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The metabolic network of a living cell is highly intricate and involves complex interactions between various pathways. In this study, we propose a computational model that integrates glycolysis, the pentose phosphate pathway (PPP), the fatty acids beta-oxidation, and the tricarboxylic acid cycle (TCA cycle) using queueing theory. The model utilizes literature data on metabolite concentrations and enzyme kinetic constants to calculate the probabilities of individual reactions occurring on a microscopic scale, which can be viewed as the reaction rates on a macroscopic scale. However, it should be noted that the model has some limitations, including not accounting for all the reactions in which the metabolites are involved. Therefore, a genetic algorithm (GA) was used to estimate the impact of these external processes. Despite these limitations, our model achieved high accuracy and stability, providing real-time observation of changes in metabolite concentrations. This type of model can help in better understanding the mechanisms of biochemical reactions in cells, which can ultimately contribute to the prevention and treatment of aging, cancer, metabolic diseases, and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

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Wastewater-based epidemiology (WBE) has emerged as a valuable epidemiologic tool to detect the presence of pathogens and track disease trends within a community. WBE overcomes some limitations of traditional clinical disease surveillance as it uses pooled samples from the entire community, irrespective of health-seeking behaviors and symptomatic status of infected individuals. WBE has the potential to estimate the number of infections within a community by using a mass balance equation, however, it has yet to be assessed for accuracy. We hypothesized that the mass balance equation-based approach using measured SARS-CoV-2 wastewater concentrations can generate accurate prevalence estimates of COVID-19 within a community. This study encompassed wastewater sampling over a 53-week period during the COVID-19 pandemic in Gainesville, Florida, to assess the ability of the mass balance equation to generate accurate COVID-19 prevalence estimates. The SARS-CoV-2 wastewater concentration showed a significant linear association (Parameter estimate = 39.43, P value < 0.0001) with clinically reported COVID-19 cases. Overall, the mass balance equation produced accurate COVID-19 prevalence estimates with a median absolute error of 1.28%, as compared to the clinical reference group. Therefore, the mass balance equation applied to WBE is an effective tool for generating accurate community-level prevalence estimates of COVID-19 to improve community surveillance. [ABSTRACT FROM AUTHOR]

Due to its role in maintaining the proper functioning of the cell, the pentose phosphate pathway (PPP) is one of the most important metabolic pathways. It is responsible for regulating the concentration of simple sugars and provides precursors for the synthesis of amino acids and nucleotides. In addition, it plays a critical role in maintaining an adequate level of NADPH, which is necessary for the cell to fight oxidative stress. These reasons prompted the authors to develop a computational model, based on queueing theory, capable of simulating changes in PPP metabolites' concentrations. The model has been validated with empirical data from tumor cells. The obtained results prove the stability and accuracy of the model. By applying queueing theory, this model can be further expanded to include successive metabolic pathways. The use of the model may accelerate research on new drugs, reduce drug costs, and reduce the reliance on laboratory animals necessary for this type of research on which new methods are tested. [ABSTRACT FROM AUTHOR]

We have developed and tested a new Eikonal first-arrival forward model scheme by combining a fast marching method (FMM) algorithm, an upwind Eikonal solver scheme first described by Sethian and Popovici in 1996, with a more accurate but less robust Eikonal scheme described by Vidale in 1990 as a finite difference method (VFD) in order to produce a robust forward model based in FMM, with application of VFD schemes for refinement of computed model times (FMM-VFD). The developed model was tested through a uniform velocity base case, and the Southern California Earthquake Center (SCEC) Harvard Velocity Model (CVM-H) of upper crust including the sedimentary basin under Los Angeles, CA. Its performance was evaluated by measuring error at different grid sizes against a set of reference times generated by an independent model. In comparison against first-order FMM (FMM-O1), second-order FMM (FMM-O2), and an improved FMM scheme known as factored FMM (FMM-F) against a set of generated reference times, FMM-VFD error was found to be significantly lower than first- and second-order FMM, and competitive with FMM-F, outperforming it in the presented scenarios. [ABSTRACT FROM AUTHOR]

