Nuclear-targeted therapy has received increasing attention as a potential strategy to improve the therapeutic efficacy of treating cancer. The main challenges include targeting, drug-delivery ...efficiency and release of anticancer agents to the cancer cell nucleus. Nanoparticles as nanocarriers have started to address some of these issues. However, a lack of understanding in how nanoconstructs interact with the nucleus has precluded detailed studies. In this article, we highlight a nanoconstruct composed of gold (Au) nanostars loaded with nucleolin-specific aptamers. This nanoconstruct induced major changes in the nuclear phenotype through nuclear envelope (NE) invaginations. Femtosecond, light-triggered release of the aptamers from the surface of the Au nanostars further increased the number of NE deformations. Cancer cells with more NE folding showed increased apoptosis as well as decreased cell viability. The author's of this article have revealed that correlation between drug-induced changes in nuclear phenotypes and increased therapeutic efficacy can provide new insight into nuclear-targeted cancer therapy.
The Quaternary stratigraphy and geochronology of the Albemarle Embayment of the North Carolina (NC) Coastal Plain is examined using amino acid racemization (AAR) in marine mollusks, in combination ...with geophysical, lithologic, and biostratigraphic analysis of 28 rotasonic cores drilled between 2002 and 2006. The Albemarle Embayment is bounded by structural highs to the north and south, and Quaternary strata thin westward toward the Suffolk paleoshoreline, frequently referred to as the Suffolk Scarp. The Quaternary section is up to ∼90
m thick, consists of a variety of estuarine, shelf, back-barrier, and lagoonal deposits, and has been influenced by multiple sea-level cycles. The temporal resolution of the amino acid racemization method is tested statistically and with the stratigraphic control provided by this geologic framework, and it is then applied to the correlation and age estimation of subsurface units throughout the region. Over 500 specimens (primarily
Mercenaria and
Mulinia) from the subsurface section have been analyzed using either gas chromatographic (GC) or reverse-phase liquid chromatographic (RPLC) techniques. The subsurface stratigraphic data are compared with AAR results from numerous natural or excavated exposures from the surrounding region, as well as results from NC beach collections, to develop a comprehensive aminostratigraphic database for the entire Quaternary record within the NC coastal system. Age mixing, recognized in the beach collections, is also seen in subsurface sections, usually where major seismic reflections or core lithology indicate the presence of stratigraphic discontinuities. Kinetic models for racemization are tested within the regional stratigraphic framework, using either radiocarbon or U-series calibrations or comparison with regional biostratigraphy. Three major Pleistocene aminozones AZ2, AZ3, and AZ4 are found throughout the region, all being found in superposition in several cores. Each can be subdivided, yielding a total of at least eight stratigraphically and statistically distinct aminozones. Kinetic modeling, supplemented with local calibration, indicates that these aminozones represent depositional events ranging from ∼80
ka to nearly 2
Ma. Three prominent seismic reflections are interpreted to represent the base of the early, middle, and late Pleistocene, respectively, roughly 2
Ma, 800
ka, and 130
ka. The large number of samples and the available stratigraphic control provide new insights into the capabilities and limitations of aminostratigraphic methods in assessing relative and numerical ages of Atlantic Coastal Plain Quaternary deposits.
Highlights • We proposed an algorithm that can find CHF cases from EMR and clinical notes. • Our NLP analytics prospectively identified 11.6% additional CHF cases in Maine. • On the manual reviewed ...dataset, the algorithm achieved an F -score of 0.753. • The algorithm was deployed to Maine HIE and identify CHF cases in real-time.
Advancement of commercial culture of the purple-hinge rock scallop,
Crassadoma gigantea, requires the development of efficient and cost-effective grow-out techniques. Use of traditional bivalve ...culture methods (e.g., lantern nets, oyster trays, pearl nets) is not feasible because rock scallops typically attach by cementing the right shell valve to the gear. Subsequent harvesting often results in damage to the animal and/or gear. We examined plasticity of attachment of rock scallops, and the effects of attachment on growth, to determine whether attachment could, and should, be facilitated when culturing this species. Laboratory and field experiments suggested that developmental and environmental factors influenced attachment, explaining some of the variation in size of attachment within and among locations. Rock scallops did not attach until reaching a minimum size (∼
25–30 mm shell height) in south-central California. Attachment was facilitated by flat, hard substrates, but inhibited by fibrous substrates. For scallops larger than the minimum size (>
30 mm shell height), attachment was not affected by prior attachment history (attached and dislodged) or scallop size. Growth rate (shell deposition and tissue growth) was higher for attached scallops. Our results suggest that attachment can, and should, be facilitated when culturing
C. gigantea.
Tropical diversity has generally exceeded temperate diversity in the present and at points in the past, but whether measured differences have remained relatively constant through time has been ...unknown. Here we examine tropical vs. temperate diversities from the Neogene to Recent using the within-habitat diversity measure Fisher's alpha of Cenozoic benthic foraminifera from the temperate Central Atlantic Coastal Plain and the tropical Central American Isthmus. During the Neogene, the mean value of alpha at temperate latitudes increased 1.4 times or 40%, whereas in the tropics it increased 2.1 times or 106%. Thus, while both areas exhibit an increase of diversity with time, past differences in the rate of increase have generated a more pronounced gradient today (164%) than existed in the Miocene (80%). These data disagree with the suggestion that the world reached an equilibrium number of species during the Paleozoic and demonstrate the need to consider both temperate and tropical components in global diversity assessments.
