tbuckley/cabot-search huggingface dataset:
Stimulation of neural stem cell self-renewal via NADPH oxidase-generated ROS and inactivation of the tumor suppressor PTEN
Authors: Janel Le Belle, Hong Wu, Paul Mischel, Harley Kornblum
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

1261 

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene that is frequently mutated or deleted in various human cancers, including glioblastoma multiforme. In addition, germline mutations in the PTEN gene have been associated with autism and other related diseases in which patients develop macrocephaly of the brain. Previously, we have found that conditional deletion of PTEN in neural stem/progenitor cells results in an increased self-renewal capacity, a potentially important mechanism for brain tumorigenesis and the etiology of autism with macrocephaly.

Reactive oxygen species (ROS) are generally thought of as damaging by-products of aerobic metabolism. However, ROS also play important regulatory roles in eukaryotic cells. For example, many growth factors stimulate the production of oxidants which can contribute to the cellular proliferative response to these factors. Several studies have established the physiological regulation of some protein tyrosine phosphatases by endogenous ROS produced in response to growth factors, including the reversible inactivation of PTEN. Thus ROS such as hydrogen peroxide can function physiologically to regulate PTEN activity. However, little is known of the role of ROS in the proliferation of neural stem and/or progenitor cells, nor of the fundamental cellular mechanisms underlying ROS-dependent signaling processes in normal and neoplastic cells.

In the current study, we have examined the influence of ROS on neural stem and progenitor cells from E14 mouse cortex. We have found that low, non-toxic levels of ROS produces a modest increase in the overall proliferation rate of neurosphere cultures (15-21% increases over controls). However, the neural stem cell pool of cells is more significantly effected with ROS stimulation generating large increases (>250%) in self-renewing divisions in a clonal assay. We next examined the role of PTEN in mediating this response. Embryonic mouse cortical progenitors with a conditional PTEN deletion and a human glioblastoma PTEN-null cell line (U87MG) do not respond to mild oxidative stress, whereas their wild-type and PTEN-over-expressing counterparts are stimulated by the low levels of cellular oxidants. Additionally, we have shown that inhibitors of endogenous, NADPH oxidase-produced ROS completely attenuates stem cell self-renewal in clonal assays only when PTEN is intact (e.g. in the wild-type and PTEN-overexpressing U87MG). We propose that this may be an important and novel signaling pathway in neural stem and progenitor cell proliferation during development, which could become dysregulated by higher levels of oxidative stress or a failure of antioxidant defenses in the pathophysiology of brain disorders with macrocephaly and in tumorigenesis.
Intervendor Differences in the Accuracy of Detecting Regional Functional Abnormalities
Authors: Oana Mirea, Efstathios D. Pagourelias, Jurgen Duchenne, Jan Bogaert, James D. Thomas, Luigi P. Badano, Jens-Uwe Voigt, Luigi P. Badano, James D. Thomas, Jamie Hamilton, Stefano Pedri, Peter Lysyansky, Gunnar Hansen, Yasuhiro Ito, Tomoaki Chono, Jane Vogel, David Prater, Sungwook Park, Jin Yong Lee, Helene Houle, Bogdan Georgescu, Rolf Baumann, Bernhard Mumm, Yashuhiko Abe, Willem Gorissen
Journal: JACC. Cardiovascular imaging (2017)
P11.02 Long-term Outcome of Infants and Young Children with Newly Diagnosed Non-Nodular/Desmoplastic Medulloblastoma Treated on “Head Start” III Protocol
Authors: G. Dhall, L. Ji, K. Haley, F. Gilles, S. Gardner, R. Sposto, J. L. Finlay
Journal: Neuro-Oncology (2017)

