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Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention.We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB).Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, PAn endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

Purpose\ud \ud There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.\ud \ud Methods\ud \ud Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.\ud \ud Results\ud \ud Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.\ud \ud Conclusion\ud \ud This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Objective To describe and explore the current literature on the rare genetic condition of 46,XX SRY-negative males. In addition, we propose comprehensive clinical guidelines in the management of this condition to aid fertility clinicians in their management of affected individuals. Design Case report with expert consensus–derived clinical management guidance. Setting Fertility outpatient clinic at a tertiary referral center. Patient(s) A 40-year-old male found to have 46,XX disorder of sex development (DSD) on routine fertility screening. Intervention(s) A review of the literature, expert consultation, and formulation of comprehensive clinical guidance. Main Outcome Measure(s) We report an interesting and rare case of a phenotypical male with the karyotype 46,XX DSD without an SRY region. There is limited literature exploring this condition, and its etiology remains poorly understood. There is currently no clinical guidance available for fertility clinicians to follow when treating this condition. Result(s) A male phenotype with a 46 karyotype without the sex-defining region of the Y chromosome. Conclusion(s) A multidisciplinary approach should be adopted in the management of 46,XX individuals. All patients with azoospermia must be karyotyped. Sperm donation remains the only fertility treatment available. The 46,XX patients need lifelong followup led by an endocrinologist with regular imaging of the gonads, bone density measurements, baseline blood tests, and T supplementation. Psychological support is a key part of a holistic approach.

We investigate simultaneous lamellar contraction and the stress-strain response in styrene-ethylene propylene (SEP) lamellar diblock copolymer melts under shear. Lamellar contraction was found in predominately parallel lamellae in three SEP copolymers during steady shear. The amount of contraction strongly depends on the molecular weight of the block copolymers as well as the rate of deformation. These molecular weight and shear rate dependences are discussed in terms of chain distortions and entanglements in the interpenetration zones of the block copolymer lamellae. For three molecular weights and three shear rates, we report a unifying correlation between lamellar contraction and applied shear stress, indicating a strong dependence of the molecular-scale chain distortion and the macroscopic strength of deformation (stress).

The sol−gel transition, or gelation, in a polymer network-forming system is defined as the critical point in the polymerization at which an infinite macromolecule is formed. There are many studies in the literature concerning the exact and accurate determination of the gel point and its interpretation in terms of the critical conversions of reactant functional groups. However, these have mainly involved step-growth polymerizations with few studies of chain-growth polymerizations such as that described in this study. Chemorheological studies on a cationically polymerized epoxy network-forming system are used to determine accurate gel times and critical conversions, which are interpreted in terms of classical branching and chemical bond percolation models for nonlinear polymerizations. Rheological studies during the polymerization of a trifunctional epoxide monomer, using BF3 as the Lewis acid initiator, yielded a gel conversion of 0.17 ± 0.02 and a power law dependence for the development of shear modulus,...

Nineteen oxybutylene/oxyethylene/oxybutylene triblock copolymers [Bn/2EmBn/2, E = oxyethylene, OCH2CH2; B = oxybutylene, OCH2CH(CH2CH3)] were prepared and characterized. Twelve of the copolymers microphase-separated in the melt. Investigation of this microphase-separation behavior using small-angle X-ray scattering (SAXS) yielded values of the domain spacing (d-spacings) in the ordered phases and of the temperature of the order−disorder transition (TODT). In several cases the ordered phase structure was deduced from a combination of 1D and 2D SAXS and rheology. Values of TODT for the triblock copolymers were ca. 100 °C lower than those for EmBn diblock copolymers of identical composition and chain length but 30 °C higher if compared with diblock copolymers of half the triblock length. Values of the d-spacings indicated that the triblock copolymers were 10% more stretched than corresponding diblock copolymers. Determination of the Flory−Huggins parameter (χ) for the diblock and triblock systems gave identi...

