485 research outputs found
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Suppression of the Proinflammatory Response of Metastatic Melanoma Cells Increases TRAIL-Induced Apoptosis
Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFα IL6 and IL8, their receptors, and constitutive NF-κB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFα or IL6), pharmacological (small molecular inhibitors of IKKβ–NF-κB and JAK2–STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas
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Resveratrol Sensitizes Melanomas to TRAIL Through Modulation of Antiapoptotic Gene Expression
Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-ÎşB that control the expression of antiapoptotic genes, including cFLIP and Bcl-xL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-ÎşB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while Îł-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by Îł-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas
Comparing Brane Inflation to WMAP
We compare the simplest realistic brane inflationary model to recent
cosmological data, including WMAP 3-year cosmic microwave background (CMB)
results, Sloan Digital Sky Survey luminous red galaxies (SDSS LRG) power
spectrum data and Supernovae Legacy Survey (SNLS) Type 1a supernovae distance
measures. Here, the inflaton is simply the position of a -brane which is
moving towards a -brane sitting at the bottom of a throat (a warped,
deformed conifold) in the flux compactified bulk in Type IIB string theory. The
analysis includes both the usual slow-roll scenario and the Dirac-Born-Infeld
scenario of slow but relativistic rolling. Requiring that the throat is inside
the bulk greatly restricts the allowed parameter space. We discuss possible
scenarios in which large tensor mode and/or non-Gaussianity may emerge. Here,
the properties of a large tensor mode deviate from that in the usual slow-roll
scenario, providing a possible stringy signature. Overall, within the brane
inflationary scenario, the cosmological data is providing information about the
properties of the compactification of the extra dimensions.Comment: 45 pages 11 figure
Cosmology of the Tachyon in Brane Inflation
In certain implementations of the brane inflationary paradigm, the exit from
inflation occurs when the branes annihilate through tachyon condensation. We
investigate various cosmological effects produced by this tachyonic era. We
find that only a very small region of the parameter space (corresponding to
slow-roll with tiny inflaton mass) allows for the tachyon to contribute some
e-folds to inflation. In addition, non-adiabatic density perturbations are
generated at the end of inflation. When the brane is moving relativistically
this contribution can be of the same order as fluctuations produced 55 e-folds
before the end of inflation. The additional contribution is very nearly
scale-invariant and enhances the tensor/scalar ratio. Additional
non-gaussianities will also be generated, sharpening current constraints on
DBI-type models which already predict a significantly non-gaussian signal.Comment: 30 pages, 2 figures; v3, minor revision, JCAP versio
Observing Brane Inflation
Linking the slow-roll scenario and the Dirac-Born-Infeld scenario of
ultra-relativistic roll (where, thanks to the warp factor, the inflaton moves
slowly even with an ultra-relativistic Lorentz factor), we find that the KKLMMT
D3/anti-D3 brane inflation is robust, that is, enough e-folds of inflation is
quite generic in the parameter space of the model. We show that the
intermediate regime of relativistic roll can be quite interesting
observationally. Introducing appropriate inflationary parameters, we explore
the parameter space and give the constraints and predictions for the
cosmological observables in this scenario. Among other properties, this
scenario allows the saturation of the present observational bound of either the
tensor/scalar ratio r (in the intermediate regime) or the non-Gaussianity f_NL
(in the ultra-relativistic regime), but not both.Comment: 31 pages, 12 figures; typo correcte
Atropselective syntheses of (-) and (+) rugulotrosin A utilizing point-to-axial chirality transfer
Chiral, dimeric natural products containing complex structures and interesting biological properties have inspired chemists and biologists for decades. A seven-step total synthesis of the axially chiral, dimeric tetrahydroxanthone natural product rugulotrosin A is described. The synthesis employs a one-pot Suzuki coupling/dimerization to generate the requisite 2,2'-biaryl linkage. Highly selective point-to-axial chirality transfer was achieved using palladium catalysis with achiral phosphine ligands. Single X-ray crystal diffraction data were obtained to confirm both the atropisomeric configuration and absolute stereochemistry of rugulotrosin A. Computational studies are described to rationalize the atropselectivity observed in the key dimerization step. Comparison of the crude fungal extract with synthetic rugulotrosin A and its atropisomer verified that nature generates a single atropisomer of the natural product.P50 GM067041 - NIGMS NIH HHS; R01 GM099920 - NIGMS NIH HHS; GM-067041 - NIGMS NIH HHS; GM-099920 - NIGMS NIH HH
Transverse-Momentum Dependence of the J/psi Nuclear Modification in d+Au Collisions at sqrt(s_NN)=200 GeV
We present measured J/psi production rates in d+Au collisions at sqrt(s_NN) =
200 GeV over a broad range of transverse momentum (p_T=0-14 GeV/c) and rapidity
(-2.2<y<2.2). We construct the nuclear-modification factor R_dAu for these
kinematics and as a function of collision centrality (related to impact
parameter for the R_dAu collision). We find that the modification is largest
for collisions with small impact parameters, and observe a suppression
(R_dAu<1) for p_T<4 GeV/c at positive rapidities. At negative rapidity we
observe a suppression for p_T1) for p_T>2
GeV/c. The observed enhancement at negative rapidity has implications for the
observed modification in heavy-ion collisions at high p_T.Comment: 384 authors, 24 pages, 19 figures, 13 tables. Submitted to Phys. Rev.