Background: High-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach used in the management young children with medulloblastoma), with the additional benefit of avoiding the late effects of craniospinal irradiation (CSI). We report the outcome of infants and young children with classic and large cell/anaplastic (LCA) medulloblastoma treated on “Head Start (HS)” III, a prospective, multi-national clinical trial. Methods: Between April 2003 and December 2009, 92 children with newly-diagnosed medulloblastoma were enrolled amongst 29 participating institutions. All children were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, high dose methotrexate - cycles 1, 3, 5), and vincristine, cyclophosphamide, oral VP-16 and temozolomide (cycles 2, 4), followed by 1 consolidation cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and AuHCR. Only children between 6-10 years old or with residual tumor pre-consolidation, were to receive irradiation after consolidation. Results: Of 92 children with medulloblastoma enrolled on HSIII, 52 patients had classic and 13 had LCA medulloblastoma. Eighteen patients with classic and 6 with LCA medulloblastoma had localized disease (M0) whereas 33 patients with classic and 7 patients with LCA medulloblastoma had evidence of dissemination (M+). The 2-year event-free (EFS) and overall survival (OS) rates (+/- SE) for patients with classic medulloblastoma (primary objective of the study) were 37 ± 7% and 62 ± 7%, and for patients with LCA medulloblastoma were 54 ± 14% and 62 ± 13%, respectively. The 5-year EFS and OS rates were 26 ± 6% and 53 ± 7% for classic medulloblastoma and 38 ± 13% and 46 ± 14% for LCA medulloblastoma patients, respectively. For patients with M0 medulloblastoma, the 5-year EFS and OS rates were 38 ± 12% and 66 ± 11% for patients with classic histology and 50 ± 20% and 67 ± 19% for patients with LCA histology. Similarly, for patients with M+ medulloblastoma, the 5-year EFS and OS rates were 21 ± 7% and 48 ± 9% for patients with classic histology and 29 ± 17% and 29 ± 17% for patients with LCA histology. In multivariate Cox regression analyses, no significant difference in EFS was found between classic and LCA tumors. 5-year irradiation free-EFS for non-nodular/desmoplastic patients was 29 +/- 6%. Conclusion: Encouraging survival figures are reported for patients with classic medulloblastoma, similar to other contemporary infant protocols, whereas patients with LCA medulloblastoma had equivalent survival when compared to patients with classic medulloblastoma when treated with high-dose chemotherapy with AuHCR. These are among the best survival data published so far on infants and young children with LCA medulloblastoma. Approximately third of the survivors were able to avoid irradiation.
The systemic nature of CKD
Authors: Carmine Zoccali, Raymond Vanholder, Ziad A. Massy, Alberto Ortiz, Pantelis Sarafidis, Friedo W. Dekker, Danilo Fliser, Denis Fouque, Gunnar H. Heine, Kitty J. Jager, Mehmet Kanbay, Francesca Mallamaci, Gianfranco Parati, Patrick Rossignol, Andrzej Wiecek, Gerard London
Journal: Nature Reviews Nephrology (2017)
P12.17 Long-term prognosis of atypical and malignant meningioma: outcome and pronostic factors
Authors: S. Lee
Journal: Neuro-Oncology (2017)

AIMS: Twenty one atypical and fifteen malignant meningiomas were analyzed for long time to under stand the long-term outcome and associated prognostic factors retrospectively. METHODS: Thirty three (92%) meningiomas were macroscopically complete-resected in Simpson Grade I resection and three (8%) meningiomas were resected in Simpson Grade II. Ninety-one percent of all patients received whole brain radiotheraphy(WBRT) with nean dose of 52 Gy.We analyze the long-term survival, recurrence-free survival and prognostic significance of the grade of surgical resection and the difference between two groups. Results: Recurrence free survival and median time to recurrence were significantly longer in atypical than malignant meningioma. But, the benefit of adjuvant radiotheraphy was not effective significantly. Also the grade of surgical resection (Simpson Grade I vs II-III) were significantly related to prognostic survival. Conclusions: Pathological grade and the grade of surgical resection can be definite prognostic factors. However, multicenter prospective studies are necessary to clarify the management and the correct timing of radiotheraphy in such a rare disease.
OS03.6 Inadvertent underdosing of patients with neoplastic meningitis
Authors: A. Ali, M. Tulchinsky
Journal: Neuro-Oncology (2017)

Introduction: Intra-cerebrospinal fluid (CSF) chemotherapy delivered through a ventricular reservoir is the mainstay of treatment for patients with neoplastic meningitis. Numerous administration strategies have been advocated in the literature, and are used in practice. This wide variation in such an important aspect of treatment suggests uncertainty about the optimum approach. We evaluated differences in drug delivery associated with the three most commonly used intraventricular treatment techniques. Methods: 104 consecutive patients with newly diagnosed neoplastic meningitis underwent conventional CSF flow studies using indium-111 DTPA. Three administration techniques (reflecting published practices) were studied for each of two volumes (3 and 5 mL, reflecting standard chemotherapy administration volumes). Techniques evaluated were: administration of indium-111 DTPA followed by repeated compression of the Ommaya bulb (16 patients at 3 mL, 22 patients at 5 mL); administration of the radionuclide mixed with an equal volume of CSF followed by compression (17 patients at 3 mL and 18 patients at 5 mL), and barbotage with 4 or 6 mL of CSF withdrawn prior to the injection (15 patients at 3 mL and 16 patients at 5 mL). A 4 mL flush was used for the 3 mL radionuclide injection volume; 6 mL for the 5 mL volume. Residual radionuclide counts were measured in the injection syringe, butterfly needle/stopcock, and reservoir bulb. In addition, U.S. neuro-oncologists were surveyed regarding their intra-CSF chemotherapy administration techniques. Results: For the 3 mL injection volume, 53.5%, 28.0% and 3.14% of the radionuclide never reached the patient (i.e. remained in the injection syringe, butterfly tubing, or reservoir bulb) using the no flushing, CSF-drug mixing, and barbotaging techniques respectively (p<0.00001). For the 5 mL injection volume the corresponding percentages were 23.3%, 18.7%, and 3.0% (p<0.0001). Most of the wasted radionuclide remained in the reservoir bulb and butterfly tubing. The survey of U.S. neuro-oncologists revealed that the overwhelming majority do not use a CSF barbotage procedure for chemotherapy administration. Conclusions: A strikingly large fraction of radionuclide injected into Ommaya reservoirs never reaches the patient unless a barbotage technique is used. This finding likely applies to intraventricular chemotherapy injections as well. Use of a suboptimal technique may compromise the efficacy of therapy for patients with neoplastic meningitis.
Abstract 156: Enalapril prevents Development of Dilated Cardiomyopathy in Lamin A/C Mutant Mice
Authors: Abdelaziz Beqqali, Ingrid van Rijsingen, Inge van der Made, Stephanie van den Oever, Yigal Pinto
Journal: Circulation Research (2013)

Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure due to systolic dysfunction. Mutations in the LMNA gene, which encodes the nuclear lamina proteins Lamin A and C, are the most common cause of familial DCM. Current treatment strategies to improve the prognosis are limited to implantable cardioverter-defibrillator and heart transplantation. Patients with LMNA-related DCM are treated in accordance with international guidelines for the management of heart failure with little consideration of the possible influence of the etiology on the response to treatment. Recent studies suggest that this might result in inappropriate therapy in some patients. The influence of genetic factors in determining the response (and timing) of drug therapy is largely unstudied in DCM. Therefore, our aim is to determine the efficacy of existing heart failure drugs in preventing or delaying LMNA-related DCM. We used a well-established mouse model of Lamin A/C mimicking human LMNA-related DCM. Mice heterozygous for the Lmna mutant gene (n=20 per group) were treated with Metoprolol (β-blocker) or Enalapril (ACE-inhibitor) before the onset of DCM and were functionally evaluated by serial echocardiography and ECG until 75 weeks of age. Hearts were harvested for histological analysis and molecular characterization. Interestingly, the experimental group treated with Enalapril had a preserved overall cardiac function comparable to wildtype mice. Mice treated with Metoprolol however, displayed progressive heart failure, and an aggravated cardiac function compared to untreated Lmna +/- mice. Both the beneficial effects of Enalapril in preventing development of systolic dysfunction as well as the detrimental effect of Metoprolol were confirmed by expression of molecular stress markers and degree of cardiac fibrosis. Our results suggest that Enalapril is effective in preventing Lmna+/- induced cardiomyopathy in mice. Strikingly, Metoprolol increases cardiac dysfunction and stress in Lmna+/- mice. Further studies will determine whether Enalapril is also effective in preventing LMNA-related DCM in patients, and whether omitting Metoprolol from the standard cocktail of prescribed heart failure medicine is beneficial for LMNA patients.
Abstract 275: Interleukins 17th and 22th in Stable Coronary Artery Disease
Authors: Dinaldo Oliveira, Maira R Pitta, Ivan R Pitta, Elayne Heide, Viviane R Gomes, Edgard V Filho, Edgar G Victor, João B Oliveira Filho
Journal: Circulation Research (2013)

Introduction: The role of the immune and inflammatory pathways in coronary artery disease (CAD) is important but not complete understood. The aim of this study was to evaluate expressions of the interleukins 17th and 22th in patients with stable coronary artery disease. Hypothesis: Interleukins 17th and 22th are not increased in stable CAD. Methods: This is a cross-sectional, prospective, analytical study, conducted from August to December 2012. We included 40 patients (P) with stable CAD, CCS III or IV, ischemic myocardial scintigraphy, who had not been subjected to any kind of myocardial revascularization and with coronary stenosis equal or major than 50% according to current coronary angiography. There were 20 healthy volunteers (C), to take up comparison of expression of interleukins (IL). We evaluated the levels of IL 17th and 22th of the patients and controls. Interleukins were evaluated in serum of patients and after 48 hours of cells in culture with and without stimulus. IL concentrations were expressed in pg / ml. Statistical analysis was performed using the Mann-Whitney or Student t test. P ≤ 0,05 was considered statistically significant. Results: There were 26 men and 14 women in the group of the patients and 12 men and 8 women in the controls. The age was similar between the groups (63.2 ± 8.9 years vs 57.9 ± 9.4, p = ns). The comparison between the groups showed: Interleukin 17th: Serum: P = 3.9 (972.2 -- 2.93) vs C = 3.90 (28.8 -- 1.74), p = 0.5; culture 48 hours without stimulus: P = 3.90 (3.90 -- 3.90) vs C = 6.37 (3.90 - 11), p = 0.8; culture 48 hours with stimulus: P = 302.42 (2200 -- 3.90) vs C = 815 (1353 -- 3.90), p = 0.06. Interleukin 22th: Serum: P = 15.62 (64.72 -- 15.62) vs C = 15.62 (121 -- 15.62), p = 0.2; Culture 48 hours without stimulus: P = 11 (128.93 -- 7.81) vs C = 7.81 (7.81 -- 7.81), P = 0.8; Culture 48 hours with stimulus: P = 135 (2486.7 -- 7, 81) vs C = 322.86 (1319.11 -- 7.81), p = 0.4. Conclusions: There were no differences in concentrations of interleukins, but the trend of higher expression of the IL 17th in the controls after cell culture with stimulus. In conclusion, in patients with stable CAD the interleukins 17th and 22th did not exhibit increased concentrations.
Differential Retention of Gene Functions in a Secondary Metabolite Cluster
Authors: Hannah T. Reynolds, Jason C. Slot, Hege H. Divon, Erik Lysøe, Robert H. Proctor, Daren W. Brown
Journal: Molecular Biology and Evolution (2017)

In fungi, distribution of secondary metabolite (SM) gene clusters is often associated with host- or environment-specific benefits provided by SMs. In the plant pathogen Alternaria brassicicola (Dothideomycetes), the DEP cluster confers an ability to synthesize the SM depudecin, a histone deacetylase inhibitor that contributes weakly to virulence. The DEP cluster includes genes encoding enzymes, a transporter, and a transcription regulator. We investigated the distribution and evolution of the DEP cluster in 585 fungal genomes and found a wide but sporadic distribution among Dothideomycetes, Sordariomycetes, and Eurotiomycetes. We confirmed DEP gene expression and depudecin production in one fungus, Fusarium langsethiae. Phylogenetic analyses suggested 6-10 horizontal gene transfers (HGTs) of the cluster, including a transfer that led to the presence of closely related cluster homologs in Alternaria and Fusarium. The analyses also indicated that HGTs were frequently followed by loss/pseudogenization of one or more DEP genes. Independent cluster inactivation was inferred in at least four fungal classes. Analyses of transitions among functional, pseudogenized, and absent states of DEP genes among Fusarium species suggest enzyme-encoding genes are lost at higher rates than the transporter (DEP3) and regulatory (DEP6) genes. The phenotype of an experimentally-induced DEP3 mutant of Fusarium did not support the hypothesis that selective retention of DEP3 and DEP6 protects fungi from exogenous depudecin. Together, the results suggest that HGT and gene loss have contributed significantly to DEP cluster distribution, and that some DEP genes provide a greater fitness benefit possibly due to a differential tendency to form network connections.
Phase I/II Study of Ruxolitinib (RUX) with Decitabine (DAC) in Patients with Post-Myeloproliferative Neoplasm Acute Myeloid Leukemia (post-MPN AML): Phase I Results
Authors: Prithviraj Bose, Srdan Verstovsek, Yvonne Gasior, Nitin Jain, Elias J. Jabbour, Zeev Estrov, Yesid Alvarado, Courtney D. DiNardo, Naveen Pemmaraju, Steven M. Kornblau, Tapan M. Kadia, Naval G. Daver, Mark Brandt, Sherry Pierce, Graciela M. Nogueras-Gonzalez, Xuelin Huang, Guillermo Garcia-Manero, Hagop M. Kantarjian, Farhad Ravandi
Journal: Blood (2016)
Global epidemiology of non-influenza RNA respiratory viruses: data gaps and a growing need for surveillance
Authors: Julian W Tang, Tommy T Lam, Hassan Zaraket, W Ian Lipkin, Steven J Drews, Todd F Hatchette, Jean-Michel Heraud, Marion P Koopmans, Ashta Mary Abraham, Amal Baraket, Seweryn Bialasiewicz, Miguela A Caniza, Paul KS Chan, Cheryl Cohen, André Corriveau, Benjamin J Cowling, Steven J Drews, Marcela Echavarria, Ron Fouchier, Pieter LA Fraaij, Todd F Hachette, Jean-Michel Heraud, Hamid Jalal, Lance Jennings, Alice Kabanda, Herve A Kadjo, Mohammed Rafiq Khanani, Evelyn SC Koay, Marion P Koopmans, Mel Krajden, Tommy T Lam, Hong Kai Lee, W. Ian Lipkin, Julius Lutwama, David Marchant, Hidekazu Nishimura, Pagbajabyn Nymadawa, Benjamin A Pinsky, Sanjiv Rughooputh, Joseph Rukelibuga, Taslimarif Saiyed, Anita Shet, Theo Sloots, JJ Muyembe Tamfum, Julian W Tang, Stefano Tempia, Sarah Tozer, Florette Treurnicht, Matti Waris, Aripuana Watanabe, Emile Okitolonda Wemakoy
Journal: The Lancet Infectious Diseases (2017)
Intensity of Statin Treatment and Mortality—Reply
Authors: Fatima Rodriguez, David J. Maron, Paul A. Heidenreich
Journal: JAMA Cardiology (2017)

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The Response Evaluation Criteria in Solid Tumors Can be Substituted for the International Workshop Criteria?: Comparison Using Japan Clinical Oncology Group Study JCOG0203 for Untreated Indolent B-Cell Lymphoma
Authors: Kenichi Miyamoto, Takashi Watanabe, Hideaki Kitahara, Masashi Wakabayashi, Kenichi Nakamura, Yuko Watanabe, Dai Maruyama, Kensei Tobinai, Kunihiro Tsukasaki, Haruhiko Fukuda
Journal: Blood (2016)
Sexual healthcare must not be allowed to become “Cinderella” of NHS, warns royal college chair
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Years of improvement in sexual and reproductive health could be reversed unless the bureaucratic, financial, and training barriers facing GPs and their teams are removed, the Royal College of General Practitioners has warned.

The difficulties faced by general practice teams were shown in a consultation of the RCGP membership, carried out by the college for a council paper not yet published, the college’s chair, Helen Stokes-Lampard, said in a speech on …