tbuckley/cabot-search huggingface dataset:
The role of Neuropilin-1 in tumor cell chemo-resistance
Authors: Anne Marie Byrne, David Bouchier-Hayes, Judith H. Harmey
Journal: Cancer Research (2006)

1288   Vascular endothelial growth factor (VEGF) is an important angiogenic factor secreted by tumour cells to stimulate new vessel formation to supply nutrients and oxygen to the tumour. In endothelial cells, VEGF signals via the tyrosine kinase receptors (RTKs) VEGF receptor 1 (VEGFR-1, flt-1) and VEGF receptor 2 (VEGFR-2, FLK-1/ KDR). Neuropilin-1 (NRP-1) is a cell surface glycoprotein, which functions in neuronal guidance by interaction with its ligand Sema-3A. It was subsequently identified in endothelial cells and some tumour cells as a specific receptor for the most potent VEGF isoform, VEGF 165 . Stress conditions such as hypoxia increase VEGF expression and high levels of VEGF have also been shown in tumour cells treated with chemotherapy or radiotherapy. VEGF impairs the efficacy of these treatments presumably by promoting pro-survival factors. In some tumour cells VEGF signals via its tyrosine kinase receptors, however, in tumour cells, which do not express the classical VEGF RTKs the signaling pathway via NRP-1 is unknown. NRP-1 cannot transduce a signal as it lacks a cytoplasmic signaling domain and presumably interacts with other proteins to transduce a VEGF signal. In neuronal cells, NRP-1 forms a complex with Plexin A-1 to transduce a signal from Sema-3A. VEGF has been shown to compete with Sema-3A for NRP-1 binding and the ratio of Sema3A to VEGF determines the rate of chemotaxis in breast tumour cells 1 . When we examined endothelial cell and neuronal cell receptor expression in a number of cell lines we identified NRP-1 but no other endothelial VEGF RTK receptors (VEGFR-1 or VEGFR-2). Blocking VEGF binding to NRP-1 using a peptide corresponding to exon 7 of VEGF 165  sensitized 4T1 mammary adenocarcinoma and Lewis Lung Carcinoma (LLC) tumour cells to Taxotere chemotherapy. These cells also expressed the PlexinA-1 and the NRP-1 ligand, Sema-3A. Both hypoxia and chemotherapy up-regulated VEGF and the cells were less sensitive to Paclitaxel chemotherapy under hypoxia relative to normoxia. NRP-1 was also elevated under hypoxic conditions. The reduced sensitivity to Paclitaxel under hypoxia may be a consequence of hypoxia-induced VEGF and NRP-1 conferring a protective effect on the tumour cells. VEGF signaling and pro-survival effects in 4T1 and LLC tumour cells may be mediated by neuronal receptor signaling pathways and could be attenuated by targeting the NRP-1 receptor. 1: Competing Autocrine Pathways Involvoing Alternative Neuropilin-1 Ligands regulate Chemotaxis of Carcinoma cells. Bachelder et al  Cancer Res  63, 5230-5233, 2003 This work was funded by the Royal College of Surgeons in Ireland Research committee
A study of the anatomic distribution of brain metastases in HER2+ breast cancer: Implications for hippocampal avoidance PCI.
Authors: Jacob Witt, Timothy J. Pluard, Daniel John Ferraro, Jerry Jeff Jaboin, Maria Anne Thomas, Imran Zoberi, Cliff Grant Robinson
Journal: Journal of Clinical Oncology (2014)

e11578 Background: While only 20% of all breast cancer is HER2+, it represents a disproportionate majority of breast cancer brain metastases, and up to half of these patients will die of CNS disease. Prophylactic cranial irradiation (PCI) reduces the risk of brain metastases and improves survival in small cell lung cancer, but at the cost of neurocognitive decline in 30-40%. RTOG 0933 demonstrated a reduction in neurocognitive decline with hippocampal-avoidance (HA) whole brain radiation compared with historic controls. HA-PCI may represent an approach to reduce the risk of symptomatic HER2+ brain metastases while simultaneously reducing the risk of neurotoxicity, presuming the incidence of metastases within the HA zone is low. Methods: Patients with HER2+ breast cancer and brain metastases treated with whole brain radiation (WBRT) or stereotactic radiosurgery (SRS) from 1/2004-2/2012 were identified from registries in the Department of Radiation Oncology. Pretreatment T1-weighted, postcontrast axial MRI images were reviewed, and metastases were scored as being within a 5 mm HA zone (as done in RTOG 0933), and further subdivided by whether (1) any portion was within the avoidance zone or (2) the nidus (assuming concentric growth of the metastasis) was within the HA zone. Results: Seventy-three patients with 513 metastases were identified. The median age was 52.2. The median number of brain metastases per patient was 7.03 (range, 1-157). 40 of the patients were treated with WBRT and 21 were treated with SRS, with the remainder undergoing unknown or no radiation therapy. Eleven patients (15.1%) and 14 metastases (2.7%) had any portion of the metastasis within the HA zone while only 5 patients (6.85%) and 5 metastases (0.97%) had the tumor nidus within the HA zone. Conclusions: Metastases within the HA zone are uncommon. Use of a 5 mm expansion from the hippocampus to create a HA zone for HA-PCI would be projected to result in a 1-3% excess risk of failure. Such a low risk of failure would be acceptable, particularly with the ability to salvage such patients with techniques such as SRS. A pilot study of HA-PCI for HER2+ metastatic breast cancer is in development.
Abstract 12067: A Genome Wide Association Study (GWAS) of the Early Repolarization Phenotype in BioVU Implicates Variants at 12q22
Authors: Jessica T Delaney, Peter E Weeke, Sara L Van Driest, Erica Bowton, Raquel Zink, Joshua C Denny, Dan M Roden
Journal: Circulation (2012)

