tbuckley/cabot-search huggingface dataset:
Neurodevelopmental Deceleration by Urban Fine Particles from Different Emission Sources: A Longitudinal Observational Study
Authors: Xavier Basagaña, Mikel Esnaola, Ioar Rivas, Fulvio Amato, Mar Alvarez-Pedrerol, Joan Forns, Mònica López-Vicente, Jesús Pujol, Mark Nieuwenhuijsen, Xavier Querol, Jordi Sunyer
Journal: Environmental Health Perspectives (2016)

Background:A few studies have reported associations between traffic-related air pollution exposure at schools and cognitive development. The role of PM components or sources other than traffic on cognitive development has been little explored.Objectives:We aimed to explore the role of PM sources in school air on cognitive development.Methods:A cohort of 2,618 schoolchildren (average age, 8.5 years) belonging to 39 schools in Barcelona (Spain) was followed up for a year. Children completed computerized tests assessing working memory, superior working memory, and inattentiveness during four visits. Particulate matter ≤ 2.5 μm (PM2.5) was measured during two 1-week campaigns in each school, both outdoors and in the classroom. Source apportionment resulted in nine sources: mineral, organic/textile/chalk, traffic, secondary sulfate and organics, secondary nitrate, road dust, metallurgy, sea spray, and heavy oil combustion. Differences in cognitive growth trajectories were assessed with mixed models with age-by-source interaction terms.Results:An interquartile range increase in indoor traffic-related PM2.5 was associated with reductions in cognitive growth equivalent to 22% (95% CI: 2%, 42%) of the annual change in working memory, 30% (95% CI: 6%, 54%) of the annual change in superior working memory, and 11% (95% CI: 0%, 22%) of the annual change in the inattentiveness scale. None of the other PM2.5 sources was associated with adverse effects on cognitive development.Conclusions:Traffic was the only source of fine particles associated with a reduction in cognitive development. Reducing air pollution from traffic at primary schools may result in beneficial effects on cognition.Citation:Basagaña X, Esnaola M, Rivas I, Amato F, Alvarez-Pedrerol M, Forns J, López-Vicente M, Pujol J, Nieuwenhuijsen M, Querol X, Sunyer J. 2016. Neurodevelopmental deceleration by urban fine particles from different emission sources: a longitudinal observational study. Environ Health Perspect 124:1630–1636; http://dx.doi.org/10.1289/EHP209
Use of axitinib, a new-generation tyrosine kinase inhibitor, to decrease glioblastoma growth despite primary resistance to the VEGF-antibody bevacizumab.
Authors: Tobias Kratzsch, Viktor Gruenwald, Peter Vajkoczy, Susanne Antje Kuhn
Journal: Journal of Clinical Oncology (2013)

2077 Background: Targeted therapies are increasingly important in oncology. Axitinib is a novel orally available tyrosine kinase inhibitor which is mainly directed against the VEGFR family. VEGF-antibody bevacizumab is the acting drug of running clinical trials in glioblastoma. Methods: In immunodeficient mice, cell line- and patient-derived glioblastoma xenografts were established and treated with axitinib. Temozolomide, bevacizumab, and phosphate buffered saline served as controls. Tumor size, vascularization (CD31), vascular pericyte coverage (NG-2), apoptosis in tumor and endothelial cells as well as expression of EGFR, VEGFR1, VEGFR2, PDGFRβ, VEGF, and PlGF were determined. Experiments were approved by local ethics committee. Results: Positive control temozolomide always caused growth inhibition whereas primary resistances to bevacizumab as primary drug were observed. As most delighting result, axitinib caused a delay of tumor growth in a glioblastoma xenograft with primary resistance to bevacizumab. Tumor cell proliferation (Ki67) was significantly lower than in controls (p&lt;.05). The number of CD31 positive endothelial cells decreased (p&lt;.001). Numbers of NG2 positive pericytes were reduced (p&lt;.001) and triple immunofluorescence showed a significant reduction of NG2 positive pericyte coverage of CD31 positive endothelial cells (p&lt;.001). Expression of EGFR, PDGFRβ, and VEGFR1 proteins showed no alterations under axitinib treatment, but RT-PCR revealed a significantly decreased mRNA expression of VEGF-A and PlGF. Conclusions: Axitinib had significant effects on glioblastoma xenografts even with primary resistance to bevacizumab in a so far untreated tumor. There are currently two recruiting phase II trials with axitinib in glioblastoma multiforme. Further comparative studies with bevacizumab should urgently define the potential of this substance in glioblastoma therapy.
Dual targeting of the thioredoxin and glutathione systems in cancer and HIV
Authors: Moran Benhar, Iart Luca Shytaj, Jonathan S. Stamler, Andrea Savarino
Journal: Journal of Clinical Investigation (2016)

Although the use of antioxidants for the treatment of cancer and HIV/AIDS has been proposed for decades, new insights gained from redox research have suggested a very different scenario. These new data show that the major cellular antioxidant systems, the thioredoxin (Trx) and glutathione (GSH) systems, actually promote cancer growth and HIV infection, while suppressing an effective immune response. Mechanistically, these systems control both the redox- and NO-based pathways (nitroso-redox homeostasis), which subserve innate and cellular immune defenses. Dual inhibition of the Trx and GSH systems synergistically kills neoplastic cells in vitro and in mice and decreases resistance to anticancer therapy. Similarly, the population of HIV reservoir cells that constitutes the major barrier to a cure for AIDS is exquisitely redox sensitive and could be selectively targeted by Trx and GSH inhibitors. Trx and GSH inhibition may lead to a reprogramming of the immune response, tilting the balance between the immune system and cancer or HIV in favor of the former, allowing elimination of diseased cells. Thus, therapies based on silencing of the Trx and GSH pathways represent a promising approach for the cure of both cancer and AIDS and warrant further investigation.
Abstract IA30: How cells survive: Single cell analysis reveals properties of non-genetic apoptosis resistance.
Authors: Douglas R. Green
Journal: Clinical Cancer Research (2015)

Abstract The mechanism of non-genetic resistance to TRAIL-induced apoptosis remains unresolved as the regulatory pathways involved are interconnected and complex. Single-cell mass cytometry was used to profile functional changes in regulatory factors while simultaneously monitoring apoptotic progression in TRAIL-treated cells. Cells resistant to TRAIL possessed diverse signaling states, however only cells within a subset of these states, termed “essential persisters” (EPs), were able to survive long-term and replicate. Constriction of the EP signaling states with kinase perturbagens decreased cell survival, however, the EPs occupied unique signaling states for each cell line tested. In order to overcome cell-type specific resistance, single peturbogen data was used to predict the effects of perturbagen combinations on survival. The level of EP signaling state constriction by a single perturbagen was a more robust predictor of combinatorial effects than extrapolating from single perturbogen cell survival data directly. These findings provide a population-level understanding of non-genetic resistance and explain the shortcoming of previous ‘bulk’ methods for identifying mechanisms of TRAIL-resistance. The use of signaling space constriction in persisters may guide design of therapies against non-genetic resistance in the future. Citation Format: Douglas R. Green. How cells survive: Single cell analysis reveals properties of non-genetic apoptosis resistance. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA30.
Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs
Authors: Jonathan S Silver, Jennifer Kearley, Alan M Copenhaver, Caroline Sanden, Michiko Mori, Li Yu, Gretchen Harms Pritchard, Aaron A Berlin, Christopher A Hunter, Russell Bowler, Jonas S Erjefalt, Roland Kolbeck, Alison A Humbles
Journal: Nature Immunology (2016)
Case 22-1962
Authors: John C. Dalton
Journal: New England Journal of Medicine (1962)

Presentation of CaseA seventy-three-year-old woman was admitted to the hospital because of pain in the chest.The patient experienced pain and a sensation of tightness beneath the sternum and in the left anterior portion of the chest intermittently during the year before entry. At times the pain was related to exertion, and it was relieved by nitroglycerin. Increasing exertional dyspnea and a mild nonproductive cough developed, and she was given digitalis. She was not incapacitated and continued to be ambulatory. During the six months before admission she became faint on arising to an erect position and had dysphagia, which . . .
A Standard, 3-Tube, 10-Color Flow Cytometry Panel for Acute Myeloid Leukemia Diagnosis Can be Used for MRD Detection at Day 30 after Induction, and Is Predictive of Early Relapse
Authors: Naheed Alam, Anne Tierens, Karen Yee, Aaron D. Schimmer, Vikas Gupta, Mark D. Minden, Matthew Seftel, Anna Porwit, Andre C Schuh
Journal: Blood (2014)
CD6-Depleted Allogeneic Bone Marrow Transplantation for Acute Leukemia in First Complete Remission
Authors: Robert J. Soiffer, Diane Fairclough, Michael Robertson, Edwin Alyea, Kenneth Anderson, Arnold Freedman, Lini Bartlett-Pandite, David Fisher, Robert L. Schlossman, Richard Stone, Christine Murray, Andrea Freeman, Karen Marcus, Peter Mauch, Lee Nadler, Jerome Ritz
Journal: Blood (1997)
Anti-carbamylated protein antibodies: a specific hallmark for rheumatoid arthritis. Comparison to conditions known for enhanced carbamylation; renal failure, smoking and chronic inflammation
Authors: M K Verheul, S J H van Erp, D van der Woude, E W N Levarht, M J K Mallat, H W Verspaget, J Stolk, R E M Toes, A E van der Meulen-de Jong, P S Hiemstra, C van Kooten, L A Trouw
Journal: Annals of the Rheumatic Diseases (2016)

Antibodies that target carbamylated proteins (anti-CarP antibodies) have been described as a biomarker in rheumatoid arthritis (RA).1 However, little is known about the factors that predispose to the production of anti-CarP antibodies. Carbamylation is a posttranslational modification resulting from the conversion of lysines into homocitrullines that requires the presence of cyanate. There are several conditions in which the concentration of cyanate (and therefore carbamylation) is increased, such as renal failure, chronic inflammation and heavy smoking.2–4 We therefore addressed the question whether conditions of enhanced carbamylation could result in the induction of anti-CarP antibodies.

To investigate this, we determined the presence of anti-CarP antibodies in serum samples from patients with renal failure,5 inflammatory bowel disease (IBD)6 and in heavy smokers with or without chronic obstructive pulmonary disease (COPD)7 (see table 1). The presence of anti-CarP antibodies in healthy controls and patients with RA was used as a comparison.1 ,8 The collection of these cohorts was approved by the Leiden University Medical Center ethics committee and informed consent …
The crucial impact of lysosomes in aging and longevity
Authors: Didac Carmona-Gutierrez, Adam L. Hughes, Frank Madeo, Christoph Ruckenstuhl
Journal: Ageing Research Reviews (2016)

Lysosomes are the main catabolic organelles of a cell and play a pivotal role in a plethora of cellular processes, including responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation. In line with this pleiotropic importance for cellular and organismal life and death, lysosomal dysfunction is associated with many age-related pathologies like Parkinson’s and Alzheimer’s disease, as well as with a decline in lifespan. Conversely, targeting lysosomal functional capacity is emerging as a means to promote longevity. Here, we analyze the current knowledge on the prominent influence of lysosomes on aging-related processes, such as their executory and regulatory roles during general and selective macroautophagy, or their storage capacity for amino acids and ions. In addition, we review and discuss the roles of lysosomes as active players in the mechanisms underlying known lifespan-extending interventions like, for example, spermidine or rapamycin administration. In conclusion, this review aims at critically examining the nature and pliability of the different layers, in which lysosomes are involved as a control hub for aging and longevity.
Sequential administration of sunitinib (SU) and docetaxel (D) in women with advanced breast cancer (ABC): an exploratory evaluation
Authors: G. Mariani, F. Cardoso, T. Besse-Hammer, L. Viganò, A. Liljegren, L. Verkh, X. Huang, C. Giorgetti, J. Bergh, L. Gianni
Journal: Journal of Clinical Oncology (2008)

