Understanding the malignant potential of gastric metaplasia of the oesophagus and its relevance to Barrett's oesophagus surveillance: individual-level data analysis.

OBJECTIVE: Whether gastric metaplasia (GM) of the oesophagus should be considered as Barrett's oesophagus (BO) is controversial. Given concern intestinal metaplasia (IM) may be missed due to sampling, the UK guidelines include GM as a type of BO. Here, we investigated whether the risk of misdiagnosis and the malignant potential of GM warrant its place in the UK surveillance. DESIGN: We performed a thorough pathology and endoscopy review to follow clinical outcomes in a novel UK cohort of 244 patients, covering 1854 person years of follow-up. We complemented this with a comparative genomic analysis of 160 GM and IM specimens, focused on early molecular hallmarks of BO and oesophageal adenocarcinoma (OAC). RESULTS: We found that 58 of 77 short-segment (<3 cm) GM (SS-GM) cases (75%) continued to be observed as GM-only across a median of 4.4 years of follow-up. We observed that disease progression in GM-only cases and GM+IM cases (cases with reported GM on some occasions, IM on others) was significantly lower than in the IM-only cases (Kaplan-Meier, p=0.03). Genomic analysis revealed that the mutation burden in GM is significantly lower than in IM (p<0.01). Moreover, GM does not bear the mutational hallmarks of OAC, with an absence of associated signatures and driver gene mutations. Finally, we established that GM found adjacent to OAC is evolutionarily distant from cancer. CONCLUSION: SS-GM is a distinct entity from SS-IM and the malignant potential of GM is lower than IM. It is questionable whether SS-GM warrants inclusion in BO surveillance.

Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia.

Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM. We demonstrate that BE-IM and GIM share molecular features, and individual cells simultaneously possess transcriptional properties of gastric and intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles atrophic gastritis; genetically, it is clonal and has a lower mutational burden than BE-IM. Finally, we show that GIM and BE-IM acquire a protumorigenic, activated fibroblast microenvironment. These findings suggest that BE-IM and GIM can be considered molecularly similar entities in adjacent organs, opening the path for shared detection and treatment strategies. SIGNIFICANCE: Our data capture the gradual molecular and phenotypic transition from a gastric to intestinal phenotype (IM) in the esophagus and stomach. Because BE-IM and GIM can predispose to cancer, this new understanding of a common developmental trajectory could pave the way for a more unified approach to detection and treatment. See related commentary by Stachler, p. 1291. This article is highlighted in the In This Issue feature, p. 1275.

Photon-in/photon-out spectroscopy at the I20-scanning beamline at diamond light source.

A scanning multi-crystal x-ray emission spectrometer to perform photon-in/photon-out spectroscopy at the I20-Scanning beamline at Diamond Light Source is described. The instrument, equipped with three analyzer crystals, is based on a 1 m Rowland circle spectrometer operating in the vertical plane. The energy resolution of the spectrometer is of the order of 1 eV, having sufficient resolving power to overcome the core-hole lifetime broadening of most of the transition metalsK-edges. Examples showing the capability of the beamline for performing high energy resolution fluorescence detection x-ray absorption spectroscopy (HERFD-XAS), non-resonant x-ray emission spectroscopy (XES) and resonant x-ray emission spectroscopy are presented. The comparison of the Zn and MnK-edge HERFD-XANES of ZnO and MnO withab initiocalculations shows that the technique provides enhanced validation of the models by making subtle spectral features more visible.

UV-cured gel polymer electrolytes with improved stability for advanced aqueous Li-ion batteries.

We report the development of a new class of "water-in-salt" electrolytes based on UV photopolymerized acrylic polymers. Incorporation of "water-in-bisalt" in a polymer matrix reduces water activity, expands the electrochemical stability window to 4.1 V, and dramatically improves cycle life in full cells with lithium titanate anodes compared to liquid water-based electrolytes.

The scanning four-bounce monochromator for beamline I20 at the Diamond Light Source.

A description of the technical and design details of a scanning four-bounce crystal monochromator that has recently been commissioned for the Versatile X-ray Absorption Spectroscopy (XAS) beamline at Diamond Light Source is presented. This device consists of two independent rotary axes of unique design which are synchronized using a multiple read-head encoder system. This monochromator is shown to be capable of maintaining the flux throughput of the Bragg axes without the need of any external feedback mechanism from 4 to 20 keV. The monochromator is currently equipped with cryogenically cooled crystals with the upstream axis consisting of two independent Si(111) crystals and a pair of channel-cut crystals in the downstream axis. The possibility of installing an additional Si(311) crystal-set to extend the energy range to 34 keV is incorporated into the preliminary design of the device. Experimental data are presented showing the exceptional mechanical stability and repeatability of the monochromator axes.

The Spectroscopy Village at Diamond Light Source.

This manuscript presents the current status and technical details of the Spectroscopy Village at Diamond Light Source. The Village is formed of four beamlines: I18, B18, I20-Scanning and I20-EDE. The village provides the UK community with local access to a hard X-ray microprobe, a quick-scanning multi-purpose XAS beamline, a high-intensity beamline for X-ray absorption spectroscopy of dilute samples and X-ray emission spectroscopy, and an energy-dispersive extended X-ray absorption fine-structure beamline. The optics of B18, I20-scanning and I20-EDE are detailed; moreover, recent developments on the four beamlines, including new detector hardware and changes in acquisition software, are described.

Use of a Novel Nonparametric Version of DEPTH to Identify Genomic Regions Associated with Prostate Cancer Risk.

