Targeting hypoxia in cancer therapy Wilson, William R; Hay, Michael P
Nature reviews. Cancer,
06/2011, Letnik:
11, Številka:
6
Journal Article
Recenzirano
Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple ...contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Container Aedes mosquitoes are the most important vectors of human arboviruses (i.e., dengue, chikungunya, Zika, or yellow fever). Invasive and native container Aedes spp. potentially utilize natural ...and artificial containers in specific environments for oviposition. Several container Aedes spp. display ‘skip-oviposition’ behavior, which describes the distribution of eggs among multiple containers during a single gonotrophic cycle. In this study, we compared individual skip-oviposition behavior using identical eight-cup testing arenas with three container Aedes species: Aedes aegypti (Linnaeus), Aedes albopictus (Skuse), and Aedes triseriatus (Say). We applied the index of dispersion, an aggregation statistic, to individual mosquitoes’ oviposition patterns to assess skip-oviposition behavior. Aedes aegypti and Ae. albopictus utilized more cups and distributed eggs more evenly among cups than Ae. triseriatus under nutritionally enriched oviposition media (oak leaf infusion) conditions. When presented with a nutritionally unenriched (tap water) oviposition media, both Ae. aegypti and Ae. albopictus increased egg spreading behavior. Aedes albopictus did not modify skip-oviposition behavior when reared and assessed under fall-like environmental conditions, which induce diapause egg production. This study indicates specific oviposition site conditions influence skip-oviposition behavior with ‘preferred’ sites receiving higher amounts of eggs from any given individual and ‘non-preferred’ sites receive a limited contribution of eggs. A further understanding of skip-oviposition behavior is needed to make the best use of autodissemination trap technology in which skip-ovipositing females spread a potent larvicide among oviposition sites within the environment.
We describe a new algorithm for answering a given set of range queries under ε-differential privacy which often achieves substantially lower error than competing methods. Our algorithm satisfies ...differential privacy by adding noise that is adapted to the input data
and
to the given query set. We first privately learn a partitioning of the domain into buckets that suit the input data well. Then we privately estimate counts for each bucket, doing so in a manner well-suited for the given query set. Since the performance of the algorithm depends on the input database, we evaluate it on a wide range of real datasets, showing that we can achieve the benefits of data-dependence on both "easy" and "hard" databases.
Differential privacy is a robust privacy standard that has been successfully applied to a range of data analysis tasks. We describe the
matrix mechanism
, an algorithm for answering a workload of ...linear counting queries that adapts the noise distribution to properties of the provided queries. Given a workload, the mechanism uses a different set of queries, called a query strategy, which are answered using a standard Laplace or Gaussian mechanism. Noisy answers to the workload queries are then derived from the noisy answers to the strategy queries. This two-stage process can result in a more complex, correlated noise distribution that preserves differential privacy but increases accuracy. We provide a formal analysis of the error of query answers produced by the mechanism and investigate the problem of computing the optimal query strategy in support of a given workload. We show that this problem can be formulated as a rank-constrained semidefinite program. We analyze two seemingly distinct techniques proposed in the literature, whose similar behavior is explained by viewing them as instances of the matrix mechanism. We also describe an extension of the mechanism in which nonnegativity constraints are included in the derivation process and provide experimental evidence of its efficacy.
We identify privacy risks associated with releasing network data sets and provide an algorithm that mitigates those risks. A network consists of entities connected by links representing relations ...such as friendship, communication, or shared activity. Maintaining privacy when publishing networked data is uniquely challenging because an individual's network context can be used to identify them even if other identifying information is removed. In this paper, we quantify the privacy risks associated with three classes of attacks on the privacy of individuals in networks, based on the knowledge used by the adversary. We show that the risks of these attacks vary greatly based on network structure and size. We propose a novel approach to anonymizing network data that models aggregate network structure and then allows samples to be drawn from that model. The approach guarantees anonymity for network entities while preserving the ability to estimate a wide variety of network measures with relatively little bias.
ABSTRACT
An essential component of vector-borne disease monitoring programs is mosquito surveillance. Surveillance efforts employ various collection traps depending on mosquito species and targeted ...life-history stage, i.e., eggs, larvae, host-seeking, resting, or gravid adults. Surveillance activities often use commercial traps, sometimes modified to accept specific mosquito species attractants. The advent of widely available and affordable 3D printing technology allows the construction of novel trap designs and components. The study goal was to develop and assess a cost-effective, multipurpose, 6-volt mosquito trap integrating features of both host-seeking and gravid mosquito traps to collect undamaged live specimens: a multifunctional mosquito trap (MMT). We tested the MMT in comparison to commercial traps, targeting gravid Aedes albopictus, host-seeking Ae. albopictus, and total number of host-seeking mosquitos regardless of species. Field evaluations found the MMT performed as well as or better than comparable commercial traps. This project demonstrates an easy to construct, inexpensive, and versatile mosquito trap, potentially useful for surveying multiple mosquito species and other hematophagous insects by varying attractants into the MMT.
Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to ...identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by (18)Ffluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.
Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic ...radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5-nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay.
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