For many elderly patients, a disproportionate amount of health care resources and expenditures is spent during the last year of life, despite the discomfort and reduced quality of life associated ...with many aggressive medical approaches. However, few prognostic tools have focused on predicting all-cause 1-year mortality among elderly patients at a statewide level, an issue that has implications for improving quality of life while distributing scarce resources fairly.
Using data from a statewide elderly population (aged ≥65 years), we sought to prospectively validate an algorithm to identify patients at risk for dying in the next year for the purpose of minimizing decision uncertainty, improving quality of life, and reducing futile treatment.
Analysis was performed using electronic medical records from the Health Information Exchange in the state of Maine, which covered records of nearly 95% of the statewide population. The model was developed from 125,896 patients aged at least 65 years who were discharged from any care facility in the Health Information Exchange network from September 5, 2013, to September 4, 2015. Validation was conducted using 153,199 patients with same inclusion and exclusion criteria from September 5, 2014, to September 4, 2016. Patients were stratified into risk groups. The association between all-cause 1-year mortality and risk factors was screened by chi-squared test and manually reviewed by 2 clinicians. We calculated risk scores for individual patients using a gradient tree-based boost algorithm, which measured the probability of mortality within the next year based on the preceding 1-year clinical profile.
The development sample included 125,896 patients (72,572 women, 57.64%; mean 74.2 SD 7.7 years). The final validation cohort included 153,199 patients (88,177 women, 57.56%; mean 74.3 SD 7.8 years). The c-statistic for discrimination was 0.96 (95% CI 0.93-0.98) in the development group and 0.91 (95% CI 0.90-0.94) in the validation cohort. The mortality was 0.99% in the low-risk group, 16.75% in the intermediate-risk group, and 72.12% in the high-risk group. A total of 99 independent risk factors (n=99) for mortality were identified (reported as odds ratios; 95% CI). Age was on the top of list (1.41; 1.06-1.48); congestive heart failure (20.90; 15.41-28.08) and different tumor sites were also recognized as driving risk factors, such as cancer of the ovaries (14.42; 2.24-53.04), colon (14.07; 10.08-19.08), and stomach (13.64; 3.26-86.57). Disparities were also found in patients' social determinants like respiratory hazard index (1.24; 0.92-1.40) and unemployment rate (1.18; 0.98-1.24). Among high-risk patients who expired in our dataset, cerebrovascular accident, amputation, and type 1 diabetes were the top 3 diseases in terms of average cost in the last year of life.
Our study prospectively validated an accurate 1-year risk prediction model and stratification for the elderly population (≥65 years) at risk of mortality with statewide electronic medical record datasets. It should be a valuable adjunct for helping patients to make better quality-of-life choices and alerting care givers to target high-risk elderly for appropriate care and discussions, thus cutting back on futile treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The increasing rate of health care expenditures in the United States has placed a significant burden on the nation's economy. Predicting future health care utilization of patients can provide useful ...information to better understand and manage overall health care deliveries and clinical resource allocation.
This study developed an electronic medical record (EMR)-based online risk model predictive of resource utilization for patients in Maine in the next 6 months across all payers, all diseases, and all demographic groups.
In the HealthInfoNet, Maine's health information exchange (HIE), a retrospective cohort of 1,273,114 patients was constructed with the preceding 12-month EMR. Each patient's next 6-month (between January 1, 2013 and June 30, 2013) health care resource utilization was retrospectively scored ranging from 0 to 100 and a decision tree-based predictive model was developed. Our model was later integrated in the Maine HIE population exploration system to allow a prospective validation analysis of 1,358,153 patients by forecasting their next 6-month risk of resource utilization between July 1, 2013 and December 31, 2013.
Prospectively predicted risks, on either an individual level or a population (per 1000 patients) level, were consistent with the next 6-month resource utilization distributions and the clinical patterns at the population level. Results demonstrated the strong correlation between its care resource utilization and our risk scores, supporting the effectiveness of our model. With the online population risk monitoring enterprise dashboards, the effectiveness of the predictive algorithm has been validated by clinicians and caregivers in the State of Maine.
The model and associated online applications were designed for tracking the evolving nature of total population risk, in a longitudinal manner, for health care resource utilization. It will enable more effective care management strategies driving improved patient outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Cretaceous-Tertiary biotic transition Macleod, N; Rawson, P. F; Forey, P. L ...
Journal of the Geological Society,
03/1997, Letnik:
154, Številka:
2
Journal Article
Recenzirano
Mass extinctions are recognized through the study of fossil groups across event horizons, and from analyses of long-term trends in taxonomic richness and diversity. Both approaches have inherent ...flaws, and data that once seemed reliable can be readily superseded by the discovery of new fossils and/or the application of new analytical techniques. Herein the current state of the Cretaceous-Tertiary (K-T) biostratigraphical record is reviewed for most major fossil clades, including: calcareous nannoplankton, dinoflagellates, diatoms, radiolaria, foraminifera, ostracodes, scleractinian corals, bryozoans, brachio-pods, molluscs, echinoderms, fish, amphibians, reptiles and terrestrial plants (macrofossils and palynomorphs). These reviews take account of possible biasing factors in the fossil record in order to extract the most comprehensive picture of the K-T biotic crisis available. Results suggest that many faunal and floral groups (ostracodes, bryozoa, ammonite cephalopods, bivalves, archosaurs) were in decline throughout the latest Maastrichtian while others (diatoms, radiolaria, benthic foraminifera, brachiopods, gastropods, fish, amphibians, lepidosaurs, terrestrial plants) passed through the K-T event horizon with only minor taxonomic richness and/or diversity changes. A few microfossil groups (calcareous nannoplankton, dinoflagellates, planktonic foraminifera) did experience a turnover of varying magnitudes in the latest Maastrichtian-earliest Danian. However, many of these turnovers, along with changes in ecological dominance patterns among benthic foraminifera, began in the latest Maastrichtian. Improved taxonomic estimates of the overall pattern and magnitude of the K-T extinction event must await the development of more reliable systematic and phylogenetic data for all Upper Cretaceous clades.
Abstract
Background: MGPT for hereditary cancer syndromes allows for concurrent analysis of genes associated with many different cancer types. This may lead to the identification of unexpected ...mutations in genes with no BC link. The objective of this study was to examine the landscape of pathogenic mutations in a BC cohort who underwent MGPT, to assess if there was clinical suspicion for identified mutations and if the results would affect subjects' medical management.
Methods: Retrospective review of subjects with BC seen at a single institution who underwent MGPT from 1/1/15- 5/31/18 was conducted. MGPT was defined as testing of more than the 9 genes associated with BC (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53). Deidentified pedigrees were analyzed by genetic counselors to determine whether there was clinical suspicion of the presence of the mutations using national testing guidelines or clinical diagnostic criteria.
Results: Among 3044 subjects, 365 (12%) were found to have one pathogenic mutation in at least one cancer susceptibility gene. Subjects with mutations in APC I307K, moderate-penetrance BC genes (NBN, RAD50, BARD1), and MUTYH were excluded from further analysis. We identified 52 pathogenic mutations in genes not typically associated with risk for BC in 51 (2%) subjects (table 1). There was clinical suspicion for the identified mutation in 17 (33%).
Table 1:Non-BC gene mutation landscape Number of MutationsClinical Suspicion (%)Lynch syndrome117 (64%)MLH110MSH221MSH632PMS254Ovarian181 (6%)BRIP1*111RAD51C40RAD51D30SHDx62 (33%)SDHA*30SDHC*32Other156 (40%)FH10HOXB13*32MITF32NF142VHL40CDKN2A21 (50%)Total5217 (33%)*Contains individuals that also have a mutation in a BC susceptibility gene
Conclusion: Of 3044 BC patients who underwent MGPT, 2% were found to have a pathogenic gene mutation that would have been missed by a smaller BC gene panel. Medical or surgical management would be affected by the MGPT result in 86% of subjects. Only 6% of subjects with genetic risk for ovarian cancer had a family history of this disease. The single FH and 3 of 4 VHL mutations are only associated with disease in the biallelic state; these findings do not affect the subjects' care, but have implications for reproductive risk. The HOXB13 mutations were found in female subjects only, but would have implications for their male relatives. NF1 mutations are associated with BC risk, but were included in this analysis due to a historically distinct clinical phenotype. Only 50% of NF1+ subjects had a clinical diagnosis or family history of NF1. In all cases, cascade testing was offered to at-risk family members, allowing for cancer and reproductive risk stratification and management. This study demonstrates how comprehensive MGPT can provide a more complete and personalized cancer risk assessment for BC patients and their families.
Citation Format: Culver S, Kipnis L, Stokes S, Bychkovsky B, Scheib R, Rana H, Garber J. Casting a wide net: Finding actionable results in non-breast cancer (BC) genes on multi-gene panel testing (MGPT) in a BC cohort abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-02.
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