: Recent technical advances in combinatorial chemistry, genomics, and proteomics have made available large databases of biological and chemical information that have the potential to dramatically ...improve our understanding of cancer biology at the molecular level. Such an understanding of cancer biology could have a substantial impact on how we detect, diagnose, and manage cancer cases in the clinical setting. One of the biggest challenges facing clinical oncologists is how to extract clinically useful knowledge from the overwhelming amount of raw molecular data that are currently available. In this paper, we discuss how the exploratory data analysis techniques of machine learning and high‐dimensional visualization can be applied to extract clinically useful knowledge from a heterogeneous assortment of molecular data. After an introductory overview of machine learning and visualization techniques, we describe two proprietary algorithms (PURS and RadViz™) that we have found to be useful in the exploratory analysis of large biological data sets. We next illustrate, by way of three examples, the applicability of these techniques to cancer detection, diagnosis, and management using three very different types of molecular data. We first discuss the use of our exploratory analysis techniques on proteomic mass spectroscopy data for the detection of ovarian cancer. Next, we discuss the diagnostic use of these techniques on gene expression data to differentiate between squamous and adenocarcinoma of the lung. Finally, we illustrate the use of such techniques in selecting from a database of chemical compounds those most effective in managing patients with melanoma versus leukemia.
The myeloperoxidase system of neutrophils uses hydrogen peroxide and chloride to generate hypochlorous acid, a potent bactericidal oxidant in vitro. In a mouse model of polymicrobial sepsis, we ...observed that mice deficient in myeloperoxidase were more likely than wild-type mice to die from infection. Mass spectrometric analysis of peritoneal inflammatory fluid from septic wild-type mice detected elevated concentrations of 3-chlorotyrosine, a characteristic end product of the myeloperoxidase system. Levels of 3-chlorotyrosine did not rise in the septic myeloperoxidase-deficient mice. Thus, myeloperoxidase seems to protect against sepsis in vivo by producing halogenating species. Surprisingly, levels of 3-bromotyrosine also were elevated in peritoneal fluid from septic wild-type mice and were markedly reduced in peritoneal fluid from septic myeloperoxidase-deficient mice. Furthermore, physiologic concentrations of bromide modulated the bactericidal effects of myeloperoxidase in vitro. It seems, therefore, that myeloperoxidase can use bromide as well as chloride to produce oxidants in vivo, even though the extracellular concentration of bromide is at least 1,000-fold lower than that of chloride. Thus, myeloperoxidase plays an important role in host defense against bacterial pathogens, and bromide might be a previously unsuspected component of this system.
We measured
Bosmina
spp. mucro and antennule lengths in surface sediment samples from Wisconsin lakes to test whether such measures could be used to reconstruct zooplankton community composition and ...size structure in paleolimnological studies. Our data set included 58 lakes of various depths, water chemistry, trophic state, macrophyte cover, and zooplankton community composition. We used non-metric multidimensional scaling ordination (NMS) and simple correlation analysis to assess whether mucro and antennule measurements reflect the zooplankton community size structure.
Bosmina
mucro length (
r
= 0.727,
p
< 0.05) and antennule length (
r
= 0.360,
p
< 0.05) correlated with the NMS axis, which essentially represents zooplankton community size structure.
Bosmina
mucro length correlated positively with the abundance of the large-bodied zooplankter
Epischura lacustris
(
r
= 0.364,
p
< 0.01), as well as
Diacyclops thomasi
(
r
= 0.256,
p
< 0.05), and
Leptodiaptomus minutus
(
r
= 0.578,
p
≤ 0.001), but correlated negatively with the abundance of the small-bodied zooplankter
Tropocyclops prasinus
(
r
= −0.385,
p
< 0.01).
Bosmina
antennule length correlated positively with the abundance of
L. minutus
(
r
= 0.344,
p
< 0.01) and negatively with
T. prasinus
(
r
= −0.258,
p
< 0.05). This broad, spatial scale assessment supports the use of
Bosmina
mucro and antennule lengths as a proxy for zooplankton community size structure. Mucro length is a stronger indicator of zooplankton community size structure as seen in its strong correlation with the NMS axis 1 and the significant correlations with abundance of predatory copepods.
Polymorphic expressed sequence tag - simple sequence repeat (EST-SSR) markers derived from major cereal crops were used to assess the genetic diversity of the USDA temperate bamboo collection ...consisting of 92 accessions classified in 11 separate genera and 44 species. A total of 211 bands were detected with a mean number of alleles per locus of 8.440. Phylogenetic relationships were determined by calculating genetic distances between all pairwise combinations and assessing differences in character data. The resulting dendrograms (unweighted pair group method with arithmetic means (UPGMA) and parsimony) clustered the accessions into 2 main clades, which corresponded to accessions characterized morphologically as either clumping (sympodial) or running (monopodial) bamboos. The majority of the accessions clustered according to their current taxonomic classification. These markers were also beneficial in identifying contaminated and (or) misidentified plots. Overall, these transferred markers were informative in differentiating the various bamboo accessions and determining the level of genetic variation within and among species and genera.
Recent reports to the U.S. Food and Drug Administration Adverse Event Reporting System implicate sildenafil citrate in adverse emotional and aggressive behaviors. Sildenafil citrate (Viagra™) is ...widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase Type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP). Cyclic-GMP is synthesized by guanylyl cyclase that is directly activated by the messenger molecule, nitric oxide (NO), formed throughout the CNS by the enzyme nitric oxide synthase (NOS). Elevated concentrations of cGMP have been associated with increased aggressive behavior. In addition, the potential effect of cGMP accumulation on NO-mediated behavioral and neuroendocrine function through possible feedback mechanisms remains unspecified; however, neuronal NOS (nNOS) inhibition by pharmacologic agents or ablation of the gene encoding nNOS increases aggressive behavior in male mice. We tested the hypothesis that sildenafil citrate may increase aggression via its actions on cGMP and potential feedback inhibition of NO concentrations. Male C57BL/6 mice were injected with saline vehicle (0), 2, 5, 8, or 10 mg/kg of sildenafil citrate thrice weekly for 4 weeks. Latency to display aggressive behavior, frequency, and duration of aggressive behavior were recorded during neutral-arena aggression tests. No change in agonistic behavior was observed in mice during treatment with sildenafil citrate. However, sildenafil-treated mice given the highest dose were generally more aggressive 1 week post-cessation of drug treatment as compared to vehicle-treated mice. Additional investigation into potential withdrawal effects or abuse doses seems warranted.
The hydrodynamic behavior of high-methoxy (HM) and low-methoxy (LM) pectin solutions was examined by capillary viscometric analysis. The LM-pectin was produced from the HM-pectin by ...PME-deesterification. As a result of the viscometric analysis, the PME-deesterified LM-pectin showed quite different solution behavior from the HM-pectin. The LM-pectin had larger intrinsic viscosity (
η) than HM-pectin when dissolved in 0.005 and 0.05
M concentrations of monovalent salts whereas HM-pectin had a higher value of
η when dissolved in 0.2
M salt than LM-pectin. The concentration dependence of HM-pectin
η
red values was fairly constant, whereas the concentration dependence of LM-pectin
η
red values had a tendency to decrease as the pectin concentration approached zero. The effect of salt-type on the hydrodynamic behavior of both HM- and LM-pectin solutions was almost negligible. The precipitous drop in LM-pectin
η upon increasing the salt concentration from 0.05 to 0.2
M is interpreted as arising from its disaggregation. This interpretation is based in part on data from HPSEC with online light scattering and viscosity detection.
The angiogenic factor thymidine phosphorylase (TP) is highly expressed in many human solid tumors, and the level of its expression is associated with tumor neovascularization, invasiveness, and ...metastasis and with shorter patient survival time. TP promotes endothelial cell (EC) migration in vitro and angiogenesis in vivo, and these have been linked to its enzymatic activity. The mechanism by which TP stimulates EC migration was investigated using human umbilical vein ECs (HUVECs). TP induced concentration-dependent HUVEC migration, which required a TP gradient and thymidine and which was abrogated by the TP inhibitor CIMU (5-chloro-6(1-imidazolylmethyl)uracil). The chemotactic actions of TP plus thymidine were duplicated by the TP metabolite, 2-deoxyribose-1-phosphate (dR-1-P), and 10-fold more potently by its subsequent metabolite, 2-deoxyribose (2dR). Migration induced by dR-1-P, but not 2dR, was blocked by an alkaline phosphatase inhibitor, suggesting that the actions of dR-1-P first required its conversion to 2dR. In the migration assay, 5'-3HdThd was metabolized to dR-1-P (96%) and 2dR (3.8%), and a gradient of both metabolites was maintained between the lower and upper chambers over the entire 5-h assay. TP expression in human solid tumors occurs in both tumor epithelial cells and in tumor-associated macrophages. The migration assay was adapted to use TP-transfected carcinoma cells to stimulate HUVEC migration, and they were found to induce more migration than did control vector-transfected cells. Human monocyte cells U937 and THP1, which constitutively expressed high levels of TP, also strongly induced HUVEC migration in the coculture assay. CIMU inhibited tumor-cell and monocyte-induced migration. In contrast, a neutralizing antibody to TP had no effect on cell-stimulated HUVEC migration, even though it completely blocked the migration mediated by purified TP. Thus, the intracellular actions of TP were sufficient to stimulate HUVEC chemotaxis. In contrast to purified TP, when incubated with 5'-3H-thymidine, cells expressing TP released up to 20-fold more 2dR into the medium than dR-1-P. These studies demonstrate that TP-expressing cells mediate EC migration via the intracellular metabolism of thymidine and subsequent extracellular release of 2dR, which forms a chemotactic gradient.
