ overall conclusions.
Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms
Authors: Paul G. Kluetz, Ashley Slagle, Elektra J. Papadopoulos, Laura Lee Johnson, Martha Donoghue, Virginia E. Kwitkowski, Wen-Hung Chen, Rajeshwari Sridhara, Ann T. Farrell, Patricia Keegan, Geoffrey Kim, Richard Pazdur
Journal: Clinical Cancer Research (2016)

Abstract Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient-reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials. Clin Cancer Res; 22(7); 1553–8. ©2016 AACR.
P220 Using funnel plots to make meaningful centre comparisons
Authors: L Pierotti, MA Mohammed, M Wildman, D Bilton, J Boote, SB Carr, K Collins, P Cullinan, C Elston, S Harrison, P Norman, SJ MacNeill
Journal: Thorax (2015)

<h3>Objectives</h3> The UK CF Registry annual reports include comparisons between centres on key outcomes such as FEV1 using rankings. While illustrating the distribution between centres, they promote the assumption that those with the highest measures provide “better” care. We hypothesised a more scientific approach based on statistical “process control” using funnel plots and adjustment for case-mix may help to identify exceptional CF care services in terms of clinically meaningful outcomes. <h3>Methods</h3> We extracted data from annual reviews (2007–2012) on the CF Registry. Our outcomes included FEV1 (% predicted) at 15 years and change in FEV1 between 18 and 21 years. Funnel plots were generated with confidence limits at 2 and 3 standard deviations (SD). Centres with mean values outside these limits are said to display “special cause variation” -variability outside what one would expect. Outcomes were then adjusted for case mix (including gender, genotype, pancreatic sufficiency and socio-economic deprivation) and analysed using funnel plots. <h3>Results</h3> 31 paediatric centres provided FEV1 data on 15 year olds between 2007 and 2012. Funnel plots of unadjusted FEV1 (% predicted) showed few centres with evidence of special cause variation (2SD limits). Initial case-mix adjustment reduced the number of centres outside these limits to 3. We also identified 28 adult centres providing sufficient data to calculate change in FEV1 (% predicted) between 18–21 years. While there was some evidence of special cause variation (at 2SD limits) in prior to case-mix adjustment, after adjustment none were outside the 2SD limits. None of the centres were outside the 3SD limits in either analysis. <h3>Conclusion</h3> In conclusion the work to-date illustrates that funnel plots can be used to explore potential differences in FEV<sub>1</sub> between specialist centres. Case-mix adjustment models should develop into a useful tool for making centre comparisons which can continue to be used by stakeholders. This is early work, however, and we need to bear in mind that by examining outcomes in small populations risk missing true differences due to low statistical power. Further work is required to assess whether any observed differences are due to chance or are related to the care patients receive.
267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation
Authors: Joaquín Dopazo, Alicia Amadoz, Marta Bleda, Luz Garcia-Alonso, Alejandro Alemán, Francisco García-García, Juan A. Rodriguez, Josephine T. Daub, Gerard Muntané, Antonio Rueda, Alicia Vela-Boza, Francisco J. López-Domingo, Javier P. Florido, Pablo Arce, Macarena Ruiz-Ferrer, Cristina Méndez-Vidal, Todd E. Arnold, Olivia Spleiss, Miguel Alvarez-Tejado, Arcadi Navarro, Shomi S. Bhattacharya, Salud Borrego, Javier Santoyo-López, Guillermo Antiñolo
Journal: Molecular Biology and Evolution (2016)

Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ∼10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms.
Von Hippel-Lindau disease: an evaluation of natural history and functional disability
Authors: Alberto Feletti, Mariagiulia Anglani, Bruno Scarpa, Francesca Schiavi, Francesca Boaretto, Stefania Zovato, Elisa Taschin, Mario Gardi, Elisabetta Zanoletti, Stefano Piermarocchi, Alessandra Murgia, Giacomo Pavesi, Giuseppe Opocher
Journal: Neuro-Oncology (2016)

Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities. We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients' quality of life, thereby tailoring the follow-up schedule accordingly. We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ-specific disabilities caused by VHL disease. Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities. Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function.
Homodimerization of Erythropoietin Receptor by a Bivalent Monoclonal Antibody Triggers Cell Proliferation and Differentiation of Erythroid Precursors
Authors: Helmut Schneider, Warak Chaovapong, David J. Matthews, Cyrus Karkaria, Robert T. Cass, Hangjun Zhan, Mark Boyle, Tony Lorenzini, Steve G. Elliott, Lutz B. Giebel
Journal: Blood (1997)
The Effect of Prolonged X-Radiation on the Congo Red Index of Rabbits
Authors: Cornelia Hoch-Ligeti
Journal: Cancer Research (1941)

SUMMARY Treatment with x-rays continued for i year induced fluctuations in the Congo red index of the rabbit which range between those of normal rabbits and those seen in rabbits treated with carcinogenic hydrocarbons. Five out of 6 rabbits showed changes in the circu- lating removal factor resembling those seen in ani- mals treated with carcinogenic hydrocarbons, while in I rabbit the removal factor retained normal positive character. I am much indebted to Dr. J. Iball anti to Dr. E. M. F. Roe for carrying out the treatment with x-radiation. It is a pleasure to express my thanks to the Sir Halley Stewart Trust for a Fellowship held during this work. The British Empire Cancer Campaign makes a grant in support of the Institute where this work was carried out. REFERENCES I. ADLER, it., and F. REIMAXX. Beitrag zur Funktionsprfif- ung des Reticulo-endothelialen Apparates. Ztschr. f. d. ges. exper. Med. 47:617-633. 1925 9 2. BLocit, B. Die ext)erimentelle Erzeugung von Riintgen- Carcinomen beim Kaninchen nebst allgcmeinen Bemcrk- ungen fibcr die Gencsc der expcrimentellen ('arcinome. Schweiz. med. Wchnschr. $4:857-865. x924 9 3. BURROWS, H., W. V. MAVXl-ORD, and J. E. ROBERTS. Neo- plasia Following Application of X-rays to Inflammatory Lesions. Proc. Roy Soc., London, s. B. I23:213-217. 1937. 4. CSATO, T., C. WE1ZLI-:R-LIGETI, and B. P. WIESX~:R. Effect of the Prolonged Administration of l:2:5:6-I)iben- zanthracene on the Rcticulo-endothelial System of Rabbits. Am. I. Cancer ,t6:257-261. 1939. 5. CSATO, T., C. WI':TZLER-LIGETI, anti B. P. WIt.:SXER. The l)eveloplnent of Malignancy in Animals and Changes in the Restropic Activity of Blood. Am. J. Cancer a6: 262-268. 1939.