45 research outputs found
On Profit-Maximizing Pricing for the Highway and Tollbooth Problems
In the \emph{tollbooth problem}, we are given a tree \bT=(V,E) with
edges, and a set of customers, each of whom is interested in purchasing a
path on the tree. Each customer has a fixed budget, and the objective is to
price the edges of \bT such that the total revenue made by selling the paths
to the customers that can afford them is maximized. An important special case
of this problem, known as the \emph{highway problem}, is when \bT is
restricted to be a line.
For the tollbooth problem, we present a randomized -approximation,
improving on the current best -approximation. We also study a
special case of the tollbooth problem, when all the paths that customers are
interested in purchasing go towards a fixed root of \bT. In this case, we
present an algorithm that returns a -approximation, for any
, and runs in quasi-polynomial time. On the other hand, we rule
out the existence of an FPTAS by showing that even for the line case, the
problem is strongly NP-hard. Finally, we show that in the \emph{coupon model},
when we allow some items to be priced below zero to improve the overall profit,
the problem becomes even APX-hard
Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9
To investigate clonal hematopoiesis associated gene mutations in vitro and to unravel the direct impact on the human stem and progenitor cell (HSPC) compartment, we targeted healthy, young hematopoietic progenitor cells, derived from umbilical cord blood samples, with CRISPR/Cas9 technology. Site-specific mutations were introduced in defined regions of DNMT3A, TET2, and ASXL1 in CD34(+) progenitor cells that were subsequently analyzed in short-term as well as long-term in vitro culture assays to assess self-renewal and differentiation capacities. Colony-forming unit (CFU) assays revealed enhanced self-renewal of TET2 mutated (TET2(mut)) cells, whereas ASXL1(mut) as well as DNMT3A(mut) cells did not reveal significant changes in short-term culture. Strikingly, enhanced colony formation could be detected in long-term culture experiments in all mutants, indicating increased self-renewal capacities. While we could also demonstrate preferential clonal expansion of distinct cell clones for all mutants, the clonal composition after long-term culture revealed a mutation-specific impact on HSPCs. Thus, by using primary umbilical cord blood cells, we were able to investigate epigenetic driver mutations without confounding factors like age or a complex mutational landscape, and our findings provide evidence for a direct impact of clonal hematopoiesis-associated mutations on self-renewal and clonal composition of human stem and progenitor cells
Assortment optimisation under a general discrete choice model: A tight analysis of revenue-ordered assortments
The assortment problem in revenue management is the problem of deciding which
subset of products to offer to consumers in order to maximise revenue. A simple
and natural strategy is to select the best assortment out of all those that are
constructed by fixing a threshold revenue and then choosing all products
with revenue at least . This is known as the revenue-ordered assortments
strategy. In this paper we study the approximation guarantees provided by
revenue-ordered assortments when customers are rational in the following sense:
the probability of selecting a specific product from the set being offered
cannot increase if the set is enlarged. This rationality assumption, known as
regularity, is satisfied by almost all discrete choice models considered in the
revenue management and choice theory literature, and in particular by random
utility models. The bounds we obtain are tight and improve on recent results in
that direction, such as for the Mixed Multinomial Logit model by
Rusmevichientong et al. (2014). An appealing feature of our analysis is its
simplicity, as it relies only on the regularity condition.
We also draw a connection between assortment optimisation and two pricing
problems called unit demand envy-free pricing and Stackelberg minimum spanning
tree: These problems can be restated as assortment problems under discrete
choice models satisfying the regularity condition, and moreover revenue-ordered
assortments correspond then to the well-studied uniform pricing heuristic. When
specialised to that setting, the general bounds we establish for
revenue-ordered assortments match and unify the best known results on uniform
pricing.Comment: Minor changes following referees' comment
Combinatorial Auctions without Money
Algorithmic Mechanism Design attempts to marry computation and incentives, mainly by leveraging monetary transfers between designer and selfish agents involved. This is principally because in absence of money, very little can be done to enforce truthfulness. However, in certain applications, money is unavailable, morally unacceptable or might simply be at odds with the objective of the mechanism. For example, in Combinatorial Auctions (CAs), the paradigmatic problem of the area, we aim at solutions of maximum social welfare, but still charge the society to ensure truthfulness. We focus on the design of incentive-compatible CAs without money in the general setting of k-minded bidders. We trade monetary transfers with the observation that the mechanism can detect certain lies of the bidders: i.e., we study truthful CAs with verification and without money. In this setting, we characterize the class of truthful mechanisms and give a host of upper and lower bounds on the approximation ratio obtained by either deterministic or randomized truthful mechanisms. Our results provide an almost complete picture of truthfully approximating CAs in this general setting with multi-dimensional bidders
Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo
BACKGROUND: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. METHODS AND RESULTS: In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. CONCLUSIONS: We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model
Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history
Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods: The study comprised 802 women (median age 40Â years, range 19â76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: nâ=â118, 14.7%; BRCA2: nâ=â9, 1.1%). The mutation prevalence was 32.9% in the age group 20â29Â years compared to 6.9% in the age group 60â69Â years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10Â year decrease, 95%CI 1.50â2.32, pâ<â0.001). gBRCA mutation risk was predicted to be >â10% for women diagnosed below approximately 50Â years.
Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50Â years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation
Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? â A preclinical assessment in vitro and in vivo
Background: Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors suc
Frequent ZNF217 mutations lead to transcriptional deregulation of interferon signal transduction via altered chromatin accessibility in B cell lymphoma
Recent exome-wide studies discovered frequent somatic mutations in the epigenetic modifier ZNF217 in primary mediastinal B cell lymphoma (PMBCL) and related disorders. As functional consequences of ZNF217 alterations remain unknown, we comprehensively evaluated their impact in PMBCL. Targeted sequencing identified genetic lesions affecting ZNF217 in 33% of 157 PMBCL patients. Subsequent gene expression profiling (nâ=â120) revealed changes in cytokine and interferon signal transduction in ZNF217-aberrant PMBCL cases. In vitro, knockout of ZNF217 led to changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors. This led to disturbed expression of interferon-responsive and inflammation-associated genes, altered cell behavior, and aberrant differentiation. Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure