How reliable is Ki-67 immunohistochemistry in grade 2 breast carcinomas? A QA study of the Swiss Working Group of Breast- and Gynecopathologists

Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. Methods Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. Results The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56–0.72). However, we found very high inter-observer variabilities (Kappa 0.04–0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01–0.04) and intra-observer agreement was likewise poor (Kappa 0.00–0.35). Conclusion Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas.

Alterations of the thoracic spine in Marfan's syndrome

OBJECTIVE: The purpose of this study was to determine if the thoracic vertebral elements are altered in patients with Marfan's syndrome. MATERIALS AND METHODS: Thirty patients underwent helical CT of the thorax because of suspected thoracic aortic dilatation and acute dissection. Thirteen had Marfan's syndrome and 17 did not. Two reviewers, unaware of the final diagnosis, evaluated the images by consensus for laminar thickness, foraminal width, dural sac ratios, and vertebral scalloping for T2-T12. RESULTS: At T9-T12, dural sac ratios at the midcorpus level (p = 0.031) and foraminal width (p = 0.0124) were significantly greater in the patients with Marfan's syndrome than in the patients without. Dural sac ratios at lower endplate levels (p = 0.0685), laminar thickness (p = 0.951), and vertebral scalloping (p = 0.24) were not significantly greater in the patients with Marfan's syndrome than in the patients without. CONCLUSION: Because the phenotypic expression of Marfan's syndrome is variable, information on the spine from thoracic studies in combination with major criteria may be helpful clinically.

Beta1 integrin deficiency results in multiple abnormalities of the knee joint

The lack of beta1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of beta1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the beta1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to beta1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. beta1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of beta1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways.

Oblivion, Erasure and Forgetting in the Digital Age

In light of the recent European Court of Justice ruling (ECJ C-131/12, Google Spain v Spanish Data Protection Agency),the “right to be forgotten” has once again gained worldwide media attention. Already in 2012, whenthe European Commission proposed aright to be forgotten,this proposal received broad public interest and was debated intensively. Under certain conditions, individuals should thereby be able todelete personal data concerning them. More recently – in light of the European Parliament’s approval of the LIBE Committee’samendments onMarch 14, 2014 – the concept seems tobe close to its final form.Although it remains, for the most part,unchanged from the previously circulated drafts, it has beenre-labelled as a“right of erasure”. This article argues that, despite its catchy terminology, the right to be forgotten can be understood as a generic term, bringing together existing legal provisions: the substantial right of oblivion and the rather procedural right to erasure derived from data protection. Hereinafter, the article presents an analysis of selected national legal frameworks and corresponding case law, accounting for data protection, privacy, and general tort law as well as defamation law. This comparative analysis grasps the practical challenges which the attempt to strengthen individual control and informational self-determination faces. Consequently, it is argued that narrowing the focus on the data protection law amendments neglects the elaborate balancing of conflicting interests in European legal tradition. It is shown thatthe attemptto implement oblivion, erasure and forgetting in the digital age is a complex undertaking.

Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey.

BACKGROUND Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children. METHODS Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was "useful", i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence. RESULTS Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %). CONCLUSIONS Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.

Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure.

Prior research has shown that mothers with Interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) report greater difficulty in parenting their toddlers. Relative to their frequent early exposure to violence and maltreatment, these mothers display dysregulation of their hypothalamic pituitary adrenal axis (HPA-axis), characterized by hypocortisolism. Considering methylation of the promoter region of the glucocorticoid receptor gene NR3C1 as a marker for HPA-axis functioning, with less methylation likely being associated with less circulating cortisol, the present study tested the hypothesis that the degree of methylation of this gene would be negatively correlated with maternal IPV-PTSD severity and parenting stress, and positively correlated with medial prefrontal cortical (mPFC) activity in response to video-stimuli of stressful versus non-stressful mother-child interactions. Following a mental health assessment, 45 mothers and their children (ages 12-42 months) participated in a behavioral protocol involving free-play and laboratory stressors such as mother-child separation. Maternal DNA was extracted from saliva. Interactive behavior was rated on the CARE-Index. During subsequent fMRI scanning, mothers were shown films of free-play and separation drawn from this protocol. Maternal PTSD severity and parenting stress were negatively correlated with the mean percentage of methylation of NR3C1. Maternal mPFC activity in response to video-stimuli of mother-child separation versus play correlated positively to NR3C1 methylation, and negatively to maternal IPV-PTSD and parenting stress. Among interactive behavior variables, child cooperativeness in play was positively correlated with NR3C1 methylation. Thus, the present study is the first published report to our knowledge, suggesting convergence of behavioral, epigenetic, and neuroimaging data that form a psychobiological signature of parenting-risk in the context of early life stress and PTSD.

Renal Blood Oxygenation Level-dependent Imaging in Longitudinal Follow-up of Donated and Remaining Kidneys

Purpose To determine renal oxygenation changes associated with uninephrectomy and transplantation in both native donor kidneys and transplanted kidneys by using blood oxygenation level-dependent (BOLD) MR imaging. Materials and Methods The study protocol was approved by the local ethics committee. Thirteen healthy kidney donors and their corresponding recipients underwent kidney BOLD MR imaging with a 3-T imager. Written informed consent was obtained from each subject. BOLD MR imaging was performed in donors before uninephrectomy and in donors and recipients 8 days, 3 months, and 12 months after transplantation. R2* values, which are inversely related to tissue partial pressure of oxygen, were determined in the cortex and medulla. Longitudinal R2* changes were statistically analyzed by using repeated measures one-way analysis of variance with post hoc pair-wise comparisons. Results R2* values in the remaining kidneys significantly decreased early after uninephrectomy in both the medulla and cortex (P < .003), from 28.9 sec(-1) ± 2.3 to 26.4 sec(-1) ± 2.5 in the medulla and from 18.3 sec(-1) ± 1.5 to 16.3 sec(-1) ± 1.0 in the cortex, indicating increased oxygen content. In donors, R2* remained significantly decreased in both the medulla and cortex at 3 (P < .01) and 12 (P < .01) months. In transplanted kidneys, R2* remained stable during the first year after transplantation, with no significant change. Among donors, cortical R2* was found to be negatively correlated with estimated glomerular filtration rate (R = -0.47, P < .001). Conclusion The results suggest that BOLD MR imaging may potentially be used to monitor renal functional changes in both remaining and corresponding transplanted kidneys. (©) RSNA, 2016.

Diatom biostratigraphy and datum levels of sediments from ODP Leg 167 sites

Ocean Drilling Program Leg 167 represents the first time since 1978 that the North American Pacific margin was drilled to study ocean history. More than 7500 m of Quaternary to middle Miocene (14 Ma) sediments were recovered from 13 sites, representing the most complete stratigraphic sequence on the California margin. Diatoms are found in most samples in variable abundance and in a moderately well-preserved state throughout the sequence, and they are often dominated by robust, dissolution-resistant species. The Neogene North Pacific diatom zonation of Yanagisawa and Akiba (1998, doi:10.5575/geosoc.104.395) best divides the Miocene to Quaternary sequences, and updated ages of diatom biohorizons estimated based on the geomagnetic polarity time scale of Cande and Kent (1995, doi:10.1029/94JB03098) are slightly revised to adjust the differences between the other zonations. Most of the early middle Miocene through Pleistocene diatom datum levels that have been proven to be of stratigraphic utility in the North Pacific appear to be nearly isochronous within the level of resolution constrained by sample spacing. The assemblages are characterized by species typical of middle-to-high latitudes and regions of high surface-water productivity, predominantly by Coscinodiscus marginatus, Stephanopyxis species, Proboscia barboi, and Thalassiothrix longissima. Latest Miocene through Pliocene assemblages in the region of the California Current, however, are intermediate between those of subarctic and subtropical areas. As a result, neither the existing tropical nor the subarctic (high latitude) zonal schemes were applicable for this region. An interval of pronounced diatom dissolution detected throughout the Pliocene sequence apparently correspond to a relatively warmer paleoceanographic condition resulting in a slackening of the southward flow of the California Current.

Un mundo escrito: Construcción de un espacio virtual-institucional para archivos de escritores de Misiones. 16H346

Este proyecto es continuación de proyectos de crítica genética que se llevaron a cabo, o están en marcha en la Secretaría de Investigación de la Facultad de Humanidades de la UNaM, que tienen como objeto manuscritos de la literatura provincial. La labor de este proyecto implica una red de acuerdos teóricos, críticos y metodológicos iniciales, un rastreo e identificación de documentos en la región y la tramitación de préstamos ante poseedores actuales de los manuscritos a la que se suma lo interdisciplinario con el diálogo entre la crítica genética y la ciencia de la computación. A la luz de este diálogo el proyecto se propone en esta primera etapa promover tres acciones: a) desarrollar un sitio virtual-institucional que facilite el acceso en línea a archivos de escritores regionales que se vienen estudiando en la UNaM. b) hacer un relevamiento de los archivos de manuscritos que en la actualidad se encuentran diseminados, invisibles a las investigaciones para, en ese gesto, recuperarlos e incentivar su estudio. c) diseñar y construir una base de datos y un repositorio digital de manuscritos, utilizando para esta tarea software Open Source. d) sentar las bases para un estudio sobre la factibilidad de implementar un proceso de Text Mining que automatice la recuperación de información relevante, categorice los documentos y los agrupe de acuerdo a características comunes. e) Afianzar lazos institucionales con otros proyectos existentes en Argentina (UNLP), Francia (CRLA-Archivos), Bélgica (UCLovaina), España ( Universidad de Castilla La Mancha) y con UNNE y la UNLa con quien ya tenemos un convenio de colaboración en Minería de datos.

