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1.  Resolution of constipation, anal stricture, and iron deficiency anemia after iron infusion: an analogy with Plummer Vinson syndrome 
SpringerPlus  2016;5(1):1976.
Background
Anal stricture is a disabling condition which is often unresponsive to conservative medical management. The complications of surgical procedures such as dilatations and anoplasty make it a formidable treatment challenge. Through this case, we report and explore a new medical treatment for ano-rectal strictures with an analogy to Plummer Vinson syndrome.
A 69-year-old male presented with chronic constipation, rectal pain, and easy fatigability. The physical exam was negative for anal fissure and a digital rectal examination could not be completed because an index finger could not be advanced through the narrowed anus. Laboratory reports revealed microcytic hypochromic anemia with iron deficiency. A colonoscopy performed with a GIF XQ180 OLYMPUS scope, confirmed anal stricture with non-specific colitis. Conservative management with laxatives, high fiber diet, local anesthetics with a trial of mesalamine was initiated but the patient continued to have symptoms. He was referred to a hematologist for an evaluation of anemia and was started on intravenous (IV) iron infusion.
Findings
The patient’s symptoms of constipation, anal stricture and iron deficiency anemia resolved with iron infusion over 3 months. A repeat rectal exam was painless and confirmed resolution of anal stricture.
Conclusion
IV iron supplementation combined with conventional anal dilatation presents as a promising approach toward the treatment of anal strictures.
doi:10.1186/s40064-016-3629-8
PMCID: PMC5108749  PMID: 27917348
Plummer Vinson syndrome; Iron deficiency anemia; Anal stricture
2.  Topological properties of some sequences defined over 2-normed spaces 
SpringerPlus  2016;5(1):1974.
The paper investigates some classes of real number sequences over 2-normed spaces defined by means of Orlicz functions, a bounded sequence of strictly positive real numbers, a multiplier and a normal paranormed sequence space. Relevant properties of such classes have been investigated. Moreover, relationships among different such classes of sequences have also been studied under various parameters and conditions. Finally, the spaces are investigated for some other useful properties. The conclusion section provides many interesting facts for further research.
doi:10.1186/s40064-016-3646-7
PMCID: PMC5108750  PMID: 27900239
Orlicz function; 2-Norm; Paranormed space; Completeness; Solidity; 40A35; 40A05; 40C05; 40D05; 46A45
3.  Interferometric Scattering Microscopy for the Study of Molecular Motors 
Methods in enzymology  2016;581:517-539.
Our understanding of molecular motor function has been greatly improved by the development of imaging modalities, which enable real-time observation of their motion at the single-molecule level. Here, we describe the use of a new method, interferometric scattering microscopy, for the investigation of motor protein dynamics by attaching and tracking the motion of metallic nanoparticle labels as small as 20 nm diameter. Using myosin-5, kinesin-1, and dynein as examples, we describe the basic assays, labeling strategies, and principles of data analysis. Our approach is relevant not only for motor protein dynamics but also provides a general tool for single-particle tracking with high spatiotemporal precision, which overcomes the limitations of single-molecule fluorescence methods.
doi:10.1016/bs.mie.2016.08.016
PMCID: PMC5098560  PMID: 27793291
4.  Genome-Wide Detection of Selective Signatures in Chicken through High Density SNPs 
PLoS ONE  2016;11(11):e0166146.
Chicken is recognized as an excellent model for studies of genetic mechanism of phenotypic and genomic evolution, with large effective population size and strong human-driven selection. In the present study, we performed Extended Haplotype Homozygosity (EHH) tests to identify significant core regions employing 600K SNP Chicken chip in an F2 population of 1,534 hens, which was derived from reciprocal crosses between White Leghorn and Dongxiang chicken. Results indicated that a total of 49,151 core regions with an average length of 9.79 Kb were identified, which occupied approximately 52.15% of genome across all autosomes, and 806 significant core regions attracted us mostly. Genes in candidate regions may experience positive selection and were considered to have possible influence on beneficial economic traits. A panel of genes including AASDHPPT, GDPD5, PAR3, SOX6, GPC1 and a signal pathway of AKT1 were detected with the most extreme P-values. Further enrichment analyses indicated that these genes were associated with immune function, sensory organ development and neurogenesis, and may have experienced positive selection in chicken. Moreover, some of core regions exactly overlapped with genes excavated in our previous GWAS, suggesting that these genes have undergone positive selection may affect egg production. Findings in our study could draw a comparatively integrate genome-wide map of selection signature in the chicken genome, and would be worthy for explicating the genetic mechanisms of phenotypic diversity in poultry breeding.
doi:10.1371/journal.pone.0166146
PMCID: PMC5098818  PMID: 27820849
5.  The β-amyloid peptide compromises Reelin signaling in Alzheimer’s disease 
Scientific Reports  2016;6:31646.
Reelin is a signaling protein that plays a crucial role in synaptic function, which expression is influenced by β-amyloid (Aβ). We show that Reelin and Aβ oligomers co-immunoprecipitated in human brain extracts and were present in the same size-exclusion chromatography fractions. Aβ treatment of cells led to increase expression of Reelin, but secreted Reelin results trapped together with Aβ aggregates. In frontal cortex extracts an increase in Reelin mRNA, and in soluble and insoluble (guanidine-extractable) Reelin protein, was associated with late Braak stages of Alzheimer’s disease (AD), while expression of its receptor, ApoER2, did not change. However, Reelin-dependent induction of Dab1 phosphorylation appeared reduced in AD. In cells, Aβ reduced the capacity of Reelin to induce internalization of biotinylated ApoER2 and ApoER2 processing. Soluble proteolytic fragments of ApoER2 generated after Reelin binding can be detected in cerebrospinal fluid (CSF). Quantification of these soluble fragments in CSF could be a tool to evaluate the efficiency of Reelin signaling in the brain. These CSF-ApoER2 fragments correlated with Reelin levels only in control subjects, not in AD, where these fragments diminished. We conclude that while Reelin expression is enhanced in the Alzheimer’s brain, the interaction of Reelin with Aβ hinders its biological activity.
doi:10.1038/srep31646
PMCID: PMC4987719  PMID: 27531658
6.  Chinese Eye Exercises and Myopia Development in School Age Children: A Nested Case-control Study 
Scientific Reports  2016;6:28531.
Chinese eye exercises have been implemented in China as an intervention for controlling children’s myopia for over 50 years. This nested case-control study investigated Chinese eye exercises and their association with myopia development in junior middle school children. Outcome measures were the onset and progression of myopia over a two-year period. Cases were defined as 1. Myopia onset (cycloplegic spherical equivalent ≤ −0.5 diopter in non-myopic children). 2. Myopia progression (myopia shift of ≥1.0 diopter in those who were myopic at baseline). Two independent investigators assessed the quality of Chinese eye exercises performance at the end of the follow-up period. Of 260 children at baseline (mean age was 12.7 ± 0.5 years), 201 were eligible for this study. There was no association between eye exercises and the risk of myopia-onset (OR = 0.73, 95%CI: 0.24–2.21), nor myopia progression (OR = 0.79, 95%CI: 0.41–1.53). The group who performed high quality exercises had a slightly lower myopia progression of 0.15 D than the children who did not perform the exercise over a period of 2 years. However, the limited sample size, low dosage and performance quality of Chinese eye exercises in children did not result in statistical significance and require further studies.
doi:10.1038/srep28531
PMCID: PMC4916489  PMID: 27329615
7.  Cross talk between ABC transporter mRNAs via a target mRNA-derived sponge of the GcvB small RNA 
The EMBO Journal  2015;34(11):1478-1492.
There is an expanding list of examples by which one mRNA can posttranscriptionally influence the expression of others. This can involve RNA sponges that sequester regulatory RNAs of mRNAs in the same regulon, but the underlying molecular mechanism of such mRNA cross talk remains little understood. Here, we report sponge-mediated mRNA cross talk in the posttranscriptional network of GcvB, a conserved Hfq-dependent small RNA with one of the largest regulons known in bacteria. We show that mRNA decay from the gltIJKL locus encoding an amino acid ABC transporter generates a stable fragment (SroC) that base-pairs with GcvB. This interaction triggers the degradation of GcvB by RNase E, alleviating the GcvB-mediated mRNA repression of other amino acid-related transport and metabolic genes. Intriguingly, since the gltIJKL mRNA itself is a target of GcvB, the SroC sponge seems to enable both an internal feed-forward loop to activate its parental mRNA in cis and activation of many trans-encoded mRNAs in the same pathway. Disabling this mRNA cross talk affects bacterial growth when peptides are the sole carbon and nitrogen sources.
doi:10.15252/embj.201490546
PMCID: PMC4474525  PMID: 25630703
GcvB; Hfq; noncoding RNA; RNase E; SroC
8.  Synthetic viability genomic screening defines Sae2 function in DNA repair 
The EMBO Journal  2015;34(11):1509-1522.
DNA double-strand break (DSB) repair by homologous recombination (HR) requires 3′ single-stranded DNA (ssDNA) generation by 5′ DNA-end resection. During meiosis, yeast Sae2 cooperates with the nuclease Mre11 to remove covalently bound Spo11 from DSB termini, allowing resection and HR to ensue. Mitotic roles of Sae2 and Mre11 nuclease have remained enigmatic, however, since cells lacking these display modest resection defects but marked DNA damage hypersensitivities. By combining classic genetic suppressor screening with high-throughput DNA sequencing, we identify Mre11 mutations that strongly suppress DNA damage sensitivities of sae2Δ cells. By assessing the impacts of these mutations at the cellular, biochemical and structural levels, we propose that, in addition to promoting resection, a crucial role for Sae2 and Mre11 nuclease activity in mitotic DSB repair is to facilitate the removal of Mre11 from ssDNA associated with DSB ends. Thus, without Sae2 or Mre11 nuclease activity, Mre11 bound to partly processed DSBs impairs strand invasion and HR.
doi:10.15252/embj.201590973
PMCID: PMC4474527  PMID: 25899817
Mre11; Sae2; suppressor screening; synthetic viability; whole-genome sequencing
9.  Histiocytoid Sweet Syndrome Is More Frequently Associated With Myelodysplastic Syndromes Than the Classical Neutrophilic Variant 
Medicine  2016;95(15):e3033.
Abstract
Histiocytoid Sweet syndrome (H-SS) is a histological variant of Sweet syndrome (SS) differing from classical neutrophilic SS (N-SS) by a dermal infiltrate mainly composed of lymphocytes and histiocytoid myeloperoxidase-positive cells. We aimed to report a large series of H-SS and compare the frequency and type of hematological malignancies associated to H-SS and N-SS. We included 62 patients with a coding histopathologic diagnosis of SS prospectively registered between 2005 and 2014 in the database of our Department of Pathology. Overall, 22 (35.5%) and 40 (64.5%) patients had a histological diagnosis of H-SS and N-SS, respectively. Median age, sex ratio, and cutaneous lesions were similar in the 2 groups. The frequency of extra-cutaneous manifestations was similar (50% vs 37.5%, P = 0.42). Recurrent forms were significantly more frequent in H-SS than in N-SS patients (21% vs 2.5%, P = 0.01). A hematological malignancy was diagnosed in 22 patients, 12 (55.5%) with H-SS and 10 (25%) with N-SS (P = 0.019). Hematological malignancy was of myeloid origin in 8/22 (36.3%) H-SS and 5/40 (12.5%) N-SS patients (P = 0.02), and of lymphoid origin without myeloid component in 4/22 (18.1%) H-SS and 4/40 (10%) N-SS patients (P = 0.35), respectively. One N-SS patient had a hematological malignancy of mixed (myeloid and lymphoid) phenotype. A myelodysplastic syndrome (MDS) was diagnosed in 7/22 (31.8%) H-SS and 1/40 (2.5%) N-SS patients (P < 0.001). Hematological disease was diagnosed before (in 8 H-SS and 3 N-SS patients) or at the time of the occurrence of the cutaneous lesions (in 1 H-SS and 7 N-SS patients). However, in 3 H-SS patients, all with MDS, cutaneous lesions preceded the hematological disease by ≤6 months. In conclusion, H-SS was associated with MDS in one third of patients but also with lymphoid malignancies, and cutaneous lesions could precede the hematological diagnosis in patients with MDS. A complete hematological assessment is mandatory at diagnosis, and monitoring blood cell counts should be recommended for at least 6 months after the diagnosis of H-SS.
doi:10.1097/MD.0000000000003033
PMCID: PMC4839791  PMID: 27082547
10.  Extracellular matrix elasticity and topography: material-based cues that affect cell function via conserved mechanisms 
Chemical, mechanical, and topographic extracellular matrix (ECM) cues have been extensively studied for their influence on cell behavior. These ECM cues alter cell adhesion, cell shape, and cell migration, and activate signal transduction pathways to influence gene expression, proliferation, and differentiation. ECM elasticity and topography, in particular, have emerged as material properties of intense focus based on strong evidence these physical cue can partially dictate stem cell differentiation. Cells generate forces to pull on their adhesive contacts, and these tractional forces appear to be a common element of cells’ responses to both elasticity and topography. This review focuses on recently published work that links ECM topography and mechanics and their influence on differentiation and other cell behaviors, We also highlight signaling pathways typically implicated in mechanotransduction that are (or may be) shared by cells subjected to topographic cues. Finally, we conclude with a brief discussion of the potential implications of these commonalities for cell based therapies and biomaterial design.
doi:10.1002/jbm.a.35254
PMCID: PMC4258536  PMID: 24910444
topography; matrix mechanics; cell fate; mechanotransduction; differentiation
11.  Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway 
International Journal of Cancer  2015;138(7):1634-1644.
To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.
What's new?
The serrated pathway of colorectal cancer (CRC) development is characterized by the presence of saw‐toothed colonic crypts and by a high‐methylation epigenotype. Not all serrated lesions, however, give rise to CRC. Here, only sessile serrated adenoma/polyps, a potentially malignant serrated polyp subtype, were identified as precursors of high‐methylation CRC. Moreover, MLH1 expression, silencing of which previously was linked to microsatellite instability in CRC, was found to be preserved in most serrated adenoma/polyp samples. The findings suggest that the acquisition of a hypermutation phenotype in serrated CRC likely depends on extensive MLH1 methylation and mutation of additional mismatch repair genes.
doi:10.1002/ijc.29903
PMCID: PMC4737347  PMID: 26510091
colorectal cancer (CRC); sessile serrated adenoma/polyp (SSA/P); traditional serrated adenoma (TSA); DNA methylation; gene mutation
12.  Body Image Distortion and Exposure to Extreme Body Types: Contingent Adaptation and Cross Adaptation for Self and Other 
Body size misperception is common amongst the general public and is a core component of eating disorders and related conditions. While perennial media exposure to the “thin ideal” has been blamed for this misperception, relatively little research has examined visual adaptation as a potential mechanism. We examined the extent to which the bodies of “self” and “other” are processed by common or separate mechanisms in young women. Using a contingent adaptation paradigm, experiment 1 gave participants prolonged exposure to images both of the self and of another female that had been distorted in opposite directions (e.g., expanded other/contracted self), and assessed the aftereffects using test images both of the self and other. The directions of the resulting perceptual biases were contingent on the test stimulus, establishing at least some separation between the mechanisms encoding these body types. Experiment 2 used a cross adaptation paradigm to further investigate the extent to which these mechanisms are independent. Participants were adapted either to expanded or to contracted images of their own body or that of another female. While adaptation effects were largest when adapting and testing with the same body type, confirming the separation of mechanisms reported in experiment 1, substantial misperceptions were also demonstrated for cross adaptation conditions, demonstrating a degree of overlap in the encoding of self and other. In addition, the evidence of misperception of one's own body following exposure to “thin” and to “fat” others demonstrates the viability of visual adaptation as a model of body image disturbance both for those who underestimate and those who overestimate their own size.
doi:10.3389/fnins.2016.00334
PMCID: PMC4946181  PMID: 27471447
adaptation; body image; psychophysics; perception; eating disorders; aftereffects; neural representation
13.  The influence of neighbourhood-level socioeconomic deprivation on cardiovascular disease mortality in older age: longitudinal multilevel analyses from a cohort of older British men 
Background
Evidence from longitudinal studies on the influence of neighbourhood socioeconomic factors in older age on cardiovascular disease (CVD) mortality is limited. We aimed to investigate the prospective association of neighbourhood-level deprivation in later life with CVD mortality, and assess the underlying role of established cardiovascular risk factors.
Methods
A socially representative cohort of 3924 men, aged 60–79 years in 1998–2000, from 24 British towns, was followed up until 2012 for CVD mortality. Quintiles of the national Index of Multiple Deprivation (IMD), a composite score of neighbourhood-level factors (including income, employment, education, housing and living environment) were used. Multilevel logistic regression with discrete-time models (stratifying follow-up time into months) were used.
Results
Over 12 years, 1545 deaths occurred, including 580 from CVD. The risk of CVD mortality showed a graded increase from IMD quintile 1 (least deprived) to 5 (most deprived). Compared to quintile 1, the age-adjusted odds of CVD mortality in quintile 5 were 1.71 (95% CI 1.32 to 2.21), and 1.62 (95% CI 1.23 to 2.13) on further adjustment for individual social class, which was attenuated slightly to 1.44 (95% CI 1.09 to 1.89), but remained statistically significant after adjustment for smoking, body mass index, physical activity and use of alcohol. Further adjustment for blood pressure, high-density lipoprotein cholesterol and prevalent diabetes made little difference.
Conclusions
Neighbourhood-level deprivation was associated with an increased risk of CVD mortality in older people independent of individual-level social class and cardiovascular risk factors. The role of other specific neighbourhood-level factors merits further research.
doi:10.1136/jech-2015-205542
PMCID: PMC4680118  PMID: 26285580
DEPRIVATION; AGEING; Cardiovascular disease; INEQUALITIES; MULTILEVEL MODELLING
14.  Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids 
Annals of the Rheumatic Diseases  2015;74(12):2188-2192.
Objectives
To determine whether whole-body MRI defines clinically relevant subgroups within polymyalgia rheumatica (PMR) including glucocorticoid responsiveness.
Methods
22 patients with PMR and 16 with rheumatoid arthritis (RA), untreated and diagnosed by consultant rheumatologists, underwent whole-body, multiple-joint MRI, scored by two experts. Patients with PMR reported whether they felt ‘back to normal’ on glucocorticoid therapy and were followed for a median of 2 years.
Results
All patients with PMR were deemed to respond to glucocorticoids clinically. A characteristic pattern of symmetrical, extracapsular inflammation, adjacent to greater trochanter, acetabulum, ischial tuberosity and/or symphysis pubis, was observed in 14/22 of the PMR cases. In PMR, this pattern was associated with complete glucocorticoid response (p=0.01), higher pretreatment C-reactive protein (CRP) and serum interleukin-6 (IL-6), and better post-treatment fatigue and function. Only 1/14 in the extracapsular group could stop glucocorticoids within 1 year, compared with 4/7 of the others. A score derived from the five sites discriminating best between PMR and RA correlated with IL-6 (p<0.002). IL-6 levels ≥16.8 pg/mL had 86% sensitivity and 86% specificity for the extracapsular MRI pattern.
Conclusions
A subset of patients with rheumatologist-diagnosed PMR had a characteristic, extracapsular pattern of MRI inflammation, associated with elevated IL-6/CRP and with complete patient-reported glucocorticoid responsiveness.
doi:10.1136/annrheumdis-2015-207395
PMCID: PMC4680120  PMID: 26376658
Magnetic Resonance Imaging; Polymyalgia Rheumatica; Cytokines
15.  Retroviral DNA Transposition: Themes and Variations 
Microbiology spectrum  2014;2(5):MDNA3-0005-2014-.
SUMMARY
Retroviruses and LTR retrotransposons are transposable elements that encapsidate the RNAs that are intermediates in the transposition of DNA copies of their genomes (proviruses), from one cell (or one locus) to another. Mechanistic similarities in DNA transposase enzymes and retroviral/retrotransposon integrases underscore the close evolutionary relationship among these elements.
The retroviruses are very ancient infectious agents, presumed to have evolved from Ty3/Gypsy LTR retrotransposons (1), and DNA copies of their sequences can be found embedded in the genomes of most, if not all, members of the tree of life. All retroviruses share a specific gene arrangement and similar replication strategies. However, given their ancestries and occupation of diverse evolutionary niches, it should not be surprising that unique sequences have been acquired in some retroviral genomes and that the details of the mechanism by which their transposition is accomplished can vary.
While every step in the retrovirus lifecycle is, in some sense, relevant to transposition, this Chapter focuses mainly on the early phase of retroviral replication, during which viral DNA is synthesized and integrated into its host genome. Some of the initial studies that set the stage for current understanding are highlighted, as well as more recent findings obtained through use of an ever-expanding technological toolbox including genomics, proteomics, and siRNA screening. Persistence in the area of structural biology has provided new insight into conserved mechanisms as well as variations in detail among retroviruses, which can also be instructive.
doi:10.1128/microbiolspec.MDNA3-0005-2014
PMCID: PMC4383315  PMID: 25844274
16.  Cross talk between ABC transporter mRNAs via a target mRNA-derived sponge of the GcvB small RNA 
The EMBO Journal  2015;34(11):1478-1492.
There is an expanding list of examples by which one mRNA can posttranscriptionally influence the expression of others. This can involve RNA sponges that sequester regulatory RNAs of mRNAs in the same regulon, but the underlying molecular mechanism of such mRNA cross talk remains little understood. Here, we report sponge-mediated mRNA cross talk in the posttranscriptional network of GcvB, a conserved Hfq-dependent small RNA with one of the largest regulons known in bacteria. We show that mRNA decay from the gltIJKL locus encoding an amino acid ABC transporter generates a stable fragment (SroC) that base-pairs with GcvB. This interaction triggers the degradation of GcvB by RNase E, alleviating the GcvB-mediated mRNA repression of other amino acid-related transport and metabolic genes. Intriguingly, since the gltIJKL mRNA itself is a target of GcvB, the SroC sponge seems to enable both an internal feed-forward loop to activate its parental mRNA in cis and activation of many trans-encoded mRNAs in the same pathway. Disabling this mRNA cross talk affects bacterial growth when peptides are the sole carbon and nitrogen sources.
doi:10.15252/embj.201490546
PMCID: PMC4474525  PMID: 25630703
GcvB; Hfq; noncoding RNA; RNase E; SroC
17.  Synthetic viability genomic screening defines Sae2 function in DNA repair 
The EMBO Journal  2015;34(11):1509-1522.
DNA double-strand break (DSB) repair by homologous recombination (HR) requires 3′ single-stranded DNA (ssDNA) generation by 5′ DNA-end resection. During meiosis, yeast Sae2 cooperates with the nuclease Mre11 to remove covalently bound Spo11 from DSB termini, allowing resection and HR to ensue. Mitotic roles of Sae2 and Mre11 nuclease have remained enigmatic, however, since cells lacking these display modest resection defects but marked DNA damage hypersensitivities. By combining classic genetic suppressor screening with high-throughput DNA sequencing, we identify Mre11 mutations that strongly suppress DNA damage sensitivities of sae2∆ cells. By assessing the impacts of these mutations at the cellular, biochemical and structural levels, we propose that, in addition to promoting resection, a crucial role for Sae2 and Mre11 nuclease activity in mitotic DSB repair is to facilitate the removal of Mre11 from ssDNA associated with DSB ends. Thus, without Sae2 or Mre11 nuclease activity, Mre11 bound to partly processed DSBs impairs strand invasion and HR.
doi:10.15252/embj.201590973
PMCID: PMC4474527  PMID: 25899817
Mre11; Sae2; suppressor screening; synthetic viability; whole-genome sequencing
18.  Platelet derived growth factor (PDGF) contained in Platelet Rich Plasma (PRP) stimulates migration of osteoblasts by reorganizing actin cytoskeleton 
Cell Adhesion & Migration  2014;8(6):595-602.
Platelet-rich plasma (PRP) is a platelet concentrate in a small volume of plasma. It is highly enriched in growth factors able to stimulate the migration and growth of bone-forming cells. PRP is often used in clinical applications, as dental surgery and fracture healing. Platelet derived growth factor (PDGF), is highly concentrated in PRP and it was shown in our previous studies to provide the chemotactic stimulus to SaOS-2 osteoblasts to move in a microchemotaxis assay. Aim of the present studies is to analyze the effects of a PRP pretreatment (short time course: 30–150 min) of SaOS-2 cells with PRP on the organization of actin cytoskeleton, the main effector of cell mobility. The results indicate that a pretreatment with PRP increases chemokinesis and chemotaxis and concomitantly induces the organization of actin microfilaments, visualized by immunocytochemistry, in a directionally elongated phenotype, which is characteristic of the cells able to move. PRP also produces a transient increase in the expression of PGDF α receptor. This reorganization is blocked by the immunoneutralization of PDGF demonstrating the responsibility of this growth factor in triggering the mechanisms responsible for cellular movements.
doi:10.4161/19336918.2014.972785
PMCID: PMC4594427  PMID: 25482626
actin; chemotaxis; cytoskeleton; migration; osteoblasts; PRP; PDGF receptor; SaOS-2
19.  Primary Care Utilization and Colorectal Cancer Incidence and Mortality Among Medicare Beneficiaries 
Annals of internal medicine  2013;159(7):437-446.
Background
Utilization of primary care may decrease colorectal cancer (CRC) incidence and death through greater receipt of CRC screening tests.
Objective
To examine the association of primary care utilization with CRC incidence, CRC deaths, and all-cause mortality.
Design
Population-based, case–control study.
Setting
Medicare program.
Participants
Persons aged 67 to 85 years diagnosed with CRC between 1994 and 2005 in U.S. Surveillance, Epidemiology, and End Results (SEER) regions matched with control patients (n = 205 804 for CRC incidence, 54 160 for CRC mortality, and 121 070 for all-cause mortality).
Measurements
Primary care visits in the 4- to 27-month period before CRC diagnosis, CRC incidence, CRC mortality, and all-cause mortality.
Results
Compared with persons having 0 or 1 primary care visit, persons with 5 to 10 visits had lower CRC incidence (adjusted odds ratio [OR], 0.94 [95% CI, 0.91 to 0.96]) and mortality (adjusted OR, 0.78 [CI, 0.75 to 0.82]) and lower all-cause mortality (adjusted OR, 0.79 [CI, 0.76 to 0.82]). Associations were stronger in patients with late-stage CRC diagnosis, distal lesions, and diagnosis in more recent years when there was greater Medicare screening coverage. Ever receipt of CRC screening and polypectomy mediated the association of primary care utilization with CRC incidence.
Limitation
This study used administrative data, which made it difficult to identify potential confounders and prevented examination of the content of primary care visits.
Conclusion
Medicare beneficiaries with higher utilization of primary care have lower CRC incidence and mortality and lower overall mortality. Increasing and promoting access to primary care in the United States for Medicare beneficiaries may help decrease the national burden of CRC.
Primary Funding Source
American Cancer Society.
doi:10.7326/0003-4819-159-7-201310010-00003
PMCID: PMC4605549  PMID: 24081284
20.  Cucurbit [7] uril encapsulated cisplatin overcomes resistance to cisplatin induced by Rab25 overexpression in an intraperitoneal ovarian cancer model 
Background
Ovarian cancer is the most fatal of gynaecological malignancies, usually detected at a late stage with intraperitoneal dissemination. Appropriate preclinical models are needed that recapitulate both the histopathological and molecular features of human ovarian cancer for drug-efficacy analysis.
Methods
Longitudinal studies comparing cisplatin performance either alone or in a novel cisplatin-based delivery-system, cucurbit[7]uril-encapsulated cisplatin (cisplatin@CB[7]) were performed on subcutaneous (s.c.) and intraperitoneal (i.p.) xenografts using the human ovarian cancer cell line A2780 stably expressing the small GTPase Rab25, which allows A2780 intraperitoneal growth; and luciferase, to allow tumour load measurement by non-invasive bioluminescent imaging.
Results
Rab25 expression induced cisplatin resistance compared to the parental cell line as assessed by the MTT assay in vitro. These findings did not translate in vivo, where cisplatin resistance was determined by the microenvironment. Subcutaneous xenografts of either parental A2780 or cisplatin-resistant Rab25-expressing A2780 cells presented similar responses to cisplatin treatment. In contrast, increased cisplatin resistance was only detected in i.p. tumours. Treatment of the cisplatin-resistant i.p. model with the novel cisplatin@CB[7] delivery system resulted in a substantial reduction of i.p. tumour load and increased necrosis.
Conclusions
Poor clinical performance of novel chemotherapeutics might reflect inappropriate preclinical models. Here we present an ovarian i.p. model that recapitulates the histopathological and chemoresistant features of the clinical disease. In addition, we demonstrate that the novel cisplatin-delivery system, cisplatin@CB[7] may have utility in the treatment of drug-resistant ovarian human cancers.
doi:10.1186/s13048-015-0189-4
PMCID: PMC4575495  PMID: 26384969
21.  The Use of Biospecimens in Population-Based Research: A Review of the National Cancer Institute's Division of Cancer Control and Population Sciences Grant Portfolio 
Biopreservation and Biobanking  2014;12(4):240-245.
Over the past two decades, researchers have increasingly used human biospecimens to evaluate hypotheses related to disease risk, outcomes and treatment. We conducted an analysis of population-science cancer research grants funded by the National Cancer Institute (NCI) to gain a more comprehensive understanding of biospecimens and common derivatives involved in those studies and identify opportunities for advancing the field. Data available for 1,018 extramural, peer-reviewed grants (active as of July 2012) supported by the Division of Cancer Control and Population Sciences (DCCPS), the NCI Division that supports cancer control and population-science extramural research grants, were analyzed. 455 of the grants were determined to involve biospecimens or derivatives. The most common specimen types included were whole blood (51% of grants), serum or plasma (40%), tissue (39%), and the biospecimen derivative, DNA (66%). While use of biospecimens in molecular epidemiology has become common, biospecimens for behavioral and social research is emerging, as observed in our analysis. Additionally, we found the majority of grants were using already existing biospecimens (63%). Grants that involved use of existing biospecimens resulted in lower costs (studies that used existing serum/plasma biospecimens were 4.2 times less expensive) and more publications per year (1.4 times) than grants collecting new biospecimens. This analysis serves as a first step at understanding the types of biospecimen collections supported by NCI DCCPS. There is room to encourage increased use of archived biospecimens and new collections of rarer specimen and cancer types, as well as for behavioral and social research. To facilitate these efforts, we are working to better catalogue our funded resources and make that data available to the extramural community.
doi:10.1089/bio.2014.0009
PMCID: PMC4150371  PMID: 25162460
22.  Assessment of DNA Encapsulation, a New Room-Temperature DNA Storage Method 
Biopreservation and Biobanking  2014;12(3):176-183.
A new procedure for room-temperature storage of DNA was evaluated whereby DNA samples from human tissue, bacteria, and plants were stored under an anoxic and anhydrous atmosphere in small glass vials fitted in stainless-steel, laser-sealed capsules (DNAshells®). Samples were stored in DNAshells® at room temperature for various periods of time to assess any degradation and compare it to frozen control samples and those stored in GenTegra™ tubes. The study included analysis of the effect of accelerated aging by using a high temperature (76°C) at 50% relative humidity. No detectable DNA degradation was seen in samples stored in DNAshells® at room temperature for 18 months. Polymerase chain reaction experiments, pulsed field gel electrophoresis, and amplified fragment length polymorphism analyses also demonstrated that the protective properties of DNAshells® are not affected by storage under extreme conditions (76°C, 50% humidity) for 30 hours, guaranteeing 100 years without DNA sample degradation. However, after 30 hours of storage at 76°C, it was necessary to include adjustments to the process in order to avoid DNA loss. Successful protection of DNA was obtained for 1 week and even 1 month of storage at high temperature by adding trehalose, which provides a protective matrix. This study demonstrates the many advantages of using DNAshells® for room-temperature storage, particularly in terms of long-term stability, safety, transport, and applications for molecular biology research.
doi:10.1089/bio.2013.0082
PMCID: PMC4128249  PMID: 24955733
23.  Factors Associated with Willingness to Participate in Biospecimen Research Among Chinese Americans 
Biopreservation and Biobanking  2014;12(2):131-138.
A paucity of information exists on the recruitment of Asian Americans for biospecimen research. Although studies show that Chinese Americans are at high risk for hepatitis B virus (HBV) infection, little is known about their willingness to participate in HBV-related biospecimen research and how knowledge, attitudes, and cultural factors impact their willingness to participate. The study was guided by Community-Based Participatory Research principles. Data were derived from an assessment study on HBV-related biospecimen research participation among Chinese Americans in the Philadelphia region. The assessment was conducted with 415 Chinese Americans recruited from eight Chinese community-based organizations. Cultural beliefs, knowledge, and attitudes toward biospecimen research were examined for associations with their willingness to participate in biospecimen banking research. Overall, 192 (46.3%) of 415 participants who completed the assessment indicated they were willing to participate if they were invited to donate blood to be frozen and stored for future HBV biospecimen studies. Cultural variables significant in bivariate analysis included collectivism, knowledge about biospecimen research, and Yin-Yang beliefs. Fatalism and individualism were not associated with participation willingness. In multivariate analysis, age, health care attitudes, and trust were significantly associated with willingness to participate in biospecimen banking research. Asian American communities have little knowledge of biospecimen banking and will benefit from educational campaigns that emphasize collective benefits and attitudes towards and trust in the health care system. Understanding cultural factors is important for improving Chinese Americans' knowledge, awareness, and intentions of participation in biospecimen research. Similar efforts need to be undertaken to develop culturally appropriate educational intervention programs to increase participation in biospecimen research among other Asian American groups.
doi:10.1089/bio.2013.0081
PMCID: PMC3995351  PMID: 24749880
24.  Introducing Research Initiatives into Healthcare: What Do Doctors Think? 
Biopreservation and Biobanking  2014;12(2):91-98.
Background: Current national and international policies emphasize the need to develop research initiatives within our health care system. Institutional biobanking represents a modern, large-scale research initiative that is reliant upon the support of several aspects of the health care organization. This research project aims to explore doctors' views on the concept of institutional biobanking and to gain insight into the factors which impact the development of research initiatives within healthcare systems.
Methods: Qualitative research study using semi-structured interviews. The research was conducted across two public teaching hospitals in Sydney, Australia where institutional biobanking was being introduced. Twenty-five participants were interviewed, of whom 21 were medical practitioners at the specialist trainee level or above in a specialty directly related to biobanking; four were key stakeholders responsible for the design and implementation of the biobanking initiative.
Results: All participants strongly supported the concept of institutional biobanking. Participants highlighted the discordance between the doctors who work to establish the biobank (the contributors) and the researchers who use it (the consumers). Participants identified several barriers that limit the success of research initiatives in the hospital setting including: the ‘resistance to change’ culture; the difficulties in engaging health professionals in research initiatives; and the lack of incentives offered to doctors for their contribution. Doctors positively valued the opportunity to advise the implementation team, and felt that the initiative could benefit from their knowledge and expertise.
Conclusion: Successful integration of research initiatives into hospitals requires early collaboration between the implementing team and the health care professionals to produce a plan that is sensitive to the needs of the health professionals and tailored to the hospital setting. Research initiatives must consider incentives that encourage doctors to adopt operational responsibility for hospital research initiatives.
doi:10.1089/bio.2013.0069
PMCID: PMC3995354  PMID: 24749875
25.  Cancer Patient Perceptions about Biobanking and Preferred Timing of Consent 
Biopreservation and Biobanking  2014;12(2):106-112.
Little is known about how cancer patients feel about donating their tissue, especially in a multiethnic population. Structured interviews were conducted with 30 patients recently diagnosed with cancer, referred to the study by six cancer surgeons and oncologists and by other patients in the study. The participants reported a variety of cancers, and the sample reflected the racial distribution of Hawai`i, including Caucasians (23%), Native Hawaiians and Pacific Islanders (27%), Asians (37%), Hispanics (7%), Native Americans (3%), and African Americans (3%). The interview questions and analysis were guided by the Framework Approach, with interview questions based on pre-set aims. Findings suggest that most cancer patients would donate cancer tissue to science, especially if informed that doing so could help researchers find causes of and cures for cancer. Patients varied on when in their cancer journey they would be most receptive to being asked for a donation, however two-thirds thought they would be more receptive if approached after surgery. Only three of the 30 patients said they would want to be re-consented each time their tissue is requested for research. They identified their physician as the preferred messenger regarding tissue donation. No obvious differences were seen by race. Findings confirm those of other researchers who have reported broad support for biobank participation if informed consent and confidentiality could be assured. Given that the physician was seen as the key messenger about biobanking, more education is needed around cancer tissue collection for physicians, as well as for cancer patients.
doi:10.1089/bio.2013.0083
PMCID: PMC3995435  PMID: 24749877

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