60 research outputs found
A century of fish growth in relation to climate change, population dynamics and exploitation
Marine ecosystems, particularly in highâlatitude regions such as the Arctic, have been significantly affected by human activities and contributions to climate change. Evaluating how fish populations responded to past changes in their environment is helpful for evaluating their future patterns, but is often hindered by the lack of longâterm biological data available. Using otolith increments of Northeast Arctic cod (Gadus morhua) as a proxy for individual growth, we developed a centuryâscale biochronology (1924â2014) based on the measurements of 3,894 fish, which revealed significant variations in cod growth over the last 91 years. We combined mixedâeffect modeling and path analysis to relate these growth variations to selected climate, population and fishingârelated factors. Cod growth was negatively related to cod population size and positively related to capelin population size, one of the most important prey items. This suggests that densityâdependent effects are the main source of growth variability due to competition for resources and cannibalism. Growth was also positively correlated with warming sea temperatures but negatively correlated with the Atlantic Multidecadal Oscillation, suggesting contrasting effects of climate warming at different spatial scales. Fishing pressure had a significant but weak negative direct impact on growth. Additionally, path analysis revealed that the selected growth factors were interrelated. Capelin biomass was positively related to sea temperature and negatively influenced by herring biomass, while cod biomass was mainly driven by fishing mortality. Together, these results give a better understanding of how multiple interacting factors have shaped cod growth throughout a century, both directly and indirectly.publishedVersio
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Anatomical localization of progenitor cells in human breast tissue reveals enrichment of uncommitted cells within immature lobules
Introduction: Lineage tracing studies in mice have revealed the localization and existence of lineage-restricted mammary epithelial progenitor cells that functionally contribute to expansive growth during puberty and differentiation during pregnancy. However, extensive anatomical differences between mouse and human mammary tissues preclude the direct translation of rodent findings to the human breast. Therefore, here we characterize the mammary progenitor cell hierarchy and identify the anatomic location of progenitor cells within human breast tissues. Methods: Mammary epithelial cells (MECs) were isolated from disease-free reduction mammoplasty tissues and assayed for stem/progenitor activity in vitro and in vivo. MECs were sorted and evaluated for growth on collagen and expression of lineages markers. Breast lobules were microdissected and individually characterized based on lineage markers and steroid receptor expression to identify the anatomic location of progenitor cells. Spanning-tree progression analysis of density-normalized events (SPADE) was used to identify the cellular hierarchy of MECs within lobules from high-dimensional cytometry data. Results: Integrating multiple assays for progenitor activity, we identified the presence of luminal alveolar and basal ductal progenitors. Further, we show that Type I lobules of the human breast were the least mature, demonstrating an unrestricted pattern of expression of luminal and basal lineage markers. Consistent with this, SPADE analysis revealed that immature lobules were enriched for basal progenitor cells, while mature lobules consisted of increased hierarchal complexity of cells within the luminal lineages. Conclusions: These results reveal underlying differences in the human breast epithelial hierarchy and suggest that with increasing glandular maturity, the epithelial hierarchy also becomes more complex. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0453-3) contains supplementary material, which is available to authorized users
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Digital Quantification of Gene Expression in Sequential Breast Cancer Biopsies Reveals Activation of an Immune Response
Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted
TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer
The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates
Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2âPositive Breast Cancer
Purpose: One third of women with advanced human epidermal growth factor receptor 2 (HER-2)âpositive
breast cancer develop brain metastases; a subset progress in the CNS despite standard
approaches. Medical therapies for refractory brain metastases are neither well-studied nor
established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth
factor receptor (EGFR) and HER-2, in patients with HER-2âpositive brain metastases.
Patients and Methods: Patients had HER-2âpositive breast cancer, progressive brain metastases, prior trastuzumab
treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg
orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks.
The primary end point was objective response (complete response [CR] plus partial response [PR])
in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points
included objective response in non-CNS sites, time to progression, overall survival, and toxicity.
Results: Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving
trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by
RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%)
were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified
additional patients with some degree of volumetric reduction in brain tumor burden. The most
common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%).
Conclusion: The study did not meet the predefined criteria for antitumor activity in highly refractory patients
with HER-2âpositive brain metastases. Because of the volumetric changes observed in our
exploratory analysis, further studies are underway utilizing volumetric changes as a primary end
point
A century of fish growth in relation to climate change, population dynamics and exploitation
Marine ecosystems, particularly in highâlatitude regions such as the Arctic, have been significantly affected by human activities and contributions to climate change. Evaluating how fish populations responded to past changes in their environment is helpful for evaluating their future patterns, but is often hindered by the lack of longâterm biological data available. Using otolith increments of Northeast Arctic cod (Gadus morhua) as a proxy for individual growth, we developed a centuryâscale biochronology (1924â2014) based on the measurements of 3,894 fish, which revealed significant variations in cod growth over the last 91 years. We combined mixedâeffect modeling and path analysis to relate these growth variations to selected climate, population and fishingârelated factors. Cod growth was negatively related to cod population size and positively related to capelin population size, one of the most important prey items. This suggests that densityâdependent effects are the main source of growth variability due to competition for resources and cannibalism. Growth was also positively correlated with warming sea temperatures but negatively correlated with the Atlantic Multidecadal Oscillation, suggesting contrasting effects of climate warming at different spatial scales. Fishing pressure had a significant but weak negative direct impact on growth. Additionally, path analysis revealed that the selected growth factors were interrelated. Capelin biomass was positively related to sea temperature and negatively influenced by herring biomass, while cod biomass was mainly driven by fishing mortality. Together, these results give a better understanding of how multiple interacting factors have shaped cod growth throughout a century, both directly and indirectly
Differences in metabolic rate between two Atlantic cod (Gadus morhua) populations estimated with carbon isotopic composition in otoliths
The isotopic composition of inorganic carbon in otoliths (δ13Coto) can be a useful tracer of metabolic rates and a method to study ecophysiology in wild fish. We evaluated environmental and physiological sources of δ13Coto variation in Icelandic and Northeast Arctic (NEA) cod (Gadus morhua) over the years 1914â2013. Individual annual growth increments of otoliths formed at age 3 and 8 were micromilled and measured by isotope-ratio mass spectrometry. Simultaneously, all annual increment widths of the otoliths were measured providing a proxy of fish somatic growth. We hypothesized that changes in the physiological state of the organism, reflected by the isotopic composition of otoliths, can affect the growth rate. Using univariate and multivariate mixed-effects models we estimated conditional correlations between carbon isotopic composition and growth of fish at different levels (within individuals, between individuals, and between years), controlling for intrinsic and extrinsic effects on both otolith measurements. δ13Coto was correlated with growth within individuals and between years, which was attributed to the intrinsic effects (fish age or total length). There was no significant correlation between δ13Coto and growth between individuals, which suggests that caution is needed when interpreting δ13Coto signals. We found a significant decrease in δ13Coto through the century which was explained by the oceanic Suess effect-admixture of isotopically light carbon from fossil fuel. We calculated the proportion of the respired carbon in otolith carbonate (Cresp) using carbon isotopic composition in diet and dissolved inorganic carbon of the seawater. This approach allowed us to correct the values for each stock in relation to these two environmental baselines. Cresp was on average 0.275 and 0.295 in Icelandic and NEA stock, respectively. Our results provide an insight into the physiological basis for differences in growth characteristics between these two cod stocks, and how that may vary over time
The voluntary medical male circumcision Site Capacity and Productivity Assessment Tool (SCPT): An innovative visual management tool to optimize site service delivery.
Given constrained funding for HIV, achieving global goals on VMMC scale-up requires that providers improve service delivery operations and use labor and capital inputs as efficiently as possible to produce as many quality VMMCs as feasible. The Voluntary Medical Male Circumcision Site Capacity and Productivity Assessment Tool (SCPT) is an electronic visual management tool developed to help VMMC service providers to understand and improve their site's performance. The SCPT allows VMMC providers to: 1) track the most important human resources and capital inputs to VMMC service delivery, 2) strategically plan site capacity and targets, and 3) monitor key site-level VMMC service delivery performance indicators. To illustrate a real-world application of the SCPT, we present selected data from two provinces in Mozambique-Manica and Tete, where the SCPT was piloted We looked at the data prior to the introduction of SCPT (October 2014 to August 2016), and during the period when the tool began to be utilized (September 2016 to September 2017). The tool was implemented as part of a broader VMMC site optimization strategy that VMMC implementers in Mozambique put in place to maximize programmatic impact. Routine program data for Manica and Tete from October 2014 to September 2017 showcase the turnaround of the VMMC program that accompanied the implementation of the SCPT together with the other components of the VMMC site optimizatio strategy. From October 2016, there was a dramatic increase in the number of VMMCs performed. The number of fixed service delivery sites providing VMMC services was expanded, and each fixed site extended service delivery by performing VMMCs in outreach sites. Alignment between site targets and the number of VMMCs performed improved from October 2016. Utilization rates stabilized between October 2016 and September 2017, with VMMCs performed closely tracking VMMC site capacity in most sites. The SCPT is designed to address the need for site level data for programmatic decision-making during site planning, implementation, monitoring and evaluation. Deployment of the SCPT can help VMMC providers monitor the performance of VMMC service delivery sites and improve their performance. We recommend use of the customized version of this tool and model to the need of other programs
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