BACKGROUND: We have developed a genome-wide association study analysis method called DEPTH (DEPendency of association on the number of Top Hits) to identify genomic regions potentially associated with disease by considering overlapping groups of contiguous markers (e.g., SNPs) across the genome. DEPTH is a machine learning algorithm for feature ranking of ultra-high dimensional datasets, built from well-established statistical tools such as bootstrapping, penalized regression, and decision trees. Unlike marginal regression, which considers each SNP individually, the key idea behind DEPTH is to rank groups of SNPs in terms of their joint strength of association with the outcome. Our aim was to compare the performance of DEPTH with that of standard logistic regression analysis. METHODS: We selected 1,854 prostate cancer cases and 1,894 controls from the UK for whom 541,129 SNPs were measured using the Illumina Infinium HumanHap550 array. Confirmation was sought using 4,152 cases and 2,874 controls, ascertained from the UK and Australia, for whom 211,155 SNPs were measured using the iCOGS Illumina Infinium array. RESULTS: From the DEPTH analysis, we identified 14 regions associated with prostate cancer risk that had been reported previously, five of which would not have been identified by conventional logistic regression. We also identified 112 novel putative susceptibility regions. CONCLUSIONS: DEPTH can reveal new risk-associated regions that would not have been identified using a conventional logistic regression analysis of individual SNPs. IMPACT: This study demonstrates that the DEPTH algorithm could identify additional genetic susceptibility regions that merit further investigation. Cancer Epidemiol Biomarkers Prev; 25(12); 1619-24. ©2016 AACR.

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

Dimensional Review of Scales for Forensic Photography.

Scales for photography provide a geometrical reference in the photographic documentation of a crime scene, pattern, or item of evidence. The ABFO No. 2 Standard Reference Scale (1) is used by the forensic science community as an accurate reference scale. We investigated the overall accuracy of the major centimeter graduations, internal/external diameters of the circles, error in placement of the circle centers, and leg perpendicularity. Four vendors were selected for the scales, and the features were measured on a vision-based coordinate measurement system. The scales were well within the specified tolerance for the length graduations. After 4 years, the same scales were measured to determine what change could be measured. The scales demonstrated acceptable stability in the scale length and center-to-center measurements; however, the perpendicularity exhibited change. The study results indicate that scale quality checks using certified metal rulers are good practice.

Seven hundred seventy eight bite marks: analysis by anatomic location, victim and biter demographics, type of crime, and legal disposition.

A study of the etiology, anatomic location, victim demographics and legal disposition of bite mark cases was made with the purpose of updating and augmenting previous research in the field. The information may be of interest to a myriad of professional disciplines including Forensic Odontologists, Medical Examiners, Detectives, Profilers, Emergency Room Personnel, Coroners, Psychologists, and Family Service Counselors, as bite marks provide both physical and biological data. While bite marks were found on all anatomic regions of the body some sites are significantly more likely to receive bites, and the frequency that an area is bitten may vary with the type of crime. Sex and age of the victim may also impact the resulting location and frequency of bites. A survey form for bite mark cases was created and mailed to all Diplomates of the American Board of Forensic Odontology. The survey form was also included in the American Society of Forensic Odontology newsletter. The survey requested that the recipient fill out a separate form for each case for which the recipient was the primary investigator of a patterned injury. The data from the resulting surveys were entered into a Microsoft Excel spreadsheet. The responses detailed two hundred thirty two (259) bite mark cases that included seven hundred (778) individual bite marks. Harvey (1976) and Sweet and Pretty (2000) published studies finding the highest percentage of bites to the breasts. In 1983 Vale and Noguchi published the paper indicating that the most frequently bitten area was the upper extremities. The survey forms were sent to approximately 1100 forensic dentist in 26 countries. The forensic experience level of the dentists varied from neophyte to very experienced. The data were analyzed and the results reported and organized in the following categories; Victim Distribution by Gender, Victim Distribution by Age, Child Abuse Distribution by Age and Gender, Sexual Assault Distribution by age and Gender, Homicide Distribution by Age and Gender, Bite Mark Distribution by Gender and Location, Number of Bite Marks per Victim, Bite mark Distribution Comparison to Previous Research, Child Abuse Suspect Age Distribution by Age and Sex, Homicide Suspect Age Distribution by Age and Sex, Sexual Crimes Suspect Age Distribution by Age and Sex, and Bite Mark Incidence by Anatomical Area and Type of Crime. Fifty-two forensic odontologists from seven countries responded. Nineteen responders were Diplomates of the American Board of Forensic Odontology. The number of cases reported by each responder ranged from one to thirty-three and the average number of cases reported was 4.5. In this broad based study, females were bitten more often than males. The average male victim was younger than the average female victim. Males that were victims tended to be either very young or very old. The youngest victim was a two-month-old boy and the oldest victim a 95-year-old woman. Perpetrators were male more often than female and there was an average of 1.4 suspects per case. The results show that most bites occurred on the arm, followed by the breast. If broken down by gender, males were bitten on the arm more than females, and females were bitten on the breast more often than males. The data show patterns in location and number of bites that seem related to both the type of crime and the age of the victim.

Triphenylphosphine-mediated reductive cyclization of 2-nitrobiphenyls: a practical and convenient synthesis of carbazoles.

The synthesis of a series of substituted carbazoles from the corresponding 2-nitrobiphenyl derivatives using a novel modification of the Cadogan reaction is described. Cyclization of the 2-nitrobiphenyls was achieved via reductive deoxygenation of the nitro groups using a slight excess of triphenylphosphine in a suitable solvent. We have observed a temperature dependence on the extent of conversion under these conditions, with higher boiling solvents affording higher yields across a range of substrates. The new reaction conditions are very straightforward and convenient to execute, tolerate a broad range of functional groups, and yield carbazole products in the absence of unwanted side products.