To determine if postharvest treatments of 1-methylcyclopropene (1-MCP) retard the senescence of highbush blueberries (Vaccinium corymbosum L.) removed from storage, `Burlington' (early) and `Coville' (late) fruit were harvested from four experimental sites and treated for 24 hours at 20 °C with 0 (control), 25 (low), 100 (medium), or 400 (high) nL·L-1 of 1-MCP. All fruit were then stored in a controlled atmosphere of 10-15 kPa O2 and 10 kPa CO2 at -1 to 1 °C for 4, 8, and 12 weeks, followed by a 20 °C shelf-life of up to 20 days. During the shelf-life period immediately after harvest and those following each storage removal, percent marketable fruit (PMF) were calculated daily as: [fruit in good condition]/[total berry number] × 100. Changes in PMF were not affected by 1-MCP treatment; hence, we conclude that 1-MCP at rates up to 400 nL·L-1 does not alter the shelf-life quality of the highbush blueberry cultivars tested.

The major metabolites of the carcinogen dibenz[a,j]acridine formed in rodent liver microsomal preparations were trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine (DBAJAC-3,4-DHD) and dibenz[a,j]acridine 5,6-oxide (DBAJAC 5,6-oxide) [Gill et al. (1987) Carcinogenesis 8, 425-431]. The enantiomers of DBAJAC-3,4-DHD were prepared from the separable diastereoisomeric esters with (+)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxyl ic acid (HCA). The absolute configuration of trans-3(R),4(R)-dihydroxy-1,2,3,4-tetrahydrodibenz[a,j]acridine was assigned by conversion to the bis[p-(dimethylamino)benzoate] and examination of the exciton coupling in its circular dichroic (CD) spectrum. The 3(R),4(R)-tetrahydrodiol was converted to DBAJAC-3(R),4(R)-DHD. The enantiomers of DBAJAC 5,6-oxide were partially resolved by chiral stationary-phase chromatography, and subsequent methoxide attack afforded two enantiomerically enriched isomeric ethers from each fraction. The structures of the two ethers from each enantiomer were determined, and from their 1H NMR spin-spin coupling between the H5 and H6 signals and the CD spectra of the ethers, the absolute configuration of the ethers, and hence the 5,6-oxides, was determined. The enantiomeric composition of the 3,4-dihydrodiol and 5,6-oxide formed as microsomal metabolites of rat liver preparations was 69% 3R,4R and 81% 5R,6S, respectively. When rats were pretreated with 3-methylcholanthrene (MC), these percentages were 70% and 5%, indicating a reversed stereochemical preference for oxide formation in the MC-induced preparation. Results are also presented for phenobarbitone-induced rat liver and mouse liver preparations.

Blood levels of three aryldihydro-s-triazines in rats were followed: 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-phenyl-s-triazine (I), the prototype of the series; 4,6-diamino-1-(3,4-dichlorophenyl)-1,2-dihydro-2,2-dimethyl-s-triazine (II); and N-(m-tolyl)-p-(4,6-diamino-1,2-dihydro-2,2-dimethyl-s-triazin-1-yl)hydrocinnamide (III). The blood profiles obtained provide substantial evidence that III, but not II, was precipitated in the peritoneal cavity where it was injected. Precipitation after intraperitoneal injection may explain why III and similar triazines with long nonpolar chains have been reported to be more active against intraperitoneal Walker 256 tumor than is II, even though the latter compound is a far more potent inhibitor of Walker 256 dihydrofolate reductase and of tumor cell cultures in vitro. Precipitation in the peritoneal cavity also may be involved in the difficulty of obtaining the toxicity-free antineoplastic activity expected from certain aryldihydrotriazines selectively inhibiting neoplastic dihydrofolate reductase.

Methylglucamine is a commonly used cation in radiocontrast media. The present study sheds light on its fate in the rat. When administered intraperitoneally, 93% of the compound was excreted unchanged in the urine in 24 hr. When administered orally, about 15% of the dose was found in the urine, about 40% in the faeces and 20% in expired air in 24 hr. When administered orally to rats whose gut flora had been depleted by treatment with neomycin sulphate, 19% was excreted in the urine, 69% in the faeces and 3% in expired air in 72 hr. This indicated that the gut flora played a role in the degradation of the compound and its eventual loss as expired carbon dioxide.

