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Abstract Background Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules. Results We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell. Conclusions Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

We experimentally study the effects of normal stress differences in the immiscible radial viscous fingering instability in a Hele–Shaw cell. Dilute low molecular weight poly(ethylene oxide) (PEO) solutions are used as the displaced fluid to focus on elastic effects without shear-thinning behavior. The molecular weight of PEO is varied to investigate the effects of normal stress differences. The experimental observations reveal that nonmonotonic and opposing effects are evident depending on the molecular weight of the PEO and the stage of the radial viscous fingering evolution. Decreases in the PEO molecular weight reduce the number of fingers and widen the finger width in the early stage. However, the increase in the PEO molecular weight promotes tip splitting and narrows finger width in the early stage but suppresses tip splitting in the intermediate stage. Weissenberg numbers are estimated at different stages of radial viscous fingering instabilities. Tip splitting occurs at the highest Weissenberg number covered in this study and suppression of tip splitting is observed at intermediate Weissenberg numbers. At low Weissenberg numbers, we observe an increased finger width and a reduced number of fingers. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for new therapeutics that otherwise have shown significant successes in disease control. Hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and is widely targeted in drug development. We found that resistance to the HGF-neutralizing antibody drug candidate rilotumumab in glioblastoma cells was acquired through HGF overproduction and misfolding, which led to stress-response signaling and redirected transport inside cells that sequestered rilotumumab and misfolded HGF from native HGF and activated Met receptor. Resistant cells were more malignant but retained their sensitivity to Met kinase inhibition and gained sensitivity to inhibition of stress signaling and cholesterol biosynthesis. Defining this rapidly acquired, multisystem scheme improves our understanding of drug resistance and suggests strategies for early detection and intervention. Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that soluble VEGF receptor domains that compete for VEGF binding may inhibit tumor angiogenesis, growth and metastatic spread. We tested whether soluble FLT-1 (sFLT-1) could inhibit breast cancer tumor growth in mice by blocking angiogenesis. A viral vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the receptor in MCF-7 cells, which produce VEGF. After six weeks, tumors were treated either with Adsflt or a negative control virus. After six months, average tumor volume in the Adsflt-treated group was decreased by 91% and vascular density was reduced 50%, relative to negative controls (p < 0.05), yet mice treated with Adsflt showed no delay in healing cutaneous wounds. These results provide evidence that viral sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects. Two vascular endothelial growth factor (VEGF) receptors, FLT-1 and KDR, are expressed preferentially in proliferating endothelium. There is increasing evidence that recombinant, soluble VEGF receptor domains interfering with VEGF signaling may inhibit in vivo neoangiogenesis, tumor growth and metastatic spread. We hypothesized that a soluble form of FLT-1 receptor (sFLT-1) could inhibit the growth of pre-established tumors via an anti-angiogenic mechanism. A replication-deficient adenovirus (Ad) vector carrying the sflt-1 cDNA (Adsflt) was used to overexpress the sFLT-1 receptor in a breast cancer animal model. MCF-7 cells, which produce VEGF, were used to establish solid tumors in the mammary fat pads of female nude mice. After six weeks, tumors were injected either with Adsflt or a negative control virus (AdCMV.βgal). After six months, average tumor volume in the Adsflt-infected group (33 ± 22 mm3) decreased by 91% relative to that of the negative control group (388 ± 94 mm3; p < 0.05). Moreover, 10 of 15 Adsflt-infected tumors exhibited complete regression. The vascular density of Adsflt-infected tumors was reduced by 50% relative to that of negative controls (p < 0.05), which is consistent with sFLT-1-mediated tumor regression through an anti-angiogenic mechanism. Moreover, cell necrosis and fibrosis associated with long-term regression of Adsflt–infected tumors were preceded by apoptosis of tumor vascular endothelial cells. Mice treated with Adsflt intratumorally showed no delay in the healing of cutaneous wounds, providing preliminary evidence that Ad-mediated sFLT-1 overexpression may be an effective anti-angiogenic therapy for cancer without the risk of systemic anti-angiogenic effects. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is critical for tissue homeostasis and repair in many organs including the lung, heart, kidney, liver, nervous system, and skin. HGF is a heterodimeric protein containing 20 disulfide bonds distributed among an amino-terminal hairpin, four kringle domains, and a serine protease-like domain. Due to its complex structure, recombinant production of HGF in prokaryotes requires denaturation and refolding, processes that are impractical for large-scale manufacture. Thus, pharmaceutical quantities of HGF are not available despite its potential applications. A fragment of the Listeria monocytogenes internalin B protein from amino acids 36-321 ([InlB.sub.36-321]) was demonstrated to bind to and partially activate the HGF receptor Met. [InlB.sub.36-321] has a stable [beta]-sheet structure and is easily produced in its native conformation by Escherichia coli. We cloned [InlB.sub.36-321] (1x[InlB.sub.36-321]) and engineered a head-to-tail repeat of [InlB.sub.36-321] with a linker peptide (2x[InlB.sub.36-321]); 1x[InlB.sub.36-321] and 2x[InlB.sub.36-321] were purified from E. coli. Both 1x and 2x[InlB.sub.36-321] activated the Met tyrosine kinase. We subsequently compared signal transduction of the two proteins in primary lung endothelial cells. 2x[InlB.sub.36-321] activated ERK1/2, STAT3, and phosphatidylinositol 3-kinase/Akt pathways, whereas 1x[InlB.sub.36-321] activated only STAT3 and ERK1/2. The 2x[InlB.sub.36-321] promoted improved motility compared with 1x[InlB.sub.36-321] and additionally stimulated proliferation equivalent to full-length HGF. Both the 1x and 2x[InlB.sub.36-321] prevented apoptosis by the profibrotic peptide angiotensin II in cell culture and ex vivo lung slice cultures. The ease of large-scale production and capacity of 2x[InlB.sub.36-321] to mimic HGF make it a potential candidate as a pharmaceutical agent for tissue repair. apoptosis, angiotensin II; Akt; ERK1/2 doi: 10.1152/ajplung.00094.2010.

Bleomycin, a chemotherapeutic agent, can cause pulmonary fibrosis in humans and is commonly used to induce experimental pulmonary fibrosis in rodents. In cell culture, bleomycin causes single- and double-stranded DNA breaks and produces reactive oxidative species, both of which require iron ([Fe.sup.2+]) and [O.sub.2]. The mechanism of bleomycin-induced apoptosis is controversial due to its complexity. We investigated bleomycin apoptotic signaling events in primary pulmonary endothelial cells. Time course experiments revealed that bleomycin induced apoptosis within 4 h. Caspase-8, the initiator caspase for the extrinsic pathway, was activated within 2 h and preceded activation of the effector caspases-3 and -6 (4 h). Caspase-9, the initiator of the intrinsic pathway and release of cytochrome c from the mitochondria were not detected at these time points. Bleomycin induced the expression of Bcl-2 and Bcl-[x.sub.L], Bcl-2 family member proteins that protect cells from the mitochondria-dependent intrinsic apoptosis. Real-time quantitative RT-PCR results demonstrated that. at 4-8 h, bleomycin induced expression of TNF and TNF receptor family genes known to induce the extrinsic apoptotic pathway. Silencing of the death receptor adaptor protein Fas-associated death domain by short interfering RNA significantly reduced bleomycin-induced apoptosis. Apoptosis was also abrogated by caspase-8 inhibition, but only slightly reduced by caspase-3 inhibition. Together, these data suggest that bleomycin initiates apoptosis via the extrinsic pathway. deoxyribonucleic acid damage; deoxyribonucleic acid laddering; death receptor; Fas-associated death domain; caspase doi: 10.1152/ajplung.00322.2009.

Objective: This study aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin in patients with antiphospholipid syndrome (APS). Methods: We performed a literature search using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. We also performed a meta-analysis of randomized controlled trials (RCTs) investigating the effectiveness and safety of DOACs versus warfarin in patients with APS. Results: Five RCTs involving 648 patients with APS (330 in DOAC-treated and 318 in control groups) were included in the meta-analysis. Among the patients included in the analysis, 29 (8.8%) patients experienced recurrent thrombosis in the DOAC treatment group, and 10 patients (3.1%) had thrombosis recurrence in the warfarin treatment group, resulting in a higher incidence in DOAC-treated than in the warfarin-treated groups [odds ratio (OR) = 2.163, 95% CI = 0.985–4.748, p = 0.055]. Incidence of arterial thrombosis was significantly higher in DOAC-treated patients than in warfarin-treated patients (OR = 5.168, 95% CI = 1.567–17.04, p = 0.007). Stroke and thrombosis occurrences were significantly higher in the triple positivity group than in the warfarin therapy group (OR = 12.03, 95% CI = 2.249–64.36, p = 0.004; OR = 2.940, 95% CI = 1.016–8.504, p = 0.047). However, venous thrombosis occurrences did not differ significantly between the DOAC-treated and warfarin-treated groups. There were no significant differences between the DOAC and warfarin groups in terms of any bleeding, major bleeding, minor bleeding, and all-cause mortality. Conclusion: DOACs were associated with higher rates of arterial thrombosis than warfarin in patients with APS, especially in the triple-positive group. However, a higher risk of recurrent venous thrombosis was not found in APS patients treated with DOACs compared to those treated with warfarin. [ABSTRACT FROM AUTHOR]

Knowledge about phase transitions in doped HfO2 and ZrO2‐based films is crucial for developing future ferroelectric devices. These devices should perform in ambient temperature ranges with no degradation of device performance. Here, the phase transition from the polar orthorhombic to the nonpolar tetragonal phase in thin films is of significant interest. Detailed electrical and structural characterization is performed on 10 nm mixed HfxZr1‐xO2 binary oxides with different ZrO2 in HfO2 and small changes in oxygen content. Both dopant and oxygen content directly impact the phase transition temperature between the polar and nonpolar phase. A first‐order phase transition with thermal hysteresis is observed from the nonpolar to the polar phase with a maximum in the dielectric constant. The observed phase transition temperatures confirm trends as obtained by DFT calculations. Based on the outcome of the measurements, the classification of the ferroelectric material is discussed. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is upregulated in response to lung injury and has been implicated in tissue repair through its antiapoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play a role in cell growth. Here, we report that HGF induces gene transcription of COX-2 in human bronchial epithelial cells (HBEpC). Treatment of HBEpC with HGF resulted in phosphorylation of the HGF receptor (c-Met), activation of Akt, and upregulation of COX-2 mRNA. Adenovirus-mediated gene transfer of a dominant negative (DN) Akt mutant revealed that HGF increased COX-2 mRNA in an Akt-dependent manner. COX-2 promoter analysis in luciferase reporter constructs showed that HGF regulation required the [beta]-catenin-responsive T cell factor-4 binding element (TBE). The HGF activation of the COX-2 gene transcription was blocked by DN mutant of [beta]-catenin or by inhibitors that blocked activation of Akt. Inhibition of p42/p44 MAPK pathway blocked HGF-mediated activation of [beta]-catenin gene transcription but not Akt activation, suggesting that p42/p44 MAPK acts in a parallel mechanism for [beta]-catenin activation. We also found that inhibition of COX-2 with NS-398 blocked HGF-induced growth in HBEpC. Together, the results show that the HGF increases COX-2 gene expression via an Akt-, MAPK-, and [beta]-catenin-dependent pathway in HBEpC. fibrosis; signal transduction; proliferation; tissue repair; T cell factor-4 binding element

Theories of rational addiction posit that certain habit-forming goods--characterized by an increasing marginal utility of consumption--generate predictable dynamic patterns of consumer behavior. It has been suggested that attendance at sporting events represents an example of such a good, as evidenced by the pricing strategies of commercial sports interests. In this essay, we provide new evidence in support of rational addiction for the case of Major League Baseball but fail to find such support in data from the Korean Professional Baseball League. We then review the scientific literature on sports fans from the perspective of human behavioral ecology and propose a theory of endogenous habit formation among sports fans that could explain our findings. (JEL C32, D83, D87, D91, L83), Men's natures are alike; it is their habits that separate them. --Confucius I. INTRODUCTION Static microeconomic theory predicts that profit-maximizing monopolists will price in the elastic range of demand. The [...]

The instability at the interface between two parallel flows of immiscible liquids through a uniform planar pore is studied by using linear stability analysis. A characteristic equation determines the growth rate versus wavenumber, and instability conditions are determined. The instability is governed by a dimensionless group relating the ratio of gravity to interfacial tension. Interfacial tension has a stabilizing effect resisting the destabilizing gravitational force, limiting the range of wavelengths of unstable disturbances to be longer than a minimum critical wavelength. Application to flow of steam condensate and mobilized bitumen in the steam‐assisted gravity drainage process shows that the instability is possible only over a specific range of temperatures given the densities of the steam condensate and oil in the reservoir. This instability may contribute to forming an emulsion which could help support oil drainage if the oil is hosted by the more mobile water phase. [ABSTRACT FROM AUTHOR]

Particle-in-cell/Monte Carlo (PIC/MC) simulations of capacitively coupled radio-frequency (RF) glow discharges were carried out for low pressure C[H.sub.4] plasmas. The present computational scheme includes the motions and collisions of both neutral and charged particles. The C[H.sub.4] plasma is modeled by combining a one-dimensional PIC/MC method with a polyatomic particle collision scheme. The model considers the motions of C[H.sub.4], [Mathematical Expression Omitted], C[H.sub.3], [C.sub.2][H.sup.5], [H.sub.2], H, and electrons. Space and time dependent results show ionization rate is high at the sheath region. The dissociation rate of C[H.sub.4] is found to be high at the sheath as well as in the plasma bulk. Deposition rate of carbon film is calculated by sampling impinging particles at the powered electrode. The calculations show that neutral radicals are the major depositing species for the cases studied. Ion energy impinging to the electrode was found to be strongly dependent on the 'imposed' dc bias (as opposed to self-bias) voltage for a given RF voltage. Deposition rate was found to be almost independent of the 'imposed' dc bias voltage as the RF voltage remained constant. Index Terms - Capacitively coupled plasma, carbon film, simulation.

Analysis of insulin responses of obese prediabetic and diabetic Zucker diabetic fatty (ZDF) rats to glucose and to the glucose metabolites, D-glyceraldehyde and monomethyl succinate, help determine the defects associated with loss of the glucose transporter GLUT-2 in beta-cells of non insulin-dependent diabetic obese rats. Diabetic ZDF rats show impaired insulin responses to glyceradehyde, monomethyl succinate and glucose. The impaired responses are greatest for glucose and lowest for monomethyl succinate, confirming the occurrence of defects at multiple sites in glucose metabolism.

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes. [ABSTRACT FROM AUTHOR]

We extend the literature on unbiased estimators of sports league outcomes to include outcome uncertainty. While competitive balance and outcome uncertainty are related, generally, they are not the same thing. We show that an extant unbiased estimator of competitive balance, and our new unbiased estimator of outcome uncertainty, bear this out. The impacts on both competitive balance and outcome uncertainty, moving from a balanced to an unbalanced schedule, are demonstrated via numerical analysis. Finally, the unbiased estimators are employed to test the implications of our numerical analysis on the move by the Scottish Professional Football League to an unbalanced schedule. Results conform to our simulations. [ABSTRACT FROM AUTHOR]

The National Aeronautics and Space Administration (NASA) Radioisotope Power Systems (RPS) Program Mission Analysis Team at the Jet Propulsion Laboratory (JPL) requested a JPL Innovation Foundry Architecture Team (A-Team) study to assess mission pull for small RPS [1 to 40 W(electric)] and define the focus of future power system developments required to enable small RPS missions. The A-Team is JPL's concurrent engineering design team for science definition and early mission concept development, targeting concept maturation levels of 1, 2, and 3. The requested small RPS study aimed to identify the architecture space of potential small RPS missions and suggest power levels that could enable or enhance potential future small spacecraft missions. This technical note describes the collaborative engineering processes that the A-Team and Mission Analysis Team used to reach results quickly and presents the findings on power requirements for small RPS mission concepts. [ABSTRACT FROM AUTHOR]

Plasma variables are predicted using a glow discharge physics model and compared with experimental data obtained from plasma assisted chemical vapor deposition (PACVD) reactors. The present study provides insights to charged species dynamics and their effects on deposition in a polyatomic gas (methane) discharge. Swarm data as a function of electron energy are provided as input to the model. The necessary dc bias for the discharge is also predicted such that the cycle-averaged current to the powered electrode becomes zero. The simulations are performed for the operating conditions of two different experimental reactors. The model predictions of electron density, self-generated dc bias, and power requirement compare very well with the experimental results. The model predictions of axial and radial variations of plasma density also compare well with the experimental data. The radial and axial variations of plasma variables in the reactors are also presented. Index Terms--Chemical vapor deposition, experiment, Langmuir probe, methane plasma, simulation.