Mammaglobin as a potential molecular target for breast cancer drug delivery

<p>Abstract</p> <p>Background</p> <p>Mammaglobin (MAM) has been used as a specific molecular marker for breast cancer diagnosis. Recently, several groups of researchers proposed a number of therapeutic strategies targeting this molecule. Some of the strategies are based upon an essential but not demonstrated hypothesis – mammaglobin is associated with the surface of breast cancer cells, which strongly disputes the therapeutic strategies.</p> <p>Results</p> <p>We conducted a computer-based predictive analysis and identified a small fragment at the N-end of MAM as a potential transmembrane domain. We provided several evidences to demonstrate the presence of the membrane-associated MAM. We isolated the membrane protein components from known MAM positive breast cancer cells (MDA-MB361 and MDA-MB415). We showed that about 22–64% of MAM proteins, depending upon the types of the cancer cells, directly attached on the membrane of breast cancer cells, by Western blotting assays. To directly visualize the presence of the membrane-bound MAM protein, we incubated the MAM positive cancer cells with FITC labeled anti-MAM antibody, and observed clear fluorescent signals on the surface of the cells. In studying the MAM protein distribution in human breast cancer tissues, we first identified two immunostain patterns that are associated with the membrane-bound MAM: the membrane stain pattern and luminary surface stain pattern. To test whether the membrane-associated MAM can serve as a molecular target for drug delivery, we conjugated anti-MAM antibody to human low-density lipoprotein (LDL) and loaded doxorubicin (Dox) in the core of LDL. Specific binding and cytotoxicity of the MAM targeted and Dox loaded LDL was tested in the MAM positive breast cancer cells <it>in vitro</it>.</p> <p>Conclusion</p> <p>We first showed that some of MAM protein directly associated with the surface of breast cancer cells. The membrane-associated MAM protein may be utilized as a useful molecular marker for breast cancer targeted drug delivery.</p

FilaminA and Formin2 regulate skeletal, muscular, and intestinal formation through mesenchymal progenitor proliferation

The effects of actin dependent molecular mechanisms in coordinating cellular proliferation, migration and differentiation during embryogenesis are not well-understood. We have previously shown that actin-binding Filamin A (FlnA) and actin-nucleating Formin 2 (Fmn2) influence the development of the brain causing microcephaly in mice. In this study, we broaden this phenotype to explore the effects of these two proteins in the development of extra-CNS organ systems, including the gut, muscle, and skeleton. We observed defects in rib and sternum midline closure leading to thoracoabdominal schisis in FlnA+Fmn2 knockout mice, reminiscent of the pentalogy of Cantrell syndrome. These mice exhibit shortened guts, as well as thinned thoracic muscle mass. Immunostaining showed these changes are partially caused by a decrease in the number of presumptive mesenchymal proliferating cells with loss of either FlnA or FlnA+Fmn2. This proliferation defect appears to be in part due to delayed differentiation in these regions. While both FlnA and FlnA+Fmn2 mice show reduced cell death relative to WT control, increased caspase staining was seen in the double null relative to FlnA null suggesting that this could also contribute to the FlnA+Fmn2 phenotype. Therefore FlnA and Fmn2 are likely essential to cell proliferation, differentiation and cell death in a variety of tissues and organs, further reiterating the importance of vesicle trafficking in regulation of development

Tourist satisfaction dimension in Kinabalu park, Sabah, Malaysia

This paper aims to identify the tourist satisfaction dimensions in Kinabalu Park as a World Heritage Site, to come out with the tourist satisfaction indicators for responsible rural tourism framework at Kinabalu Park, Sabah, Malaysia, in terms of satisfaction and dissatisfaction dimension. One of the data sources to achieve this aim is the in-depth interview session with the tourist in Kinabalu Park, specifically the mountain climbers. The interview was conducted with Herzberg’s Critical Incident Technique (CIT), which is a method that asks the respondents to recall their exceptionally good feeling as well as their exceptionally bad feeling during their experience in Kinabalu Park. The data were analyzed thematically based on Driver’s Recreation Experience Preference (REP) scale to identify the tourists’ satisfaction dimension. Our study found that “scenery enjoyment” was the most prevalent domain for a satisfying experience or the source of good feeling. Along with the “scenery enjoyment”, there were other three emerging experience domains that could contribute to understanding the tourist satisfaction dimensions in Kinabalu Par

Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function

Aging is associated with conduit artery stiffening that is a risk factor for and can precede hypertension and ventricular dysfunction. Increases in mitochondria DNA (mtDNA) frequency have been correlated with aging. Mice with a mutation in the encoding domain (D257A) of a proof-reading deficient version of mtDNA polymerase-γ (POLG) have musculoskeletal features of premature aging and a shortened lifespan. However, few studies using these mice have investigated the effects of mtDNA mutations on cardiovascular function. We hypothesized that the proof-reading deficient mtDNA POLG leads to arterial stiffening, hypertension, and ventricular hypertrophy. Ten to twelve month-old D257A mice (n=13) and age- and sex-matched wild-type controls (n=13) were catheterized for hemodynamic and ventricular function measurements. Left common carotid arteries (LCCA) were harvested for mechanical tests followed by histology. Male D257A mice had pulmonary and systemic hypertension, arterial stiffening, larger LCCA diameter (701±45 vs. 597±60 μm), shorter LCCA axial length (8.96±0.56 vs. 10.10±0.80 mm), and reduced hematocrit (29.1±6.1 vs. 41.3±8.1; all p<0.05). Male and female D257A mice had biventricular hypertrophy (p<0.05). Female D257A mice did not have significant increases in pressure or arterial stiffening, suggesting that the mechanisms of hypertension or arterial stiffening from mtDNA mutations differ based on sex. Our results lend insight into the mechanisms of age-related cardiovascular disease and may point to novel treatment strategies to address cardiovascular mortality in the elderly

