We have completed a second-generation linkage map that incorporates sequence-based positional information. This new map, the Rutgers Map v.2, includes 28,121 polymorphic markers with physical positions corroborated by recombination-based data. Sex-averaged and sex-specific linkage map distances, along with confidence intervals, have been estimated for all map intervals. In addition, a regression-based smoothed map is provided that facilitates interpolation of positions of unmapped markers on this map. With nearly twice as many markers as our first-generation map, the Rutgers Map continues to be a unique and comprehensive resource for obtaining genetic map information for large sets of polymorphic markers.Accurate and comprehensive linkage maps continue to be critical for linkage analyses (Daw et al. 2000;Barber et al. 2006;Fingerlin et al. 2006;Dietter et al. 2007), positional cloning projects, and even for some aspects of genome-wide association analyses (Maniatis et al. 2002;Tapper et al. 2005). Previously, we constructed the first-generation combined linkage-physical map (Rutgers Map v.1; Kong et al. 2004) containing 14,759 markers, genotyped in a mixture of CEPH (Center d'Etude du Polymorphisme Humain) (Dausset et al. 1990) and deCODE (Kong et al. 2002) families. Now, we have pooled this data set with 13,666 singlenucleotide polymorphisms (SNPs) genotyped in the CEPH reference pedigrees at the companies Applied Biosystems, Affymetrix, and Illumina. We used the pooled data to construct a secondgeneration combined linkage-physical map (Rutgers Map v.2), which has nearly twice the number of markers and increased marker density relative to the Rutgers Map v.1. The physical positions of 28,121 markers were corroborated by recombinationbased data, making the Rutgers Map v.2, to our knowledge, the most dense and accurate linkage map of the human genome.The Rutgers Map v.2 also provides three novel features that are not generally offered by other publicly available maps. First, we have estimated approximate 95% confidence intervals for the size of all 24,145 map intervals, both on the sex-averaged and sex-specific maps. This feature may be useful for assessing sensitivity of an analysis to map uncertainty and for combining the information in the Rutgers Map v.2 with map estimates derived from independent studies. In addition, we have applied local regression to create a smoothed version of the Rutgers Map that separates all markers by non-zero map distances. Overall, this alternative map should provide better estimates of map distance since nearly half of the map intervals in the Rutgers Map v.2, while physically distinct, show no evidence of recombination. Third, the smoothed map facilitates interpolation of map positions for markers that are not on our map. For example, a cMscale map position can be easily estimated for any of the millions of SNP markers that have not been genotyped in the CEPH reference pedigrees and hence are not present on any of the CEPHbased linkage maps. Results Markers and genotype dataThe ...
Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic's commonly used microsatellite-based screening set.
Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood-brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)-polysorbate 80-grafted-starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. In vivo magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and ex vivo fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox-loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by in vivo bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases.
A polymeric fluorescent sensor PNME, consisting of A4 and N-isopropylacrylamide (NIPAM) units, was synthesized. PNME exhibited dual responses to pH and temperature, and could be used as an intracellular pH sensor for lysosomes imaging. Moreover, it also could sense different temperature change in living cells at 25 and 37 °C, respectively.
A glucose-responsive controlled-release system based on the competitive combination between glucose oxidase, glucosamine and glucose has been described, which exhibits perfect controlled release properties and high selectivity for glucose over other monosaccharides. This paved the way for a new generation of stimuli-responsive delivery systems.
Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention. In this review, we discuss important pharmacological mechanisms, physiological characteristics, and pathological factors that have been integrated into the design of nanotechnology-enabled drug delivery systems and therapies. Firsthand examples are presented to illustrate the principles and advantages of such integrative design strategies for cancer treatment by exploiting 1) intracellular synergistic interactions of drug-drug and drug-nanomaterial combinations to overcome multidrug-resistant cancer, 2) the blood flow direction of the circulatory system to maximize drug delivery to the tumor neovasculature and cells overexpressing integrin receptors for lung metastases, 3) endogenous lipoproteins to decorate nanocarriers and transport them across the blood-brain barrier for brain metastases, and 4) distinct pathological factors in the tumor microenvironment to develop pH- and oxidative stress-responsive hybrid manganese dioxide nanoparticles for enhanced radiotherapy. Regarding the application in diabetes management, a nanotechnology-enabled closed-loop insulin delivery system was devised to provide dynamic insulin release at a physiologically relevant time scale and glucose levels. These examples, together with other research results, suggest that utilization of the interplay of pharmacology, (patho-)physiology and nanotechnology is a facile approach to develop innovative drug delivery systems and therapies with high efficiency and translational potential.
Owing to the low expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), endocrine and anti-HER2 therapies are ineffective against TNBC. Thus currently, standard adjuvant and neoadjuvant treatments of TNBC are limited to conventional anthracycline-taxanebased chemotherapy. [1] Despite the initial response to chemotherapy, TNBC patients have a high risk of relapse and distal metastases, especially to the brain, leading to shortened survival times. [2] A number of targeted therapies have been investigated to treat TNBC including poly(ADPribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors, antiandrogen agents, phosphoinositide 3-kinase inhibitors, mitogen-activated protein kinase inhibitors, antiangiogenic antibody, and integrin inhibitors. [1,3] Upregulation of cell surface αvβ3 and αvβ5 integrins in aggressive TNBC, especially in brain metastases and tumorassociated vasculature, has presented an opportunity for targeted therapy of TNBC using integrin-targeted peptides. [4] Of various peptide-based inhibitors of αv integrins, Cilengitide, an Arg-Gly-Asp (RGD) peptide mimetic, with high selectivity against integrins αvβ3 and αvβ5, reached phase 3 clinical trial; however, the results were negative. [5] This disappointing outcome may be caused by insufficient amounts of inhibitor reaching tumor cells to generate a direct cytotoxic effect against αvβ3 and αvβ5 positive cancer cells due to the short half-life of Cilengitide in vivo. [5] Nonetheless, RGD-conjugated nanoparticulate drug delivery systems have shown an ability to target chemotherapeutic drugs to integrin-overexpressing tumor vasculature and cancer cells. [6] Despite the promising results in preclinical models, it is challenging to find an optimal RGD particle coverage to balance tumor accumulation against liver uptake. For example, our previous studies on cyclic RGDfK (Arg-Gly-Asp-D-Phe-Lys; cRGD) peptide-conjugated solid-lipid nanoparticles (SLN) or polymer-lipid hybrid nanoparticles (PLN) revealed that a high density of cRGD on the surface led to increased liver uptake Patients with brain metastases of triple negative breast cancer (TNBC) have a poor prognosis owing to the lack of targeted therapies, the aggressive nature of TNBC, and the presence of the blood-brain barrier (BBB) that blocks penetration of most drugs. Additionally, infiltration of tumor-associated macrophages (TAMs) promotes tumor progression. Here, a terpolymer-lipid hybrid nanoparticle (TPLN) system is designed with multiple targeting moieties to first undergo synchronized BBB crossing and then actively target TNBC cells and TAMs in microlesions of brain metastases. In vitro and in vivo studies demonstrate that covalently bound polysorbate 80 in the terpolymer enables the low-density lipoprotein receptor-mediated BBB crossing and TAM-targetability of the TPLN. Conjugation of cyclic internalizing peptide (iRGD) enhances cellular uptake, cytotoxicity, and drug delivery to brain metastases of integrinoverexpressing TNB...
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