Illawarra Health and Medical Research Institute

Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding

M K. Montgomery — Sun, 16 Jun 2013 17:20:10 PDT

Aims/hypothesis: Metabolic disorders are commonly investigated using knockout and transgenic mouse models. A variety of mouse strains have been used for this purpose. However, mouse strains can differ in their inherent propensities to develop metabolic disease, which may affect the experimental outcomes of metabolic studies. We have investigated strain-dependent differences in the susceptibility to diet-induced obesity and insulin resistance in five commonly used inbred mouse strains (C57BL/6J, 129X1/SvJ, BALB/c, DBA/2 and FVB/N). Methods: Mice were fed either a low-fat or a high-fat diet (HFD) for 8 weeks. Whole-body energy expenditure and body composition were then determined. Tissues were used to measure markers of mitochondrial metabolism, inflammation, oxidative stress and lipid accumulation. Results: BL6, 129X1, DBA/2 and FVB/N mice were all susceptible to varying degrees to HFD-induced obesity, glucose intolerance and insulin resistance, but BALB/c mice exhibited some protection from these detrimental effects. This protection could not be explained by differences in mitochondrial metabolism or oxidative stress in liver or muscle, or inflammation in adipose tissue. Interestingly, in contrast with the other strains, BALB/c mice did not accumulate excess lipid (triacylglycerols and diacylglycerols) in the liver; this is potentially related to lower fatty acid uptake rather than differences in lipogenesis or lipid oxidation. Conclusions/interpretation: Collectively, our findings indicate that most mouse strains develop metabolic defects on an HFD. However, there are inherent differences between strains, and thus the genetic background needs to be considered carefully in metabolic studies.

Age-dependent modification of proteins: N-terminal racemization

Brian Lyons — Mon, 10 Jun 2013 18:10:09 PDT

Age-dependent deterioration of long-lived proteins in humans may have wide-ranging effects on health, fitness and diseases of the elderly. To a large extent, denaturation of old proteins appears to result from the intrinsic instability of certain amino acids; however, these reactions are incompletely understood. One method to investigate these reactions involves exposing peptides to elevated temperatures at physiological pH. Incubation of PFHSPSY, which corresponds to a region of human αB-crystallin that is susceptible to age-related modification, resulted in the appearance of a major product. NMR spectroscopy confirmed that this novel peptide formed via racemization of the N-terminal Pro. This phenomenon was not confined to Pro, because peptides with N-terminal Ser and Ala residues also underwent racemization. As N-terminal racemization occurred at 37 degrees celsius, a long-lived protein was examined. LC-MS/MS analysis revealed that approximately one third of aquaporin 0 polypeptides in the centre of aged human lenses were racemized at the N-terminal methionine.

Genetic modulation of the long-term effects of cannabis on brain structure, function and symptomatology

Nadia Solowij — Tue, 04 Jun 2013 16:10:13 PDT

Published abstract from the 3rd Biennial Schizophrenia International Research Conference Florence, Italy 14-18 April 2012

Endogenous proBDNF is a negative regulator of migration of cerebellar granule cells in neonatal mice

Zhi-Qiang Xu — Tue, 21 May 2013 16:50:15 PDT

The majority of newborn neurons migrate from their birthplace to final destination in the developing brain. Migration of cerebellar granule cells (CGCs) requires multiple factors. Mature brain-derived neurotrophic factor (BDNF) positively regulates the proliferation, migration, survival and differentiation of CGCs in rodents. However, the role of the BDNF precursor, proBDNF, in neuronal development remains unknown. In this study, we investigated the effect of proBDNF in vivo and in vitro on migration of CGCs. We demonstrate that proBDNF and its receptors p75 neurotrophin receptor (p75NTR) and sortilin are highly expressed in the cerebella as determined by immunohistochemistry and Western blot. ProBDNF is released from cultured cerebellar neurons, and this release is increased by high potassium stimulation. ProBDNF inhibits migration of CGCs in vitro, and the neutralizing antibodies to proBDNF enhance such migration as assayed by transwell culture. In addition, proBDNF incorporated into an agarose plug reduces granule cell migration from such plugs, whereas the neutralizing antibodies attract these cells towards the plug. The application of proBDNF into the lateral ventricle significantly inhibits migration of CGCs out of the proliferative zone into the internal granular cell layer, whereas the neutralizing antibodies enhance this migration. Furthermore, the effects of proBDNF on cell migration are lost in p75NTR^-/- mice. Our data suggest that proBDNF negatively regulates migration of CGCs and this effect is mediated by p75NTR. We conclude that proBDNF has an opposing role in migration of CGCs to that of mature BDNF.

Novel behavioural characteristics of the APPSwe/PS1ΔE9 transgenic mouse model of Alzheimer's disease

David Cheng — Mon, 13 May 2013 18:25:11 PDT

In order to better understand animal models of Alzheimer's disease, novel phenotyping strategies have been established for transgenic mouse models. In line with this, the current study characterised male APPxPS1 transgenic mice on mixed C57BL/6JxC3H/HeJ background for the first time for social recognition memory, sensorimotor gating, and spatial memory using the cheeseboard test as an alternative to the Morris water maze. Furthermore, locomotion, anxiety, and fear conditioning were evaluated in transgenic and wild type-like animals. APPxPS1 males displayed task-dependent hyperlocomotion and anxiety behaviours and exhibited social recognition memory impairments compared to wild type-like littermates. Spatial learning and memory, fear conditioning, and sensorimotor gating were unaffected in APPxPS1 transgenic mice. In conclusion, this study describes for the first time social recognition memory deficits in male APPxPS1 mice and suggests that spatial learning and memory deficits reported in earlier studies are dependent on the sex and genetic background of the APPxPS1 mouse line used. Furthermore, particular test conditions of anxiety and spatial memory paradigms appear to impact on the behavioural response of this transgenic mouse model for Alzheimer's disease.

Neurotrophin signaling and Alzheimer's Disease neurodegeneration - Focus on BDNF/TrkB signaling

Jenny Wong — Tue, 07 May 2013 16:05:11 PDT

Neurotrophins are small proteins vital for neuronal growth, differentiation, survival, and plasticity. Members of the mammalian neurotrophin family include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin- 4/5 (NT-4/5). Their neurotrophic effects are mediated by the tropomyosin receptor kinase (Trk) receptors, membrane-bound receptor tyrosine kinases (NGF for TrkA, BDNF and NT4/5 for TrkB, and NT-3 for TrkC) which activate various cell signaling pathways linked to growth, differentiation, and survival. The importance of neurotrophin signaling in brain development is highlighted by findings showing that knockout mice for any one of the neurotrophins or their receptors are fatal or exhibit severe neural defects.

Altered expression of RNA splicing proteins in Alzheimer's disease patients: evidence from two microarray studies

Jenny Wong — Mon, 06 May 2013 23:35:08 PDT

Background/Aims: Dysregulation of pre-mRNA splicing from an altered expression of RNA splice-regulatory proteins may act as the convergence point underlying aberrant gene expression changes in Alzheimer's disease (AD). Methods: Two microarray datasets from a control/AD postmortem brain cohort of 31 subjects - 9 controls and 22 AD subjects (National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database) - were used. Results: Between the two microarray studies, the expression of six splice-regulatory protein genes showed concordant changes in AD. These genes were then correlated with gene expression changes of transcripts reported to be altered in AD. Amyloid beta (A4) pre- cursor protein and tropomyosin receptor kinase B transcripts were found to correlate significantly with the same splice-regulatory proteins in the two studies. Conclusion: This study highlights a susceptibility network that can potentially link a number of susceptibility genes.

Expression of NPAS3 in the human cortex and evidence of its posttranscriptional regulation by miR-17 during development, with implications for schizophrenia

Jenny Wong — Mon, 06 May 2013 20:25:08 PDT

NPAS3 is a developmentally important transcription factor that has been associated with psychiatric illness. Our aim is to better define the regulation of NPAS3 mRNA (messenger RNA) levels during normal human prefrontal cortical development and in schizophrenia. Utilizing postmortem tissue from 134 human brains, we assessed: 60 normal brains ranging in age from birth to adulthood, 37 chronic individuals with schizophrenia, and 37 matched controls. mRNA and micro- RNA (miRNA) expressions were measured by microarray and quantitative real-time PCR. Protein expression was measured by Western blotting. During human postnatal cortical development (neonate to adult), we found decreased NPAS3 mRNA yet increased NPAS3 protein expression,suggesting the involvement of posttranscriptional regulation. Through screening, we identified one NPAS-targeted miRNA (miR-17) that changed in a pattern consistent with the developmental regulation of NPAS3. Using luciferase reporter assays, we assessed the impact of miR-17 on NPAS3 translation and demonstrated that miR-17 alters NPAS3 biosynthesis by binding to the NPAS3 3#untranslated region (UTR). In schizophrenia prefrontal cortex, we found significant elevations in miR-17 expression. While NPAS3 mRNA was unaltered, reduced NPAS3 protein expression was detected in a subpopulation of people with schizophrenia.The reciprocal expression of NPAS3 mRNA and protein during postnatal development mediated by a schizophrenia-associated change in miR-17 suggests that there is complex control over NPAS3 synthesis in the human prefrontal cortex and that if NPAS3 is dysregulated in schizophrenia, it is not evident by large changes in NPAS3 expression. Further studies into how changes in NPAS3 or its miRNA regulator may influence the development of schizophrenia are warranted.

Interconversion of the peptide isoforms of aspartate: Stability of isoaspartates

Michelle Yu Sung Hooi — Mon, 22 Apr 2013 16:35:14 PDT

A common modification of human long-lived proteins is spontaneous isomerisation of aspartate residues, and its biological importance can be inferred from the ubiquitous presence of protein isoaspartate methyl transferase (PIMT), that repairs this damage. Cyclisation of _L-Asp residues yields four isomers: _L-Asp, _L-isoAsp,_D-Asp and _D-isoAsp, however little is known about their rate of formation or interconversion. This is important because PIMT is inactive towards _D-isoAsp. Peptides containing the four Asp isoforms corresponding to a susceptible site (Asp 151) in the chaperone, αA-crystallin, were examined for their interconversion at pH 7. _D-Asp formed from _L-Asp readily, whereas _L-isoAsp was not detected until significantly later. _D-isoAsp formed very slowly, with just 1% present after 8 days at 60 degrees C. These findings can be used to rationalise the substrate specificity of PIMT. In addition, both the _D-isoAsp and _L-isoAsp peptides were found to be remarkably stable, showing little conversion to other isomers, even after weeks of incubation. Therefore _L-isoAsp and _D-isoAsp appear to represent "terminal" stages of _L-Asp modification. If PIMT is present, _L-isoAsp may be reverted to _L-Asp, however there appears to be no prospect of reversing _D-isoAsp formation in aged proteins. Interestingly, Asp 151 in recombinant αA crystallin isomerised more rapidly than in the _L-Asp peptide.

Prevention of obesity-associated colon cancer by (-)-epigallocatechin-3 gallate and curcumin

Jiezhong Chen — Tue, 16 Apr 2013 22:30:17 PDT

Obesity is now recognised as a major global health problem. It accounts for a large proportion of the population and is increasing in both developed and developing countries. Epidemiological evidence and studies in animal models showed that obesity increased the incidence of colon cancer. As obesity is difficult to prevent and treat, it is important to find effective approaches to prevent obesity-associated colon cancer. The prevention strategy should be different from that used for the treatment as clinically used drugs are not suitable for the prevention due to side-effects and cost. Phytochemicals are ideal for the prevention. This review summarises the effect of green tea component (-)-epigallocatechin-3 gallate and turmeric component curcumin in the prevention of obesity-associated colon cancer and the mechanisms for their preventive effects. Both agents have been demonstrated to reduce obesity increased polyp formation in animal models and inhibit PI3K/Akt and MAPK signal pathways.

Lipid Anti-Lipid Antibody Responses Correlate with Disease Activity in Systemic Lupus Erythematosus

Vojislav Jovanovic — Sun, 07 Apr 2013 19:20:11 PDT

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by broad clinical manifestations including cardiovascular and renal complications with periodic disease flares and significant morbidity and mortality. One of the main contributing factors to the pathology of SLE is the accumulation and impaired clearance of immune complexes of which the principle components are host auto-antigens and antibodies. The contribution of host lipids to the formation of these autoimmune complexes remains poorly defined. The aim of the present study was to identify and analyze candidate lipid autoantigens and their corresponding anti-lipid antibody responses in a well-defined SLE patient cohort using a combination of immunological and biophysical techniques. Disease monitoring in the SLE cohort was undertaken with serial British Isles Lupus Assessment Group (BILAG) scoring. Correlations between specific lipid/anti-lipid responses were investigated as disease activity developed from active flares to quiescent during a follow up period. We report a significant negative correlation between anti-lipid antibodies for 24S-hydroxycholesterol, cardiolipin and phosphatidylserine with SLE disease activity. Taken together, these data suggest that lipid autoantigens represent a new family of biomarkers that can be employed to monitor disease activity plus the efficacy of therapeutic intervention in SLE.

An Improved High-Throughput Lipid Extraction Method for the Analysis of Human Brain Lipids

Sarah K. Abbott — Sun, 24 Mar 2013 17:21:56 PDT

We have developed a protocol suitable for high-throughput lipidomic analysis of human brain samples. The traditional Folch extraction (using chloroform and glass-glass homogenization) was compared to a high-throughput method combining methyl-tert-butyl ether (MTBE) extraction with mechanical homogenization utilizing ceramic beads. This high-throughput method significantly reduced sample handling time and increased efficiency compared to glass-glass homogenizing. Furthermore, replacing chloroform with MTBE is safer (less carcinogenic/toxic), with lipids dissolving in the upper phase, allowing for easier pipetting and the potential for automation (i.e., robotics). Both methods were applied to the analysis of human occipital cortex. Lipid species (including ceramides, sphingomyelins, choline glycerophospholipids, ethanolamine glycerophospholipids and phosphatidylserines) were analyzed via electrospray ionization mass spectrometry and sterol species were analyzed using gas chromatography mass spectrometry. No differences in lipid species composition were evident when the lipid extraction protocols were compared, indicating that MTBE extraction with mechanical bead homogenization provides an improved method for the lipidomic profiling of human brain tissue.

TNF-α promotes IFN-γ-Induced CD40 expression and antigen process in Myb-transformed hematological cells

Wenyi Gu — Mon, 18 Mar 2013 16:30:15 PDT

Tumour necrosis factor-α, interferon-γ and interleukin-4 are critical cytokines in regulating the immune responses against infections and tumours. In this study, we investigated the effects of three cytokines on CD40 expression in Myb-transformed hematological cells and their regulatory roles in promoting these cells into dendritic cells. We observed that both interleukin-4 and interferon-γ increased CD40 expression in these hematological cells in a dose-dependent manner, although the concentration required for interleukin-4 was significantly higher than that for interferon-γ. We found that tumour necrosis factor-α promoted CD40 expression induced by interferon-γ, but not by interleukin-4. Our data showed that tumour necrosis factor-α plus interferon-γ-treated Myb-transformed hematological cells had the greatest ability to take up and process the model antigen DQ-Ovalbumin. Tumour necrosis factor-α also increased the ability of interferon-γ to produce the mixed lymphocyte reaction to allogenic T cells. Furthermore, only cotreatment with tumour necrosis factor-α and interferon-γ induced Myb-transformed hematological cells to express interleukin-6. These results suggest that tumour necrosis factor-α plays a key regulatory role in the development of dendritic cells from hematological progenitor cells induced by interferon-γ.

Factors associated with chronic kidney disease progression in Australian nephrology practices

Neil Boudville — Mon, 18 Mar 2013 16:25:12 PDT

Background/Aims: Chronic kidney disease (CKD) is a major health issue worldwide. The aim of this study was to explore factors associated with CKD progression in Australian nephrology practices. Methods: This was a retrospective study utilising an electronic medical record (EMR), Audit4 (Software for Specialists, Australia). The baseline visit was defined as the first entry into the EMR. The primary outcome was the rate of change in estimated glomerular filtration rate (eGFR). Results: 1,328 patients were included with a mean eGFR at baseline of 37.4 ± 0.7 ml/min/1.73 m2, a mean follow-up of 17.7 months and a mean annual rate of change in eGFR of –0.84 ± 0.26 ml/min/1.73 m2. Univariate analysis demonstrated that women, smokers, and patients prescribed erythropoiesis-stimulating agents (ESA) had a significantly more rapid decline in eGFR (p = 0.007, 0.033, and 0.003, respectively). On multivariate analysis: gender, age, prescription of ESA and phosphate binders, and baseline eGFR were significantly associated with CKD progression (p = 0.003, 0.004, <0.001, 0.029, and <0.001, respectively). Conclusions: This study identifies potential factors associated with CKD progression in a population referred to nephrologists, but current data quality may result in bias. Implementation of changes in the format of data collection is required so that busy clinicians record essential information to enable this to become a more accurate and reliable research tool.

The possible mechanisms for β-glucans to prevent atherosclerotic lesions

Tiphaine Gislette — Mon, 18 Mar 2013 16:25:11 PDT

Foods enriched in β-glucans including oat and edible fungi as well as some purified β-glucans have been shown to reduce atherosclerotic lesions. The multiple mechanisms may be involved to affect several aspects of the pathogenesis of atherosclerosis such as phagocytosis of macrophages, NO production, epithelial cell functions and blood levels of cholesterol. Structurally different β-glucans may have different effects in the pathogenesis of atherosclerosis. The study of structure-function relationship may provide an approach for optimizing β-glucans to be used in the prevention of atherosclerosis.

Age-dependent racemization of serine residues in a human chaperone protein

Michelle Yu Sung Hooi — Wed, 06 Mar 2013 18:26:53 PST

Racemization is one of the most abundant modifications in long-lived proteins. It has been proposed that the accumulation of such modifications over time could lead to changes in tissues and ultimately human age-related diseases. Serine is one of the main amino acids involved in racemization; however, the site of D-Ser in any aged protein has yet to be reported. In this study, racemization of two residues, Ser 59 and Ser 62, has been demonstrated in an unstructured region of the small heat shock protein, aA-crystallin. aA-crystallin is also the most abundant structural protein in the human lens. D-Ser increased linearly with age in normal lenses, until it accounted for approximately 35% of the Ser at both sites by the age of 75 years. In agreement with a possible role in human age-related disease, levels were significantly higher in cataract lenses. It is likely that such prevalent age-related changes contribute to the denaturation of a-crystallin, and therefore its ability to act as a chaperone. Racemization of amino acids, such as serine, in flexible regions of long-lived proteins, could be associated with the development of human age-related conditions such as cataract.

From the city to the bush: Increases in patient co-payments for medicines have impacted on medicine use across Australia

Anna Kemp — Wed, 06 Mar 2013 18:26:53 PST

Aim. To determine whether the national declines in prescription medicine use occurring after the 2005 21% increase in co-payments affected all areas of Australia or were specific to remote and disadvantaged areas. Methods. Observed dispensing of proton pump inhibitors (PPIs) and statins were obtained for 1392 statistical local areas (SLA) of Australia in 2004 and 2006. Expected dispensing was based on national dispensing rates and was age standardised to each SLA. Expected dispensing for 2006 was based on pre-2005 prescription trends. Ratios of observed to expected dispensing (dispensing ratios) for each SLA were calculated. Mean dispensing ratios for each medicine and year were calculated for all remoteness and disadvantage groups. Generalised regression models compared the percentage change in dispensing ratios from 2004 to 2006. Results. Between 2004 and 2006 PPI dispensing fell significantly in major cities (-13.7%, 95% CI less than or equal to -17.3 - 9.8), inner regional (-14.0, 95%CI less than or equal to -19.5 - 8.2), outer regional (-14.6%, 95%CI less than or equal to -19.9 - 9.0) and remote areas (-9.4%, 95%CI less than or equal to -16.4 - 1.8). Statin dispensing fell in all groups but the most remote (range 6-7%). When focussing on disadvantage, PPI dispensing fell significantly in all groups (range 12-15%). Statins dispensing did not fall significantly in the most disadvantaged areas (-2.9%, 95%CI less than or equal to -8.6-3.2) but did in the least (-6.5%, -11.3 - 1.5) and second-least (-5.8, -10.5 - 0.9) disadvantaged areas. Dispensing of PPIs and statins in the most remote and disadvantaged areas remained substantially below levels expected for Australia after the 21% co-payments increase. Conclusions. The findings suggest that the 2005 21% in patient co-payments adversely affected prescription medicine use in all areas of Australia and was not specific to remote or disadvantaged areas. Indeed, dispensing of statins fell significantly in all but the most remote and disadvantaged areas, and the existing gap in dispensing of PPIs and statins was not widened by the co-payments increase. PPIs, which are used at above-prevalence rates in Australia and have cheaper over-the-counter substitutes available, were more sensitive to co-payment increases than were statins. What is known about the topic? Despite high levels of chronic illness in geographically remote and socially disadvantaged areas of Australia, prescription medicine use is generally lowest in these areas. In 2005, co-payments for publically subsidised medicines increased by 21%. After this increase, utilisation of many medicines fell at the national level. It is not known whether these falls in utilisation were specific to remote or disadvantaged areas or if decreases occurred across all areas of Australia. What does this paper add? Between 2004 and 2006 PPI dispensing decreased significantly across all remoteness groups (major cities, inner regional, outer regional and remote areas) and statin dispensing fell significantly in all but remote areas. When focusing on disadvantage groups, dispensing of PPIs fell across Australia, and statins fell significantly in all but the most disadvantaged areas. What are the implications for practitioners? The effect of the 2005 21% increase in co-payments was not specific to remote or disadvantaged areas and was associated with decreases in dispensing across Australia.

Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia

S Fillman — Wed, 06 Mar 2013 18:26:52 PST

Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1b and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1b expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in 40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.

The validity of prescription and other health service claims and self-report in identifying cases of invasive breast cancer in Australia

Anna Kemp — Wed, 06 Mar 2013 18:26:51 PST

Background: Routinely-collected and self-reported health data are increasingly being used to identify health status and service use. Australian state-based cancer registries are the ''gold standard'' for identifying breast cancer, but researchers working with other datasets (i.e., prescription claims) may need to identify cases without linkage to these registries. Objectives: To determine the validity of prescription claims for selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI) , hospital procedures, claims for outpatient procedures and radiotherapy, and self- report in identifying cases of invasive breast cancer in Aus- tralia against the Cancer Registry. Methods: Invasive breast cancers recorded on the Cancer Register between 2004 and 2008 for women in the New South Wales 4 5 and Up Study were compared with cases identified by: (1) SERM and AI prescription claims and (2) outpatient procedures and radiotherapy from 2004 to 2009; (3) NSW Admitted Patients Data Collection (hospital records) between July 2004-February 2009; and self- reported diagnosis of breast cancer between 2003 and 2009 in the 45 and Up Study baseline survey. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated for each dataset compared with the Cancer Registry. Results: Of 143,010 women in the 45 and Up cohort , 2,661 (1.9%) had breast cancer recorded on the registry. Sensitivity for self-report o f breast cancer diagnosis was 73.0%, with hospital records, PBS and MBS claims data being 86.4%, 65.7% and 58.0%, respectively. PPV was highest for hospital (84.0%) and MBS data (80.4%) and lower for self-report (40.9%) and PBS claims (49.4%). Specificity and NPV were >99% for all comparison data- sets evaluated. Conclusions: In the absence of cancer registrations, cases of breast cancer were most accurately detected using hospital records, and to a lesser extent self-report. Prescription and outpatient claims had only moderate sensitivity and/or PPV, likely reflecting that not all patients have post-surgical pharmacological or medical treatment. However, all of the datasets accurately identified cases without breast cancer, so are suitable for researchers wishing to exclude breast cancer cases from their data.

Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells

Meihua Yu — Wed, 06 Mar 2013 18:26:50 PST

In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs). HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis. Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles. Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors.