Exhaustive expansion: A novel technique for analyzing complex data generated by higher-order polychromatic flow cytometry experiments

<p>Abstract</p> <p>Background</p> <p>The complex data sets generated by higher-order polychromatic flow cytometry experiments are a challenge to analyze. Here we describe Exhaustive Expansion, a data analysis approach for deriving hundreds to thousands of cell phenotypes from raw data, and for interrogating these phenotypes to identify populations of biological interest given the experimental context.</p> <p>Methods</p> <p>We apply this approach to two studies, illustrating its broad applicability. The first examines the longitudinal changes in circulating human memory T cell populations within individual patients in response to a melanoma peptide (gp100_209-2M) cancer vaccine, using 5 monoclonal antibodies (mAbs) to delineate subpopulations of viable, gp100-specific, CD8+ T cells. The second study measures the mobilization of stem cells in porcine bone marrow that may be associated with wound healing, and uses 5 different staining panels consisting of 8 mAbs each.</p> <p>Results</p> <p>In the first study, our analysis suggests that the cell surface markers CD45RA, CD27 and CD28, commonly used in historical lower order (2-4 color) flow cytometry analysis to distinguish memory from naïve and effector T cells, may not be obligate parameters in defining central memory T cells (T_CM). In the second study, we identify novel phenotypes such as CD29+CD31+CD56+CXCR4+CD90+Sca1-CD44+, which may characterize progenitor cells that are significantly increased in wounded animals as compared to controls.</p> <p>Conclusions</p> <p>Taken together, these results demonstrate that Exhaustive Expansion supports thorough interrogation of complex higher-order flow cytometry data sets and aids in the identification of potentially clinically relevant findings.</p

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

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Tidal and seasonal effects on survival rates of the endangered California clapper rail: Does invasive Spartina facilitate greater survival in a dynamic environment?

Invasive species frequently degrade habitats, disturb ecosystem processes, and can increase the likelihood of extinction of imperiled populations. However, novel or enhanced functions provided by invading species may reduce the impact of processes that limit populations. It is important to recognize how invasive species benefit endangered species to determine overall effects on sensitive ecosystems. For example, since the 1990s, hybrid Spartina (Spartina foliosa × alterniflora) has expanded throughout South San Francisco Bay, USA, supplanting native vegetation and invading mudflats. The endangered California clapper rail (Rallus longirostris obsoletus) uses the tall, dense hybrid Spartina for cover and nesting, but the effects of hybrid Spartina on clapper rail survival was unknown. We estimated survival rates of 108 radio-marked California clapper rails in South San Francisco Bay from January 2007 to March 2010, a period of extensive hybrid Spartina eradication, with Kaplan-Meier product limit estimators. Clapper rail survival patterns were consistent with hybrid Spartina providing increased refuge cover from predators during tidal extremes which flood native vegetation, particularly during the winter when the vegetation senesces. Model averaged annual survival rates within hybrid Spartina dominated marshes before eradication (Ŝ = 0.466) were greater than the same marshes posttreatment (Ŝ = 0.275) and a marsh dominated by native vegetation (Ŝ = 0.272). However, models with and without marsh treatment as explanatory factor for survival rates had nearly equivalent support in the observed data, lending ambiguity as to whether hybrid Spartina facilitated greater survival rates than native marshland. Conservation actions to aid in recovery of this endangered species should recognize the importance of available of high tide refugia, particularly in light of invasive species eradication programs and projections of future sea-level rise. © 2014 Springer Science+Business Media Dordrecht (outside the USA)

Sea-level rise and refuge habitats for tidal marsh species: Can artificial islands save the California Ridgway's rail?

Terrestrial species living in intertidal habitats experience refuge limitation during periods of tidal inundation, which may be exacerbated by seasonal variation in vegetation structure, tidal cycles, and land-use change. Sea-level rise projections indicate the severity of refuge limitation may increase. Artificial habitats that provide escape cover during tidal inundation have been proposed as a temporary solution to alleviate these limitations. We tested for evidence of refuge habitat limitation in a population of endangered California Ridgway's rail (Rallus obsoletus obsoletus; hereafter California rail) through use of artificial floating island habitats provided during two winters. Previous studies demonstrated that California rail mortality was especially high during the winter and periods of increased tidal inundation, suggesting that tidal refuge habitat is critical to survival. In our study, California rail regularly used artificial islands during higher tides and daylight hours. When tide levels inundated the marsh plain, use of artificial islands was at least 300 times more frequent than would be expected if California rails used artificial habitats proportional to their availability (0.016%). Probability of use varied among islands, and low levels of use were observed at night. These patterns may result from anti-predator behaviors and heterogeneity in either rail density or availability of natural refuges. Endemic saltmarsh species are increasingly at risk from habitat change resulting from sea-level rise and development of adjacent uplands. Escape cover during tidal inundation may need to be supplemented if species are to survive. Artificial habitats may provide effective short-term mitigation for habitat change and sea-level rise in tidal marsh environments, particularly for conservation-reliant species such as California rails

Bessel sequences, Riesz-like bases and operators in Triplets of Hilbert spaces

Riesz-like bases for a triplet of Hilbert spaces are investigated, in connection with an analogous study for more general rigged Hilbert spaces performed in a previous paper. It is shown, in particular, that every ω-independent, complete (total) Bessel sequence is a (strict) Riesz-like basis in a convenient triplet of Hilbert spaces. An application to non self-adjoint Schrödinger-type operators is considered. Moreover, some of the simplest operators we can define by them and their dual bases are studied

Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection

Background & Aims: Hepatocellular carcinoma (HCC) is a frequent complication of liver disease. When feasible, hepatic resection is the first-choice therapy. However, tumor recurrence complicates at least 2/3 hepatic resections at 5 years. Early recurrences are mainly tumor or treatment-related, but predictors of late recurrences are undefined. We aimed to evaluate the factors related to HCC recurrence after curative resection, with liver and spleen stiffness measurement (LSM and SSM) as markers of severity and duration of the underlying liver disease. Methods: We enrolled patients with chronic liver disease and primary HCC suitable for hepatic resection. We followed up patients for at least 30 months or until HCC recurrence. We performed uni- and multivariate analyses to evaluate the predictive role of tumor characteristics, laboratory data, LSM and SSM for both early and late recurrence of HCC. Results: We prospectively enrolled 175 patients. Early HCC recurrence at multivariate analysis was associated with viral etiology, HCC grading (3 or 4), resection margins <1 cm and being beyond the Milan criteria. HCC late recurrence at univariate analysis was associated with esophageal varices (hazard ratio [HR] 3.321, 95% CI 1.564\u20137.053), spleen length (HR 3.123, 95% CI 1.377\u20137.081), platelet/spleen length ratio if <909 (HR 2.170, 95% CI 1.026\u20134.587), LSM (HR 1.036, 95% CI 1.005\u20131.067), SSM (HR 1.046, 95% CI 1.020\u20131.073). HCC late recurrence at multivariate analysis was independently associated only with SSM (HR 1.046, CI 1.020\u20131.073). Late HCC recurrence-free survival was significantly different according to the SSM cut-off of 70 kPa (p = 0.0002). Conclusions: SSM seems to be the only predictor of late HCC recurrence, since it is directly correlated with the degree of liver disease and portal hypertension, both of which are involved in carcinogenesis. Lay summary: The main result of this study is that spleen stiffness measurement, evaluated by transient elastography, seems to be the only predictor of the late recurrence of hepatocellular carcinoma, defined as recurrence after 24 months from liver resection. Indeed, spleen stiffness measurement is directly correlated with the degree of liver disease and portal hypertension, which are both involved in carcinogenesis