14534 Background: SU is an oral broadly multitargeted tyrosine kinase inhibitor with major inhibitory activity on VEGFRs, PDGFRs, KIT, FLT3 and RET. This multitargeted approach may be beneficial in heterogeneous diseases such as BC. SU has shown single- agent activity in patients (pts) with heavily pretreated metastatic (M) BC (objective response rate 11%) and its antitumor activity is enhanced by D in mouse BC xenografts. In a phase I study, MTDs in solid tumor pts were SU 37.5 mg/d on Schedule 2/1 and D 75 mg/m2. Here we report on an exploratory study of SU+D given at their MTDs as first-line treatment to ABC pts. Methods: Pts with unresectable, locally recurrent or MBC who relapsed after anthracycline-based adjuvant chemotherapy received IV D at 75 mg/m2 q3w on day 1 and oral SU at 37.5 mg/d for 2 wks starting on day 2 of a 3-wk cycle (Schedule 2/1). The target number of pts was 20. The primary objective was the PK profile of SU+D. Secondary endpoints were safety and preliminary activity. After discontinuation of D, responders (partial response [PR] or stable disease [SD]) could continue SU as a single agent until progressive disease. Results: As of Oct 2007, 22 pts have received SU+D. Of these, 11 pts have discontinued therapy, 7 related to treatment (lack of efficacy, n=5; adverse events [AEs], n=2). Pts received a median of 8 cycles (Cs) SU (range: 1–15) and 6 Cs D (range: 1–11). SU dose was reduced to 25 mg/d in 3 pts and was increased to 50 mg/d in 1 pt. D was reduced to 60 mg/m2 in 6 pts. PK data (n=7) revealed no drug-drug interaction with co-administration. AEs were mostly mild or moderate in severity. G3 AEs were few and included 1 case each of fatigue, diarrhea, stomatitis and hand-foot syndrome. Neutropenia was reported at least once in all pts, with G4 events in 20 pts. Febrile neutropenia occurred in 4 pts. Preliminary tumor response data are available for 18 pts; 13 (72.2%) pts showed PR and 5 (27.7%) SD as best response (RECIST). Conclusions: SU 37.5 mg/d on a 2/1 schedule with D 75 mg/m2 q3w had a manageable safety profile when given as first- line treatment in ABC pts. Preliminary PK analysis indicated no drug-drug interaction. Early efficacy results warrant further exploration and a phase III study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer, sanofi-aventis Pfizer Pfizer, sanofi-aventis Pfizer
Phase I study to determine the safety of oral administration of TAS-102 on a twice daily (BID) schedule for five days a week (wk) followed by two days rest for two wks, every (Q) four wks in patients (pts) with metastatic breast cancer (MBC)
Authors: M. C. Green, L. Pusztai, R. L. Theriault, R. B. Adinin, M. Hofweber, M. Fukushima, A. Mita, N. Bindra, G. N. Hortobagyi
Journal: Journal of Clinical Oncology (2006)

10576 Background: TAS-102 is an oral combination of 5-trifluorothymidine (FTD) and a thymidine phosphorylase (TP) inhibitor. FTD is an antineoplastic antimetabolite that causes DNA-fragmentation after passive incorporation into DNA. The TP inhibitor prevents degradation of FTD when orally administered. This agent is active against many tumor cell lines including breast cancer. In animal studies, the use of divided daily dosing of TAS-102 has resulted in increased FTD incorporation into tumor DNA. This study was conducted to determine the phase II dose and the dose limiting toxicity (DLT) of TAS-102 in pts with solid tumors/MBC. Methods: Pts with MBC refractory to standard therapy (tx) or for whom no standard tx existed were eligible to participate on study. Pts with either measurable or evaluable MBC were enrolled at an initial dose level of 80 mg/m 2 /day given in divided doses BID days 1–5 of 7 days for 2 wks q 4 wks with standard 3+3 design. DLT was defined as any of the following in cycle 1 a. ≥ grade (gr) 3 non-hematologic toxicity (excluding nausea/vomiting); b. inability to take ≥ 75% of planned study dose per cycle; c. gr 4 granulocytopenia (GCP) lasting ≥ 3 days or febrile ≥ gr 3 GCP of any duration or gr 4 thrombocytopenia (TCP); d. &gt; 1 week delay in administration of the next scheduled dose. Evaluation of response was conducted every 8 wks. The recommended phase II dose was defined as the highest dose level that did not cause a DLT in 1/3 or more pts in that cohort. Results: 19 pts with MBC (median age: 56; median prior tx: 4) received tx with TAS-102. A median of 2 cycles were received (range 1–24) with one pt still on study. The initial starting dose resulted in DLT in 2/3 pts. Two additional dose levels were studied. The main cycle 1 toxicities were gr 3–4 GCP in 11/19 pts; gr 4 TCP in 1/19 pt. Other grade 3–4 toxicities were rare with minimal alopecia. The recommended phase II dose was determined to be 50 mg/m 2 /day given in divided doses BID days 1–5 of 7 days for 2 wks q 4 wks. Clinical activity was seen including prolonged disease control (&gt; 12 weeks) in 7 pts. Conclusions: TAS-102 given BID as described is an active agent against heavily pretreated MBC with primarily hematologic toxicity. [Table: see text]
Brain metastasis from renal cell carcinoma: Presentation, recurrence, survival and implications for systemic therapy
Authors: B. Shuch, J. C. La Rochelle, T. Klatte, S. B. Riggs, F. F. Kabbinavar, A. J. Pantuck, A. S. Belldegrun
Journal: Journal of Clinical Oncology (2008)

5097 Background: Patients with renal cell carcinoma brain metastasis (RCCBM) are frequently excluded from clinical trials. NCCN guidelines do not give clear recommendations regarding central nervous system (CNS) surveillance or therapy. We set out to define who should be screened and who should be considered for clinical trials after treatment of CNS lesions. Methods: A database of information was reviewed to determine presentation, clinical symptoms, number and size of lesions, use of and response to systemic therapy, treatment of BM, CNS disease free survival after treatment of original BM (CNS recurrence), and overall survival from time of diagnosis of BM. Results: A total of 138 patients with RCCBM were identified of whom 95% underwent treatment for their BM. Clear cell histology accounted for 92% of patients and 93% of patients had concomitant metastasis. Patients had CNS symptoms in 67% of cases. Symptomatic CNS tumors were larger (2.1 vs 1.3 cm, p <0.001) and more likely to receive a craniotomy (p<0.001). Number of lesions did not affect symptoms or risk of craniotomy. Median overall survival after diagnosis of BM was 10.7 months and the 1, 2, and 5 year survival was 48%, 30% and 12%, respectively. Performance status was the only independent predictor for survival (HR 6.1 p<0.001, CI 3–12.6). Local CNS recurrence was observed in 6.5% of patients, but new CNS lesions developed in 48%. Median time to CNS recurrence was 9 months. The initial number of CNS lesions (> 1 tumor) was an independent risk factors for CNS recurrence (HR 3.72, p <0.001, CI 2.0–7.1) Those with 1 and >1 BM had median CNS recurrence free survival of 13 and 4 months (p<0.001). Of patients receiving IL-2 based therapy after CNS treatment, 3/18 had an objective response. Conclusions: Patients with metastatic RCC should be evaluated with CNS imaging allowing identification of smaller lesions amenable to radiosurgery. Some patients exhibit prolonged survival and those with good performance status should be treated aggressively. Those with a solitary BM are less likely to recur and can be considered for therapy despite concerns over CNS penetration. No significant financial relationships to disclose.
Nearly six in 10 medical colleges in India did not publish any research in past 10 years
Authors: Sanjeet Bagcchi
Journal: BMJ (2016)

More than half (57%) of India’s 579 medical colleges did not publish any research in peer reviewed medical journals during the past 10 years, a study has found. States with the most private medical colleges performed the worst.

Researchers led by Samiran Nundy, dean of the Ganga Ram Institute for Postgraduate Medical Education and Research, New Delhi, used Scopus, a research database, to assess research output from Indian medical colleges during 2005-14. The study was published in Current Medicine Research and Practice .1

Of the 579 medical colleges in India, 316 (mostly public sector) are registered with …
RARE-18EXCEPTIONAL RESPONDERS: A PERSONALIZED APPROACH TO TARGETED TREATMENT OF UNCOMMON BRAIN TUMORS
Authors: Vinay Puduvalli, Pierre Giglio, Norman Lehman, Mario Ammirati, Daniel Prevedello, Wayne Slone, Jose Otero, Kristin Huntoon, Heather Cunningham, Sherry Cavezza
Journal: Neuro-Oncology (2015)

Targeted agents against brain tumors bearing specific pathway activation are postulated to provide significant responses but the utility of this approach has not been consistently shown. We report the use of such targeted therapy in two patients with rare tumors who demonstrated exceptional responses. The first was a 36 year old female who had a temporal dural based tumor with features of an atypical meningioma but with GFAP expression and brain invasion raising the possibility of a dural invasive glial malignancy. After two resections and radiation therapy, the patient rapidly deteriorated due to aggressive recurrence with extensive pan-neuraxis leptomeningeal disease causing quadriparesis, encephalopathy and status epilepticus needing ventilator support and consideration of hospice care. Based on detection of BRAFv600E mutation in the tumor, an IRB approved compassionate IND application for an investigational liquid formulation of dabrafenib was filed with the FDA and treatment initiated. The patient responded to dabrafenib with radiological improvement and respiratory recovery, normalization of mental status, resolution of seizures and recovery of normal strength in her upper extremities but with persistent paraplegia. The improvement remained durable for several months but was compromised by treatment-independent neurologic complications. The second patient was a 68 year old female with a right sphenoid wing skull base mass causing VII and VIII nerve palsies, which on resection was consistent with a perivascular epithelioid cell tumor (PEComa). FDG-PET scan-based staging showed extensive asymptomatic hypermetabolic malignancy including a left ovarian mass, a large retroperitoneal mass, and multiple liver and lung metastases. Given that PEComas often demonstrate mTOR pathway activation, the patient was treated with everolimus. Subsequent PET scan showed significant reduction in size and activity of the systemic lesions. These cases illustrate the utility of rationally selected molecular targeted therapy against rare brain neoplasms that can potentially yield exceptional responses.