Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

background: The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer. methods: The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined. results: A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%. conclusions: Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer

History of oceanic front development in the New Zealand sector of the Southern Ocean during the Cenozoic--a synthesis

The New Zealand sector of the Southern Ocean (NZSSO) has opened about the Indian-Pacific spreading ridge throughout the Cenozoic. Today the NZSSO is characterised by broad zonal belts of antarctic (cold), subantarctic (cool), and subtropical (warm) surface-water masses separated by prominent oceanic fronts: the Subtropical Front (STF) c. 43deg.S, Subantarctic Front (SAF) c. 50deg.S, and Antarctic Polar Front (AAPF) c. 60deg.S. Despite a meagre database, the broad pattern of Cenozoic evolution of these fronts is reviewed from the results of Deep Sea Drilling Project-based studies of sediment facies, microfossil assemblages and diversity, and stable isotope records, as well as from evidence in onland New Zealand Cenozoic sequences. Results are depicted schematically on seven paleogeographic maps covering the NZSSO at 10 m.y. intervals through the Cenozoic. During the Paleocene and most of the Eocene (65-35 Ma), the entire NZSSO was under the influence of warm to cool subtropical waters, with no detectable oceanic fronts. In the latest Eocene (c. 35 Ma), a proto-STF is shown separating subantarctic and subtropical waters offshore from Antarctica, near 65deg.S paleolatitude. During the earliest Oligocene, this front was displaced northwards by development of an AAPF following major global cooling and biotic turnover associated with ice sheet expansion to sea level on East Antarctica. Early Oligocene full opening (c. 31 Ma) of the Tasmanian gateway initiated vigorous proto-circum-Antarctic flow of cold/cool waters, possibly through a West Antarctic seaway linking the southern Pacific and Atlantic Oceans, including detached northwards "jetting" onto the New Zealand plateau where condensation and unconformity development was widespread in cool-water carbonate facies. Since this time, a broad tripartite division of antarctic, subantarctic, and subtropical waters has existed in the NZSSO, including possible development of a proto-SAF within the subantarctic belt. In the Early-early Middle Miocene (25-15 Ma), warm subtropical waters expanded southwards into the northern NZSSO, possibly associated with reduced ice volume on East Antarctica but particularly with restriction of the Indonesian gateway and redirection of intensified warm surface flows southwards into the Tasman Sea, as well as complete opening of the Drake gateway by 23 Ma allowing more complete decoupling of cool circum-Antarctic flow from the subtropical waters. During the late Middle-Late Miocene (15-5 Ma), both the STF and SAF proper were established in their present relative positions across and about the Campbell Plateau, respectively, accompanying renewed ice buildup on East Antarctica and formation of a permanent ice sheet on West Antarctica, as well as generally more expansive and intensified circum-Antarctic flow. The ultimate control on the history of oceanic front development in the NZSSO has been plate tectonics through its influence on the paleogeographic changes of the Australian-New Zealand-Antarctic continents and their intervening oceanic basins, the timing of opening and closing of critical seaways, the potential for submarine ridges and plateaus to exert some bathymetric control on the location of fronts, and the evolving ice budget on the Antarctic continent. The broad trends of the Cenozoic climate curve for New Zealand deduced from fossil evidence in the uplifted marine sedimentary record correspond well to the principal paleoceanographic events controlling the evolution and migration of the oceanic fronts in the NZSSO

'To live and die [for] Dixie': Irish civilians and the Confederate States of America

Around 20,000 Irishmen served in the Confederate army in the Civil War. As a result, they left behind, in various Southern towns and cities, large numbers of friends, family, and community leaders. As with native-born Confederates, Irish civilian support was crucial to Irish participation in the Confederate military effort. Also, Irish civilians served in various supporting roles: in factories and hospitals, on railroads and diplomatic missions, and as boosters for the cause. They also, however, suffered in bombardments, sieges, and the blockade. Usually poorer than their native neighbours, they could not afford to become 'refugees' and move away from the centres of conflict. This essay, based on research from manuscript collections, contemporary newspapers, British Consular records, and Federal military records, will examine the role of Irish civilians in the Confederacy, and assess the role this activity had on their integration into Southern communities. It will also look at Irish civilians in the defeat of the Confederacy, particularly when they came under Union occupation. Initial research shows that Irish civilians were not as upset as other whites in the South about Union victory. They welcomed a return to normalcy, and often 'collaborated' with Union authorities. Also, Irish desertion rates in the Confederate army were particularly high, and I will attempt to gauge whether Irish civilians played a role in this. All of the research in this paper will thus be put in the context of the Drew Gilpin Faust/Gary Gallagher debate on the influence of the Confederate homefront on military performance. By studying the Irish civilian experience one can assess how strong the Confederate national experiment was. Was it a nation without a nationalism

Beyond dis-identification: A discursive approach to self-alienation in contemporary organizations

Dis-identification has become a key research area in organization studies, demonstrating how employees subjectively distance themselves from managerial domination by protecting/constructing their more ‘authentic’ identities. But how should we understand situations where even these ‘real’ selves are experienced as alien and foreign? We revise the theory of self-alienation to explain cases beyond disidentification, where even back-stage identities (‘who we really are’) are considered something polluted, objectified and foreign. Drawing on an illustrative empirical vignette of a consultant, we demonstrate how a revised version of self-alienation might usefully capture experiences of work where the back-stage/front-stage boundary breaks down. We tentatively posit three causes of this self-alienation in relation to contemporary organizations, and discuss their significance in the context of organizational dis identification

Decrease in Incidence of Colorectal Cancer Among Individuals 50 Years or Older After Recommendations for Population-based Screening

BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in the United States is increasing among adults younger than 50 years, but incidence has decreased among older populations after population-based screening was recommended in the late 1980s. Blacks have higher incidence than whites. These patterns have prompted suggestions to lower the screening age for average-risk populations or in blacks. At the same time, there has been controversy over whether reductions in CRC incidence can be attributed to screening. We examined age-related and race-related differences in CRC incidence during a 40-year time period. METHODS: We determined the age-standardized incidence of CRC from 1975 through 2013 by using the population-based Surveillance, Epidemiology, and End Results (SEER) program of cancer registries. We calculated incidence for 5-year age categories (20-24 years through 80-84 years and 85 years or older) for different time periods (1975-1979, 1980-1984, 1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, and 2010-2013), tumor subsite (proximal colon, descending colon, and rectum), and stages at diagnosis (localized, regional, and distant). Analyses were stratified by race (white vs black). RESULTS: There were 450,682 incident cases of CRC reported to the SEER registries during the entire period (1975-2013). Overall incidence was 75.5/100,000 white persons and 83.6/100,000 black persons. CRC incidence peaked during 1980 through 1989 and began to decrease in 1990. In whites and blacks, the decreases in incidence between the time periods of 1980-1984 and 2010-2013 were limited to the screening-age population (ages 50 years or older). Between these time periods, there was 40% decrease in incidence among whites compared with 26% decrease in incidence among blacks. Decreases in incidence were greater for cancers of the distal colon and rectum, and reductions in these cancers were greater among whites than blacks. CRC incidence among persons younger than 50 years decreased slightly between 1975-1979 and 1990. However, among persons 20-49 years old, CRC incidence increased from 8.3/100,000 persons in 1990-1994 to 11.4/100,000 persons in 2010-2013; incidence rates in younger adults were similar for whites and blacks. CONCLUSIONS: On the basis of an analysis of the SEER cancer registries from 1975 through 2013, CRC incidence decreased only among individuals 50 years or older between the time periods of 1980-1984 and 2010-2013. Incidence increased modestly among individuals 20-49 years old between the time periods of 1990-1994 and 2010-2013. The decision of whether to recommend screening for younger populations requires a formal analysis of risks and benefits. Our observed trends provide compelling evidence that screening has had an important role in reducing CRC incidence

Relationships of PBMC microRNA expression, plasma viral load, and CD4+ T-cell count in HIV-1-infected elite suppressors and viremic patients

<p>Abstract</p> <p>Background</p> <p>HIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy. The mechanisms of suppression are incompletely understood. Modulation of HIV-1 replication by miRNAs has been reported, but the role of small RNAs in ES is unknown. Using samples from a well-characterized ES cohort, untreated viremic patients, and uninfected controls, we explored the PBMC miRNA profile and probed the relationships of miRNA expression, CD4+ T-cell counts, and viral load.</p> <p>Results</p> <p>miRNA profiles, obtained using multiple acquisition, data processing, and analysis methods, distinguished ES and uninfected controls from viremic HIV-1-infected patients. For several miRNAs, however, ES and viremic patients shared similar expression patterns. Differentially expressed miRNAs included those with reported roles in HIV-1 latency (miR-29 family members, miRs -125b and -150). Others, such as miR-31 and miR-31*, had no previously reported connection with HIV-1 infection but were found here to differ significantly with uncontrolled HIV-1 replication. Correlations of miRNA expression with CD4+ T-cell count and viral load were found, and we observed that ES with low CD4+ T-cell counts had miRNA profiles more closely related to viremic patients than controls. However, expression patterns indicate that miRNA variability cannot be explained solely by CD4+ T-cell variation.</p> <p>Conclusions</p> <p>The intimate involvement of miRNAs in disease processes is underscored by connections of miRNA expression with the HIV disease clinical parameters of CD4 count and plasma viral load. However, miRNA profile changes are not explained completely by these variables. Significant declines of miRs-125b and -150, among others, in both ES and viremic patients indicate the persistence of host miRNA responses or ongoing effects of infection despite viral suppression by ES. We found no negative correlations with viral load in viremic patients, not even those that have been reported to silence HIV-1 in vitro, suggesting that the effects of these miRNAs are exerted in a focused, cell-type-specific manner. Finally, the observation that some ES with low CD4 counts were consistently related to viremic patients suggests that miRNAs may serve as biomarkers for risk of disease progression even in the presence of viral suppression.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy