Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

“To laugh in tragic joy” – a linguagem poética de W. B. Yeats em Lapis Lazuli

Artigo em texto integral no link da versão do editor

Ser mulher, aqui: teatro, género e comunidade

Dissertação apresentada à Escola Superior de Educação de Lisboa para obtenção de grau de mestre em Educação Artística, na especialização de Teatro na Educação

Análise da competitividade e desenvolvimento dos destinos turísticos da grande Lisboa e Oeste

Dissertação apresentada ao Instituto Politécnico do Porto para obtenção do Grau de Mestre em Gestão das Organizações, Ramo de Gestão de Empresas Orientada por: Professora Doutora Paula Odete Fernandes Professor Doutor Rui da Assunção Esteves Pimenta

Género e Media: estereótipos das masculinidades na publicidade das revistas masculinas em Portugal

Tese apresentada para cumprimento dos requisitos necessários à obtenção do grau de Doutor em Ciências da Comunicação

Ajustamento pelo risco : da conceptualização à operacionalização

RESUMO - As organizações de saúde, em geral, e os hospitais, em particular, são frequentemente reconhecidos por terem particularidades e especificidades que conferem uma especial complexidade ao seu processo produtivo e à sua gestão (Jacobs, 1974; Butler, 1995). Neste sentido, na literatura hospitalar emergem alguns temas como prioritários tanto na investigação como na avaliação do seu funcionamento, nomeadamente os relacionados com a produção, com o financiamento, com a qualidade, com a eficiência e com a avaliação do seu desempenho. O estado da arte da avaliação do desempenho das organizações de saúde parece seguir a trilogia definida por Donabedian (1985) — Estrutura, Processo e Resultados. Existem diversas perspectivas para a avaliação do desempenho na óptica dos Resultados — efectividade, eficiência ou desempenho financeiro. No entanto, qualquer que seja a utilizada, o ajustamento pelo risco é necessário para se avaliar a actividade das organizações de saúde, como forma de medir as características dos doentes que podem influenciar os resultados de saúde. Como possíveis indicadores de resultados, existem a mortalidade (resultados finais), as complicações e as readmissões (resultados intermédios). Com excepção dos estudos realizados por Thomas (1996) e Thomas e Hofer (1998 e 1999), praticamente ninguém contesta a relação entre estes indicadores e a efectividade dos cuidados. Chamando, no entanto, a atenção para a necessidade de se definirem modelos de ajustamento pelo risco e ainda para algumas dificuldades conceptuais e operacionais para se atingir este objectivo. Em relação à eficiência técnica dos hospitais, os indicadores tradicionalmente mais utilizados para a sua avaliação são os custos médios e a demora média. Também neste domínio, a grande maioria dos estudos aponta para que a gravidade aumenta o poder justificativo do consumo de recursos e que o ajustamento pelo risco é útil para avaliar a eficiência dos hospitais. Em relação aos sistemas usados para medir a severidade e, consequentemente, ajustar pelo risco, o seu desenvolvimento apresenta, na generalidade, dois tipos de preocupações: a definição dos suportes de recolha da informação e a definição dos momentos de medição. Em última instância, o dilema que se coloca reside na definição de prioridades e daquilo que se pretende sacrificar. Quando se entende que os aspectos financeiros são determinantes, então será natural que se privilegie o recurso quase exclusivo a elementos dos resumos de alta como suporte de recolha da informação. Quando se defende que a validade de construção e de conteúdo é um aspecto a preservar, então o recurso aos elementos dos processos clínicos é inevitável. A definição dos momentos de medição dos dados tem repercussões em dois níveis de análise: na neutralidade económica do sistema e na prospectividade do sistema. O impacto destas questões na avaliação da efectividade e da eficiência dos hospitais não é uma questão pacífica, visto que existem autores que defendem a utilização de modelos baseados nos resumos de alta, enquanto outros defendem a supremacia dos modelos baseados nos dados dos processos clínicos, para finalmente outros argumentarem que a utilização de uns ou outros é indiferente, pelo que o processo de escolha deve obedecer a critérios mais pragmáticos, como a sua exequibilidade e os respectivos custos de implementação e de exploração. Em relação às possibilidades que neste momento se colocam em Portugal para a utilização e aplicação de sistemas de ajustamento pelo risco, verifica-se que é praticamente impossível a curto prazo aplicar modelos com base em dados clínicos. Esta opção não deve impedir que a médio prazo se altere o sistema de informação dos hospitais, de forma a considerar a eventualidade de se utilizarem estes modelos. Existem diversos problemas quando se pretendem aplicar sistemas de ajustamento de risco a populações diferentes ou a subgrupos distintos das populações donde o sistema foi originalmente construído, existindo a necessidade de verificar o ajustamento do modelo à população em questão, em função da sua calibração e discriminação.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.

OBJECTIVES: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. BACKGROUND: Inflammation is associated with HF risk factors and also directly affects myocardial function. METHODS: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). RESULTS: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). CONCLUSIONS: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Association of major and minor ECG abnormalities with coronary heart disease events.

CONTEXT: In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle-aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction. OBJECTIVE: To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997-1998 and 2006-2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events. MAIN OUTCOME MEASURE: Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization). RESULTS: At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02-1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20-1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%-19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32%-2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33-3.02; and HR, 1.66; 95% CI, 1.18-2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, -0.4% to 11.8%). CONCLUSIONS: Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors.

1969-70 Men's Basketball

Pictured here from left to right: Back Row - Les Korchok (Coach), Ken Cripps, Mike McGinnis, Bill Butler, Tim McKillop, Gary Jellum, Fred Kovacs (Manager). Front Row - Jim Leach, Wally Dick, Bob Tatti, Paul Zutautas, Tom Kearney (Trainer). Kneeling - Dave Luff, Dave Brent. Missing - Bill Levesque.

Localization of the mechanism of pH-dependent non- photochemical fluorescence quenching in thylakoid membranes

Higher plants have evolved a well-conserved set of photoprotective mechanisms, collectively designated Non-Photochemical Quenching of chlorophyll fluorescence (qN), to deal with the inhibitory absorption of excess light energy by the photosystems. Their main contribution originates from safe thermal deactivation of excited states promoted by a highly-energized thylakoid membrane, detected via lumen acidification. The precise origins of this energy- or LlpH-dependent quenching (qE), arising from either decreased energy transfer efficiency in PSII antennae (~ Young & Frank, 1996; Gilmore & Yamamoto, 1992; Ruban et aI., 1992), from alternative electron transfer pathways in PSII reaction centres (~ Schreiber & Neubauer, 1990; Thompson &Brudvig, 1988; Klimov et aI., 1977), or from both (Wagner et aI., 1996; Walters & Horton, 1993), are a source of considerable controversy. In this study, the origins of qE were investigated in spinach thylakoids using a combination of fluorescence spectroscopic techniques: Pulse Amplitude Modulated (PAM) fluorimetry, pump-probe fluorimetry for the measurement of PSII absorption crosssections, and picosecond fluorescence decay curves fit to a kinetic model for PSII. Quenching by qE (,..,600/0 of maximal fluorescence, Fm) was light-induced in circulating samples and the resulting pH gradient maintained during a dark delay by the lumenacidifying capabilities of thylakoid membrane H+ ATPases. Results for qE were compared to those for the addition of a known antenna quencher, 5-hydroxy-1,4naphthoquinone (5-0H-NQ), titrated to achieve the same degree of Fm quenching as for qE. Quenching of the minimal fluorescence yield, F0' was clear (8 to 130/0) during formation of qE, indicative of classical antenna quenching (Butler, 1984), although the degree was significantly less than that achieved by addition of 5-0H-NQ. Although qE induction resulted in an overall increase in absorption cross-section, unlike the decrease expected for antenna quenchers like the quinone, a larger increase in crosssection was observed when qE induction was attempted in thylakoids with collapsed pH gradients (uncoupled by nigericin), in the absence of xanthophyll cycle operation (inhibited by DTT), or in the absence of quenching (LlpH not maintained in the dark due to omission of ATP). Fluorescence decay curves exhibited a similar disparity between qE-quenched and 5-0H-NQ-quenched thylakoids, although both sets showed accelerated kinetics in the fastest decay components at both F0 and Fm. In addition, the kinetics of dark-adapted thylakoids were nearly identical to those in qEquenched samples at F0' both accelerated in comparison with thylakoids in which the redox poise of the Oxygen-Evolving Complex was randomized by exposure to low levels of background light (which allowed appropriate comparison with F0 yields from quenched samples). When modelled with the Reversible Radical Pair model for PSII (Schatz et aI., 1988), quinone quenching could be sufficiently described by increasing only the rate constant for decay in the antenna (as in Vasil'ev et aI., 1998), whereas modelling of data from qE-quenched thylakoids required changes in both the antenna rate constant and in rate constants for the reaction centre. The clear differences between qE and 5-0H-NQ quenching demonstrated that qE could not have its origins in the antenna alone, but is rather accompanied by reaction centre quenching. Defined mechanisms of reaction centre quenching are discussed, also in relation to the observed post-quenching depression in Fm associated with photoinhibition.

Rick Bell Family fonds, 1874-1875, 1879, 1884, 1886, 1888-1889, 1896, 1898, 1909-1910, 1939, 1945, n.d.

Lewis Tyrell married Jane Gains on August 31, 1849 in Culpeper Court House, Virginia. Jane Gains was a spinster. Lewis Tyrell died September 25, 1908 at his late residence, Vine St. and Welland Ave., St. Catharines, Ont. at the age of 81 years, 5 months. Jane Tyrell died March 1, 1886, age 64 years. Their son? William C. Tyrell died January 15, 1898, by accident in Albany, NY, age 33 years, 3 months. John William Taylor married Susan Jones were married in St. Catharines, Ont. on August 10, 1851 by William Wilkinson, a Baptist minister. On August 9, 1894 Charles Henry Bell (1871-1916), son of Stephen (1835?-1876) and Susan Bell, married Mary E. Tyrell (b. 1869?) daughter of Lewis and Alice Tyrell, in St. Catharines Ontario. By 1895 the Bell’s were living in Erie, Pennsylvania where children Delbert Otto (b. 1895) and Edna Beatrice (b. 1897) were born. By 1897 the family was back in St. Catharines where children Lewis Tyrell (b. 1899), Gertrude Cora (b. 1901), Bessie Jane (b. 1902), Charles Henry (b. 1906), Richard Nelson (b. 1911) and William Willoughby (b. 1912) were born. Charles Henry Bell operated a coal and ice business on Geneva Street. In the 1901 Census for St. Catharines, the Bell family includes the lodger Charles Henry Hall. Charles Henry Hall was born ca. 1824 in Maryland, he died in St. Catharines on November 11, 1916 at the age of 92. On October 24, 1889 Charles Hall married Susan Bell (1829-1898). The 1911 Census of Canada records Charles Henry Hall residing in the same household as Charles Henry and Mary Bell. The relationship to the householder is step-father. It is likely that after Stephen Bell’s death in 1876, his widow, Susan Bell married Hall. In 1939, Richard Nelson Bell, son of Charles Henry and Mary Tyrell Bell, married Iris Sloman. Iris (b. 22 May 1912 in Biddulph Township, Middlesex, Ontario) was the daughter of Albert (son of Joseph b. 1870 and Elizabeth Sloman, b. 1872) and Josie (Josephine Ellen) Butler Sloman of London, Ont. Josie (b. 1891) was the daughter of Everett Richard and Elizabeth McCarthy (or McCarty) Butler, of Lucan Village, Middlesex North. According to the 1911 Census of Canada, Albert, a Methodist, was a porter on the railroad. His wife, Josephine, was a Roman Catholic. Residing with Albert and Josie were Sanford and Sadie Butler and Sidney Sloman, likely siblings of Albert and Josephine. The Butler family is descended from Peter Butler, a former slave, who had settled in the Wilberforce Colony in the 1830s. Rick Bell b. 1949 in Niagara Falls, Ont. is the son of Richard Nelson Bell. In 1979, after working seven years as an orderly at the St. Catharines General Hospital while also attending night school at Niagara College, Rick Bell was hired by the Thorold Fire Dept. He became the first Black professional firefighter in Niagara. He is a founding member of the St. Catharines Junior Symphony; attended the Banff School of Fine Arts in 1966 and also performed with the Lincoln & Welland Regimental Band and several other popular local groups. Upon the discovery of this rich archive in his mothers’ attic he became passionate about sharing his Black ancestry and the contributions of fugitive slaves to the heritage Niagara with local school children. He currently resides in London, Ont.

William Van Every fonds, 1784, 1804-1806, 1815-1816, 1828, 1832, n.d.

William Van Every, son of McGregory and Mary Wilcox (Jaycocks) Van Every, was born in New York state in 1765. During the Revolutionary War he joined Butler’s Rangers and served under Captain John McDonnell. He was granted three lots of land in the Township of Niagara, with additional lands granted at later dates. William married Elizabeth, daughter of George Young. Elizabeth was the widow of Col. Frederick Dochstader and mother of Catherine Dochstader, b. 1781. William Van Every died in 1832, his wife Elizabeth in 1851. Both are buried in the Warner Cemetery, in present day Niagara Falls. The children of William Van Every and Elizabeth Young were Mary, Elizabeth, Phoebe, John, Peter, William, Rebecca, Samuel and Joseph. Source: Mary Blackadar Piersol, The Records of the Van Every Family, Toronto : Best Printing, 1947. And, Patricia M. Orr, Historic Woodend, sponsored by Niagara Peninsula Conservation Authority, 1980?

Photograph of Josephine Sloman [n.d.]

Josephine Sloman pictured in this undated photograph taken in Niagara Falls. Josephine (Ellen Butler) Sloman was born in 1891 in London, Ontario. This small photo was among the family memorabilia in the possession of Rick Bell, of St. Catharines, whose ancestors include former Black slaves from the United States.

Baltimore Patriot and Evening Advertiser Vol. 3 No. 89- April 15, 1814

This daily paper, except Sundays, began publication on August 17, 1813 and ceased April 30, 1817. It was also published tri-weekly for a "COUNTRY" edition. The paper later became the Baltimore Patriot. Topics of interest include: Page 1: announcement Capt. M. Simmones Burnbury is seeking men to form a company of Sea Fencibles; Page 2: U.S. Legislature authorizes bill to increase the Marine Corps; U.S. Legislature authorizes bill to purchase vessels captured on Lake Erie; U.S. Senate bill authorizes the appointment of officers for the flotilla service; President of United States authorized to accept service of volunteer corps for defence of United States; Letter from Capt. A. H. Holmes to Lieut. Col. Butler detailing an American victory over the British near Detroit; announcement of British forces building barges for the purpose of attacking Detroit; War sloop Erie returns to Baltimore unable to reach sea due to British forces in the Chesapeake; Page 3: Death notice of Mr. Ward Fairchild of the U.S. Army; Page 4: Commander of the U.S. Flotilla seeks men for the Chesapeake Flotilla.