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1.  Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas 
Oncogene  2011;31(24):3002-3008.
Our recent study demonstrated miR-15a/16-1 downregulation in mantle cell lymphoma (MCL). Here, we investigated mechanisms of miR-15a/16-1 transcriptional repression and its epigenetic regulation by c-Myc and histone deacetylase (HDAC) in MCL. c-Myc expression was detected in MCL cell lines and in the primary MCL samples, and pri-miR-15a/16-1 mRNAs were significantly upregulated in Mino and Jeko-1 cells with c-Myc knockdown by small interfering RNAs (siRNAs). Our co-immunoprecipitation analysis showed that c-Myc interacted with HDAC3. Moreover, using chromatin immunoprecipitation, we demonstrated that both c-Myc and HDAC3 co-localized to the two promoters of the miR-15a/16-1 cluster gene, DLEU2, and inhibition of HDAC3 increased histone acetylation of the DLEU2 promoters. Luciferase reporter assay confirmed the dependence of Myc-mediated DLEU2 transcriptional repression on HDAC3. Treatment with the pan-HDAC inhibitor, suberoylanilide hydroxamic acid and HDAC3 siRNA resulted in increased miR-15a/16-1 expression. The regulatory mechanism of miR-15a/16-1 was further demonstrated in Burkitt lymphoma and Myc overexpressing cell lines. These findings highlight the role of HDAC3 in Myc-induced miR-15a/16-1 changes and reveal novel mechanisms for c-Myc-driven microRNA suppression and malignant transformation in aggressive B-cell malignancies.
doi:10.1038/onc.2011.470
PMCID: PMC3982396  PMID: 22002311
Myc; miR15a/miR-16-1; lymphoma
2.  IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1 
Cell Death and Differentiation  2012;20(2):248-258.
The IκB kinase (IKK)/NF-κB pathway has been shown to be a major regulator in cell survival. However, the mechanisms through which IKK mediates cell death are not clear. In this study, we showed that IKK-β contributed to hydrogen peroxide (H2O2)-induced cell death independent of the NF-κB pathway. Our results demonstrated that the pro-death function of IKK-β under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism. We found that IKK-β associated with p85, but not p70 S6K1, which was required for H2O2-induced activation of p85 S6K1. IKK-β and p85 S6K1 contributed to H2O2-induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-β-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-β, p85 S6K1 and Mdm2, which is response for H2O2-induced cell death. Our results have important implications for IKK-β and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death.
doi:10.1038/cdd.2012.115
PMCID: PMC3554328  PMID: 22955948
IKK-β; hydrogen peroxide; S6K1; mammalian target of rapamycin
3.  Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation 
Mucosal immunology  2013;6(5):921-930.
This study identified a novel phenomenon that dendritic cells (DCs) produced interleukin (IL)-33 via Toll-like receptor (TLR)-mediated innate pathway. Mouse bone marrow–derived DCs were treated with or without microbial pathogens or recombinant murine IL-33. IL-33 mRNA and protein were found to be expressed by DCs and largely induced by several microbial pathogens, highly by lipopolysaccharide (LPS) and flagellin. Using two mouse models of topical challenge by LPS and flagellin and experimental allergic conjunctivitis, IL-33-producing DCs were observed in ocular mucosal surface and the draining cervical lymph nodes in vivo. The increased expression levels of myeloid differentiation primary-response protein 88 (MyD88), nuclear factor (NF)-κB1, NF-κB2, and RelA accompanied by NF-κB p65 nuclear translocation were observed in DCs exposed to flagellin. IL-33 induction by flagellin was significantly blocked by TLR5 antibody or NF-κB inhibitor quinazoline and diminished in DCs from MyD88 knockout mice. IL-33 stimulated the expression of DC maturation markers, CD40 and CD80, and proallergic cytokines and chemokines, OX40L, IL-4, IL-5, IL-13, CCL17 (C-C motif chemokine ligand 17), TNF-α (tumor necrosis factor-α), and IL-1β. This stimulatory effect of IL-33 in DCs was significantly blocked by ST2 antibody or soluble ST2. Our findings demonstrate that DCs produce IL-33 via TLR/NF-κB signaling pathways, suggesting a molecular mechanism by which local allergic inflammatory response may be amplified by DC-produced IL-33 through potential autocrine regulation.
doi:10.1038/mi.2012.130
PMCID: PMC3904307  PMID: 23299617
4.  Magnetic and structural transitions of SrFe2As2 at high pressure and low temperature 
Scientific Reports  2014;4:3685.