Molecular excitons play a central role in natural and artificial light harvesting, organic electronics, and nanoscale computing. The structure and dynamics of molecular excitons, critical to each application, are sensitively governed by molecular packing. Deoxyribonucleic acid (DNA) templating is a powerful approach that enables controlled aggregation via sub-nanometer positioning of molecular dyes. However, finer sub-Angstrom control of dye packing is needed to tailor excitonic properties for specific applications. Here, we show that adding rotaxane rings to squaraine dyes templated with DNA promotes an elusive oblique packing arrangement with highly desirable optical properties. Specifically, dimers of these squaraine:rotaxanes exhibit an absorption spectrum with near-equal intensity excitonically split absorption bands. Theoretical analysis indicates that the transitions are mostly electronic in nature and only have similar intensities over a narrow range of packing angles. Compared with squaraine dimers, squaraine:rotaxane dimers also exhibit extended excited-state lifetimes and less structural heterogeneity. The approach proposed here may be generally useful for optimizing excitonic materials for a variety of applications ranging from solar energy conversion to quantum information science. DNA templating is a useful strategy to control the positioning and aggregation of molecular dyes on a sub-nanometer scale, but sub-angstrom control is desirable for the precise tailoring of excitonic properties. Here, the authors show that templating squaraine dyes functionalized with rotaxane rings promotes an elusive oblique packing arrangement and extended excited-state lifetimes. [ABSTRACT FROM AUTHOR]

Activated platelets may contribute to the metastatic behavior of tumor cells when the cancer cells and platelets interact. The interaction requires cell and platelet surface integrin. Thyroid hormone as L-thyroxine (T4) is the principal ligand for a hormone receptor on integrin αvβ3 on tumor cells and platelets. T4 activates the integrin, promoting platelet aggregation and degranulation (local ATP release) and stimulating tumor cell proliferation. By a variety of molecular mechanisms reviewed here, extracellular ATP promotes tumor cell invasiveness and metastasis and supports a role for T4 as a pro-metastatic factor. [ABSTRACT FROM AUTHOR]

The objective of this study was to describe changes in the gene expression in the Chilean catfish, Trichomycterus areolatus, based on their geographic location within the Choapa River. Genes of choice included those that are biomarkers of exposure to metals, oxidative stress, and endocrine disruption. Male and female T. areolatus were sampled from four sites in January 2015 differently impacted by human activities. In males, but not females, hepatic gene expression of heat shock protein (HSP70) and cytochrome P450 1A (CYP1A) were significantly elevated at the site adjacent to the small city of Salamanca, relative to the other sites. In females, hepatic HSP70, the aryl hydrocarbon receptor (AHR), and the estrogen responsive genes, vitellogenin (VTG) and estrogen receptor alpha (ERα), were significantly lower at the site located furthest downstream. A similar downstream pattern of lower expression levels also was found in ovarian tissue for the genes, HSP70 and ERα. Gill gene expression showed a unique pattern in females as levels of metallothionein were elevated at the site furthest downstream. While analytical chemistry of water samples provided limited evidence of agrichemical contamination, the gene expression data are consistent with an exposure to agrichemicals and metals. T. areolatus may be a valuable sentinel organism and its use as a bioindicator species in some rivers within Chile can provide considerable insight, particularly in situations analytical chemistry is limited by environmental constraints. [ABSTRACT FROM AUTHOR]