Introduction:  Early repolarization (ER) is a common ECG finding that has previously been reported to be heritable (h 2 =0.49). When ER is localized to the inferior and/or lateral leads, there has been an association with unexplained sudden cardiac death. We tested the hypothesis that common genetic variation plays a role in its manifestation.   Methods and Results:  Cases (N=442) with inferolateral early repolarization, defined as ≥0.1-mV elevation of the J point or ST segment with notching or slurring in at least 2 inferior and/or lateral leads confirmed by physician review, were identified from the BioVU DNA biobank. Cases were genotyped with the Illumina Human Omni1M_Quad platform. Controls (N=2310) were selected from a cohort of individuals with normal ECGs in BioVU as determined by manual review and previously genotyped on the Illumina 660W-Quadv1 platform. A merged set of 332,624 SNPs common to both platforms was created. Logistic regression with the covariates of age and gender was performed separately for individuals self-reported to be Caucasian (260 cases; 1937 controls) and African-American (140; 228). Principle component analysis for the first eigenvector, an indicator of ancestry, was included as a covariate. Two linked SNPs (r 2  =0.76) at chr12q22 were associated with ER at genome-wide significance in self-reported Caucasians (P=1.62 x 10 -9  and P=6.33 x 10 -9 , respectively). The first SNP is located in the 3’-UTR of closest gene (found to be expressed in heart), while the second SNP is intergenic. No association was found among the African American subjects.   Conclusion:  This GWAS has identified the 12q22 region of self-reported Caucasians to be a possible modulator of malignant early repolarization on the electrocardiogram. The next steps are further replication followed by functional assessment.
Abstract 165: Initial Middle Latency Auditory Evoked Potentials Index Helps to Predict Neurological Outcomes in Patients With Out-of-Hospital Return of Spontaneous Circulation (OH-ROSC)
Authors: Junya Tsurukiri, Taihei Okita, Taishi Oomura, Masahito Ueno
Journal: Circulation (2013)

Objective:  Survival rates for cardiac arrest are known to be higher with out-of-hospital return of spontaneous circulation (OH-ROSC). However, data pertaining to OH-ROSC is limited. We speculated that initial middle latency auditory evoked potential index (MLAEPi) measured using an MLAEPi monitor (Fig.) at the emergency department (ED) can predict neurological outcomes among patients with OH-ROSC.   Design:  A prospective study  Setting:  A tertiary emergency center in Tokyo, Japan (January 2012 to May 2013).   Patients:  A total of 23 patients who had witnessed cardiac arrest and determined OH-ROSC after undergoing cardiopulmonary resuscitation (CPR).   Measurements and Results:  The parameters comprised, age, gender, medical history, Glasgow Coma Scale (GCS), vital signs, blood gas, initial electrical rhythm, MLAEPi, bystander CPR, resuscitation intervals and neurological outcome. Neurological outcomes were evaluated 3 months after OH-ROSC, using cerebral performance category (CPC) score and classified into two groups: good outcome (GO) for a score of 1 or 2, and worse outcome (WO) for a score of 3-5. Among 23 patients with OH-ROSC, 10 patients were grouped under GO (CPC 1, n = 5; CPC 2, n = 5) and 13 were grouped under WO (CPC 3, n = 2; CPC 4, n = 6 and CPC 5, n = 5). The following values were significantly better in cases with GO than in those with WO (p    Conclusion:  Among patients with OH-ROSC, the initial MLAEPi at the ED was strongly associated with good neurological outcomes at 3 month after the event.
Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria
Authors: Tomas Majtan, Wendell Jones, Jakub Krijt, Insun Park, Warren D. Kruger, Viktor Kožich, Steven Bassnett, Erez M. Bublil, Jan P. Kraus
Journal: Molecular Therapy (2017)

Classical homocystinuria (HCU) is the most common inherited disorder of sulfur amino acid metabolism caused by deficiency in cystathionine beta-synthase (CBS) activity and characterized by severe elevation of homocysteine in blood and tissues. Treatment with dietary methionine restriction is not optimal, and poor compliance leads to serious complications. We developed an enzyme replacement therapy (ERT) and studied its efficacy in a severe form of HCU in mouse (the I278T model). Treatment was initiated before or after the onset of clinical symptoms in an effort to prevent or reverse the phenotype. ERT substantially reduced and sustained plasma homocysteine concentration at around 100 μM and normalized plasma cysteine for up to 9 months of treatment. Biochemical balance was also restored in the liver, kidney, and brain. Furthermore, ERT corrected liver glucose and lipid metabolism. The treatment prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass. In addition, structurally defective ciliary zonules in the eyes of I278T mice contained low density and/or broken fibers, while administration of ERT from birth partially rescued the ocular phenotype. In conclusion, ERT maintained an improved metabolic pattern and ameliorated many of the clinical complications in the I278T mouse model of HCU. Classical homocystinuria (HCU) is the most common inherited disorder of sulfur amino acid metabolism caused by deficiency in cystathionine beta-synthase (CBS) activity and characterized by severe elevation of homocysteine in blood and tissues. Treatment with dietary methionine restriction is not optimal, and poor compliance leads to serious complications. We developed an enzyme replacement therapy (ERT) and studied its efficacy in a severe form of HCU in mouse (the I278T model). Treatment was initiated before or after the onset of clinical symptoms in an effort to prevent or reverse the phenotype. ERT substantially reduced and sustained plasma homocysteine concentration at around 100 μM and normalized plasma cysteine for up to 9 months of treatment. Biochemical balance was also restored in the liver, kidney, and brain. Furthermore, ERT corrected liver glucose and lipid metabolism. The treatment prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass. In addition, structurally defective ciliary zonules in the eyes of I278T mice contained low density and/or broken fibers, while administration of ERT from birth partially rescued the ocular phenotype. In conclusion, ERT maintained an improved metabolic pattern and ameliorated many of the clinical complications in the I278T mouse model of HCU.
LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker
Authors: Christian Bressy, Sophie Lac, Jérémy Nigri, Julie Leca, Julie Roques, Marie-Nöelle Lavaut, Véronique Secq, Fabienne Guillaumond, Thi-Thien Bui, Daniel Pietrasz, Samuel Granjeaud, Jean-Baptiste Bachet, Mehdi Ouaissi, Juan Iovanna, Sophie Vasseur, Richard Tomasini
Journal: Cancer Research (2017)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell-promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients. Cancer Res; 78(4); 909-21. ©2017 AACR.
Working time rules must be kept after Brexit, say medical leaders
Authors: Abi Rimmer
Journal: BMJ (2017)

Working time protections must not be undermined as part of the UK’s departure from the European Union, medical leaders have said.

Representatives from the BMA, the British Dental Association, and 11 medical, nursing, and midwifery royal colleges have written to the prime minister asking her not to remove European Working Time Regulations from UK law.

The regulations ensure that doctors do not work more than an average of 48 hours a week and guarantee rights such as rest breaks and statutory paid leave and were fully incorporated into the NHS in 2009.

The letter, sent on 20 December, …
A Baby-Led Approach to Complementary Feeding—Reply
Authors: Rachael W. Taylor, Anne-Louise M. Heath, Jillian J. Haszard
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Looking at the Moon
Authors: William R. Barclay
Journal: JAMA (1980)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract P007: Association of Plasma Lactate with Incident Atrial Fibrillation in the ARIC Study
Authors: Satish Misra, Kunihiro Matsushita, Yingying Sang, Lin Chen, Josef Coresh, Maria Ines Schmidt, Ron Hoogeveen, Christie Ballantyne, Alvaro Alonso, J. Hunter Young
Journal: Circulation (2016)

Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting up to six million persons in the United States. The mechanism underlying AF has been extensively investigated in recent years. Reduction in oxidative capacity has been described as a contributor to several aging-related diseases including hypertension and diabetes mellitus. In vitro studies of atrial myocardium have described mitochondrial dysfunction related to reduced oxidative capacity in patients with AF. We sought to evaluate the association of plasma lactate, a marker of impaired oxidative capacity, with incident AF in a large population-based cohort. Methods: The Atherosclerotic Risk in Communities (ARIC) study has followed 15,792 men and women from 4 US communities since 1987. We identified 11,191 participants at the 4 th visit (1996-1998) without prevalent AF for whom plasma lactate levels were available. Incident AF was identified using hospital discharge codes and death certificates. The association of plasma lactate with incident AF was evaluated using Cox proportional hazards models. Results: During a mean follow-up of 13.1 years, there were 1498 cases of incident AF. In unadjusted analysis, there was a statistically significant difference in incident AF when comparing plasma lactate by quartiles and continuously (Model 1). This association remained significant in adjusted models including age, gender, race, body-mass index, smoking, alcohol use, history of cardiovascular disease, aspirin use, statin use, total cholesterol, and glomerular filtration rate (Models 2 and 3). When adjusting for diabetes or hypertension alone, potential mediators to which reduced oxidative capacity may contribute, this association was strongly attenuated (HR per standard deviation of log(lactate) 1.04, 95% CI: 0.99, 1.10 and 1.04, 95% CI: 0.99, 1.09 respectively). Conclusion: Plasma lactate is independently associated with incident AF, and its contribution to AF may be, at least in part, mediated by diabetes and/or hypertension.
OC-048 Filgotinib, a selective jak1 inhibitor, induces clinical remission and a reduction in pstat3 levels in patients with active crohn’s disease: results from the phase ii fitzroy study
Authors: S Keshav, J Goh, A Hart, S Levison, S McLaughlin, Avan Aa der, R Galien, Y Pan, L Meuleners, C Jamoul, C Tasset, P Harrison, S Vermeire
Journal: Gut (2017)

Introduction  Filgotinib (FIL), an oral, selective Janus kinase 1 (JAK1) inhibitor that blocks cytokine signalling by inhibiting STAT phosphorylation, which previously demonstrated efficacy in rheumatoid arthritis, is being evaluated in active Crohn’s disease (CD).  Method  174 patients with moderate-to-severe CD and ulcerations confirmed by centrally read endoscopy were randomised 3:1 to 200 mg FIL or placebo (PBO) QD for 10 weeks. Thereafter, patients continued to receive FIL 200 mg, 100 mg or PBO QD for another 10 weeks. Immunosuppressive agents had to be discontinued, and steroid dosage was kept stable until Week 10 (W10). Key efficacy and safety data, and phosphorylation of STAT3 in intestinal biopsies from the 10 week induction period are presented.  Results  Mean baseline characteristics were similar between the FIL and PBO group. The primary endpoint (clinical remission CDAI   pSTAT3 levels were significantly reduced at W10 in FIL-patients (−36% (95% CI: −51%, −17%)). However, in patients in clinical remission at W10, pSTAT3 levels were significantly reduced irrespective of treatment (PBO −62% (95% CI: −83%, −16%) and FIL −42% (95% CI: −57%,−21%)). In patients without clinical remission, pSTAT3 levels numerically decreased with FIL (−28% (95% CI: −51%,+7%)) and not with PBO (+12% (95% CI:−21%,+94%).  Conclusion  Filgotinib is the first JAK inhibitor to demonstrate clinical efficacy in CD, as demonstrated by induction of clinical remission and response, and is associated with a significant reduction in pSTAT3 levels, suggesting that pSTAT3 behaves both as a pharmacodynamic marker for filgotinib and a disease activity marker.  Disclosure of Interest  S. Keshav Conflict with: Abbvie, ChemoCentryx, GSK, Merck, Conflict with: Abbvie, Allergan, Astra-Zeneca, Boehringer Ingelheim, ChemoCentryx, Dr Falk Pharma, Ferring, Gilead, GSK, Merck, Mitsubishi Tanabe Pharma, Pharmacosmos, Pfizer, Takeda, Vifor Pharma, J. Goh: None Declared, A. Hart: None Declared, S. Levison: None Declared, S. McLaughlin Conflict with: AbbVie, Conflict with: AbbVie, A. Van der Aa Conflict with: Galapagos NV, R. Galien Conflict with: Galapagos SASU, Y. Pan Conflict with: Gilead Sciences Inc, L. Meuleners Conflict with: Galapagos NV, C. Jamoul Conflict with: Galapagos NV, C. Tasset Conflict with: Galapagos NV, P. Harrison Conflict with: Galapagos NV, S. Vermeire Conflict with: AbbVie, Galapagos, MSD, Takeda, Conflict with: AbbVie, Galapagos, MSD, Takeda, Ferring, Genentech/Roche, Shire, Pfizer,Mundipharma, Hospira, Celgene, Second genome, Janssen, Conflict with: AbbVie
Cutaneous Diphtheria Mimicking Pyoderma Gangrenosum
Authors: Daniel Morgado-Carrasco, Constanza Riquelme-Mc Loughlin, Xavier Fustá-Novell, Mariana J. Fernández-Pittol, Jordi Bosch, José M. Mascaró
Journal: JAMA Dermatology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal