146 research outputs found
Revenue Loss in Shrinking Markets
We analyze the revenue loss due to market shrinkage. Specifically, consider a
simple market with one item for sale and bidders whose values are drawn
from some joint distribution. Suppose that the market shrinks as a single
bidder retires from the market. Suppose furthermore that the value of this
retiring bidder is fixed and always strictly smaller than the values of the
other players. We show that even this slight decrease in competition might
cause a significant fall of a multiplicative factor of
in the revenue that can be obtained by a dominant
strategy ex-post individually rational mechanism.
In particular, our results imply a solution to an open question that was
posed by Dobzinski, Fu, and Kleinberg [STOC'11]
PAR Genes: Molecular Probes to Pathological Assessment in Breast Cancer Progression
Taking the issue of tumor categorization a step forward and
establish molecular imprints to accompany histopathological
assessment is a challenging task. This is important since often
patients with similar clinical and pathological tumors may respond
differently to a given treatment. Protease-activated receptor-1
(PAR1), a G protein-coupled receptor (GPCR),
is the first member
of the mammalian PAR family consisting of four genes. PAR1 and
PAR2 play a central role in breast cancer. The release of
N-terminal peptides during activation and the exposure of a
cryptic internal ligand in PARs, endow these receptors with the
opportunity to serve as a “mirror-image”
index reflecting the level of cell surface PAR1&2-in body fluids. It is possible to
use the levels of PAR-released peptide in patients and
accordingly determine the choice of treatment. We have both
identified PAR1 C-tail as a scaffold site for the immobilization
of signaling partners, and the critical minimal binding site. This
binding region may be used for future therapeutic modalities in
breast cancer, since abrogation of the binding inhibits PAR1
induced breast cancer. Altogether, both PAR1 and PAR2 may serve as
molecular probes for breast cancer diagnosis and valuable targets
for therapy
Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen
A pivotal role is attributed to the estrogenreceptor
(ER) pathway in mediating the effect of estrogen
in breast cancer progression. Yet the precise mechanisms
of cancer development by estrogen remain poorly understood.
Advancing tumor categorization a step forward,
and identifying cellular gene fingerprints to accompany
histopathological assessment may provide targets for therapy
as well as vehicles for evaluating the response to
treatment. We report here that in breast carcinoma,
estrogen may induce tumor development by eliciting
protease-activated receptor-1 (PAR1) gene expression.
Induction of PAR1 was shown by electrophoretic mobility
shift assay, luciferase reporter gene driven by the hPar1
promoter, and chromatin-immunoprecipitation analyses.
Functional estrogen regulation of hPar1 in breast cancer
was demonstrated by an endothelial tube-forming network.
Notably, tissue-microarray analyses from an established
cohort of women diagnosed with invasive breast
carcinoma exhibited a significantly shorter disease-free
(P 0.006) and overall (P 0.02) survival of patients that
were positive for ER and PAR1, compared to ER-positive
but PAR1-negative patients. We propose that estrogen
transcriptionally regulates hPar1, culminating in an aggressive
gene imprint in breast cancer. While ER patients are
traditionally treated with hormone therapy, the presence
of PAR1 identifies a group of patients that requires
additional treatment, such as anti-PAR1 biological vehicles
or chemotherapy.—Salah, Z., Uziely, B., Jaber, M., Maoz,
M., Cohen, I., Hamburger, T., Maly, B., Peretz, T., B.-S,
R. Regulation of human protease-activated receptor 1
(hPar1) gene expression in breast cancer by estrogen
Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin
Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX®/Doxil®) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS)
Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect
to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR
Etk/Bmx Regulates Proteinase-Activated-Receptor1 (PAR1) in Breast Cancer Invasion: Signaling Partners, Hierarchy and Physiological Significance
BACKGROUND: While protease-activated-receptor 1 (PAR(1)) plays a central role in tumor progression, little is known about the cell signaling involved. METHODOLOGY/PRINCIPAL FINDINGS: We show here the impact of PAR(1) cellular activities using both an orthotopic mouse mammary xenograft and a colorectal-liver metastasis model in vivo, with biochemical analyses in vitro. Large and highly vascularized tumors were generated by cells over-expressing wt hPar1, Y397Z hPar1, with persistent signaling, or Y381A hPar1 mutant constructs. In contrast, cells over-expressing the truncated form of hPar1, which lacks the cytoplasmic tail, developed small or no tumors, similar to cells expressing empty vector or control untreated cells. Antibody array membranes revealed essential hPar1 partners including Etk/Bmx and Shc. PAR(1) activation induces Etk/Bmx and Shc binding to the receptor C-tail to form a complex. Y/A mutations in the PAR(1) C-tail did not prevent Shc-PAR(1) association, but enhanced the number of liver metastases compared with the already increased metastases obtained with wt hPar1. We found that Etk/Bmx first binds via the PH domain to a region of seven residues, located between C378-S384 in PAR(1) C-tail, enabling subsequent Shc association. Importantly, expression of the hPar1-7A mutant form (substituted A, residues 378-384), which is incapable of binding Etk/Bmx, resulted in inhibition of invasion through Matrigel-coated membranes. Similarly, knocking down Etk/Bmx inhibited PAR(1)-induced MDA-MB-435 cell migration. In addition, intact spheroid morphogenesis of MCF10A cells is markedly disrupted by the ectopic expression of wt hPar1. In contrast, the forced expression of the hPar1-7A mutant results in normal ball-shaped spheroids. Thus, by preventing binding of Etk/Bmx to PAR(1) -C-tail, hPar1 oncogenic properties are abrogated. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration that a cytoplasmic portion of the PAR(1) C-tail functions as a scaffold site. We identify here essential signaling partners, determine the hierarchy of binding and provide a platform for therapeutic vehicles via definition of the critical PAR(1)-associating region in the breast cancer signaling niche
A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours
To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m−2, respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m−2, PCX 110 mg m−2 and GEM 1000 mg m−2 with neutropaenia being the dose-limiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m−2, PCX 100 mg m−2 and GEM 1000 mg m−2 administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours
Combination of pegylated liposomal doxorubicin (PLD) and paclitaxel in patients with advanced soft tissue sarcoma: a phase II study of the Hellenic Cooperative Oncology Group
A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship
We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets
Distinct Polymer Architecture Mediates Switching of Complement Activation Pathways at the Nanosphere−Serum Interface: Implications for Stealth Nanoparticle Engineering
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