Since the beginning of the coronavirus disease 2019 pandemic, hundreds of thousands of patients have been treated in ICUs across the globe. The severe acute respiratory syndrome-associated ...coronavirus 2 virus enters cells via the angiotensin-converting enzyme 2 receptor and activates several distinct inflammatory pathways, resulting in hematologic abnormalities and dysfunction in respiratory, cardiac, gastrointestinal renal, endocrine, dermatologic, and neurologic systems. This review summarizes the current state of research in coronavirus disease 2019 pathophysiology within the context of potential organ-based disease mechanisms and opportunities for translational research.
Investigators from the Research Section of the Society of Critical Care Medicine were selected based on expertise in specific organ systems and research focus. Data were obtained from searches conducted in Medline via the PubMed portal, Directory of Open Access Journals, Excerpta Medica database, Latin American and Caribbean Health Sciences Literature, and Web of Science from an initial search from December 2019 to October 15, 2020, with a revised search to February 3, 2021. The medRxiv, Research Square, and clinical trial registries preprint servers also were searched to limit publication bias.
Content experts selected studies that included mechanism-based relevance to the severe acute respiratory syndrome-associated coronavirus 2 virus or coronavirus disease 2019 disease.
Not applicable.
Not applicable.
Efforts to improve the care of critically ill coronavirus disease 2019 patients should be centered on understanding how severe acute respiratory syndrome-associated coronavirus 2 infection affects organ function. This review articulates specific targets for further research.
Using multivariate analyses, we evaluated the roles of landscape position and human development in the presence, composition, and abundance of freshwater macrophyte communities among 60 study lakes ...located in Vilas County, Wisconsin. These lakes varied in their position in a drainage network and surrounding land use as well as size, maximum depth, chemistry, and clarity. We used non-metric multidimensional scaling ordination, cluster analyses, and classification tree analyses to assess the multivariate relationships among macrophyte communities and environmental variables including an index of human development. Macrophyte communities in lakes high in the landscape were found to be dominated by isoetids while lakes low in the drainage network were dominated by elodeids due to the difference in bicarbonate concentrations. The presence of the human-introduced crayfish,
Orconectes rusticus, had a high and significant correlation with the absence of macrophytes. An increase in human development correlated with a decrease in macrophyte abundance.
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Biomaterial surface properties including chemistry, topography, and wettability regulate cell response. Previous studies have shown that increasing surface roughness of metallic ...orthopaedic and dental implants improved bone formation around the implant. Little is known about how implant surface properties can affect immune cells that generate a wound healing microenvironment. The aim of our study was to examine the effect of surface modifications on macrophage activation and cytokine production. Macrophages were cultured on seven surfaces: tissue culture polystyrene (TCPS) control; hydrophobic and hydrophilic smooth Ti (PT and oxygen-plasma-treated (plasma) PT); hydrophobic and hydrophilic microrough Ti (SLA and plasma SLA), and hydrophobic and hydrophilic nano-and micro-rough Ti (aged modSLA and modSLA). Smooth Ti induced inflammatory macrophage (M1-like) activation, as indicated by increased levels of interleukins IL-1β, IL-6, and TNFα. In contrast, hydrophilic rough titanium induced macrophage activation similar to the anti-inflammatory M2-like state, increasing levels of interleukins IL-4 and IL-10. These results demonstrate that macrophages cultured on high surface wettability materials produce an anti-inflammatory microenvironment, and this property may be used to improve the healing response to biomaterials.
Metals like titanium (Ti) are common in orthopaedics and dentistry due to their ability to integrate with surrounding tissue and good biocompatibility. Roughness- and wettability-increasing surface modifications promote osteogenic differentiation of stem cells on Ti. While these modifications increase production of osteoblastic factors and bone formation, little is known about their effect on immune cells. The initial host response to a biomaterial is controlled primarily by macrophages and the factors they secrete in response to the injury caused by surgery and the material cues. Here we demonstrate the effect of surface roughness and wettability on the activation and production of inflammatory factors by macrophages. Control of inflammation will inform the design of surface modification procedures to direct the immune response and enhance the success of implanted materials.
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