Improved Bounds on Information Dissemination by Manhattan Random Waypoint Model

With the popularity of portable wireless devices it is important to model and predict how information or contagions spread by natural human mobility -- for understanding the spreading of deadly infectious diseases and for improving delay tolerant communication schemes. Formally, we model this problem by considering $M$ moving agents, where each agent initially carries a \emph{distinct} bit of information. When two agents are at the same location or in close proximity to one another, they share all their information with each other. We would like to know the time it takes until all bits of information reach all agents, called the \textit{flood time}, and how it depends on the way agents move, the size and shape of the network and the number of agents moving in the network. We provide rigorous analysis for the \MRWP model (which takes paths with minimum number of turns), a convenient model used previously to analyze mobile agents, and find that with high probability the flood time is bounded by $O\big(N\log M\lceil(N/M) \log(NM)\rceil\big)$, where $M$ agents move on an $N\times N$ grid. In addition to extensive simulations, we use a data set of taxi trajectories to show that our method can successfully predict flood times in both experimental settings and the real world.Comment: 10 pages, ACM SIGSPATIAL 2018, Seattle, U

Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic

Determinants of Mortality and Disease Progression of Kaposi Sarcoma in a Primary care ART Programme in Khayelitsha, South Africa

CROI 200

An overview of the rare parotid gland cancer

Cancer of the parotid gland is relatively rare, but carries poor prognosis owing to its prevailing distant metastases. In addition to the disease's basic epidemiology and pathology, we review some current discoveries of its tumorigenesis molecular mechanism. Based on published salivary gland cancer clinical trial data, non-surgical antitumor efficacies amongst a range of chemotherapy, radiation, and concurrent therapy regimens are compared. We also present the current development status of novel radiation therapy and targeted therapeutics, focusing on intensity-modulated radiation therapy (IMRT), and epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) blockages, which are showing promise for improving parotid gland cancer management

High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability

Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) for expression of prospective CSC markers CD44/CD24 and CD133, and for functional activity of aldehyde dehydrogenase (ALDH), an enzyme involved in stem cell self-protection. We then used fluorescence-activated cell sorting and functional assays to characterize differences in malignant/metastatic behaviour in vitro (proliferation, colony-forming ability, adhesion, migration, invasion) and in vivo (tumorigenicity and metastasis). Sub-populations of cells demonstrating stem-cell-like characteristics (high expression of CSC markers and/or high ALDH) were identified in all cell lines except MCF-7. When isolated and compared to ALDHlowCD44low/- cells, ALDHhiCD44+CD24- (MDA-MB-231) and ALDHhiCD44+CD133+ (MDA-MB-468) cells demonstrated increased growth (P \u3c 0.05), colony formation (P \u3c 0.05), adhesion (P \u3c 0.001), migration (P \u3c 0.001) and invasion (P \u3c 0.001). Furthermore, following tail vein or mammary fat pad injection of NOD/SCID/IL2 gamma receptor null mice, ALDHhiCD44+CD24- and ALDHhiCD44+CD133+ cells showed enhanced tumorigenicity and metastasis relative to ALDHlowCD44low/- cells (P \u3c 0.05). These novel results suggest that stem-like ALDHhiCD44+CD24- and ALDHhiCD44+CD133+ cells may be important mediators of breast cancer metastasis

Magellanic Cloud X-ray Sources: III. Completion of a ROSAT Survey

This paper concludes a series of three papers presenting ROSAT High-Resolution Imager (HRI) observations of unidentified Einstein and serendipitous ROSAT X-ray sources in the direction of the Magellanic Clouds. Accurate positions and fluxes have been measured for these sources. Optical photometry and spectroscopy were obtained to search for identifications in order to determine the physical nature of these sources. The present paper includes new data for 24 objects; identifications are given or confirmed for 30 sources. For six sources optical finding charts showing the X-ray positions are provided. The results from this program are summarized, showing the populations of luminous X-ray sources in the Magellanic Clouds are quite different from those in the Galaxy.Comment: 28 pages, 2 figures; to appear in Astronomical Journa

Molecular characterization, biofilm analysis and experimental biofouling study of Fusarium isolates from recent cases of fungal keratitis in New York State

BACKGROUND: To characterize Fusarium isolates from recent cases of fungal keratitis in contact lens wearers, and to investigate fungal association with MoistureLoc solution. METHODS: We studied six fungal isolates from recent cases of keratitis in New York State. The isolates were characterized by nucleotide sequencing and phylogenetic analyses of multiple genes, and then typed using minisatellite and microsatellite probes. Experimental fungal biofilm formation was tested by standard methods. MoistureLoc solutions were tested in biofouling studies for their efficacy in elimination of Fusarium contamination. RESULTS: Fusarium solani – corneal ulcers (2 isolates), lens case (1 isolate), and F. oxysporum – corneal ulcer (1 isolate), eye (1 isolate), were recovered from five patients. An opened bottle of MoistureLoc solution provided by a patient also yielded F. solani. Two distinct genotypes of F. solani as well as of F. oxysporum were present in the isolated strains. Remarkably, F. solani strains from the lens case and lens solution in one instance were similar, based on phylogenetic analyses and molecular typing. The solution isolate of F. solani formed biofilm on contact lenses in control conditions, but not when co-incubated with MoistureLoc solution. Both freshly opened and 3-month old MoistureLoc solutions effectively killed F. solani and F. oxysporum, when fungal contamination was simulated under recommended lens treatment regimen (4-hr). However, simulation of inappropriate use (15 – 60 min) led to the recovery of less than 1% of original inoculum of F. solani or F. oxysporum. CONCLUSION: Temporary survival of F. solani and F. oxysporum in MoistureLoc suggested that improper lens cleaning regimen could be a possible contributing factor in recent infections

Investigating the photosensitizer-potential of targeted gallium corrole using multimode optical imaging

We recently developed a novel therapeutic particle, HerGa, for breast cancer treatment and detection. HerGa consists of a tumor-targeted cell penetration protein noncovalently assembled with a gallium-metallated corrole. The corrole is structurally similar to porphyrin, emits intense fluorescence, and has proven highly effective for breast tumor treatment preclinically, without light exposure. Here, we tested HerGa as a photosensitizer for photodynamic therapy and investigated its mechanism of action using multimode optical imaging. Using confocal fluorescence imaging, we observed that HerGa disrupts the mitochondrial membrane potential in situ, and this disruption is substantially augmented by light exposure. In addition, spectral and fluorescence lifetime imaging were utilized to both validate the mitochondrial membrane potential disruption and investigate HerGa internalization, allowing us to optimize the timing for light dosimetry. We observed, using advanced multimode optical imaging, that light at a specific wavelength promotes HerGa cytotoxicity, which is likely to cause disruption of mitochondrial function. Thus, we can identify for the first time the capacity of HerGa as a photosensitizer for photodynamic therapy and reveal its mechanism of action, opening possibilities for therapeutic intervention in human breast cancer management

Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy

<p>Abstract</p> <p>Background</p> <p>Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [¹¹C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired.</p> <p>Results</p> <p>We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible.</p> <p>Conclusions</p> <p>To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.</p