C. Plain text data tables for the points plotted in figures for this and
previous PHENIX publications are publicly available at
http://www.phenix.bnl.gov/phenix/WWW/info/data/ppg123_data.htm
Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival
Impaired apoptosis is one of the hallmarks of cancer. Caspase-3 and -8 are key regulators of the apoptotic response and have been shown to interact with the calpain family, a group of cysteine proteases, during tumorigenesis. The current study sought to investigate the prognostic potential of caspase-3 and -8 in breast cancer, as well as the prognostic value of combinatorial caspase and calpain expression. A large cohort (n = 1902) of early stage invasive breast cancer patients was used to explore the expression of caspase-3 and -8. Protein expression was examined using standard immunohistochemistry on tissue microarrays. High caspase-3 expression, but not caspase-8, is significantly associated with adverse breast cancer-specific survival (P = 0.008 and P = 0.056, respectively). Multivariate analysis showed that caspase-3 remained an independent factor when confounding factors were included (hazard ratio (HR) 1.347, 95% confidence interval (CI) 1.086–1.670; P = 0.007). The analyses in individual subgroups demonstrated the significance of caspase-3 expression in clinical outcomes in receptor positive (ER, PR or HER2) subgroups (P = 0.001) and in non-basal like subgroup (P = 0.029). Calpain expression had been previously assessed. Significant association was also found between high caspase-3/high calpain-1 and breast cancer-specific survival in the total patient cohort (P = 0.005) and basal-like subgroup (P = 0.034), as indicated by Kaplan–Meier analysis. Caspase-3 expression is associated with adverse breast cancer-specific survival in breast cancer patients, and provides additional prognostic values in distinct phenotypes. Combinatorial caspase and calpain expression can predict worse prognosis, especially in basal-like phenotypes. The findings warrant further validation studies in independent multi-centre patient cohorts
Cold Nuclear Matter Effects on J/psi Yields as a Function of Rapidity and Nuclear Geometry in Deuteron-Gold Collisions at sqrt(s_NN) = 200 GeV
We present measurements of J/psi yields in d+Au collisions at sqrt(s_NN) =
200 GeV recorded by the PHENIX experiment and compare with yields in p+p
collisions at the same energy per nucleon-nucleon collision. The measurements
cover a large kinematic range in J/psi rapidity (-2.2 < y < 2.4) with high
statistical precision and are compared with two theoretical models: one with
nuclear shadowing combined with final state breakup and one with coherent gluon
saturation effects. To remove model dependent systematic uncertainties we also
compare the data to a simple geometric model. We find that calculations where
the nuclear modification is linear or exponential in the density weighted
longitudinal thickness are difficult to reconcile with the forward rapidity
data.Comment: 449 authors from 66 institutions, 6 pages, 3 figures. Submitted to
Physical Review Letters. Plain text data tables for the points plotted in
figures for this and previous PHENIX publications are (or will be) publicly
available at http://www.phenix.bnl.gov/papers.htm
Functional vascularized lung grafts for lung bioengineering
End-stage lung disease is the third leading cause of death worldwide, accounting for 400,000 deaths per year in the United States alone. To reduce the morbidity and mortality associated with lung disease, new therapeutic strategies aimed at promoting lung repair and increasing the number of donor lungs available for transplantation are being explored. Because of the extreme complexity of this organ, previous attempts at bioengineering functional lungs from fully decellularized or synthetic scaffolds lacking functional vasculature have been largely unsuccessful. An intact vascular network is critical not only for maintaining the blood-gas barrier and allowing for proper graft function but also for supporting the regenerative cells. We therefore developed an airway-specific approach to removing the pulmonary epithelium, while maintaining the viability and function of the vascular endothelium, using a rat model. The resulting vascularized lung grafts supported the attachment and growth of human adult pulmonary cells and stem cell–derived lung-specified epithelial cells. We propose that de-epithelialization of the lung with preservation of intact vasculature could facilitate cell therapy of pulmonary epithelium and enable bioengineering of functional lungs for transplantation
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