tbuckley/cabot-search huggingface dataset:
Mafosfamide: A New Intra-CSF Chemotherapy?
Authors: Marc C. Chamberlain
Journal: Journal of Clinical Oncology (2005)

The data reported by Dr Normanno et al show that the administration of systemic chemotherapy can modulate epidermal growth factor receptor (EGFR) expression in cancer patients.This observation is consistent with our data, and agrees with the principle that the expression of a growth-factor receptor is not a static phenomenon and can be modulated by the cells as response to external events.Therefore, the main conclusion of the two studies is that clinicians cannot ignore the time of tumor cells collection when analyzing EGFR expression.The evaluation of EGFR expression on circulating tumor cells (CTCs) is a fascinating new approach.It would be much better than analysis performed on tumor specimens because it does not require an invasive procedure and easily allows repeated receptor status analysis during treatment and follow-up.At present, as reported by many investigators and confirmed by Dr Normanno, this technique is still penalized by a high rate of false-positive results.In fact, EGFR-positive CTCs were still found by Dr Normanno in 10% of healthy volunteers, though under stringent conditions.Since this low specificity might be due to illegitimate transcription, it is possible to imagine that the use of a more quantitative approach, such as quantitative reverse transcriptase polymerase chain reaction, can obtain a better standardization of the CTCs analysis.Although the difference in the rate of EGFR-positive CTCs positive tests between cancer patients (60%) and healthy volunteers (10%), as already published by Dr Normanno et al, is statistically significant (allowing this method to be used for "proofs of principle"), it highlights the difficulties in the development of a method with a sufficient specificity and reproducibility to be used in clinical decision making.We trust that CTCs analysis is a major effort in the era of molecular medicine.Although it is already a reliable method for research, the increase of its precision is an inescapable step before translating its use in the clinical practice.
Novel regulation of TNFα-induced-IL-18 bioactivity in rheumatoid arthritis synovial fibroblasts by reducing caspase-1 Via JAK2 inhibition
Authors: Hubert Marotte, Tatiana Fedorova, Adam J Pinney, Benjamin Lewis, Alisa E Koch
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background/purpose</h3> Rheumatoid arthritis (RA) is the most common inflammatory chronic joint disorder. Interleukin-1 (IL-1) family members play a key part in the pathogenesis of RA. Among the IL-1 cytokine family members, IL-18 is a proinflammatory cytokine, which modulates Th1 development and induces angiogenesis. The authors previously described a regulation of TNFα-induced-IL-18 bioactivity by blocking the ERK pathway. Here, the authors focused on modulation of TNFα-induced-IL-18 bioactivity by reduction of caspase-1 expression. <h3>Method</h3> Caspase-1 expression in RA synovial fibroblasts treated with TNFα was assessed by qRT-PCR and Western blot. The critical pathways for TNFα-induced caspase-1 expression were determined by using chemical inhibitors: pyrrolidine dithiocarbamate (PDTC; a nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) inhibitor; 200 μM), MAPK inhibitors (ERK1/2, PD98059; p38, SB202190; or JNK2, SP600125; 10 μM), or AG-490 (a Jak2 inhibitor; 10 μM) followed by TNFα stimulation. Caspase-1 expression was determined by qRT-PCR and Western blot. Immunofluorescence (IF) staining was performed to check IL-18 production induced by TNFα with or without preinhibition of ERK1/2 or JAK2 by using antibody recognised immature and mature IL-18. IL-18 functional activity was assessed using an IL-18 bioactivity assay using KG-1 cells and culture supernatants. <h3>Result</h3> TNFα induced RA synovial fibroblast caspase-1 expression at the mRNA and protein levels in a time-dependant manner (p&lt;0.05; n≥6 patients). Blocking the Jak2 pathway reduced TNFα-induced-caspase-1 expression at the transcriptional and protein level by approximately 60% and 40%, respectively (p&lt;0.05; n≥4). Blocking NFκB, ERK1/2, JNK or p38 pathways had no effect on TNFα-induced-caspase-1 mRNA expression. The authors then confirmed by IF that TNFα-induced IL-18 and investigated roles of ARK1/2 and JAK2 pathways. Blocking the ERK1/2 pathway dramatically decreased IL-18 expression induced by TNFα. However, blocking the JAK2 pathway, TNFα induced intracytoplasmic granularly IL-18 expression suggesting a defect of caspase-1. Finally, blocking the Jak2 pathway, the authors observed a reduction of IL-18 bioactivity by 52% in RA synovial fibroblasts. <h3>Conclusion</h3> These results show a new way to block TNFα-induced-IL-18 bioactivity by blocking capase-1. These data provide a new role for the Jak2 pathway in RA patients and emphasise the use of Jak inhibitors as a new therapeutic option in the management of RA.
Randomized Trial of Weekly, Twice-Monthly, and Monthly Interpersonal Psychotherapy as Maintenance Treatment for Women With Recurrent Depression
Authors: Ellen Frank, David J. Kupfer, Daniel J. Buysse, Holly A. Swartz, Paul A. Pilkonis, Patricia R. Houck, Paola Rucci, Danielle M. Novick, Victoria J. Grochocinski, Deborah M. Stapf
Journal: American Journal of Psychiatry (2007)