Women with uncomplicated urinary tract infection (UTI) symptoms are commonly treated with empirical antibiotics, resulting in overuse of antibiotics, which promotes antimicrobial resistance. Available diagnostic tools are either not cost-effective or diagnostically sub-optimal. Here, we identified clinical and urinary immunological predictors for UTI diagnosis. We explored 17 clinical and 42 immunological potential predictors for bacterial culture among women with uncomplicated UTI symptoms using random forest or support vector machine coupled with recursive feature elimination. Urine cloudiness was the best performing clinical predictor to rule out (negative likelihood ratio [LR−] = 0.4) and rule in (LR+ = 2.6) UTI. Using a more discriminatory scale to assess cloudiness (turbidity) increased the accuracy of UTI prediction further (LR+ = 4.4). Urinary levels of MMP9, NGAL, CXCL8 and IL-1β together had a higher LR+ (6.1) and similar LR− (0.4), compared to cloudiness. Varying the bacterial count thresholds for urine culture positivity did not alter best clinical predictor selection, but did affect the number of immunological predictors required for reaching an optimal prediction. We conclude that urine cloudiness is particularly helpful in ruling out negative UTI cases. The identified urinary biomarkers could be used to develop a point of care test for UTI but require further validation. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1038/s41598-023-41765-3. Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-023-41765-3, published online 02 September 2023 The original version of this Article contained an error in the spelling of the author Tadeusz A. Wysocki, which was incorrectly given as Tadeusz A. Wysoki. [Extracted from the article]

Drug resistance complicates the clinical use of gefitinib. Tetraiodothyroacetic acid (tetrac) and nano-diamino-tetrac (NDAT) have been shown in vitro and in xenografts to have antiproliferative/angiogenic properties and to potentiate antiproliferative activity of other anticancer agents. In the current study, we investigated the effects of NDAT on the anticancer activities of gefitinib in human colorectal cancer cells. β-Galactoside α-2,6-sialyltransferase 1 (ST6Gal1) catalyzes EGFR sialylation that is associated with gefitinib resistance in colorectal cancers, and this was also investigated. Gefitinib inhibited cell proliferation of HT-29 cells (K-ras wild-type), and NDAT significantly enhanced the antiproliferative action of gefitinib. Gefitinib inhibited cell proliferation of HCT116 cells (K-ras mutant) only in high concentration, and this was further enhanced by NDAT. NDAT enhancedd gefitinib-induced antiproliferation in gefitinib-resistant colorectal cancer cells by inhibiting ST6Gal1 activity and PI3K activation. Furthermore, NDAT enhanced gefitinib-induced anticancer activity additively in colorectal cancer HCT116 cell xenograft-bearing nude mice. Results suggest that NDAT may have an application with gefitinib as combination colorectal cancer therapy. [ABSTRACT FROM AUTHOR]

Cancer resistance to chemotherapeutic agents is a major issue in the management of cancer patients. Overexpression of the ribonucleotide reductase regulatory subunit M2 (RRM2) has been associated with aggressive cancer behavior and chemoresistance. Nano-diamino-tetrac (NDAT) is a nanoparticulate derivative of tetraiodothyroacetic acid (tetrac), which exerts anticancer properties via several mechanisms and downregulates RRM2 gene expression in cancer cells. Resveratrol is a stilbenoid phytoalexin which binds to a specific site on the cell surface integrin αvβ3 to trigger cancer cell death via nuclear translocation of COX-2. Here we report that resveratrol paradoxically activates RRM2 gene expression and protein translation in colon cancer cells. This unanticipated effect inhibits resveratrol-induced COX-2 nuclear accumulation. RRM2 downregulation, whether achieved by RNA interference or treatment with NDAT, enhanced resveratrol-induced COX-2 gene expression and nuclear uptake which is essential to integrin αvβ3-mediated-resveratrol-induced antiproliferation in cancer cells. Elsewhere, NDAT downregulated resveratrol-induced RRM2 expression in vivo but potentiated the anticancer effect of the stilbene. These findings suggest that RRM2 appears as a cancer cell defense mechanism which can hinder the anticancer effect of the stilbene via the integrin αvβ3 axis. Furthermore, the antagonistic effect of RRM2 against resveratrol is counteracted by the administration of NDAT. [ABSTRACT FROM AUTHOR]

There is preclinical and recent epidemiological evidence that thyroid hormone supports breast cancer. These observations raise the issue of whether management of breast cancer in certain settings should include consideration of reducing the possible contribution of thyroid hormone to the advancement of the disease. In a preliminary experience, elimination of the clinical action of endogenous L-thyroxine (T4) in patients with advanced solid tumors, including breast cancer, has favorably affected the course of the cancer, particularly when coupled with administration of exogenous 3,5,3′-triiodo-L-thyronine (T3) (euthyroid hypothyroxinemia). We discuss in the current brief review the possible clinical settings in which to consider whether endogenous thyroid hormone—or exogenous thyroid hormone in the patient with hypothyroidism and coincident breast cancer—is significantly contributing to breast cancer outcome. [ABSTRACT FROM AUTHOR]

Thyroid hormone status has long been implicated in cancer development. Here we investigated the role of thyroxine (T4) in colorectal cancer cell lines HCT 116 (APC wild type) and HT-29 (APC mutant), as well as the primary cultures of cancer cells derived from patients. Cell proliferation was evaluated with standard assay and proliferation marker expression. β-Catenin activation was examined according to nuclear β-catenin accumulation and β-catenin target gene expression. The results showed that T4 increased colorectal cancer cell proliferation while cell number and viability were elevated by T4 in both established cell lines and primary cells. Moreover, the transcriptions of proliferative genes PCNA, CCND1, and c-Myc were enhanced by T4 in the primary cells. T4 induced nuclear β-catenin accumulation, as well as high cyclin D1 and c-Myc levels compared to the untreated cells. In addition, the β-catenin-directed transactivation of CCND1 and c-Myc promoters was also upregulated by T4. CTNNB1 transcription was raised by T4 in HCT 116, but not in HT-29, while the boosted β-catenin levels were observed in both. Lastly, the T4-mediated gene expression could be averted by the knockdown of β-catenin. These results suggested that T4 promotes β-catenin activation and cell proliferation in colorectal cancer, indicating that an applicable therapeutic strategy should be considered. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a highly metastatic disease. The metastatic potential is enhanced by epithelial to mesenchymal transition (EMT) in which αvβ3 integrin plays a role. Thyroid hormones ( l-thyroxine, T4, and 3,5,3′-triiodo- l-thyronine, T3) bind this integrin, and we hypothesized that the thyroid hormone-αvβ3 axis may be involved in EMT activity in ovarian cancer. The transcription (mRNA), protein abundance (westerns), and protein localization (fluorescence microscopy) of several EMT markers were studied in ovarian cancer cells (OVCAR-3, A2780, and SKOV-3) treated with 1 nM T3 or 100 nM T4 for 1-24 h. The protein levels of β-catenin, and its downstream targets, zeb-1, slug, and vimentin, were significantly induced by both hormones, while the effect on transcription was limited. The pre-incubation of the cells overnight with two integrin inhibitors, RGD (0.1-10 μM) or αvβ3 blocking antibody (1-100 ng/mL), prevented the induction of β-catenin by T3 and zeb-1 by T4, indicating direct integrin involvement. The transcription of the mesenchymal markers, β-catenin, zeb-1, slug/snail, vimentin, and n-cadherin was hardly affected by T3 and T4, while that of the epithelial markers, e-cadherin and zo-1, was inhibited. Our results suggest a novel role for the thyroid hormone-αvβ3 axis in EMT, with possible implications for ovarian cancer metastasis. [ABSTRACT FROM AUTHOR]

Thyroid hormone as L-thyroxine (T) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions ( p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days ( p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields ( p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields ( p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts. [ABSTRACT FROM AUTHOR]

Infantile hemangioma (IH), the most common tumor of infancy, is characterized by rapid growth during infancy, followed by spontaneous involution over 5-10 years. Certain clinical observations have led to the suggestion that IH is triggered and maintained by hypoxia. We review the literature on the possible role of hypoxia in the etiology of IH, in particular, (1) the role of hypoxia inducible factor-1α (HIF-1α) and its downstream targets including GLUT-1 and VEGF; (2) the pathophysiological link between IH and retinopathy of prematurity; (3) hypoxic events in the early life including placental insufficiency, pre-eclampsia and low birthweight that have the potential to promote hypoxic stress; and (4) the evidence supporting the development of IH independent of HIF-1α. We also discuss these observations in the context of recent evidence of the crucial role of stem cells and the cytokines niche that governs their proliferation and inevitable differentiation, offering novel insights into the biology of IH. We propose that various triggers may simultaneously up-regulate HIF-1α, which is downstream of the renin-angiotensin system, specifically angiotensin II, which promotes production of HIF-1α. These developments shed light to the understanding of this enigmatic condition. [ABSTRACT FROM AUTHOR]

The nongenomic actions of thyroid hormone begin at receptors in the plasma membrane, mitochondria or cytoplasm. These receptors can share structural homologies with nuclear thyroid hormone receptors (TRs) that mediate transcriptional actions of T3, or have no homologies with TR, such as the plasma membrane receptor on integrin αvβ3. Nongenomic actions initiated at the plasma membrane by T4 via integrin αvβ3 can induce gene expression that affects angiogenesis and cell proliferation, therefore, both nongenomic and genomic effects can overlap in the nucleus. In the cytoplasm, a truncated TRα isoform mediates T4-dependent regulation of intracellular microfilament organization, contributing to cell and tissue structure. p30 TRα1 is another shortened TR isoform found at the plasma membrane that binds T3 and mediates nongenomic hormonal effects in bone cells. T3 and 3,5-diiodo-L-thyronine are important to the complex nongenomic regulation of cellular respiration in mitochondria. Thus, nongenomic actions expand the repertoire of cellular events controlled by thyroid hormone and can modulate TR-dependent nuclear events. Here, we review the experimental approaches required to define nongenomic actions of the hormone, enumerate the known nongenomic effects of the hormone and their molecular basis, and discuss the possible physiological or pathophysiological consequences of these actions. [ABSTRACT FROM AUTHOR]

Well-standardized primary treatment and long-term management of differentiated thyroid carcinoma (DTC) include lowering or suppression of host thyrotropin (TSH) with exogenous L-thyroxine (T). This treatment recognizes the trophic action of TSH on DTC cells. Suppression of endogenous TSH with T is continued in recurrent disease. However, T can induce proliferation of follicular and papillary thyroid carcinoma cell lines and of other human carcinoma cells. The proliferative mechanism is initiated at a cell surface receptor for T on integrin αvβ3, a receptor by which the hormone also inhibits p53-dependent apoptosis in tumor cells. In recurrent DTC with satisfactory suppression of endogenous TSH, we discuss here the possibility that the tumor is no longer TSH dependent and that T has become a critical growth factor for the cancer. [ABSTRACT FROM AUTHOR]

The manner in which coaches regulate their emotions has implications for their performance and well-being. Drawing on research that has found perfectionism to predict emotion regulation in other settings, this study adopted the 2 × 2 model of perfectionism to examine whether subtypes of perfectionism among coaches were associated with variation in the use of emotion regulation strategies. Coaches ( N = 238, M age = 23.92, SD = 10.32) from various sports completed measures of perfectionism (personal standards and evaluative concerns) and emotion regulation strategies (expressive suppression, cognitive reappraisal, and control of anger directed inwards and outwards). Moderated hierarchical regression provided mixed support for the 2 × 2 model. As expected, pure personal standards perfectionism (high standards/low concerns) was generally associated with the highest capacity for emotion regulation and pure evaluative concerns perfectionism (low standards/high concerns) with the lowest. Unexpectedly, mixed perfectionism (high standards/high concerns) was associated with the highest level of expressive suppression, suggesting that in some instances standards might exacerbate rather than attenuate concerns. [ABSTRACT FROM AUTHOR]

Acting via a cell surface receptor on integrin αvβ3, thyroid hormone is pro-angiogenic. Nongenomic mechanisms of actions of the hormone and hormone analogues at αvβ3 include modulation of activities of multiple vascular growth factor receptors and their ligands (vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor), as well as of angiogenic chemokines (CX family). Thyroid hormone also may increase activity of small molecules that support neovascularization (bradykinin, angiotensin II) and stimulate endothelial cell motility. Therapeutic angio-inhibition in the setting of cancer may be opposed by endogenous thyroid hormone, particularly when a single vascular growth factor is the treatment target. This may be a particular issue in management of aggressive or recurrent tumors. It is desirable to have access to chemotherapies that affect multiple steps in angiogenesis and to examine as alternatives in aggressive cancers the induction of subclinical hypothyroidism or use of antagonists of the αvβ3 thyroid hormone receptor that are under development. [ABSTRACT FROM AUTHOR]

This study aims to explore the different connotations and potential offensiveness of ten mechanistic labels in newly referred Mexican patients with rheumatic symptoms as well as in Mexican and Canadian rheumatologists. Patients with musculoskeletal complaints newly referred for a rheumatology assessment were interviewed consecutively before they saw the rheumatologist. Patients were asked to choose one of nine feelings provoked by ten different illness mechanism labels. Rheumatologists gave a medical diagnosis after seeing the patients. Mexican and Canadian rheumatologists were invited to answer a structured questionnaire about their feelings at the moment they identified each of the ten different provided scenarios. Patients' and rheumatologists' feelings were classified as 'offended' or 'nonoffended.' The 'offensive score' was used to calculate a 'number needed to offend' (NNO). One hundred and fifty patients were included. Inherited, immunological, and inflammatory labels had the fewest negative connotations (NNOs 17, 12, and 14, respectively), and psychological, functional, idiopathic, and sleep disturbance labels had the most (NNO 2 and 3, respectively). Functional labels were almost four times more offensive than organic labels. Stratified by rheumatologist diagnosis, patients with functional disorders were more accepting of organic-based mechanistic labels. A higher potential to offend was observed when patients with functional somatic conditions were given functional mechanistic labels (NNOs 1 to 4). The survey was completed by 186 Mexican rheumatologists and 71 Canadian rheumatologists. Primarily functional disorders such as somatization and anxiety had a high potential to evoke offensive feelings (NNOs 3 to 7). No significant differences in the NNO were found between Mexican and Canadian rheumatologists. Getting or giving mechanistic/explanatory labels is emotional. Both patients and rheumatologists experienced offended feelings with functional or idiopathic labels. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a growing health problem, at least in part due to the concurrent obesity epidemic plaguing developed countries. However, once a patient develops HF, an elevated BMI appears to confer a survival benefit - a phenomenon termed the 'obesity paradox.' The exact explanation for this paradox has been difficult to ascertain. Numerous plausible mechanisms have been asserted, including the fact that obese patients tend to be younger and more symptomatic, leading them to seek medical attention earlier in the course of their HF. Obese patients may also have larger energy reserves that help to offset the catabolic changes seen with HF. Other hypotheses highlight the limitations of BMI as an obesity classifier. The purpose of this review is to examine the various theories for the obesity paradox in HF and discuss the implications for the clinical management of obese patients with HF. [ABSTRACT FROM AUTHOR]

Integrins are heterodimeric structural components of the plasma membrane whose ligands include a large number of extracellular matrix (ECM) proteins. The ligands contain Arg–Gly–Asp (RGD) sequences that enable recognition of ECM proteins by as many as eight integrins, but other distinguishing features of the proteins permit the integrins to generate intracellular signals specific to the ECM molecules. Recently, integrin αvβ3 has been shown to have a panel of previously unappreciated small molecule receptor sites for thyroid hormone and hormone analogues, for dihydrotestosterone, and for resveratrol, a polyphenol that has certain estrogen-like features. These binding sites are close to the RGD recognition site of αvβ3. The thyroid hormone receptor site on the extracellular domain of αvβ3 contains two domains with discrete functions in terms of intracellular protein trafficking and gene expression. Occupancy of the receptor by a deaminated thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), prevents cell responses to agonist thyroid hormones ( l-thyroxine; 3, 5, 3′-triiodo- l-thyronine) and modulates expression of a number of cancer cell survival pathway genes in an up- or downregulation pattern coherent to induction of cell death. The small molecule thyroid hormone receptor on the integrin also regulates activity of five vascular growth factor receptors and/or their ligands, providing control of angiogenesis via specific pharmacologic regulation of this thyroid hormone receptor. The resveratrol receptor induces programmed cancer cell death via p53, even when the latter has undergone specific mutations. There is also evidence for the presence of several receptors on integrin αvβ3 for authentic steroids, including a dihydrotestosterone site that supports proliferation of breast cancer cells that lack nuclear androgen and estrogen receptors. The existence of these small molecule hormone receptors on an integrin with a remarkably complex functional profile defines novel pharmacologic options via individual small molecule receptor manipulation for control of cancer cell behavior. This refinement of up-down control at the level of discrete receptors is not a function of the use of αvβ3 antibody or RGD peptides that occlude regions of the integrin. [ABSTRACT FROM AUTHOR]

Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC-1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (* P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caused accumulation of pro-apoptotic protein BcLx-s. Tetrac NP was more effective than tetrac in increasing cellular abundance of mRNAs of pro-apoptotic p53 and p21 and anti-angiogenesis thrombospondin 1 protein in PANC-1 and MPanc96 cancer cell lines. Tetrac NP noticeably decreased expression of EGFR and of anti-apoptosis gene XIAP; tetrac did not affect EGFR and increased XIAP mRNA in both MPanc96 and PANC-1. In conclusion, tetrac or Tetrac NP effectively inhibited human pancreatic xenograft growth and tumor angiogenesis via a plasma membrane receptor that downstream modulated cellular abundance of proteins or mRNAs relevant to apoptosis and angiogenesis. [ABSTRACT FROM AUTHOR]

The archetypical komatiite-hosted Alexo Ni-Cu-(PGE) deposit occurs in the 2,720-2,710-Ma Kidd-Munro Assemblage of the western Abitibi greenstone belt in Dundonald Township, Ontario. Detailed mapping of a 200-m long glacially polished outcrop provides unequivocal evidence that the host komatiite flow thermomechanically eroded footwall andesites: (1) the contact between komatiite and andesite is very sharp but delicately scalloped, marked by a <1-cm-thick selvedge of black aphanitic komatiite and clearly transgresses pillow structures and interpillow breccias in the andesite without any evidence of a regolith, shearing, or folding, producing multiple nested embayments on scales from hundreds of meters to a few centimeters; (2) the andesites have been contact metamorphosed and altered along the entire length of the outcrop and the degree of metamorphism/alteration is thicker and more intense around embayments; (3) xenoliths of andesite in komatiite are more common within embayments; (4) komatiitic dikes penetrate downward into underlying andesites, primarily along the lateral margins of embayments; and (5) many of the dikes and marginal rocks exhibit geochemical evidence of contamination. This physical and geochemical evidence for thermomechanical erosion, combined with S isotopic evidence for a major component of non-magmatic country-rock S in the ores, provides additional support for the roles of thermomechanical erosion and incorporation of country-rock S in the genesis of komatiite-associated Ni-Cu-(PGE) deposits. The detailed mapping also reveals that the stratigraphy of the ore zone is considerably more complex than previously reported, indicating that the sulfides were emplaced in several stages, confirming the dynamic nature of the ore emplacement process in komatiite-associated Ni-Cu-(PGE) deposits. [ABSTRACT FROM AUTHOR]

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery. [ABSTRACT FROM AUTHOR]