One of key issues in studying iron based superconductors is to understand how the magnetic phase of the parent compounds evolves. Here we report the systematic investigation of paramagnetic to antiferromagnetic and tetragonal to orthorhombic structural transitions of “122” SrFe2As2 parent compound using combined high resolution synchrotron Mössbauer spectroscopy and x-ray diffraction techniques in a cryogenically cooled high pressure diamond anvil cell. It is found that although the two transitions are coupled at 205 K at ambient pressure, they are concurrently suppressed to much lower temperatures near a quantum critical pressure of approximately 4.8 GPa where the antiferromagnetic state transforms into bulk superconducting state. Our results indicate that the lattice distortions and magnetism jointly play a critical role in inducing superconductivity in iron based compounds.
doi:10.1038/srep03685
PMCID: PMC3890939  PMID: 24418845
5.  A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: Effects on mental health, cognition, and telomerase activity 
BACKGROUND
This study examined the effects of brief daily yogic meditation on mental health, cognitive functioning, and immune cell telomerase activity in family dementia caregivers with mild depressive symptoms.
METHODS
Thirty-nine family dementia caregivers (mean age 60.3 years old (SD=10.2)) were randomized to practicing Kirtan Kriya or listening to relaxation music for 12 minutes per day for eight weeks. The severity of depressive symptoms, mental and cognitive functioning were assessed at baseline and follow-up. Telomerase activity in peripheral blood mononuclear cells (PMBC) was examined in peripheral PBMC pre- and post-intervention.
RESULTS
The meditation group showed significantly lower levels of depressive symptoms and greater improvement in mental health and cognitive functioning compared to the relaxation group. In the meditation group, 65.2% showed 50% improvement on the Hamilton Depression Rating scale and 52% of the participants showed 50% improvement on the Mental Health Composite Summary score (MCS) of the SF-36 scale; compared to 31.2% and 19% respectively in the relaxation group (pp<0.05). The meditation group showed 43% improvement in telomerase activity compared to 3.7% in the relaxation group (p=0.05).
CONCLUSION
This pilot study found that brief daily meditation practices by family dementia caregivers can lead to improved mental and cognitive functioning, and lower levels of depressive symptoms. This improvement is accompanied by an increase in telomerase activity suggesting improvement in stress-induced cellular aging. These results need to be confirmed in a larger sample.
doi:10.1002/gps.3790
PMCID: PMC3423469  PMID: 22407663
Dementia caregiver; stress; depression; resilience; cognition; Kirtan Kriya; yoga; meditation; relaxation; telomerase; NFkB
6.  Randomized trial of nutrition education added to internet-based information and exercise at the work place for weight loss in a racially diverse population of overweight women 
Nutrition & Diabetes  2013;3(12):e98-.
Objective:
Obesity in the United States is highly prevalent, approaching 60% for black women. We investigated whether nutrition education sessions at the work place added to internet-based wellness information and exercise resources would facilitate weight and fat mass loss in a racially diverse population of overweight female employees.
Methods:
A total of 199 (average body mass index 33.9±6.3 kg m−2) nondiabetic women (57% black) at our institution were randomized to a 6-month program of either internet-based wellness information (WI) combined with dietitian-led nutrition education group sessions (GS) weekly for 3 months and then monthly with shift in emphasis to weight loss maintenance (n=99) or to WI alone (n=100). All were given access to exercise rooms convenient to their work site. Fat mass was measured by dual-energy X-ray absorptiometry.
Results:
WI+GS subjects lost more weight than WI subjects at 3 months (−2.2±2.8 vs −1.0±3.0 kg, P>0.001). Weight (−2.7±3.9 vs −2.0±3.9 kg) and fat mass (−2.2±3.1 vs −1.7±3.7 kg) loss at 6 months was significant for WI+GS and WI groups (both P<0.001), but without significant difference between groups (both P>0.10); 27% of the WI+GS group achieved ⩾5% loss of initial weight as did 18% of the WI group (P=0.180). Blacks and whites similarly completed the study (67 vs 74%, P=0.303), lost weight (−1.8±3.4 vs −3.3±5.2 kg, P=0.255) and fat mass (−1.6±2.7 vs −2.5±4.3 kg, P=0.532), and achieved ⩾5% loss of initial weight (21 vs 32%, P=0.189), irrespective of group assignment.
Conclusion:
Overweight women provided with internet-based wellness information and exercise resources at the work site lost weight and fat mass, with similar achievement by black and white women. Additional weight loss benefit of nutrition education sessions, apparent at 3 months, was lost by 6 months and may require special emphasis on subjects who fail to achieve weight loss goals to show continued value.
doi:10.1038/nutd.2013.39
PMCID: PMC3877430  PMID: 24366370
obesity; adiposity; weight loss program; racial disparity; women's health
7.  Large-angular separation of particles induced by cascaded deflection angles in optical sorting 
Applied physics letters  2008;93(26):263901-363903.
A composite microlens array (MLA) with two cascaded guiding axes has been fabricated to achieve a large lateral separation of an object with different refractive indices or sizes. The MLA projects a composite pattern formed by its focal spots into a microchamber for optical sorting in a microscopic system. This approach enables passive, high power, efficient, and continuous microfluidic sorting without requiring complicated optical assembly. Separation of particles with different refractive indices to a lateral angle of 40° is experimentally demonstrated with moderate laser power.
doi:10.1063/1.3040697
PMCID: PMC3757087  PMID: 23997243
8.  A critical role of toll-like receptor 4 (TLR4) and its' in vivo ligands in basal radio-resistance 
Cell Death & Disease  2013;4(5):e649-.
Toll-like receptor-4 (TLR4) plays a critical role in innate and acquired immunity, but its role in radio-resistance is unknown. We used TLR4 knockout (KO,−/−) mice and gut commensal depletion methods, to test the influence of TLR4 and its' in vivo agonist on basal radio-resistance. We found that mice deficient in TLR4 were more susceptible to IR-induced mortality and morbidity. Mortality of TLR4-deficient mice after IR was associated with a severe and persistent bone marrow cell loss. Injection of lipopolysaccharide into normal mice, which is known to activate TLR4 in vivo, induced radio-resistance. Moreover, TLR4 in vivo ligands are required for basal radio-resistance. We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation. The circulating endotoxins appear to originate from the gut, as sterilization of the gut with antibiotics lead to increased mortality from radiation. Further data indicated that Myd88, but not TRIF, may be the critical adaptor in TLR4-induced radio-resistance. Taken together, these data strongly suggest that TLR4 plays a critical role in basal radio-resistance. Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation. Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.
doi:10.1038/cddis.2013.161
PMCID: PMC3674368  PMID: 23722538
ionizing radiation; toll-like receptor 4; lipopolysaccharide; commensal microflora; Myd88
9.  Coding regions of INHBA, SFRP4 and HOXA10 are not implicated in familial endometriosis linked to chromosome 7p13–15 
Molecular Human Reproduction  2011;17(10):605-611.
Endometriosis is a common, chronic gynaecological disease affecting up to 10% of women in their reproductive years. Its aetiology still remains unclear, but evidence indicates genetic factors play a role. We previously identified a region of significant linkage on chromosome 7 in 52 families comprising at least three affected women, stretching ∼6.4 Mb. We screened coding regions and parts of the regulatory regions of three candidate genes with a known role in endometrial development and function—INHBA, SFRP4 and HOXA10—located under or very near the linkage peak, for potential causal mutations using Sanger sequencing. Sequencing was conducted in 47 cases from the 15 families contributing most to the linkage signal (Zmean ≥ 1). Minor allele frequencies (MAFs) of observed variants were compared with MAFs from two publicly available reference populations of European ancestry: 60 individuals in HapMap and 150 individuals in the 1000 Genomes Project. A total of 11 variants were found, 5 (45%) of which were common (MAF > 0.05) among the 15 case families and the reference populations (P-values for MAF difference: 0.88–1.00). The remaining six were rare and unlikely to be individually or cumulatively responsible for the linkage signal. The results indicate that the coding regions of these three genes do not harbour mutations responsible for linkage to endometriosis in these families.
doi:10.1093/molehr/gar035
PMCID: PMC3172037  PMID: 21576276
endometriosis; aetiology; PCR sequencing; candidate gene; coding region
10.  MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme 
Cell Death & Disease  2012;3(10):e398-.
Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.
doi:10.1038/cddis.2012.134
PMCID: PMC3481123  PMID: 23034333
microRNA-10b; angiogenicity; invasion; apoptosis; glioblastoma
11.  Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1 
Oncogene  2007;26(49):6989-6996.
In lung cancer, frequent loss of one allele of chromosome 3p is seen in both small cell lung cancer and non-small cell lung cancer (NSCLC), providing evidence of tumor suppressor genes (TSGs) in this chromosomal region. The mechanism of Fus1 tumor suppressor activity is unknown. We have found that a Fus1 peptide inhibits the Abl tyrosine kinase in vitro (IC50 35 μM). The inhibitory Fus1 sequence was derived from a region that was deleted in a mutant FUS1 gene (FUS1 (1–80)) detected in some lung cancer cell lines. Importantly, a stearic acid-modified form of this peptide was required for the inhibition, but stearic acid alone was not inhibitory. Two NSCLC cell lines, which lack expression of wild-type Fus1, contain activated c-Abl. Forced expression of an inducible FUS1 cDNA in H1299 NSCLC cells decreased levels of activated c-Abl and inhibited its tyrosine kinase activity. Similarly, treatment of c-Abl immune complexes with the inhibitory Fus1 peptide also reduced the level of c-Abl in these immune complexes. The size and number of colonies of the NSCLC cell line, H1299, in soft agar was strongly inhibited by the Abl kinase inhibitor imatinib mesylate. Co-expression of FUS1 and c-ABL in COS1 cells blocked activation of c-Abl tyrosine kinase. In contrast, co-expression of mutant FUS1 (1–80) with c-ABL had little inhibitory activity against c-Abl. These findings provide strong evidence that c-Abl is a possible target in NSCLC patients that have reduced expression of Fus1 in their tumor cells.
doi:10.1038/sj.onc.1210500
PMCID: PMC3457636  PMID: 17486070
c-Abl; FUS1; NSCLC; lung cancer; imatinib
12.  Targeting colon cancer stem cells using a new curcumin analogue, GO-Y030 
British Journal of Cancer  2011;105(2):212-220.
Background:
Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown.
Methods:
Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulations (ALDH+/CD133+). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined.
Results:
Our results observed that ALDH+/CD133+ colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model.
Conclusion:
Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer.
doi:10.1038/bjc.2011.200
PMCID: PMC3142799  PMID: 21694723
STAT3; curcumin analogue; colon cancer; cancer stem cells; ALDH; CD133
13.  WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3β 
Cell Death and Differentiation  2011;19(6):1049-1059.
WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.
doi:10.1038/cdd.2011.188
PMCID: PMC3354054  PMID: 22193544
SH-SY5Y; WWOX; GSK3β; Tau
14.  Planar Steering of a Single Ferrofluid Drop by Optimal Minimum Power Dynamic Feedback Control of Four Electromagnets at a Distance 
Any single permanent or electro magnet will always attract a magnetic fluid. For this reason it is difficult to precisely position and manipulate ferrofluid at a distance from magnets. We develop and experimentally demonstrate optimal (minimum electrical power) 2-dimensional manipulation of a single droplet of ferrofluid by feedback control of 4 external electromagnets. The control algorithm we have developed takes into account, and is explicitly designed for, the nonlinear (fast decay in space, quadratic in magnet strength) nature of how the magnets actuate the ferrofluid, and it also corrects for electro-magnet charging time delays. With this control, we show that dynamic actuation of electro-magnets held outside a domain can be used to position a droplet of ferrofluid to any desired location and steer it along any desired path within that domain – an example of precision control of a ferrofluid by magnets acting at a distance.
doi:10.1016/j.jmmm.2010.08.024
PMCID: PMC3014617  PMID: 21218157
Magnetic particles; magnetic carriers; nano-particles; ferrofluid; magnetic drug delivery; manipulation at a distance; control; feedback; electromagnets; dielectrophoresis
15.  Establishment of a New Human Pneumococcal Standard Reference Serum, 007sp ▿ 
Clinical and Vaccine Immunology : CVI  2011;18(10):1728-1736.
Lot 89SF has been the reference standard serum pool used in pneumococcal enzyme-linked immunosorbent assays (ELISAs) since 1990. In 2005, it was estimated that there remained between 2 and 5 years' supply of lot 89SF. Since lot 89SF was the reference standard used in the evaluation of the seven-valent pneumococcal conjugate vaccine Prevnar (PCV7), the link to clinical efficacy would be severed if stocks became completely depleted. Furthermore, demonstration of immune responses comparable to those elicited by PCV7 is a licensure approach used for new pneumococcal conjugate vaccines, so a replacement reference standard was required. A total of 278 volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II, and a unit of blood was obtained twice within 120 days following immunization. Plasma was prepared, pooled, and confirmed to be free from hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV. The pooled serum was poured at 6 ml per vial into 15,333 vials and lyophilized. Immunological bridging of 007sp to 89SF was used to establish equivalent reference values for 13 pneumococcal capsular serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) by five independent laboratories. Antibody concentrations in 007sp were established relative to the lot 89SF reference preparation using the WHO reference ELISA. Subsequently, 12 existing WHO calibration sera had concentrations reassigned for 13 pneumococcal serotypes using new serum 007sp as the reference, and these were compared to concentrations relative to the original reference serum. Agreement was excellent for the 12 WHO calibration sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantity of this new preparation is available such that, with judicious use, it should be available for at least 25 years.
doi:10.1128/CVI.05252-11
PMCID: PMC3187044  PMID: 21852547
16.  Endogenous insulin secretion in critically ill patients 
Critical Care  2012;16(Suppl 1):P168.
doi:10.1186/cc10775
PMCID: PMC3363586
17.  Menopausal symptoms within a Hispanic cohort: SWAN, the Study of Women’s Health Across the Nation 
Women's Health (London, England)  2009;5(2):127-133.
Introduction
Since the designation of people as Hispanic involves the amalgamation of a number of different cultures and languages, we sought to test the hypothesis that menopausal symptoms would differ among Hispanic women, based upon country of origin and degree of acculturation.
Methods
A total of 419 women, aged 42–52 years at baseline, were categorized as: Central American (CA, n = 29) or South American (SA, n = 106), Puerto Rican (PR, n = 56), Dominican (D, n = 42), Cuban (Cu, n = 44) and non-Hispanic Caucasian (n = 142). We assessed vasomotor symptoms, vaginal dryness and trouble in sleeping. Hispanics and non-Hispanic Caucasians were compared using the χ2 test, t test or non-parametric alternatives; ANOVA or Kruskal–Wallis testing examined differences among the five Hispanic sub-groups. Multivariable regression models used PR women as the reference group.
Results
Hispanic women were overall less educated, less acculturated (p < 0.001 for both) than non-Hispanic Caucasians and more of them reported vasomotor symptoms (34.1–72.4% vs. 38.3% among non-Hispanic Caucasians; p = 0.0293) and vaginal dryness (17.9–58.6% vs. 21.1% among non-Hispanic Caucasians, p = 0.0287). Among Hispanics, more CA women reported vasomotor symptoms than D, Cu, SA, or PR women (72.4% vs. 45.2%, 34.1%, 50.9%, and 51.8%, respectively). More CA (58.6%) and D women (38.1%) reported vaginal dryness than PR (17.9%), Cu (25.0%) and SA (31.4%) women. More PR and D women reported trouble in sleeping (66.1 and 64.3%, respectively) compared to CA (51.7%), Cu (36.4%), and SA (45.3%) women.
Conclusion
Symptoms associated with menopause among Hispanic women differed by country of origin but not acculturation. Central American women appear to be at greatest risk for both vasomotor symptoms and vaginal dryness.
doi:10.2217/17455057.5.2.127
PMCID: PMC3270699  PMID: 19245351
MENOPAUSE; VASOMOTOR SYMPTOMS; HISPANIC; HOT FLUSHES; VAGINAL DRYNESS
18.  Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression 
British Journal of Cancer  2011;104(3):464-468.
Background:
Oncogenic BRAF mutation had been considered to be a founder event in the formation of melanocytic tumours; however, we recently argued against this notion by showing marked polyclonality of BRAF mutations in acquired melanocytic nevi (Lin et al, J Natl Cancer Inst., 2009; 101:1423–7). Here, we tested whether similar heterogeneity of BRAF mutations exists in primary melanomas.
Methods:
We isolated and sequenced single melanoma cells from five primary melanoma tissues using antibodies against human high-molecular-weight melanoma-associated antigen. We also examined 10 primary melanomas by the sensitive Mutector assay detecting the BRAFV600E mutation, as well as by cloning and sequencing of separated alleles. Furthermore, we estimated the frequency of BRAF mutant alleles in paired samples of primary tumour and recurrence or metastasis in three patients.
Results:
Single-cell mutation analyses revealed that four of five primary melanomas contained both BRAF-wild-type and BRAF-mutant tumour cells. Tumour heterogeneity in terms of BRAF mutations was also shown in 8 of 10 primary melanomas. Selection of BRAF mutant alleles during progression was demonstrated in all the three patients.
Conclusion:
Acquisition of a BRAF mutation is not a founder event, but may be one of the multiple clonal events in melanoma development, which is selected for during the progression.
doi:10.1038/sj.bjc.6606072
PMCID: PMC3049568  PMID: 21224857
laser-capture microdissection; oncogene mutation; single-cell PCR; targeted therapy; V-raf murine sarcoma viral oncogene homologue B1
19.  Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response 
Molecular Psychiatry  2011;17(2):164-172.
Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pretreatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P = 0.007) and was directly correlated with depression ratings (P< 0.05) across all subjects. In the depressed group, individuals with relatively lower pretreatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P < 0.05 and P < 0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.
doi:10.1038/mp.2010.133
PMCID: PMC3130817  PMID: 21242992
antidepressant; cell aging; depression; leukocytes; telomeres; telomerase
20.  Menopausal symptoms within a Hispanic cohort: SWAN, the Study of Women’s Health Across the Nation 
Climacteric  2010;13(4):376-384.
Introduction
Since the designation of people as Hispanic involves the amalgamation of a number of different cultures and languages, we sought to test the hypothesis that menopausal symptoms would differ among Hispanic women, based upon country of origin and degree of acculturation.
Methods
A total of 419 women, aged 42–52 years at baseline, were categorized as: Central American (CA, n = 29) or South American (SA, n = 106), Puerto Rican (PR, n = 56), Dominican (D, n = 42), Cuban (Cu, n = 44) and non-Hispanic Caucasian (n = 142). We assessed vasomotor symptoms, vaginal dryness and trouble in sleeping. Hispanics and non-Hispanic Caucasians were compared using the χ2 test, t test or non-parametric alternatives; ANOVA or Kruskal–Wallis testing examined differences among the five Hispanic sub-groups. Multivariable regression models used PR women as the reference group.
Results
Hispanic women were overall less educated, less acculturated (p < 0.001 for both) than non-Hispanic Caucasians and more of them reported vasomotor symptoms (34.1–72.4% vs. 38.3% among non-Hispanic Caucasians; p = 0.0293) and vaginal dryness (17.9–58.6% vs. 21.1% among non-Hispanic Caucasians, p = 0.0287). Among Hispanics, more CA women reported vasomotor symptoms than D, Cu, SA, or PR women (72.4% vs. 45.2%, 34.1%, 50.9%, and 51.8%, respectively). More CA (58.6%) and D women (38.1%) reported vaginal dryness than PR (17.9%), Cu (25.0%) and SA (31.4%) women. More PR and D women reported trouble in sleeping (66.1 and 64.3%, respectively) compared to CA (51.7%), Cu (36.4%), and SA (45.3%) women.
Conclusion
Symptoms associated with menopause among Hispanic women differed by country of origin but not acculturation. Central American women appear to be at greatest risk for both vasomotor symptoms and vaginal dryness.
doi:10.3109/13697130903528272
PMCID: PMC3268678  PMID: 20136411
MENOPAUSE; VASOMOTOR SYMPTOMS; HISPANIC; HOT FLUSHES; VAGINAL DRYNESS
21.  Opsonophagocytic Activity Following a Reduced Dose 7-valent Pneumococcal Conjugate Vaccine Infant Primary Series and 23-valent Pneumococcal Polysaccharide Vaccine at 12 Months of Age 
Vaccine  2010;29(3):535-544.
Opsonophagocytic activity (OPA) was measured following reduced infant doses of 7-valent pneumococcal conjugate vaccine (PCV-7) with or without 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months, and subsequent re-exposure to a small dose of pneumococcal polysaccharide antigens (mPPS) at 17 months. Fijian infants were randomized to receive 0, 1, 2, or 3 PCV-7 doses. Half received PPV-23 at 12 months and all received mPPS at 17 months. OPA was performed on up to 14 serotypes. Three and 2 PCV-7 doses resulted in similar OPA for most PCV-7 serotypes up to 9 months and for half of the serotypes at 12 months. A single dose improved OPA compared with the unvaccinated group. PPV-23 significantly improved OPA for all serotypes tested but in general, was associated with diminished responses following re-challenge.
doi:10.1016/j.vaccine.2010.10.046
PMCID: PMC3011050  PMID: 21044669
pneumococcal vaccination; opsonophagocytic activity
22.  Regional differences in MRI detection of amyloid plaques in AD transgenic mouse brain 
NeuroImage  2010;54(1):113-122.
Our laboratory and others have reported the ability to detect individual Alzheimer’s disease (AD) amyloid plaques in transgenic mouse brain in vivo by magnetic resonance imaging (MRI). Since amyloid plaques contain iron, most MRI studies attempting to detect plaques in AD transgenic mouse brain have employed techniques that exploit the paramagnetic effect of iron and have had mixed results. In the present study, using five-way anatomic spatial co-registration of MR images with three different histological techniques, properties of amyloid plaques in AD transgenic mouse brain were revealed that may explain their variable visibility in gradient- and spin-echo MR images. The results demonstrate differences in the visibility of plaques in the cortex and hippocampus, compared to plaques in the thalamus, by the different MRI sequences. All plaques were equally detectable by T2SE, while only thalamic plaques were reliably detectable by T2*GE pulse sequences. Histology revealed that cortical/hippocampal plaques have low levels of iron while thalamic plaques have very high levels. However, the paramagnetic effect of iron does not appear to be the sole factor leading to the rapid decay of transverse magnetization (short T2) in cortical/hippocampal plaques. Accordingly, MRI methods that rely less on iron magnetic susceptibility effect may be more successful for eventual human AD plaque MR imaging, particularly since human AD plaques more closely resemble the cortical and hippocampal plaques of AD transgenic mice than thalamic plaques.
doi:10.1016/j.neuroimage.2010.08.033
PMCID: PMC2962679  PMID: 20728546
Alzheimer’s disease; magnetic resonance imaging; iron; thioflavine S; amyloid-β
23.  Interobserver reliability in the endoscopic diagnosis and grading of Barrett’s esophagus: an Asian multi-national study 
Endoscopy  2010;42(9):699-704.
Background and study aim
The establishment of precise and valid diagnostic criteria is the first step towards understanding the pathogenesis of Barrett’s esophagus in Asia. The present study determined the interobserver reliability in the endoscopic diagnosis and grading of Barrett’s esophagus among Asian endoscopists.
Patients and methods
Video clips of endoscopy in 21 patients with and without Barrett’s esophagus were used for training (n=3) and standardized diagnosis and grading (n=18) of Barrett’s esophagus by endoscopists from seven hospitals in different Asian regions/countries. Barrett’s esophagus, where present, was graded using the Prague C & M Criteria whereby the circumferential extent of Barrett’s segment (C value), maximum extent of Barrett’s segment (M value), location of the gastroesophageal junction, and location of the diaphragmatic hiatus were scored. The intraclass correlation coefficients (ICC) were calculated as a measure of interobserver reliability.
Results
A total of 34 endoscopists participated. The ICC values for the scores of C value, M value, location of the gastroesophageal junction, and location of the diaphragmatic hiatus were 0.92 (95% CI, 0.88–0.97), 0.94 (0.90–0.98), 0.86 (0.78–0.94), and 0.81 (0.71–0.92), respectively, indicating excellent interobserver reliability. The differences in region/country, experience of endoscopists, volume of participating center, or the primary practice type did not have significant effect on the reliability. The ICC values for recognition of Barrett’s esophagus with an extent ≥1 cm were 0.90 (0.80–1.00) and 0.92 (0.87–0.98) for the C and M values, respectively, whereas the corresponding ICC values for Barrett’s segment <1 cm were 0.18 (0.03–0.32) and 0.21 (0.00–0.51), respectively.
Conclusions
Despite the relatively uncommon occurrence of Barrett’s esophagus in Asia, endoscopists in our study exhibited excellent consistency in the endoscopic diagnosis and grading of Barrett’s esophagus using the Prague C & M Criteria. In view of the low interobserver reliability in recognizing Barrett’s esophagus segments of <1 cm, future studies in Asia should take this into account in their selection strategies as to recruit as homogeneous a population for study as possible.
doi:10.1055/s-0030-1255629
PMCID: PMC3000217  PMID: 20806154
24.  Can colorectal cancer be prevented or treated by oral hormone replacement therapy? 
Current molecular pharmacology  2009;2(3):285-292.
Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.
PMCID: PMC3151617  PMID: 20021465
25.  GCC signaling in colorectal cancer: Is colorectal cancer a paracrine deficiency syndrome? 
Drug news & perspectives  2009;22(6):313-318.
Summary
Guanylyl cyclase C (GCC) is the receptor expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin that coordinate mucosal homeostasis and its silencing contributes to intestinal transformation. It orchestrates proliferative and metabolic circuits by limiting the cell cycle and programming metabolic transitions central to regeneration along the crypt-villus axis. Mice deficient in GCC are more susceptible to colon cancer induced by germline mutations or carcinogens. Moreover, guanylin and uroguanylin are the most commonly lost gene products in colon cancer. The role of GCC as a tumor suppressor and the universal loss of its hormones in transformation suggest a paradigm in which colorectal cancer is a disease of paracrine hormone insufficiency. Indeed, GCC signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. These data suggest a pathophysiological hypothesis in which GCC is a tumor suppressor coordinating proliferative homeostasis whose silencing through hormone loss initiates transformation. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy employing GCC ligands.
doi:10.1358/dnp.2009.22.6.1395254
PMCID: PMC3136746  PMID: 19771320

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