Revisitaciones, huidas y desbordes en la novela argentina contemporánea. 16H302

El proyecto se propuso abordar distintas estrategias narrativas y novelísticas a partir de conceptos relacionados con las investigaciones que los integrantes del equipo están llevando a cabo, tales como realismo, márgenes, hibridez genérica. Habría en la novela contemporánea una suerte de desborde, idea que surge a raíz de percibir una disolución del género que viene desde muy antiguo y que sigue activa. El proyecto pretende asimismo delimitar las nociones de real y realidad para volverlos funcionales al trabajo a realizar y a la vez indagar sobre las relaciones entre los mismos y el denso concepto de realismo. Por otro lado se intenta evidenciar las relaciones entre la hibridez y la contaminación con la nombrada disolución. Las problemáticas del realismo en la novela se investigarán a la luz de la escritura y sus nexos con lo referencial. En ella se rastrearán las ascendencias de disolución del género novela, dado que los autores ya trabajan en un marco desbordado, un marco que se instaló hace casi un siglo y ha seguido proliferando en linajes variados hasta el siglo XXI. Se trata trabajar categorías que permitan una permanente revisitación del concepto y por eso mismo, un enriquecimiento de métodos, abordajes y lecturas. Las marginalidades y los márgenes son conceptos muy presentes en las investigaciones individuales de los participantes de este proyecto (de la marginalidad social presente en las historias narradas al margen físico de los libros como espacio significante.) El margen es un anclaje concreto desde el cual poner en acto el punto de partida. Por tal motivo se intentarán definiciones puntuales para los recorridos y los trabajos de cada uno, que luego podrán relacionarse en artefactos teórico-críticos productivos.

La memoria literaria de la provincia de Misiones (2ª parte). 16H301

ASISTENCIA A CONGRESOS: 17 TRABAJOS PRESENTADOS. 1- I JORNADAS TEMÁTICAS DE LITERATURA ARGENTINA CONTEMPORÁNEA: EL HUMOR EN LA LITERATURA ARGENTINA. Mendoza, del 25 al 27 de agosto de 2011 Ponencias presentadas: A) El humor de María Elena: infancia, memoria y crítica, María de las Mercedes García Saraví- María Alejandra Viana. B) Una mirada humorística en Dormir al sol, Karina Lemes y Natalia Aldana. C) De los Cambios en tu hijo adolescente a la alienación del ser. Karina Lemes. D) Isidoro Blaisten; el Humor como coartada, elaborado por Marisa Renaut; 2 - II CONGRESO INTERNACIONAL DE LITERATURA Y CULTURA ESPAÑOLAS CONTEMPORÁNEAS. Diálogos transatlánticos 3, 4 y 5 de octubre de 2011. Presentadas las siguientes ponencias: A) Laberintos y zonas de densidad: Barcelona y La Plata en dos novelas policiales de Manuel Vázquez Montalbán y Néstor Ponce. Carolina Repetto Mercedes García Saraví. B) El asedio: eco del mundo novelesco de Arturo Pérez Reverte, Haydée Borowski – Mercedes García Saraví. C) De la metaficción y otros procedimientos en La loca de la casa, Karina Beatriz Lemes. 3– XVI CONGRESO NACIONAL DE LITERATURA ARGENTINA. Resistencia, 6, 7 y 8 de octubre de 2011. Presentadas las siguientes ponencias. A) “Ceviche: una nueva cocina del policial”, María Aurelia Escalada- Mercedes García Saraví. B) Entre Santa María y Ruvichá: mundos ficcionales de Latinoamérica. Jorge Hernando Otero. C) El titirimundi de Juan Enrique Acuña: resignificaciones de un arte menor. Ana Eugenia Kushidonchi - Carina Mabel Pereira. D) Gauna: el hallazgo de un manuscrito, Mara Rabbe. E) Filiaciones en el borde. Lorca y Acuña. Karina Lemes y Natalia Aldana. F) Un Amable trasgresor de los géneros, Gabriela Román. 4- IV JORNADAS NACIONALES DE MINIFICCIÓN: HORIZONTES DE LA BREVEDAD EN EL MUNDO IBEROAMERICANO. HOMENAJE A DAVID LAGMANOVICH (1927-2010) Mendoza. 2, 3 y 4 de noviembre de 2011. Presentadas las siguientes ponencias: A) Falsificaciones, de Marco Denevi: la traducción y el apócrifo, aportes al género microrrelato Gabriela Román y Mercedes García Saraví. B) Formas breves en la narrativa de Hugo Wenceslao Amable, por Gabriela Román. Aceptado para actas. 5- IV CONGRESO CELEHIS, Mar del Plata, 7, 8 y 9 de noviembre 2011. Presentadas las siguientes ponencias. A) De la crítica y otros procedimientos en la Loca de la casa, Karina B. Lemes; b) Trayectorias y fronteras en Cádiz: El asedio (2009) de Arturo Pérez Reverte. Haydée Borowski – Mercedes García Saraví. C) Algunos mundos ficcionales de América Latina. Por Jorge Hernando Otero.// Defensa de Tesinas: Jorge Hernando Otero. Relatos ruvichenses: un espacio misionero/latinoamericano. Directora: Mercedes García Saraví. Codirectora: Karina B. Lemes. Defendida 02/11/2011, Nota: 10 (diez).