Objective: The authors sought to determine whether a greater frequency of interpersonal psychotherapy (IPT) sessions during maintenance treatment has a greater prophylactic effect than a previously validated once-a-month treatment. Method: A total of 233 women 20–60 years of age with recurrent unipolar depression were treated in an outpatient research clinic. After participants had achieved remission with weekly IPT or, if required, with weekly IPT plus antidepressant pharmacotherapy, they were randomly assigned to weekly, twice-monthly, or monthly maintenance IPT monotherapy for 2 years or until a recurrence of their depression occurred. Results: Among participants who remitted with IPT alone and entered maintenance treatment (N=99), 19 (26%) of the 74 who remained in the study throughout the 2-year maintenance phase experienced a recurrence of depression. Among participants who required the addition of a selective serotonin reuptake inhibitor to achieve remission (N=90), 32 (36%) sustained that remission through continuation treatment and drug discontinuation and began maintenance treatment; of these, 13 (50%) of the 26 who remained in the study throughout the maintenance phase experienced a recurrence. Survival analysis of time to recurrence by randomized treatment frequency showed no effect on recurrence-free survival in either treatment subgroup. Conclusions: These results suggest that maintenance IPT, even at a frequency of only one visit per month, is a good method of prophylaxis for women who can achieve remission with IPT alone. In contrast, among those who require the addition of pharmacotherapy, IPT monotherapy represents a significantly less efficacious approach to maintenance treatment.
Pegylated Liposomal Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse
Authors: Eric Pujade-Lauraine, Uwe Wagner, Elisabeth Aavall-Lundqvist, Val Gebski, Mark Heywood, Paul A. Vasey, Birgit Volgger, Ignace Vergote, Sandro Pignata, Annamaria Ferrero, Jalid Sehouli, Alain Lortholary, Gunnar Kristensen, Christian Jackisch, Florence Joly, Chris Brown, Nathalie Le Fur, Andreas du Bois
Journal: Journal of Clinical Oncology (2010)

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC).Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m(2)) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m(2)) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival.Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.
Characteristics Of Eosinophilic Esophagitis Among Children Living In Rural, Southern United States
Authors: Erin O'Brien, Troy Gibbons, Amy M. Scurlock, Jennifer Olivier, Mallikarjuna Rettiganti, Maria Melguizo Castro, Peggy L. Chandler, Audrey Fendley, Helen Casteel, Maryelle VonLanthen, Stephen Fiedorek, Tamara T. Perry, Stacie M. Jones, Robbie D. Pesek
Journal: Journal of Allergy and Clinical Immunology (2014)
The expiration reflex from the trachea and bronchi
Authors: M. Tatar, J. Hanacek, J. Widdicombe
Journal: European Respiratory Journal (2007)

The expiration reflex (ER) is a forced expiratory effort against a closed glottis that subsequently opens to eject laryngeal debris and prevent aspiration of material. It is distinct from the cough reflex. Its source is usually assumed to be restricted to the larynx and vocal folds, and its possible origin from the tracheobronchial (TB) tree has been suggested but never studied. The current authors re-analysed previous records with mechanical or chemical stimulation of the TB tree to see if an ER can consistently be elicited, and to see whether it has properties similar to that from the larynx and vocal folds. A random review was made of some of the extensive literature on TB "cough" to see if it confirmed the authors' conclusions. The TBER was consistently seen in cats and rabbits, either alone or followed by cough. These results are consistent with many studies in other species, including humans. It was enhanced, relative to cough, by inflation of the lungs and by general anaesthesia. Tracheobronchial expiration reflex occurs frequently with mechanical stimulation of the tracheobronchial tree. It differs fundamentally from many of the properties of "true" cough. Its features similar to the laryngeal expiration reflex suggest that both should be labelled "expiration reflexes" and not cough. Its existence should be taken into account in experimental, and possibly clinical, studies on tracheobronchial cough.
Increased daily activity in cystic fibrosis: time to break out the prescription pad?
Authors: D. A. Fitzgerald
Journal: European Respiratory Journal (2014)

After more than 30 years, the medical world has come to accept the virtues of newborn screening for the diagnosis of cystic fibrosis (CF). Evidence from Europe, Australia and the USA has demonstrated benefits in terms of nutrition, lung function and survival into adulthood [1, 2]. Similarly, evidence exists that children who present with meconium ileus do worse from the respiratory viewpoint than those diagnosed on newborn screening, supporting the argument that genotypic–phenotypic differences remain incompletely understood [3]. Such observations have been further reinforced by work from the AREST CF (Australian Respiratory Early Surveillance Team for Cystic Fibrosis) group from Australia, demonstrating the early onset of structural lung disease [4, 5], and the London CF consortium [6] and American researchers [7] who have recently shown the benefits on lung function in young children with CF diagnosed by newborn screening compared with those diagnosed at a later stage when symptomatic. The complementary nature of structural and functional lung assessment in providing a broader assessment of the status of young people with CF [8] highlights additional concerns for clinicians managing the routine care of “well” infants and young children with CF. The accumulated evidence argues that the lungs of young children with CF are vulnerable from birth and, whilst newborn screening is clearly beneficial, it is routine practice in many centres to place an emphasis on airway clearance [9] from the start with a view to improving short-term and long-term outcomes. However, this is not necessarily the case, according to a recent Cochrane Review which …
Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates
Authors: Y. Joy Yu, Jasvinder K. Atwal, Yin Zhang, Raymond K. Tong, Kristin R. Wildsmith, Christine Tan, Nga Bien-Ly, Maria Hersom, Janice A. Maloney, William J. Meilandt, Daniela Bumbaca, Kapil Gadkar, Kwame Hoyte, Wilman Luk, Yanmei Lu, James A. Ernst, Kimberly Scearce-Levie, Jessica A. Couch, Mark S. Dennis, Ryan J. Watts
Journal: Science Translational Medicine (2014)

Bispecific antibodies engineered to both bind to the primate transferrin receptor and inhibit β-secretase are taken up by the nonhuman primate brain and reduce brain β-amyloid.
Extrapulmonary sites of Pseudomonas aeruginosa in adults with cystic fibrosis.
Authors: R F Taylor, D W Morgan, P S Nicholson, I S Mackay, M E Hodson, T L Pitt
Journal: Thorax (1992)

BACKGROUND: Pseudomonas aeruginosa infection is seldom eradicated in patients with cystic fibrosis despite intensive antipseudomonal treatment. Upper airway sites of infection may contribute to perpetuation of lower airways infection. This study was designed to find out which extrapulmonary sites are infected and whether the strains at these sites are identical to those in the lungs. METHODS: Sputum and upper airway samples from 42 patients were cultured for P aeruginosa and stool samples from 20 patients were also tested. Nineteen isolates from sputum and extrapulmonary sites from four patients were genotyped with the pCM tox probe. RESULTS: P aeruginosa was isolated from the sputum of 36 patients, 34 of whom had infection in the upper airways. Six of the 20 patients tested were positive for P aeruginosa in the stool. The nasopharynx was colonised in 30 patients, the oropharynx in 29, the middle meatus in 13, the external nares in six, and the inferior turbinate in four. Three of four patients tested had the same strain of P aeruginosa (a different one in each individual) in the sputum and the upper airways, and in two of the three the stool isolate was a different strain. CONCLUSION: Most adults with cystic fibrosis and P aeruginosa pulmonary infection have upper airway reservoirs of the organism and strains from these sites are identical to those in the lungs.
IT-16 * COMBINATION TREATMENT WITH DELTA24-RGD AND TEMOZOLOMIDE IMPROVES SURVIVAL AND AFFECTS INTRATUMORAL IMMUNE CELL SUBSETS IN A MURINE MALIGNANT GLIOMA MODEL
Authors: A. Kleijn, W. van den Bossche, E. Haefner, Z. Belcaid, J. Kloezeman, C. Dirven, M. Lamfers
Journal: Neuro-Oncology (2014)

INTRODUCTION: The oncolytic adenovirus Delta24-RGD specifically lyses tumor cells and is currently tested in clinical phase I/II trials for recurrent glioma. We recently showed that the efficacy of Delta24-RGD is mainly dependent on an induced anti-tumor immune response. As known, TMZ has pronounced effects on the immune system, which could hamper the viral-induced anti-tumor immune response. To assess the combined effects, we tested different treatment regimens in an immune competent glioma mouse model. METHODS: C57BL/6 mice were injected intracranially with GL261 cells. TMZ was given for 5 days before (pre-treatment regimen) or after (post-treatment regimen) intratumoral injection of Delta24-RGD. Mice were followed for survival or sacrificed at earlier time-points to assess intratumoral influx of immune cells. T-cell response directed to the tumor cells was assessed by co-culture of splenocytes with GL261 tumor cells and analysis of IFNgamma production. Furthermore, to assess the type of cell death induced by the treatments, western blotting for LC3 (autophagy) and caspase 3/7 analysis (apoptosis) was performed. RESULTS: In vitro, apoptosis is highly induced in virus and combination treated cells, whereas autophagy is induced by TMZ monotherapy. In vivo, both combination treatment regimens significantly improved survival compared to TMZ alone. The post-treatment regimen also prolonged survival significantly compared to virus only. In the pre-treatment group, influx of dendritic cells is reduced, followed by a diminished influx of CD8+ T-cells. Interestingly, splenocytes from mice of virus and both combination treatment groups recognize GL261 cells, indicating that the diminished influx of immune cells did not hamper T-cell activation. CONCLUSION: The addition of TMZ to Delta24-RGD treatment in immune competent mice improves survival compared to Delta24-RGD or TMZ alone. Contrary to the post-treatment regimen, administering TMZ prior to virus injection hampers the intratumoral influx of immune cells; however, with both regimens an effective anti-tumor immune response is elicited.
PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network
Authors: Haoqiang Ying, Kutlu G. Elpek, Anant Vinjamoori, Stephanie M. Zimmerman, Gerald C. Chu, Haiyan Yan, Eliot Fletcher-Sananikone, Hailei Zhang, Yingchun Liu, Wei Wang, Xiaojia Ren, Hongwu Zheng, Alec C. Kimmelman, Ji-hye Paik, Carol Lim, Samuel R. Perry, Shan Jiang, Brian Malinn, Alexei Protopopov, Simona Colla, Yonghong Xiao, Aram F. Hezel, Nabeel Bardeesy, Shannon J. Turley, Y. Alan Wang, Lynda Chin, Sarah P. Thayer, Ronald A. DePinho
Journal: Cancer Discovery (2011)

Abstract Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-κB activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-κB network, which may serve to shape the PDAC tumor microenvironment. Significance: Detailed molecular genetics studies established that PTEN operates as a haploinsufficient tumor suppressor to promote metastatic PDAC development. The strong activation of the NF-κB–cytokine program in Pten-deficient tumors provides additional avenues for targeted therapies in tumors with altered PI3K regulation. Cancer Discovery; 1(2); 158–69. ©2011 AACR. Read the Commentary on this article by Chiao and Ling, p. 103 This article is highlighted in the In This Issue feature, p. 91
In vivo aging of red cell enzymes: Study of biotinylated red blood cells in rabbits
Authors: A. Zimran, L. Forman, T. Suzuki, G. L. Dale, E. Beutler
Journal: American Journal of Hematology (1990)

Abstract It is generally recognized that the activities of some of the red cell enzymes decline as the cell ages. However, there is still a controversy regarding the rate at which this aging occurs. In the present study we applied newly developed technology for the specific isolation of maturing reticulocytes/erythrocytes for a more comprehensive study of in vivo aging of red cell enzymes in rabbits. Anemia was induced by repeated phlebotomy, and reticulocyte‐rich erythrocytes were labeled with N‐hydroxy succinimido‐biotin and then transfused into a normal rabbit. These biotinylated cells were isolated at various time points by their affinity for an avidin support, and the enzymatic activity of 19 red cell enzymes was measured. We observed a biphasic pattern of decay for the activity of six age‐dependent enzymes—aldolase, glutamate‐oxaloacetate transaminase, glucose 6‐phosphate dehydrogenase, hexokinase, pyrimidine 5′‐nucleotidase, and pyruvate kinase.
Association Between Urinary Markers of Nucleic Acid Oxidation and Mortality in Type 2 Diabetes
Authors: Kasper Broedbaek, Volkert Siersma, Trine Henriksen, Allan Weimann, Morten Petersen, Jon T. Andersen, Espen Jimenez-Solem, Lars J. Hansen, Jan Erik Henriksen, Steen J. Bonnema, Niels de Fine Olivarius, Henrik E. Poulsen
Journal: Diabetes Care (2012)

OBJECTIVE We recently showed that RNA oxidation, estimated by urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo), independently predicted mortality in a cohort of 1,381 treatment-naive patients with newly diagnosed type 2 diabetes. In the present investigation, we analyzed urine collected 6 years after the diagnosis to assess the association between urinary markers of nucleic acid oxidation and mortality in patients with established and treated diabetes. RESEARCH DESIGN AND METHODS We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality. RESULTS During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34–2.58) and 1.72 (1.11–2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo. CONCLUSIONS The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality.