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Recent research has indicated that the Phyllagathis (raphides) clade (Sonerileae, Melastomataceae) is only distantly related to the type of Phyllagathis and should be separated as a distinct genus. Phylogeny of this clade is here reconstructed with expanded taxon sampling. Four strongly supported subclades have been identified. The possible affinities of taxa that were not sampled in the analysis are discussed, based on morphological data. Perilimnastes is resurrected as the generic name of the Phyllagathis (raphides) clade. A generic description, colour figures, map of distribution, a list of included species and a key are provided for Perilimnastes . Fifteen new combinations are made plus the description of a new species. As interpreted here, Perilimnastes consists of twenty species and two varieties., Competing Interests: The authors have declared that no competing interests exist., (Ying Liu, Jin-Hong Dai, Qi-Yuan Zhuang, Chun-Yu Zou, Kai-Nan Ma.)

Previous studies showed that Trichinella spiralis galectin (Tsgal) facilitates larval invasion of intestinal epithelium cells (IECs). However, IEC proteins binding with Tsgal were not identified, and the mechanism by which Tsgal promotes larval invasion is not clear. Toll-like receptors (TLRs) are protein receptors responsible for recognition of pathogens. The aim of this study was to investigate whether recombinant Tsgal (rTsgal) binds to TLR-4, activates inflammatory pathway in gut epithelium and mediates T. spiralis invasion. Indirect immunofluorescence (IIF), GST pull-down and co-immunoprecipitation (Co-IP) assays confirmed specific binding between rTsgal and TLR-4 in Caco-2 cells. qPCR and Western blotting showed that binding of rTsgal with TLR-4 up-regulated the TLR-4 transcription and expression in Caco-2 cells, and activated p-NF-κB p65 and p-ERK1/2. Activation of inflammatory pathway TLR-4/MAPK-NF-κB by rTsgal up-regulated pro-inflammatory cytokines (IL-1β and IL-6) and down-regulated anti-inflammatory cytokine TGF-β in Caco-2 cells, and induced intestinal inflammation. TAK-242 (TLR-4 inhibitor) and PDTC (NF-κB inhibitor) significantly inhibited the activation of TLR-4 and MAPK-NF-κB pathway. Moreover, the two inhibitors also inhibited IL-1β and IL-6 expression, and increased TGF-β expression in Caco-2 cells. In T. spiralis infected mice, the two inhibitors also inhibited the activation of TLR-4/MAPK-NF-κB pathway, ameliorated intestinal inflammation, impeded larval invasion of gut mucosa and reduced intestinal adult burdens. The results showed that rTsgal binding to TLR-4 in gut epithelium activated MAPK-NF-κB signaling pathway, induced the expression of TLR-4 and pro-inflammatory cytokines, and mediated larval invasion. Tsgal might be regarded as a candidate molecular target of vaccine against T. spiralis enteral invasive stage., (© 2023. The Author(s).)

The aim of this study was to investigate the characteristics of a novel type C lectin from Trichinella spiralis (TsCTL) and its role in larval invasion of intestinal epithelial cells (IECs). TsCTL has a carbohydrate recognition domain (CRD) of C-type lectin. The full-length TsCTL cDNA sequence was cloned and expressed in Escherichia coli BL21. The results of qPCR, Western blotting and immunofluorescence assays (IFAs) showed that TsCTL was a surface and secretory protein that was highly expressed at the T. spiralis intestinal infective larva (IIL) stages and primarily located at the cuticle, stichosome and embryos of the parasite. rTsCTL could specifically bind with IECs, and the binding site was localized in the IEC nucleus and cytoplasm. The IFA results showed that natural TsCTL was secreted and bound to the enteral epithelium at the intestinal stage of T. spiralis infection. The rTsCTL had a haemagglutinating effect on murine erythrocytes, while mannose was able to inhibit the rTsCTL agglutinating effect for mouse erythrocytes. rTsCTL accelerated larval intrusion into the IECs, whereas anti-rTsCTL antibodies and mannose significantly impeded larval intrusion in a dose-dependent manner. The results indicated that TsCTL specifically binds to IECs and promotes larval invasion of intestinal epithelium, and it might be a potential target of vaccines against T. spiralis enteral stages., (© 2022. The Author(s).)

Objective: To compare the retentions of different designs of cobalt-chromium (Co-Cr), pure titanium (CP Ti), and titanium alloy (Ti-6Al-4V) removable partial denture (RPD) circumferential clasps manufactured by selective laser melting (SLM) and to analyze the stress distribution of these clasps during the removal from abutment teeth., Methods: Clasps with clasp arm size A (1.9 mm width/1.1 mm thickness at the body and 0.8-taper) or B (1.2 times A) and 0.25 mm or 0.50 mm undercut engagement were modeled on a prepared first premolar die, named as designs A1, A2, A3, and A4, respectively. The density and elastic modulus of SLM-built Co-Cr, CP Ti, and Ti-6Al-4V were measured and given to different groups of clasps. The density, elastic modulus, and Poisson ' s ratio of enamel were given to the die. The control group was the cast Co-Cr clasp with design A1, to which the density and elastic modulus of cast Co-Cr alloy were given. The Poisson's ratio of all metals was 0.33. The initial 5 N dislodging force was applied, and the maximum displacement of the clasp along the insertion path was computed. The load was reapplied with an increment of 5 N than in the last simulation until the clasp was completely dislodged. The retentive force range of different groups of clasps was obtained. The retentive forces of the SLM-built Co-Cr, CP Ti, and Ti-6Al-4V clasps with equivalent computed retentive force range to the control group were validated through the insertion/removal experiment. The von Mises stress distributions of these three groups of SLM-built clasps under 15 N loads were analyzed., Results: SLM-built Co-Cr, CP Ti, and Ti-6Al-4V clasps with designs B1 or B2, and Co-Cr clasps with design A2 had higher retentive forces than those of the control group. SLM-built CP Ti and Ti-6Al-4V clasps with design A1 had lower retentive forces than those of the control group. SLM-built Co-Cr clasp with design A1 and SLM-built CP Ti and Ti-6Al-4V clasps with design A2 had equivalent retentive forces to those of the control group. The insertion/removal experiment showed that the measured retentive forces of these three groups of SLM-built clasps were (21.57±5.41) N, (19.75±4.47) N, and (19.32±2.04) N, respectively. No statistically significant measured retentive force difference was found among these three groups of SLM-built clasps ( P >0.05). The maximum von Mises stress of these three groups of SLM-built clasps exceeded their responding yield strength except for the Ti-6Al-4V one., Conclusion: SLM-built Co-Cr circumferential clasps had higher retention than CP Ti and Ti-6Al-4V ones with the same clasp arm size and undercut engagement. The retention of SLM-built circumferential clasps could be adjusted by changing the undercut engagement and clasp arm size. If SLM-built circumferential clasps are used in clinical practice, the Ti-6Al-4V clasp with clasp arm size A and 0.50 mm undercut engagement is recommended considering the long-term use of RPD in the patient's mouth.

Cathepsin L is one member of cysteine protease superfamily and widely distributed in parasitic organisms, it plays the important roles in worm invasion, migration, nutrient intake, molting and immune evasion. The objective of this study was to investigate the biological characteristics of a novel cathepsin L from Trichinella spiralis (TsCL) and its role in larval invasion, development and reproduction. TsCL has a functional domain of C1 peptidase, which belongs to cathepsin L family. The complete TsCL sequence was cloned and expressed in Escherichia coli BL21. The rTsCL has good immunogenicity. RT-PCR and Western blotting analysis showed that TsCL was transcribed and expressed at different T. spiralis phases (e.g., muscle larvae, intestinal infectious larvae, adult worms and newborn larvae). Immunofluorescence test revealed that TsCL was principally localized in the cuticle, stichosome, midgut and female intrauterine embryos of the nematode. rTsCL has the capacity to specially bind with intestinal epithelial cells (IECs) and the binding sites was located in the cytoplasm. rTsCL promoted larval penetration into IEC, while anti-rTsCL antibodies inhibited the invasion. The silencing of TsCL gene by specific dsRNA significantly reduced the TsCL expression and enzyme activity, and also reduced larval invasive ability, development and female reproduction. The results showed that TsCL is an obligatory protease in T. spiralis lifecycle. TsCL participates in worm invasion, development and reproduction, and may be regarded as a potential candidate vaccine/drug target against T. spiralis infection., (Copyright © 2021. Published by Elsevier B.V.)

Trichinellosis is an important zoonotic parasitic disease worldwide and is principally caused by ingesting animal meat containing Trichinella infective larvae. Aspartyl aminopeptidase is an intracytoplasmic metalloproteinase that specifically hydrolyzes the N-terminus of polypeptides free of acidic amino acids (aspartic acid and glutamate), and plays an important role in the metabolism, growth and development of organisms. In this study, a novel T. spiralis aspartyl aminopeptidase (TsAAP) was cloned and expressed, and its biological properties and roles in worm growth and development were investigated. The results revealed that TsAAP transcription and expression in diverse T. spiralis stages were detected by RT-PCR and Western blotting, and primarily localized at cuticle, stichosome and intrauterine embryos of this nematode by immunofluorescence test. rTsAAP has the enzymatic activity of native AAP to hydrolyze the substrate H-Glu-pNA. There was a specific binding between rTsAAP and murine erythrocyte, and the binding site was localized in erythrocyte membrane proteins. Silencing of TsAAP gene by specific dsRNA significantly reduced the TsAAP expression, enzymatic activity, intestinal worm burdens and female fecundity. The results demonstrated that TsAAP participates in the growth, development and fecundity of T. spiralis and it might be a potential target molecule for anti-Trichinella vaccines.

Objective: To quantitatively evaluate the accuracy of multi-color and multi-hardness dental models printed by using the photopolymer jetting (PJ) technology, and to provide protocol for the clinical application. Methods: A maxillary partially edentulous (Kennedy class Ⅱ subclass 1) standard digital model obtained through scanning and processing was selected as reference data. Five monochromatic DLP (digital light processing) models with single hardness were printed by printer DLP-800d based on DLP technology (DLP group), and five multi-color and multi-hardness PJ models were printed by printer J300Plus based on PJ technology (PJ group). Scan the printed model and register the scanning data to the reference data in Geomagic Studio 2013 software. The three-dimensional (3D) deviations of the whole and each area, including residual dentition, abutments adjacent to the edentulous area, gingiva, gingiva in the distal-extended edentulous area, gingiva in other edentulous areas, gingiva supporting the removable partial denture (RPD), were calculated and represented by the root mean square error (RMS) value. The smaller the RMS value was, the higher the trueness of printing was. The scanning data of the five models in the same group were registered in pairs to calculate the 3D deviation. The smaller the RMS value was, the higher the precision of printing was. The threshold of clinical acceptability was 200 μm. Statistical analysis was performed to compare the difference of trueness and precision between the two groups. Results: The overall trueness of the DLP group [57.70 (2.10) μm] was significantly better than that of the PJ group [71.00 (7.70) μm]. The overall precision of the DLP group [15.20 (5.05) μm] was significantly better than that of the PJ group [37.55 (15.55) μm]. The overall trueness and precision of both groups were within the clinically acceptable range. Conclusions: The domestic PJ printer used in this study can print multi-color and multi-hardness dental models with good trueness and precision, which can provide integrated 3D printing technology support for realizing the simulation of regional hardness differentiation between soft and hard tissues of dental models.

Computer aided design, numerically controlled milling, additive manufacturing and other digital technologies have been widely used in clinical practice of prosthodontics. The application of these technologies not only changed the design and manufacturing workflow of removable partial denture (RPD), but also improved the production efficiency of dentures, and changed the design and manufacturing concept of dentures. A large number of researches on computer aided design and computer aided manufacturing (CAD/CAM) of RPD have emerged in recent years, including researches on the properties of selective laser melting metal powder and other new dental materials, the innovative design of retainers, connectors, artificial teeth and other denture components, high precision manufacturing of the RPD framework, denture base and artificial teeth, quantitative laboratory evaluations of the accuracy, adaption and mechanical properties of RPD with new structures and made of new materials, clinical evaluations of RPD and others. This paper introduces these recent developments in CAD/CAM of RPD.

Our study aimed to explore the molecular mechanisms and novel target genes of neuropathic pain via bioinformatics analysis. Gene expression profiling of GSE30691 which was consisted of sciatic nerve lesion and sham control samples at 3 days, 7 days, 21 days, and 40 days (D3, D7, D21, and D40) after injury were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified for all the four time points. Overlapped DEGs for all the four time points were used for functional and weighted co-expression modular analysis. Afterwards, protein-protein interaction (PPI) network was analyzed by MCODE (Molecular Complex Detection) and BiNGO. Pathway network was constructed according to the enriched pathways of PPI network and relevant pathways selected from the Comparative Toxicogenomics Database. There were 355 overlapped DEGs for all the four time points. Two co-expression modules had significant positive correlations with disease. The top ten hub DEGs in the PPI network were Fos, Tp53, Csk, Map2k2, Stat3, Ccl2, Pxn, Tgfb1, Notch1, and Prkacb. Fos, Dusp1, Tp53, Tgfb1, and Map2k2 participated in MAPK signaling pathway, while Csk participated in chemokine signaling pathway. The expressions of Fos, Tp53, Csk, and Map2k2 were significantly increased at D3. Tp53, Csk, and Map2k2 continued overexpressing until at D7, and an elevated tendency in Csk expression could be observed until at D21. The expression of Fos reached up to the highest at D40. Fos, Tp53, Csk, and Map2k2 might be the potential biomarkers related to neuropathic pain.

Purpose: To examine demographic and clinical factors associated with glaucomatous peripapillary retinoschisis (PPRS) and assess its association with glaucoma progression., Methods: Using a case control study design and longitudinal data from a cohort of 166 subjects with a diagnosis of glaucoma or glaucoma suspect, we compared functional, structural, clinical, and demographic characteristics between PPRS cases and controls., Results: The frequency of PPRS was 6.0% (12 eyes from 10/166 subjects) with two eyes having PPRS in different sectors for a total of 15 retinoschisis events. There were no significant differences (P > 0.05) in age, sex, visual acuity, central corneal thickness, intraocular pressure, or presence of vitreous adhesion between PPRS and controls. However, eyes with PPRS tended to have a higher cup-to-disc ratio (P = 0.06), thinner RNFL (P = 0.02), and worse visual field mean deviation (MD, P = 0.06) than controls. The rate of RNFL thinning was faster in PPRS (average: -2.8%/year; range: -7.4% to 0.0%/year) than controls (-1.3%/year; range: -4.4% to 0.6%/year; P = 0.021). The rate of visual field MD change was faster in PPRS (-0.49 dB/year; range: -2.0 to 0.9 dB/year) than controls (-0.06 dB/year; range: -0.8 to 0.3 dB/year; P = 0.030). OCT scans showed hyperreflective structures spanning the PPRS whose morphology and spacing (50 ± 7 μm) are consistent with Müller glia, causing signal attenuation casting "shadows" onto distal retina., Conclusions: This is the first report showing that glaucomatous PPRS is associated with a faster overall rate of RNFL thinning and visual field deterioration and to specifically identify OCT signs of Müller cell involvement.

Purpose: To detect macular perfusion defects in glaucoma using projection-resolved optical coherence tomography (OCT) angiography., Design: Prospective observation study., Participants: A total of 30 perimetric glaucoma and 30 age-matched normal participants were included., Methods: One eye of each participant was imaged using 6×6-mm macular OCT angiography (OCTA) scan pattern by 70-kHz 840-nm spectral-domain OCT. Flow signal was calculated by the split-spectrum amplitude-decorrelation angiography algorithm. A projection-resolved OCTA (PR-OCTA) algorithm was used to remove flow projection artifacts. Four en face OCTA slabs were analyzed: the superficial vascular complex (SVC), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and all-plexus retina (SVC + ICP + DCP). The vessel density (VD), defined as the percentage area occupied by flow pixels, was calculated from en face OCTA. A novel algorithm was used to adjust the vessel density to compensate for local variations in OCT signal strength., Main Outcome Measures: Macular retinal VD, ganglion cell complex (GCC) thickness, and visual field (VF) sensitivity., Results: Focal capillary dropout could be visualized in the SVC, but not the ICP and DVP, in glaucomatous eyes. In the glaucoma group, the SVC and all-plexus retinal VD (mean ± standard deviation: 47.2%±7.1% and 73.5%±6.6%) were lower than in the normal group (60.5%±4.0% and 83.2%±4.2%, both P < 0.001, t test). The ICP and DCP VD were not significantly lower in the glaucoma group. Among the overall macular VD parameters, the SVC VD had the best diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AROC). The accuracy was even better when the worse hemisphere (inferior or superior) was used, achieving an AROC of 0.983 and a sensitivity of 96.7% at a specificity of 95%. Among the glaucoma participants, the hemispheric SVC VD values were highly correlated with the corresponding GCC thickness and VF sensitivity (P < 0.003). The reflectance compensation step in VD calculation significantly improved repeatability, normal population variation, and correlation with VF and GCC thickness., Conclusions: On the basis of PR-OCTA, glaucoma preferentially affects perfusion in the SVC in the macula more than the deeper plexuses. Reflectance-compensated SVC VD measurement by PR-OCTA detected glaucoma with high accuracy and could be useful in the clinical evaluation of glaucoma., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The authors report a new variant of idiopathic polypoidal choroidal vasculopathy (IPCV) in middle-aged Haitian men characterized by extramacular polypoidal lesions and bilateral extensive pigmentary alterations in the posterior pole in an annular wreath-like pattern surrounding the optic nerve and macular area. Two patients were seen at Massachusetts Eye and Ear Infirmary and one at Boston University Medical Center between 2010 and 2015. All three patients were middle-aged Haitian men who exhibited bilateral features of IPCV, including subretinal hemorrhages and serosanguinous pigment epithelial detachments. Indocyanine green angiography revealed extramacular polypoidal lesions located mostly along the major vascular arcades. Extensive pigmentary alterations were evident in the posterior pole surrounding the macula and optic nerve in an annular wreath-like pattern. These cases further expand the clinical spectrum of IPCV., (Copyright 2016, SLACK Incorporated.)

Cryopreserved amniotic membrane (AM) transplantation is an emerging technique that is becoming the gold standard for the management of acute Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN). We describe a novel surgical technique utilizing a single, large sheet of AM (5 x 10 cm) and a custom-made forniceal ring, which facilitates AM placement. Our technique is easy to use and minimizes suturing and manipulation of ocular tissues, resulting in decreased operative time. This technique may be applied in the management of multiple ocular surface disease processes, including chemical or thermal burns, severe ocular graft versus host disease (GVHD), and other autoimmune diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To describe bone mineral density (BMD) at the hip and spine and prevalence of low bone mass and osteoporosis in Navajo men and women across age, gender, and body mass index (BMI) compared with non-Hispanic (NH) Whites from NHANES (2005-2008)., Methods: Cross-sectional dual energy x-ray absorptiometry measurements at the hip and spine in 1,097 participants from the Education and Research Towards Health study., Results: Bone mineral density was lower among younger Navajo than NH-Whites at lower BMI, and in overweight, younger men at lumbar spine and total hip. Spine BMD was lower in Navajo women, across BMI. Prevalence of low bone mass and osteoporosis in Navajo was higher than NH-Whites, particularly among women., Conclusions: Further research is needed to understand if lower BMD among younger Navajo signals a risk for future fracture, and fracture risk relative to BMD, given the challenges in health care access and fracture morbidity among minorities.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders., (Copyright © 2015 by the American Society of Nephrology.)

Stellate ganglion blockade (SGB) protects patients from focal cerebral ischemic injury, and transection of the cervical sympathetic trunk (TCST) in a rat model can mimic SGB in humans. The purpose of this study was to investigate the mechanisms underlying the neuroprotective effects of TCST on neuronal damage in the hippocampus in a rat model of middle cerebral artery occlusion (MCAO) in an attempt to elucidate the neuroprotective effects of SGB. The modified method of Zea Longa was used to establish the permanent MCAO model. Male Wistar rats were randomly divided into three groups: sham-operated group, MCAO group, and TCST group. The animals in TCST group were sacrificed 48 h after TCST which was performed after the establishment of the MCAO model. Proteins were extracted from the ipsilateral hippocampus and analyzed by two-dimensional difference gel electrophoresis (2D-DIGE) and peptide mass fingerprinting (PMF). The levels of N-ethylmaleimide-sensitive factor (NSF) were measured as well. The results showed that 11 types of proteins were identified by 2D-DIGE. The expressions of eight proteins were changed both in the sham-operated and TCST groups, and the expressions of the other three proteins were changed in all three groups. Moreover, the expression of NSF was higher in the TCST group than in the MCAO group but lower in the MCAO group than in sham-operated group. The ratio of NSF expression between the MCAO group and shamoperated group was -1.37 (P<0.05), whereas that between the TCST group and MCAO group was 1.35 (P<0.05). Our results imply that TCST increases the expression of NSF in the hippocampus of adult rats with focal cerebral ischemia, which may contribute to the protection of the injured brain. Our study provides a theoretical basis for the therapeutic application of SGB to patients with permanent cerebral ischemia.

We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Autism spectrum disorder (ASD) is reported to be increased in neurofibromatosis type 1 (NF1), but it's unknown if ASD screening tools are sensitive and specific for NF1. This study compared the rate at which children with NF1 screen-positive for two ASD screening tools [Modified Checklist for Autism in Toddlers (M-CHAT) and Childhood Autism Spectrum Test (CAST)] to the screen-positive rate of the general population. A retrospective cross-sectional observational design to investigate the association between children with NF1 and at risk status for ASD was used. Medical records of children between 16 months and 11 years of age seen in an NF Clinic were reviewed for an ASD screening questionnaire. There were no statistically significant differences in the screen-positive rate for ASD in NF1 compared to published controls, but mean CAST scores were higher in NF1., (© 2014 Wiley Periodicals, Inc.)

Objective: Little is known about prevalence of osteoporosis risk factors among American Indians and Alaska Natives (AIAN)., Methods: We included AIAN people (n=8,039) enrolled in the Education and Research Towards Health (EARTH) Study. Prevalence ratios were used to determine cross-sectional associations of risk factors with self-reported bone fractures., Results: There is a high prevalence of multiple risk factors for osteoporosis in AIAN, although the factors that are associated with past fracture vary by gender and geographical area. In general, women who reported a fracture reported more risk behaviors, more than two medical conditions, and low physical activity. Men with higher BMI were less likely to report a fracture. Smoking history was associated with fracture for both genders, though not significantly in all sub-groups., Conclusion: We prevent a high prevalence of risk factors for osteoporosis for AIAN. Future research for osteoporosis risk reduction and prevention in AIAN people is indicated.

Purpose: Sequence variations in complement proteins are associated with age-related macular degeneration (AMD). The terminal pathway of complement results in the formation of the membrane attack complex (MAC) on the cell surface, resulting in their lysis. MAC has been documented on the retinal pigment epithelium (RPE), choroidal blood vessels, and drusen of AMD eyes. Here the investigators test the hypothesis that increasing the expression of decay accelerating factor (CD55) on RPE cells may result in reduced MAC-mediated damage., Methods: The investigators constructed a recombinant adenovirus expressing human CD55 (AdCAGCD55). Mouse hepatocytes were infected with AdCAGCD55 or negative controls and subsequently incubated with normal human serum (NHS). Cell lysis and MAC formation were measured by FACS and immunocytochemistry, respectively. Adult mice were injected in the subretinal space with either AdCAGCD55 or controls; after 1 week of CD55 transgene expression, the eyecups were excised, challenged with NHS, and quantified for human MAC formation., Results: Control-infected or uninfected mouse hepatocytes lyse at a rate of 93% and 94%, respectively. AdCAGCD55- infected mouse hepatocytes lyse at a rate of 29%. Lysis was confirmed to occur in the presence of MAC, which was reduced by 67% when cells were infected by AdCAGCD55. Mice injected in the subretinal space with AdCAGCD55 exhibited a 55.7% reduction in MAC formation on the RPE relative to controls., Conclusions: Adenovirus-mediated delivery of hCD55 to murine RPE confers protection against human complement. The investigators propose that the expression of hCD55 on RPE cells warrants investigation as a potential therapy for AMD.

Objective: We assessed reliability and relative validity of a self-administered computer-assisted dietary history questionnaire (DHQ) for use in a prospective study of diet, lifestyle, and chronic disease in American Indians in the Dakotas and Southwestern US and Alaska Native people., Design: Reliability was assessed by one-month test-retest of the dietary history questionnaire. Validity was assessed by comparison of the weighted average of up to 12 monthly 24-hour recalls collected prospectively and a dietary history questionnaire completed in the 13th month., Participants: Participants were recruited at the baseline visit of the Education and Research Toward Health Study in Alaska, the Northern Plains and the Dakotas., Results: Reliability (Pearson correlation) of the DHQ ranged from r = 0.43 for vitamin A density to r = 0.90 for energy intake. The association of nutrient and food estimates assessed by 24-hour recalls and the DHQ completed at the end of the year reflected no bias towards recent intake. Macronutrients expressed as density (nutrients per 1000 calories) did appear to be valid (r = 0.50-0.71) as did several micronutrients (range r = .22 to 0.59), fiber (r = 0.51), and servings of red meat (r = 0.67). However, the DHQ overestimated intake and gross amounts of nutrients were not strongly associated with the weighted average of the 24-hour recalls., Conclusions: The DHQ developed for estimation of dietary intake in American Indians and Native people in Alaska is reliable. Estimates of nutrient density appeared to have acceptable relative validity for use in epidemiologic studies.

Purpose: Little is known about obesity-related health issues among American Indian and Alaska Native (AIAN) populations., Approach: A large cohort of AIAN people was assembled to evaluate factors associated with health., Setting: The study was conducted in Alaska and on the Navajo Nation., Participants: A total of 11,293 AIAN people were included., Methods: We present data for body mass index (BMI, kg/m2) and waist circumference (cm) to evaluate obesity-related health factors., Results: Overall, 32.4% of the population were overweight (BMI 25-29.9 kg/m2), 47.1% were obese (BMI > or = 30 kg/m2), and 21.4% were very obese (BMI, > or = 35 kg/m2). A waist circumference greater than 102 cm for men and greater than 88 cm for women was observed for 41.7% of men and 78.3% of women. Obese people were more likely to perceive their health as fair/poor than nonobese participants (prevalence ratio [PR], 1.91; 95% CI, 1.71-2.14). Participants younger than 30 years were three times more likely to perceive their health as being fair or poor when their BMI results were 35 or greater compared with those whose BMI results were less than 25 kg/m2. A larger BMI was associated with having multiple medical conditions, fewer hours of vigorous activity, and more hours of television watching., Conclusions: Given the high rates of obesity in AIAN populations and the association of obesity with other health conditions, it is important to reduce obesity among AIAN people.

Background: Family history of diseases among American Indian and Alaska Native (AIAN) people may influence health., Methods: We examine the prevalence of family health history among a cohort of AIAN people (n= 10,374) enrolled in the Education and Research Towards Health (EARTH) Study. We evaluate the association between having a positive family history and health behaviors to determine if those reporting a family history were more likely to report lifestyles that put them at risk of developing these health conditions., Results: Among participants, 17.7% reported not knowing their family history and 23.5% preferred not to answer the family history component of the questionnaire. Eight percent of participants reported a family history of colorectal cancer, 7.9% a family history of breast cancer, 25.8% a family history of heart attack, and 46.7% a family history of diabetes. Obesity, physical activity, cholesterol, and perceived health were associated with family history., Conclusions: Individuals with a family history of diseases may have lifestyles that influence their disease risk.

Purpose: The purpose of this study was to examine the prevalence rates for cervical, breast, and colorectal cancer screening among American Indian and Alaska Native people living in Alaska and in the Southwest US, and to investigate predictive factors associated with receiving each of the cancer screening tests., Methods: We used the Education and Research Towards Health (EARTH) Study to measure self-reported cancer screening prevalence rates among 11,358 study participants enrolled in 2004-2007. We used prevalence odds ratios to examine demographic, lifestyle and medical factors associated with receiving age- and sex-appropriate cancer screening tests., Results: The prevalence rates of all the screening tests were higher in Alaska than in the Southwest. Pap test in the past 3 years was reported by 75.1% of women in Alaska and 64.6% of women in the Southwest. Mammography in the past 2 years was reported by 64.6% of women aged 40 years and older in Alaska and 44.0% of those in the Southwest. Colonoscopy or sigmoidoscopy in the past 5 years was reported by 41.1% of study participants aged 50 years and older in Alaska and by 11.7% of those in the Southwest US. Multivariate analysis found that location (Alaska versus the Southwest), higher educational status, income and the presence of one or more chronic medical condition predicted each of the three screening tests. Additional predictors of Pap test were age (women aged 25-39 years more likely to be screened than older or younger women), marital status (ever married more likely to be screened), and language spoken at home (speakers of American Indian Alaska Native language only less likely to be screened). Additional predictors of mammography were age (women aged 50 years and older were more likely to be screened than those aged 40-49 years), positive family history of breast cancer, use of smokeless tobacco (never users more likely to be screened), and urban/rural residency (urban residents more likely to be screened). Additional predictors of colonoscopy/sigmoidoscopy were age (men and women aged 60 years and older slightly more likely to be screened than those aged 50-59 years), family history of any cancer, family history of colorectal cancer, former smoking, language spoken at home (speakers of American Indian Alaska Native language less likely to be screened), and urban/rural residence (urban residents more likely to be screened)., Conclusion: Programs to improve screening among American Indian and Alaska Native people should include efforts to reach individuals of lower socioeconomic status and who do not have regular contact with the medical care system. Special attention should be made to identify and provide needed services to those who live in rural areas, and to those living in the Southwest US.

Background and Aims: Variant genotypes of uridine diphosphate glucuronsyltransferase isoenzyme 1A6 (UGT1A6) associated with decreased metabolic activity have been associated with an enhanced protective effect of aspirin on the development of colorectal adenomas. However, interactions between UGT1A6 variants or variants of another enzyme that metabolizes nonsteroidal anti-inflammatory drugs (NSAIDs), cytochrome P4502C9 (CYP2C9), and NSAIDs in the prevention of colorectal cancer have not been studied extensively., Methods: UGT1A6 and CYP2C9 genotypes were determined in 2295 individuals with colorectal cancer and 2903 controls. Interactions between these genotypes, aspirin or ibuprofen use, and colorectal cancer risk were determined., Results: Variant CYP2C9 genotypes enhanced the protective effect of ibuprofen on the prevention of colorectal cancer, and a dose-response relationship with respect to increasing numbers of variant alleles was seen (P interaction = .02). CYP2C9 variants were more effective in individuals with wild-type rather than variant UGT1A6 (P interaction < .007). Variant CYP2C9 genotypes showed no interaction with aspirin usage, and variant UGT1A6 genotypes showed no interaction with either NSAID with respect to colorectal cancer protection., Conclusions: In this study, the major effect seen was an enhancement by slower-metabolizing CYP2C9 variants of the chemopreventive activity of ibuprofen against colorectal cancer.

The transcriptional activity of the vitamin D receptor (VDR) gene is regulated, at least in part, by the androgen receptor (AR) gene. We evaluate how the number of polyglutamine (CAG) repeats of the AR gene influence colorectal cancer in conjunction with vitamin D, sunshine exposure and VDR. Studies of colon (1,580 cases and 1,968 controls) and rectal (797 cases and 1,016 controls) cancer were used. Vitamin D intake and average hours of sunshine exposure interacted with AR genotype in men. Men with low vitamin D intake or low levels of sunshine exposure who had 23+ CAG repeats of the AR gene had the greatest risk of colon cancer. ORs for men with 23 or more CAG repeats of the AR gene and in the lowest tertile of vitamin D intake or sunshine exposure were 1.71 (95% CI 1.14, 2.56) and 1.51 (95% CI 1.09, 2.09). Men with high levels of sunshine exposure were at reduced risk of developing rectal cancer if they had 23 or more CAG repeats (OR 0.62 95% CI 0.39, 0.97) than if they had fewer than 23 CAG repeats. The FF genotype of the Fok1 VDR gene was associated with reduced risk of colon cancer among women with any allele of 23+ CAG repeats (OR 0.62 95% CI 0.44, 0.88), whereas men with the LL/bb VDR genotypes were at reduced risk of rectal cancer if they also had 23+ CAG repeats (OR 0.71 95% CI 0.48, 1.05) relative to men with fewer than 23 CAG repeats of the AR gene. These data provide support for the role of vitamin D and sunshine exposure in the etiology of colorectal cancer and suggest that AR gene may modulate the association., (Copyright 2006 Wiley-Liss, Inc.)

We hypothesize that the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12Ala (P12A) PPARgamma polymorphism. We also evaluated interactions between the PPARgamma gene and other insulin-related genes and use of aspirin and non-steroidal anti-inflammatory drug use. Data were available from 1,577 cases of colon cancer that were matched to 1,971 population-based controls and 794 cases of rectal cancer that were matched to 1,001 population-based controls. Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the -200A>C IGFBP3 polymorphism. The odds ratio (OR) between the PA/AA genotypes and proximal tumors was 0.83 (95% CI: 0.69-1.01); for distal tumors was 1.00 (95% CI: 0.83-1.21); and for rectal tumors was 1.04 (95% CI: 0.86-1.25). Evaluation of specific types of tumor mutations showed that colon cancer cases with the PA or AA genotypes were less likely to have p53 tumor mutations (OR 0.78; 95% CI: 0.62-0.99), specifically transition mutations (OR 0.74; 95% CI: 0.56-0.97). Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARgamma genotype (OR 0.68; 95% CI: 0.47-0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARgamma genotype. Those who did not take ibuprofen-type drugs and had the PA or AA genotypes were at a significantly greater risk of rectal cancer (OR 2.11; 95% CI: 1.52-2.92; p interaction 0.03) than people with the PP genotype regardless of ibuprofen-type drug use. There was a significant interaction between the -200A>C IGFBP3 polymorphism and the Pro12Ala PPARgamma polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARgamma genotype. For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARgamma polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARgamma and the BB/SS VDR genotypes. These data suggest that PPARgamma may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms.

Risk factors for colon cancer may not only influence the overall risk of cancer but also the risk for specific types of mutations. We evaluated the effect of polymorphisms in four insulin-related genes (G972R in IRS1, G1057D in IRS2, a CA repeat in IGFI and an A/C polymorphism at -202 of IGFBP3) on the risk of microsatellite instability and KRAS2 and TP53 mutations in a population-based set of 1788 cases of colon cancer and 1981 controls. The GR/RR IRS1 genotypes were associated with an increased risk of colon cancers with the KRAS2 G12D mutation (OR 2.3, 95% CI 1.5, 3.5 versus controls, OR 1.7, 95% CI 1.1, 2.6 versus KRAS2 wild type), the "no 192" IGFI genotype increased the risk of the KRAS2 G13D mutation (OR 2.3, 95% CI 1.2, 4.2 versus controls, OR 2.1, 95% CI 1.1, 4.0 versus wild type), and the DD IRS2 genotype increased the risk of the G12V KRAS2 mutation (OR 1.8, 95% CI 0.9, 3.5 versus controls, OR 2.0, 95% CI 1.0, 4.0 versus wild type). Polymorphisms in IRS1 and IGF1 were also associated with an approximately two-fold increased risk of specific TP53 mutations relative to controls without cancer. We conclude that polymorphisms in some insulin-related genes are associated with an increased risk of colon cancer with specific KRAS2 and TP53 mutations, implying a link between these genetic changes and specific mutational pathways in carcinogenesis.

Modifiable risk factors in colorectal cancer etiology and their interactions with genetic susceptibility are of particular interest. Functional vitamin D receptor (VDR) gene polymorphisms may influence carcinogenesis through modification of cell growth, protection from oxidative stress, cell-cell matrix effects, or insulin and insulin-like growth factor pathways. We investigated interactions between foods (dairy products, red and processed meat, and whole and refined grains) and dietary patterns (sucrose-to-fiber ratio and glycemic index) associated with insulin resistance with the FokI polymorphism of the VDR gene and colon and rectal cancer risk. Data (diet, anthropometrics, and lifestyle) and DNA came from case-control studies of colon (1,698 cases and 1,861 controls) and rectal cancer (752 cases and 960 controls) in northern California, Utah, and the Twin Cities metropolitan area, Minnesota (colon cancer study only). Unconditional logistic regression models were adjusted for smoking, race, sex, age, body mass index, physical activity, energy intake, dietary fiber, and calcium. The lowest colon cancer risk was observed with the Ff/ff FokI genotypes and a low sucrose-to-fiber ratio. Rectal cancer risk decreased with greater consumption of dairy products and increased with red or processed meat consumption and the FF genotype. Modifiable dietary risk factors may be differentially important among individuals by VDR genotype and may act through the insulin pathway to affect colon cancer risk and through fat, calcium, or other means to influence rectal cancer risk.

Estrogen and androgens are thought to be involved in the etiology of colorectal cancer. We evaluate genetic variants of the estrogen receptor genes (ERalpha and ERbeta) and the androgen receptor gene (AR). We use data from two large case-control studies of colon (n = 1,580 cases and 1,968 controls) and rectal (n = 797 cases and 1,016 controls) cancer. We evaluated the 351A >G XbaI polymorphism of ERalpha, the 1,082 G >A and CA repeat polymorphisms of ERbeta, and the CAG repeat of AR. Having two 25 or more CA repeats in ERbeta was associated with an increased relative risk of colon cancer in women [odds ratio (OR), 2.13; 95% confidence interval (95% CI), 1.24-3.64] but not in men (P(interaction) relative excess risk from interaction < 0.01; multiplicative = 0.03). Increasing number of AR CAG repeats was directly associated with colon cancer among men (OR, 1.28; 95% CI, 1.06-1.54), but not women (OR, 0.83; 95% CI, 0.68-1.02); the interaction P value for AR gene x sex was <0.01. Taking hormone replacement therapy (HRT) was associated with a reduced risk of colon cancer in the presence of the R allele of the ERbeta gene, whereas an R allele was associated with increased risk among postmenopausal women who did not take HRT. Postmenopausal women not using HRT who had > or =25 CA repeats of the ERbeta gene had over a 6-fold increased risk of colon cancer (OR, 6.71; 95% CI, 2.89-15.6). Our results suggest that the ERbeta gene is more important than ERalpha in the etiology of colorectal cancer.

Apolipoprotein E (apoE) plays a major role in the metabolism of bile acids, cholesterol and triglycerides, and has recently been proposed as being involved in the carcinogenic process. Given the potential role of bile acids in colorectal cancer etiology, it is reasonable that colorectal cancer risk might be modified by apoE genotype. We used data collected from a case-control study of colon cancer (n=1556 cases and 1948 controls) and rectal cancer (n=777 cases and 988 controls). The absence of an e3 apoE allele significantly increased the risk of colon cancer (OR=1.37 95% CI 1.00-1.87), particularly among those diagnosed when older than 64 years (OR=1.88 95% CI 1.17-3.04; P interaction between age and apoE genotype equal to 0.05). A significant three-way interaction was detected for family history of colorectal cancer, age at diagnosis and apoE genotype (P = 0.05), in those diagnosed when older, not having an e3 allele and having a significantly increased risk of colon cancer with family history of colorectal cancer (OR=3.93 95% CI 1.23-12.6). This was compared with the risk associated with family history of colorectal cancer among those diagnosed when older, with an e3 allele of 1.61 (95% CI 1.17-2.23) or those diagnosed when younger without an e3 allele (OR=2.40 95% CI 0.56-10.3). Among those diagnosed when older than 64 years, associations of BMI and prudent diet with colon cancer were stronger among individuals without an e3 allele, although the P for interaction was not significant. We did not detect any significant associations between apoE genotype and rectal cancer, survival after diagnosis with colorectal cancer, stage of disease at diagnosis or type of tumor mutation. These findings suggest those apoE genotypes that do not include the e3 allele, the same genotypes that are associated with increased risk of coronary heart disease, may influence development of colon cancer among those who are older at diagnosis.

Energy balance, or the ability to maintain body weight by balancing energy intake with energy expenditure, appears to be important in the etiology of colon cancer. One possible mechanism whereby energy balance may be associated with colorectal cancer is through its association with insulin. In our study, we evaluate the interaction between polymorphisms in 4 genes thought to be involved in insulin-related functions and components of energy balance with risk of colorectal cancer. Data from 2 population-based case-control studies of colon and rectal cancer conducted in Utah and Northern California were used to evaluate associations between body mass index (BMI), physical activity, energy intake and sucrose-to-fiber ratio and a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the G972R polymorphism of the IRS1 gene and the G1057D polymorphism of the IRS2 gene. A total of 1,346 incident colon cancer cases and 1,544 population-based controls and 952 incident rectal cancer cases and 1,205 controls were available for analysis. Inconsistent associations were identified between BMI, physical activity, energy intake and insulin-related genes. The 192/192 IGF1 genotype was associated with significant reduction in colon cancer risk among those with high physical activity (odds ratio [OR] 0.57; 95% confidence interval [CI] 0.39-0.83; p interaction 0.01). Although there was no significant pattern of interaction between either BMI or energy intake and polymorphisms assessed, specific sources of energy did appear to be more related to colon cancer risk in the presence of specific IRS2 and IGF1 genotypes. A high sucrose-to-fiber ratio increased risk of colon cancer in men who had the IRS2 DD genotype and among men who did not have the 192/192 IGF1 genotype. In summary, these data support the importance of components of energy balance in risk of colorectal cancer. Obesity, physical activity and energy intake appear to alter risk of colorectal cancer; however, the risk appears to be minimally influenced by genetic variants evaluated., ((c) 2005 Wiley-Liss, Inc.)

The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of a group of ligand-activated nuclear receptors responsible for regulation of glucose, lipid homeostasis, cell differentiation, and apoptosis. The 12 proline-to-alanine (Pro12Ala) substitution polymorphism in PPARgamma produces proteins with lower activity. Variation in PPARgamma expression in the bowel and the role of dietary fatty acids as ligands for PPARgamma led investigation of whether the associations of diet with colon and rectal cancer risk were modified by PPARgamma genotype. Data (diet, lifestyle, and DNA) came from case-control studies of colon (1,577 cases and 1,971 controls) and rectal cancer (794 cases and 1,001 controls) conducted in Northern California, Utah, and the Twin City, Minnesota Metropolitan area (colon cancer study only). Unconditional logistic regression models were adjusted for age at selection, body mass index, physical activity, energy intake, dietary fiber, and calcium. We found no significant interactions between macronutrient (fat, protein, and carbohydrate) and colorectal cancer. High lutein intake [odds ratio (OR), 0.63; 95% confidence interval (95% CI), 0.44-0.89], low refined grain intake (OR, 0.70; 95% CI, 0.53-0.94), or a high prudent diet score (OR, 0.66; 95% CI, 0.49-0.89) and PA/AA PPARgamma genotype were associated with reduced colon cancer risk. Risk of rectal cancer was increased among those with the PA/AA PPARgamma genotype and a high mutagen index (OR, 1.63; 95% CI, 1.12, 2.36). Its unclear whether the alterations in risk in those with the less active phenotype for PPARgamma is related to activation of PPARgamma by nutrients or dietary patterns acting as ligands or direct influences of these nutrients on colon and rectal cancer processes that are important with lower PPARgamma activity.

We hypothesized that the risk of colorectal cancer associated with meat preparation methods producing heterocyclic amines or polycyclic aromatic hydrocarbons is modified by the CYP1A1 genotype alone or in combination with the GSTM1 genotype or the NAT2 imputed phenotype. A total of 952 rectal cancer cases and 1205 controls (between September 1997 and February 2002) and 1346 colon cancer cases and 1544 controls (between October 1991 and September 1994) from Utah and Northern California were recruited from a population-based case-control study. Detailed interviews ascertained lifestyle, medical history, and diet and we extracted DNA from whole blood. Risk of colorectal cancer decreased among men with the CYP1A1 *2 any variant genotype and the lowest intake of poultry and men and women with high use of white meat drippings. Risk increased among men with the CYP1A1 *1 (no variant) allele and high white meat mutagen index, but decreased among those with the CYP1A1 *2 genotype. Risk increased with a high white meat mutagen index among women with the CYP1A1 *2 genotype and the GSTM1 present genotype. Risk of colorectal cancer decreased with the CYP1A1 *2 genotype, the NAT2 slow phenotype, and the use of white meat or its drippings. The association of risk for colorectal cancer and selected red and white meat mutagen indices and the use of white meat drippings, or fried white meat variables was more evident within select combinations of the CYP1A1 genotype and either the GSTM1 genotype or NAT2 than with the CYP1A1 alone. Genetic susceptibility may modify the associations of some meat or meat preparation factors with the risk of colorectal cancer.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been hypothesized as being involved in colorectal cancer given its role in adipocyte development and insulin resistance. In this study we evaluated the association between the Pro12Ala (P12A) PPARgamma polymorphism and body mass index (BMI), waist-to-hip ratio (WHR), physical activity level, and energy intake and risk of colorectal cancer using data from a population-based, case-control study of colon cancer (1,577 cases and 1,971 controls) and rectal cancer (794 cases and 1,001 controls). We further evaluated how the P12A PPARgamma polymorphism is associated with obesity and fat pattern in the control population. The odd ratio for PPARgamma PA or AA genotype relative to the PP genotype for colon cancer was 0.9 (95% confidence interval, CI=0.8-1.0) and for rectal cancer was 1.2 (95% CI=1.0-1.5) adjusting for race, age, and sex. P12A PPARgamma did not significantly interact with BMI, WHR, energy intake, and energy expenditure to alter risk of colon or rectal cancer. Furthermore, the P12A PPARgamma polymorphism was not associated with obesity or WHR in the control population; it did not interact with energy intake or energy expenditure to alter risk of obesity or large WHR. These data do not support the hypothesis that the P12A PPARgamma polymorphism is associated with colon or rectal cancer through regulation of energy balance.

Components of energy balance are important elements associated with colorectal cancer risk. In this study we examine the association between VDR genotypes, BMI, physical activity, and energy intake and risk of colorectal cancer. Data from a population-based case-control study of colon (1174 cases and 1174 controls) and rectal (785 cases and 1000 controls) cancer was used to evaluate the associations. The Bsm1, polyA, and Fok1 VDR polymorphisms were evaluated. For colon cancer, those who are obese were at greater risk of colon cancer if they had the SS or BB (OR = 3.50; 95% CI = 1.75-7.03; p interaction 0.03) or ff (OR = 2.62; 95% CI = 1.15-5.99; p interaction 0.12/) VDR genotypes. On the other hand, those who were least physically active were at greater risk of colon cancer if they had the ff VDR genotype (OR = 3.46; 95% CI = 1.58-7.58; p interaction 0.05). The association between energy intake and colon cancer appears to be driven more by energy intake than Bsm1 or polyA VDR genotypes, although there was a significant interaction between the Fok1 VDR polymorphism and energy intake and risk of both colon and rectal cancer (p interaction 0.01 for colon and 0.04 for rectal). These data suggest a relationship between VDR genotype and factors related to energy balance in modifying colorectal cancer risk.

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n = 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3' untranslated region poly-A length polymorphism (designated S for short and L for long). The SS genotype reduced risk of colorectal cancer for men (odds ratio [OR] = 0.71; 95% confidence interval [CI] = 0.55-0.92). High levels of calcium intake reduced risk of rectal cancer in women (OR = 0.39; 95% CI = 0.24-0.64) but were not associated with rectal cancer in men (OR = 1.02; 95% CI = 0.66-1.56). Similar reduced rectal cancer risk among women was observed at high levels of vitamin D (OR = 0.52; 95% CI = 0.32-0.85) and low-fat dairy products (OR = 0.61; 95% CI = 0.39-0.94). High levels of sunshine exposure reduced risk of rectal cancer among those diagnosed when <60 years of age (OR = 0.62, 95% CI = 0.42-0.93). Examination of calcium in conjunction with VDR genotype showed that a significant 40% reduction in risk of rectal cancer was observed for the SS or BB VDR genotypes when calcium intake was low (p interaction = 0.01 for calcium interaction). For colon cancer, high levels of dietary intake of calcium, vitamin D, and low-fat dairy products reduced risk of cancer for the SS or BB VDR genotypes, although the p for interaction was not statistically significant. These data support previous observations that high levels of calcium and vitamin D reduce risk of rectal cancer and provide support for a weak protective effect for the SS and BB VDR genotypes. The risk associated with VDR genotype seems to depend upon the level of dietary calcium and vitamin D and tumor site., (Copyright 2004 Wiley-Liss, Inc.)

Introduction: Insulin, insulin-like growth factor (IGF), and IGF binding protein (IGFBP) are involved in cell growth and proliferation and are thought to be important in the etiology of colorectal cancer. We hypothesize that genetic polymorphisms of insulin receptor substrates (IRS-1 and IRS-2), IGF-I, and IGFBP-3 alter colorectal cancer risk because of their roles in the insulin-related signaling pathway., Methods: Data from a population-based incident case-control study of 1,346 colon cancer cases and 1,544 population-based controls and 952 rectal cancer cases and 1,205 controls were used to evaluate associations. Genetic polymorphisms of four genes were investigated: an IGF1 CA repeat, the IGFBP3 -202 A > C, the IRS1 G972R, and the IRS2 G1057D., Results: Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9]. The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9). Neither the IGF1 nor the IGFBP3 variants was associated independently with colon cancer, but there was an association when examined with IRS1. Individuals with an IRS1 R allele and IGF1 non-192 allele were at a 2-fold increased risk of colon cancer (95% CI 1.2-4.4). There was a 70% (95% CI 1.02-2.8) increased risk of colon cancer with an IRS1 R allele and the IGFBP3 AC or CC genotype. The IRS2 GD genotype reduced risk of colon cancer, except among those with an IRS1 R allele. No significant associations were seen in analyses of main effects or interactions of these variants and rectal cancer risk., Conclusions: Both IRS1 and IRS2 variants were associated with colon cancer risk independently. Associations were slightly stronger when polymorphisms in multiple genes were evaluated in conjunction with other genes rather than individually. These data suggest that the insulin-related pathway may be important in the etiology of colon cancer but not rectal cancer.

Introduction: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce risk of colorectal cancer. Although inhibition of cyclooxygenase (COX)-2 is generally thought to be the relevant mechanism, aspirin-like drugs apparently are involved in other pathways and mechanisms. We explore the associations between aspirin/NSAIDs, the insulin-related pathway, and the risk of colorectal cancer., Methods: Genetic polymorphisms of five genes identified as being involved in an insulin-related pathway were genotyped using data collected in a case-control study of 1346 incident colon cancer cases and 1544 population-based controls and 952 incident rectal cancer cases and 1205 controls. Genotypes assessed were the 3' untranslated region poly(A) and the intron 8 BsmI polymorphisms of the VDR gene, a CA repeat polymorphism of the IGF1 gene, the A/C polymorphism at nucleotide -202 of the IGFBP3, the Gly972Arg polymorphism of the IRS1 gene, and the Gly1057Asp polymorphism of the IRS2 gene., Results: Use of aspirin and NSAIDs was associated with a decreased risk of colorectal cancer, with slightly greater protection from NSAIDs than aspirin for rectal cancer. We observed a significant interaction between IRS1 genotype and aspirin/NSAIDs use and risk of colorectal cancer. Relative to the GR/RR IRS1 genotype, a protective effect from the GG IRS1 genotype was seen in those who did not use NSAIDs; use of NSAIDs was protective for all genotypes. These associations were especially strong for those diagnosed prior to age 65 (P interaction = 0.0006). We also observed a significant interaction between aspirin/NSAIDs use and the VDR gene. Having the SS or BB VDR genotypes reduced risk of colorectal cancer among non-aspirin/NSAID users; however, aspirin/NSAIDs reduced risk for all VDR genotypes., Conclusions: These data support the protective effect of aspirin and NSAIDs on colorectal cancer risk. In addition, the observed interactions for aspirin/NSAIDs and IRS1 and VDR genotypes suggest that mechanisms other than COX-2 inhibition may be contributing to the protective effect of aspirin and NSAIDs on colorectal cancer risk.

Meat consumption, particularly of red and processed meat, is one of the most thoroughly studied dietary factors in relation to colon cancer. However, it is not clear whether meat, red meat, heterocyclic amines (HCA), or polycyclic aromatic hydrocarbons (PAH) are associated with the risk for rectal cancer. Rectal cancer cases (n = 952) and controls (n = 1205) from Utah and Northern California were recruited from a population-based case-control study between September 1997 and February 2002. Detailed in-person interviews regarding lifestyle, medical history, and diet were conducted. DNA was extracted from peripheral lymphocytes obtained from whole-blood samples, and glutathione S-transferase (GST)M1 enzyme and N-acetyl transferase (NAT)2 enzyme genotypes were assessed. Although energy and cholesterol intakes were higher among cases than controls, adjustment for confounders accounted for the differences. Increased consumption of well-done red meat [odds ratio (OR) 1.33 95% CI 0.98, 1.79] was associated with an (P = 0.04) increase in risk for rectal cancer among men. The mutagen index, calculated on the bases of reported amount, doneness, and method of cooking meat, was also positively but not significantly (P = 0.24) associated with risk of rectal cancer for men (OR 1.37 95% CI 0.98, 1.92). NAT2-imputed phenotype and GSTM1 did not consistently modify rectal cancer risk associated with meat intake. These data suggest that mutagens such as HCA that form when meat is cooked may be culpable substances in rectal cancer risk, not red meat itself.

Little information is available about how fluid intake from beverages and sources of fluid intake influence risk of rectal cancer. We examined these associations with risk of incident rectal cancer in a population-based case-control study of 952 cases and 1,205 controls living in northern California and Utah. We also determined if intake of fiber (soluble and insoluble), physical activity, and nonsteroidal anti-inflammatory medications (NSAIDs) or aspirin modified the associations between fluid intake and rectal cancer. We identified a modest inverse association of water intake (odds ratio, OR = 0.70; 95% confidence interval, CI = 0.48, 1.02) and total fluid intake (high vs. low OR = 0.70; 95% CI = 0.46, 1.06) with risk of rectal cancer in men and a positive association with juice among women (high vs. low OR = 1.56; 95% CI = 1.00, 2.41). Risk of rectal cancer increased nonsignificantly among men with beer consumption, among women with high white wine use, and among men and women with high long-term alcohol use. NSAIDs modified the association of alcohol consumption with rectal cancer: 1) risk associated with beer increased among men who did not take NSAIDs and had a high beer intake (OR = 1.60; 95% CI = 1.08, 2.39) and 2) risk associated with long-term alcohol intake increased in a linear fashion in women who did not use NSAIDs (OR = 1.98; 95% CI = 1.15, 3.40). Risk of rectal cancer increased among estrogen-negative women if they consumed any beer or white wine but decreased among estrogen-positive women with beer. In men, low intake of water and low insoluble fiber intake were associated with increased risk of rectal cancer beyond that of either factor alone (OR = 1.82; 95% CI = 1.11, 3.00). The interactions of fiber with water intake suggest that bowel motility may be the mechanism responsible for modification of rectal cancer risk for water. Associations of alcohol to risk for rectal cancer may be related to cellular hyperproliferation and may be modified by NSAID use.

Introduction: Sex-specific differences in observed incidence rates, tumor subsite, and diet and lifestyle associations with colon cancer have been observed. We evaluate sex-specific associations with p53 mutations in colon cancer to add to understanding of these differences. Data from a large population-based incident case-control study of colon cancer were used to evaluate age and gender associations with p53 mutations. To obtain a better understanding of gender-specific associations, we evaluated the role of estrogen as a mediator of risk. For these analyses, women were classified as estrogen positive or negative, based on menopausal status and use of hormone replacement therapy (HRT)., Results: There was a significant interaction between age and sex and risk of an acquired p53 mutation compared with p53 Wt. Among men, there was an increase in p53 mutations with age, whereas among women the opposite was observed. Associations with parity, oral contraceptive use, and total ovulatory months were not associated with p53 mutations. However, recent use of HRT reduced risk of all tumors, as did being estrogen positive. Women who were estrogen positive (either premenopausal or recent users of HRT) were at a significantly increased risk of an acquired p53 mutation if they consumed a diet with a high sugar index (odds ratio = 2.94; 95% confidence interval = 1.47-5.89); similar increases in risk of p53 mutations were not observed for men or women who were estrogen negative., Conclusions: Although sex-specific associations were detected for acquired p53 mutations, they do not indicate a unique role of estrogens in the mutation of p53. These data are consistent with a role for estrogen in altering susceptibility to diet and lifestyle factors possibly via an insulin-related mechanism.

Numerous properties suggest that antioxidants and carotenoids may be valuable chemopreventive agents. A population-based case-control study of 952 rectal cancer cases and 1,205 controls from Northern California and Utah was conducted between September 1997 and February 2002. Detailed diet history, medical history, and lifestyle factors interviews were conducted. Dietary antioxidants were not associated with rectal cancer risk in men. For women, relative to the highest level of intake, low intake of dietary lycopene (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.0, 2.8) or vitamin E (OR = 2.2, 95% CI: 1.1, 4.3) was associated with an increased risk of rectal cancer. Alpha-, beta-, and gamma-tocopherol were associated with an approximate twofold increased risk of rectal cancer in women. Associations were stronger for women aged > or = 60 years for vitamin E and tocopherols (alpha-tocopherol OR = 3.6, 95% CI: 1.4, 9.4; gamma-tocopherol OR = 5.3, 95% CI: 2.1, 13.2; delta-tocopherol OR = 1.9, 95% CI: 0.9, 4.0), except for beta-tocopherol, for which risk increased twofold for all women. Associations differed by estrogen status for beta-carotene, lycopene, and vitamin E. These results suggest that vitamin E and lycopene may modestly reduce the risk of rectal cancer in women.

Some studies have reported that p53 mutations or certain types of p53 mutation are associated with poor prognosis in colon cancer, while other studies have failed to show such a relationship. None of these previous studies was population-based. We therefore evaluated the prognostic significance of p53 mutations in a large, population-based study of 1,464 individuals with colon cancer from Utah and California. Mutations in exons 5-8 were detected by SSCP analysis, followed by sequencing of aberrant bands. p53 mutations were identified in colon cancers from 665 of 1,464 (45.4%) individuals. p53 mutations were significantly more common in distal tumors (p < 0.01), tumors of relatively high stage (p = 0.04), tumors without MSI (p < 0.01) and tumors without Ki-ras mutations (p < 0.01). In a univariate analysis, tumors with p53 mutations were associated with a significantly worse 5-year survival than those with wild-type p53 (53.4% vs. 58.8%, p = 0.04); significantly worse prognosis also was seen with missense mutations, transitions, transversions, mutations affecting the structure of the p53 molecule, mutations within the beta-sandwich motif and mutations in proximal tumors. In multivariate analyses, however, the only significant predictors of poor prognosis were G245 hot spot mutations (HRR = 2.16, 95% CI 1.06-4.40) and p53 mutations in proximal tumors (HRR = 1.34, 95% CI 1.07-1.63). We conclude that overall p53 mutational status is not an independent predictor of poor prognosis in colon cancer. However, specific classes of mutations, namely, the G245 hot spot mutation and mutations in proximal tumors, are related to significantly worse survival even after adjusting for age and stage., (Copyright 2002 Wiley-Liss, Inc.)

Some previous studies have reported an improved prognosis in sporadic colon cancers with microsatellite instability, whereas others have not. In addition, relatively few of those reporting an improved prognosis controlled for tumor stage or were population-based. Therefore, we evaluated the relationship between microsatellite instability and prognosis, tumor stage, and other clinical variables in a population-based study of 1026 individuals. Microsatellite instability was determined by the noncoding mononucleotide repeat BAT-26 and the coding mononucleotide repeat in transforming growth factor-beta receptor type II. Significant relationships were seen between microsatellite instability and proximal tumor location, female gender, young and old age at diagnosis, poor histological differentiation, and low tumor stage (P < 0.01). There was a significant relationship between microsatellite instability and improved prognosis, even after adjusting for stage, with a reduction in the risk of death attributable to colon cancer of approximately 60%. Most of this risk reduction occurred in individuals with American Joint Committee on Cancer stage III tumors, although transforming growth factor-beta receptor type II mutations were associated with a significant reduction in colon cancer death in tumors with distant metastases. We conclude that microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.

Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. Other than relatively rare mutations in mismatch repair genes, the causes of MSI are not generally known. The purpose of this study was to determine if dietary intake of nutrients previously reported as being associated with colon cancer relate specifically to the MSI disease pathway. Data from a population-based case-control study of adenocarcinoma of the colon were used to evaluate associations between dietary intake and MSI. Participants were between 30 and 79 years of age at time of diagnosis and included both men and women. Dietary intake data were obtained from a computerized diet history questionnaire. MSI was evaluated in several ways: by a panel of 10 tetranucleotide repeats, and by 2 mononucleotide repeats, BAT-26 and TGFbetaRII. A total of 1,510 cases had valid study data and tumor DNA on which we were able to obtain MSI status. Cases with and without MSI were compared with dietary data reported by 2,410 population-based controls to determine dietary associations that may be different for these 2 subsets of cases. We compared dietary intake for cases with and without MSI to further determine associations that are specific to the MSI disease pathway. When comparing MSI+ to MSI- tumors we observed that long-term alcohol consumption, especially intake of liquor, increased the probability of having a tumor with MSI [odds ratio (OR) for MSI+ vs. MSI- tumors for alcohol 1.6, 95% confidence interval (CI) 1.0-2.5; OR for liquor 1.6, 95% CI 1.1-2.4]. The likelihood of having MSI in the tumor from the combined effects of high alcohol consumption and smoking cigarettes showed a 70% excess in risk from the additive model. There were some suggestions that high intakes of refined grain might also be associated with MSI+ tumors, although associations were less consistent. Risk estimates for most other dietary factors did not differ substantially by MSI status. Data from this large population-based case-control study of colon cancer indicate that alcohol consumption, especially consumption of liquor, may increase the odds of an MSI+ tumor. Most other dietary factors do not appear operate exclusively in the MSI+ disease pathway., (Copyright 2001 Wiley-Liss, Inc.)

There are sex differences in the occurrence of microsatellite instability (MSI) in colon tumors. Taken together with the epidemiological evidence that hormone replacement therapy (HRT) and, less consistently, parity, are inversely associated with colon cancer, it has been hypothesized that estrogens are associated with MSI. The purpose of this study was to evaluate sex-specific differences in the prevalence of MSI in colon tumors and to determine whether reproductive history and hormonal exposures are associated with MSI. Using data from a population-based case-control study of 1836 cases with MSI data and 2410 population-based controls, we evaluated sex, reproductive factors, and hormone exposure in relation to the presence or absence of MSI in tumors. MSI was evaluated by a panel of 10 tetranucleotide repeats, the noncoding mononucleotide repeat BAT-26, and the coding mononucleotide repeat in transforming growth factor beta receptor type II (TGFbetaRII). Exposure data on reproduction, hormone use, obesity, and physical activity were obtained from an interviewer-administered questionnaire. Women were less likely then men to have MSI+ tumors at a young age and more likely to have unstable tumors at an older age; we observed a significant interaction (P < 0.01) between age, sex, and MSI. Evaluation of reproductive factors showed that women who had ever been pregnant had half the risk of MSI+ tumors compared with women who had never been pregnant. In complementary fashion, total ovulatory months were associated with an increased risk of MSI+ tumors [odds ratio (OR), 2.1; 95% confidence interval (CI), 1.1-4.0 comparing MSI+ versus MSI- tumors]. Age at first and last pregnancy did not influence the association. The observed associations were strongest among women <60 years of age at the time of diagnosis. Having used oral contraceptives was associated with a lower risk of MSI+ tumors (OR, 0.7; 95% CI, 0.4-1.2); recent users of HRT were at a reduced risk of MSI+ tumors (OR, 0.8; 95% CI, 0.5-1.4); and women who were former HRT users were at an increased risk of MSI+ tumors (OR, 1.8; 95% CI, 1.1-3.0). Obesity and lack of physical activity were associated with an elevated risk of both MSI+ (OR, 1.7; 95% CI, 0.7-3.3) and MSI- (OR, 2.2; 95% CI, 1.7-3.) tumors in men, but only with MSI- (OR, 1.5; 95% CI, 1.1-2.2) tumors in women. The excess of MSI+ tumors in women is explained by the excess of MSI+ tumors at older ages. Our data suggest that estrogen exposure in women protects against MSI, whereas the lack of estrogen in older women increases risk of instability. HRT in these older women may, again, reduce the risk of unstable tumors. A model for the way in which estrogens (endogenous, exogenous, and obesity-associated) modify the risk of MSI+ tumors is proposed.

Trans-fatty acids have been hypothesized to be carcinogenic, although there are limited data in humans testing this hypothesis. In this study, we examine the association between trans-fatty acids and colon cancer using data from a case (n = 1,993)-control (n = 2,410) study conducted in Utah, Northern California, and Minnesota. Dietary data were collected using a detailed diet history questionnaire, and nutrient values were generated from the Nutrition Coordinating Center nutrient database. After adjustment for other variables, including age at diagnosis, body size, physical activity, aspirin and/or nonsteroidal anti-inflammatory drug (referred to collectively as NSAIDs) use, energy intake, and dietary fiber and calcium, we found a weak association in women [odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.0] but not in men (OR = 1.2, 95% CI = 0.9-1.7); no increased risk was observed for the cis form of the fatty acids. For men and women, slightly stronger associations were observed in those > or = 67 years of age (OR = 1.4, 95% CI = 0.9-2.1 for men; OR = 1.6, 95% CI = 1.0-2.4 for women). Those who did not use NSAIDs were at a 50% greater risk of developing colon cancer when they consumed high levels of trans-fatty acids. Women who were estrogen negative, i.e., postmenopausal not taking hormone replace therapy, had a twofold increase in risk from high levels of trans-fatty acids in the diet, while women who were estrogen positive did not experience an increased risk of colon cancer, regardless of level of trans-fatty acids consumed. We believe that these data have important public health implications. It seems prudent to avoid consuming partially hydrogenated fats, since no increased risk was observed for the cis form of fatty acids, while suggestions of increased risk from trans-fatty acids exist for subsets of the population.