The metabolism and excretion of the fat-soluble bisazo dyes Sudan III and Sudan IV have been studied in the rat. Limited absorption of Sudan III from the gastro-intestinal tract after oral dosage, slow back diffusion of both dyes across the intestinal wall after intraperitoneal injection and absence of either dye in urine or bile after intraperitoneal (Sudans III and IV) or oral (Sudan III) administration have been demonstrated. Studies with [ 3 H]Sudan III showed that this dye is probably cleaved and hydroxylated in the body to yield p -aminophenol after parenteral dosage. Inconsistencies between these results and those of earlier workers are discussed in relation to the composition of the pure and commercial dyes used.

The reduction of the azo food colouring, tartrazine, has been studied in whole cells and cell-free preparations of Proteus vulgaris isolated from rat-intestinal contents. The ability of whole cells to reduce this colouring is dependent upon age and nutritional status. Old starved cells are most efficient. This effect is related to cell permeability. A soluble FMN-flavoprotein, which is NADPH dependent, has been isolated as a crude enzyme and found capable of reducing tartrazine. Some reaction conditions are reported. The role of intestinal flora in mammalian detoxification mechanisms and the enzymatic mechanism of bacterial reduction of azo colourings are discussed.

The metabolism of diphenylamine has been studied in the rat, rabbit and man. The major metabolites in these species were 4-hydroxydiphenylamine and 4,4′-dihydroxydiphenylamine. The rabbit in addition excreted small amounts of 2-hydroxydiphenylamine and unchanged amine. The O-sulphate and O-glucuronide (as the tri-O-acetylmethyl ester) conjugates of 4-hydroxydiphenylamine were isolated from rabbit urine. Quantitative studies in rats showed that [14C]-diphenylamine is excreted in both urine and bile and is rapidly eliminated from the body.

Single oral doses of tartrazine and 1-(4-sulphophenyl)-3-methyl-4-(4-sulphophenylazo)-5-pyrazolone(SMSP), each labelled with 'SS in the 1-(4-sulphophenyl) group, were largely excreted in the faeces of rats. Small amounts of radioactivity excreted in the urine of animals given either compound were found to be sulphanilic acid and 4-sulphophenylhydrazine. 4-[ 35 S]Sulphophenylhydrazine was also metabolized to sulphanilic acid after oral dosage but was metabolized much less readily after intravenous dosage. SMSP, labelled with 3- 14 C, showed an excretion pattern similar to that of the 3 IS-labelled material but some 14 CO 2 was exhaled. The metabolism of these compounds after oral dosage appears to be mediated by the gut flora.

Infrared and N.M.R. spectroscopy were used to assign structures to 3,4,4-trimethyl-5-pyrazolone, 3,4-dimethyl-5-pyrazolone, 3-methyl-5-pyrazolone, and their 1-phenyl analogues, 1-(p-sulphophenyl)-3-methyl-5-pyrazolone and the corresponding 3-carbethoxy and carboxy derivatives, together with 1-phenyl-3-methyl-4-phenylazo-5-pyrazolone, the corresponding 3-carboxylic acid and its methyl ester, and 1-phenyl-3-carbethoxy-4-(p-acetoxyphenylazo)-5-pyrazolone. All the above compounds exist in a keto form and the arylazo derivatives are in the form IX stabilized by strong intramolecular hydrogen bonding.

The spectra of o-, m- and p-methyl orange, the 2′-, 3′- and 4′-sulphonated derivatives of 2-methyl-4-dimethylaminoazobenzene, the 4′-sulpho derivative of 2′- and 3′-methyl-, 2,2′-, 2,3′- and 2′,6′-dimethyl-, and 2,2′,6′-trimethyl-4′-sulpho-4-dimethylaminoazobenzene, together with 2,2′,6′-trimethyl-4-dimethylaminoazobenzene have been examined in neutral and acidic solution. The effects observed in both cases can be accounted for by the electron attracting inductive effect of the sulphonate group. The relative amounts of protonated tautomers in acidic solution have been calculated. The amount of azonium form (III) of the protonated dyes was found to be dependent upon the position of the sulphonate group, diminishing in the order 2′, 3′, 4′. The presence of methyl groups in the same ring as the sulphonate group tended to increase the amount of azonium tautomer in comparison to the unsulphonated dye.

Anaerobic incubation of 1-(4[ 35 S]sulphophenyl)-3-methyl-4-(4-sulphophenylazo)-5-pyrazolonewith Proteus vulgaris or rat-gut contents produces labelled sulphanilic acid and 4-sulphophenylhydrazine. Similar incubation with 4[ 35 S]sulphophenylhydrazine gave little conversion to sulphanilic acid with Proteus but good conversion with gut contents. The results obtained support the view that intestinal microflora are mainly responsible for the metabolism of water-soluble pyrazolone dyes in rats.

The metabolism and excretion of three aryldihydro-striazines were studied using rats. The compounds investigated were 4,6-diarnino-l,2-dihydro-2,2-dimethy-lp-hle nyl-s-triazine (I),t he prototype of the series; 4,6-diamino-1-(3,4-dichlorophenyl)-1,2-dihydro-2,2-dimethyl-s-triazine (11); and N-( m -tolyl)- p -(4,6-diamino-l,2-dihydro-2,2-dimethyl- s -triazin-1-yl)hydrocinnamide (III). All three compounds were excreted rapidly. Urinary excretion was favored by a lower molecular weight, and biliary excretion was favored by a higher molecular weight. The overall elimination rates of I and III were similar, I being excreted predominantly in urine and III (considerably metabolized) in bile. The overall elimination rate of II, excreted mainly in urine, was lower than for the other two triazines. A large percentage (and probably all) of the dose of I and 11 was unmetabolized. Metabolism of III does not appear to involve the phenyldihydrotriazine moiety. This broad view of the metabolism and excretion of the three triazines gives no particular insight into why II, although a more potent inhibitor of dihydrofolate reductase and of L-1210 tumor cell cultures, has been found to compare very poorly with III in its in uiuo antineoplastic activity in rats.

The urinary and biliary metabolites of 1-phenyl-3-carboxy-4-phenylazo-5-pyrazolone (PCPP) and 1-phenyl-3-methyl-4-phenylazo-5-pyrazolone (PMPP) have been identified. PCPP is excreted partly unchanged and partly as the 4-hydroxyphenylazo derivative. PMPP is also excreted as these compounds and so is 1-phenyl-3-hydroxymethyl-4-phenylazo-5-pyrazolone. The oxidation of the methyl group of PMPP appears to take place before hydroxylation of the 4-phenylazo ring. This hydroxylation seems to be specific since no oxidative attack was found to occur in the 1-phenyl ring. Using 14 C-labelled PCPP quantitative data for the excretion of this compound and its metabolites are reported. No reduction of this compound results from intraperitoneal injection.

The metabolism of 4-nitroaniline, 2,6-dichloro, 2,6-dibromo- and 2,6-dimethyl-4-nitroaniline has been studied in rats. 4-Nitroaniline is excreted partly unchanged and also as 4-phenylenediamine and 2-amino-5-nitrophenol. Both halogenated derivatives undergo replacement of the nitro group by hydroxyl to yield halogenated 4-aminophenols. The chloro compound gave some of the corresponding phenylenediamine. Metabolites from the methylated derivative were unidentified but no aminophenols or phenylenediamine derivatives were detected. The results have been quantitated using isotopically-labelled compounds, all of which were well absorbed and rapidly excreted. The mechanism of the metabolic replacement of the nitro group by hydroxyl is discussed.

The excretion and metabolism of tartrazine has been studied in the rat, rabbit and man. The nature of the excretory products depends upon the route of administration. Intraperitoneal injection leads to the excretion of unchanged colouring. Oral dosage results in the excretion of equivalent amounts of sulphanilic acid which is partly conjugated. A quantitative excretion study has been carried out. The reasons for the resistance of tartrazine to the action of mammalian azo reductase are discussed.