Increasing Incidence of Clostridium difficile-associated Disease, Singapore

10.3201/eid1409.070043Emerging Infectious Diseases1491487-148

Retention and loss of PIT tags and surgically implanted devices in the Eurasian beaver

Background Passive integrated transponder devices (PIT tags) are a valuable tool for individual identification of animals. Similarly, the surgical implantation of transmitters and bio-loggers can provide useful data on animal location, physiology and behavior. However, to avoid unnecessary recapture and related stress of study animals, PIT tags and bio-loggers should function reliably for long periods of time. Here, we evaluated the retention of PIT tags, and of very high frequency (VHF) transmitters and bio-loggers that were either implanted subcutaneously or into the peritoneal cavity of Eurasian beavers (Castor fiber). Results Over a 21-year period, we implanted PIT tags in 456 individuals and failed to detect a PIT tag at recapture in 30 cases, consisting of 26 individuals (6% of individuals). In all instances, we were still able to identify the individual due to the presence of unique ear tag numbers and tail scars. Moreover, we implanted 6 VHFs, 36 body temperature loggers and 21 heart rate loggers in 28 individuals, and experienced frequent loss of temperature loggers (at least 6 of 23 recaptured beavers) and heart rate loggers (10 of 18 recaptured beavers). No VHFs were lost in 2 recaptured beavers. Conclusions Possible causes for PIT tag loss (or non-detection) were incorrect implantation, migration of the tag within the body, a foreign body reaction leading to ejection, or malfunctioning of the tag. We speculate that logger loss was related to a foreign body reaction, and that loggers were either rejected through the incision wound or, in the case of temperature loggers, possibly adhered and encapsulated to intestines, and then engulfed by the gastro-intestinal tract and ejected. We discuss animal welfare implications and give recommendations for future studies implanting bio-loggers into wildlife

Direct aperture optimization using an inverse form of back-projection

Direct aperture optimization (DAO) has been used to produce high dosimetric quality intensity-modulated radiotherapy (IMRT) treatment plans with fast treatment delivery by directly modeling the multileaf collimator segment shapes and weights. To improve plan quality and reduce treatment time for our in-house treatment planning system, we implemented a new DAO approach without using a global objective function (GFO). An index concept is introduced as an inverse form of back-projection used in the CT multiplicative algebraic reconstruction technique (MART). The index, introduced for IMRT optimization in this work, is analogous to the multiplicand in MART. The index is defined as the ratio of the optima over the current. It is assigned to each voxel and beamlet to optimize the fluence map. The indices for beamlets and segments are used to optimize multileaf collimator (MLC) segment shapes and segment weights, respectively. Preliminary data show that without sacrificing dosimetric quality, the implementation of the DAO reduced average IMRT treatment time from 13 min to 8 min for the prostate, and from 15 min to 9 min for the head and neck using our in-house treatment planning system PlanUNC. The DAO approach has also shown promise in optimizing rotational IMRT with burst mode in a head and neck test case

The State of the Region: Hampton Roads 2016

This is Old Dominion University\u27s 17th annual State of the Region report. While it represents the work of many people connected in various ways to the university, the report does not constitute an official viewpoint of Old Dominion or it\u27s president, John R. Broderick. The report maintains the goal of stimulating thought and discussion that ultimately will make Hampton Roads an even better place to live. We are proud of our region\u27s many successes, but realize that it is possible to improve our performance. In order to do so, we must have accurate information about where we are and a sound understanding of the policy options open to us.https://digitalcommons.odu.edu/economics_books/1002/thumbnail.jp

Long-term self-renewing human epicardial cells generated from pluripotent stem cells under defined xeno-free conditions.

The epicardium contributes both multi-lineage descendants and paracrine factors to the heart during cardiogenesis and cardiac repair, underscoring its potential for cardiac regenerative medicine. Yet little is known about the cellular and molecular mechanisms that regulate human epicardial development and regeneration. Here, we show that the temporal modulation of canonical Wnt signaling is sufficient for epicardial induction from 6 different human pluripotent stem cell (hPSC) lines, including a WT1-2A-eGFP knock-in reporter line, under chemically-defined, xeno-free conditions. We also show that treatment with transforming growth factor beta (TGF-β)-signalling inhibitors permitted long-term expansion of the hPSC-derived epicardial cells, resulting in a more than 25 population doublings of WT1+ cells in homogenous monolayers. The hPSC-derived epicardial cells were similar to primary epicardial cells both in vitro and in vivo, as determined by morphological and functional assays, including RNA-seq. Our findings have implications for the understanding of self-renewal mechanisms of the epicardium and for epicardial regeneration using cellular or small-molecule therapies