RNA m6a Methylation Regulator Expression in Castration-Resistant Prostate Cancer Progression and Its Genetic Associations.

N6-methyladenosine (m6A) methylation, a prevalent epitranscriptomic modification, plays a crucial role in regulating mRNA expression, stability, and translation in mammals. M6A regulators have gained attention for their potential implications in tumorigenesis and clinical applications, such as cancer diagnosis and therapeutics. The existing literature predominantly addresses m6A regulators in the context of primary prostate cancer (PCa). However, a notable gap in the knowledge emerges regarding the dynamic expression patterns of these regulators as PCa progresses towards the castration-resistant stage (CRPC). Employing sequential window acquisition of all theoretical mass spectra (SWATH-MS) and RNAseq analysis, we comprehensively profiled the expression of 27 m6A regulators in hormone/androgen-dependent and -independent PCa cell lines, revealing distinct clustering between tumor and adjacent normal prostate tissues. High-grade PCa tumors demonstrated the upregulation of METTL3, RBM15B, and HNRNAPA2B1 and the downregulation of ZC3H13, NUDT21, and FTO. Notably, we identified six m6A regulators associated with PCa survival. Additionally, association analysis of the PCa-associated risk loci in the cancer genome atlas program (TCGA) data unveiled genetic variations near the WTAP, HNRNPA2B1, and FTO genes as significant expression quantitative trait loci. In summary, our study unraveled abnormalities in m6A regulator expression in PCa progression, elucidating their association with PCa risk loci. Considering the heterogeneity within the PCa phenotypes and treatment responses, our findings suggest that prognostic stratification based on m6A regulator expression could enhance PCa diagnosis and prognosis.

New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Spatial insights into immunotherapy response in non-small cell lung cancer (NSCLC) by multiplexed tissue imaging.

The spatial localisation of immune cells within tumours are key to understand the intercellular communications that can dictate clinical outcomes. Here, we demonstrate an analysis pipeline for highly multiplexed CODEX data to phenotype and profile spatial features and interactions in NSCLC patients that subsequently received PD1 axis immunotherapy. We found that regulatory T cells (Tregs) are enriched in non-responding patients and this was consistent with their localization within stromal and peripheral tumour-margins. Proximity-based interactions between Tregs and both monocytes (p = 0.009) and CD8+ T cells (p = 0.009) were more frequently found in non-responding patients, while macrophages were more frequently located in proximity to HLADR+ tumour cells (p = 0.01) within responding patients. Cellular neighbourhoods analysis indicated that both macrophages (p = 0.003) and effector CD4+ T cells (p = 0.01) in mixed tumour neighbourhoods, as well as CD8+ T cells (p = 0.03) in HLADR+ tumour neighbourhoods were associated with favorable clinical response. Evaluation of the inferred regulatory functions between immune cells relative to the tumour suggested that macrophages exhibit an immunosuppressive phenotype against both CD4+ and CD8+ T cells, and that this association scores more highly in ICI refractory patients. These spatial patterns are associated with overall survival in addition to ICI response and may thus indicate features for the functional understanding of the tumour microenvironment.

Tissue biomarkers of immune checkpoint inhibitor therapy.

Cancer immunotherapy has been rejuvenated by the growing understanding of the immune system's role in tumor activity over the past two decades. During cancer initiation and progression, tumor cells employ various mechanisms that resemble peripheral immune tolerance to evade the antitumor responses of the immune system. Immune checkpoint molecules are the major mechanism of immune resistance that are exploited by tumor cells to inhibit T-cell activation and suppress immune responses. The targeting of immune checkpoint pathways has led to substantial improvements in survival rates in a number of solid cancers. However, a lack of understanding of the heterogeneity of the tumor microenvironment (TME) has resulted in inefficient therapy responses. A greater understanding of the TME is needed to identify patients likely to respond, and those that will have resistance to immune checkpoint inhibitors (ICIs). Advancement in spatial single-cell technologies has allowed deeper insight into the phenotypic and functional diversities of cells in the TME. In this review, we provide an overview of ICI biomarkers and highlight how high-dimensional spatially resolved, single-cell approaches provide deep molecular insights into the TME and allow for the discovery of biomarkers of clinical benefit.

The effects of melatonin supplementation on neurobehavioral outcomes and clinical severity in rodent models of multiple sclerosis; a systematic review and meta-analysis.

BACKGROUND: Through the antioxidant and anti-inflammation pathways, melatonin is proposed as a safe and effective intervention in neurological diseases. This study aims to evaluate the effects of melatonin supplementation on the neurobehavioral and clinical outcomes in animal models of multiple sclerosis (MS). METHODS: This study was conducted following the PRISMA statement. Animal studies that reported the effects of melatonin in preclinical MS models, including the experimental autoimmune encephalomyelitis (EAE) and cuprizone model for demyelination are included in this study. A systematic search in PubMed, Web of Science, Embase, and Scopus up was conducted in April 2023. The collaborative Approach to Meta-Analysis and Review of Animal Experimental Studies (CAMARADES) critical appraisal tool was used for the quality assessment of the studies and the quantitative synthetizes were conducted using the comprehensive meta-analysis software. RESULTS: Out of 542 studies, finally 21 studies, including 14 studies in the EAE model and 7 studies of the toxic demyelination method with cuprizone were included. The route of administration was intraperitoneal in 18 studies, oral in 2 studies, and subcutaneous in 1 study. The quantitative synthesis of the EAE clinical severity scale was associated with significant differences (standardized mean difference [SDM]: - 2.52; - 3.61 to - 1.42; p value < 0.01). In subgroup analyses, the difference was statistically significant in the mouse subgroup (SMD: - 2.60; - 3.74 to - 1.46; p value < 0.01). DISCUSSION: This study encountered that melatonin may be associated with improved behavioral and cognitive outcomes of preclinical models of MS with acceptable safety profiles. FUNDING: The research was supported by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 71005).

Ovarian Cancer in Iran: National Based Study.

Background: Ovarian cancer (OC) is the 7th most common cancer, with 239,000 new cases per year. In Iran, it is the 8th most common cancer, with an ASIR of 3.9/100,000 women. The 5-year overall survival in Iran based on previous studies is about 61% which in comparison with eastern countries has better survival. Methods: The study included patients from the Iran National Cancer Registry from 2009-2014. Several steps were taken to control data quality. This study used a Kaplan-Meier survival curve to compare OC survival rates across geographical, pathological, and other variables. All analyses were done in R (4.02) and SPSS (26), with a 0.05 P-value considered statistically significant. Results: The study enrolled 7977 cases of OC. OC's ASIR was 4.10/100,000. In epithelial and non-specific OC, ASIR was >0.5. Five-year survival was 55% and 10-year survival was 45%. Conclusion: OC is the 8th most common cancer in Iran, with lower age-specific incidence and better overall survival than East Asia and North America. In Iran, as in Eastern Europe, OC incidence correlated with reduced total fertility rate and population aging. Five and 10-year overall survival rates were 55% and 44%, respectively, higher than the West. This may be because late stage OC patients are excluded from pathology and classified as "undiagnosed" in death certificates or hospitalization files.

Genomic and Phenotypic Biomarkers for Precision Medicine Guidance in Advanced Prostate Cancer.

OPINION STATEMENT: Prostate cancer (PCa) is the second most diagnosed malignant neoplasm and is one of the leading causes of cancer-related death in men worldwide. Despite significant advances in screening and treatment of PCa, given the heterogeneity of this disease, optimal personalized therapeutic strategies remain limited. However, emerging predictive and prognostic biomarkers based on individual patient profiles in combination with computer-assisted diagnostics have the potential to guide precision medicine, where patients may benefit from therapeutic approaches optimally suited to their disease. Also, the integration of genotypic and phenotypic diagnostic methods is supporting better informed treatment decisions. Focusing on advanced PCa, this review discusses polygenic risk scores for screening of PCa and common genomic aberrations in androgen receptor (AR), PTEN-PI3K-AKT, and DNA damage response (DDR) pathways, considering clinical implications for diagnosis, prognosis, and treatment prediction. Furthermore, we evaluate liquid biopsy, protein biomarkers such as serum testosterone levels, SLFN11 expression, total alkaline phosphatase (tALP), neutrophil-to-lymphocyte ratio (NLR), tissue biopsy, and advanced imaging tools, summarizing current phenotypic biomarkers and envisaging more effective utilization of diagnostic and prognostic biomarkers in advanced PCa. We conclude that prognostic and treatment predictive biomarker discovery can improve the management of patients, especially in metastatic stages of advanced PCa. This will result in decreased mortality and enhanced quality of life and help design a personalized treatment regimen.

Evaluation of Molecular-level Changes of Programmed Cell Death Ligand-1 after Radiation Therapy in a BALB/c CT26 Colorectal Mouse Tumor Model.

The effects of radiation therapy (RT) for cancer can be systemic and partially mediated by the immune system. However, radiation alone is unlikely to transform an immunosuppressive environment into an immunostimulatory one. Therefore, an effective combination of RT and immunotherapy may provide a new, more efficient treatment approach. Here, we investigated how the expression of programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment varied in different RT regimens with the same biologically effective dose. In this study, female BALB/c mice inoculated with CT26 tumor cells were irradiated with 3 different RT regimens using the same BED of 40 gray (Gy). These included ablative RT (1*15 Gy), hypo-fractionated RT (2*10 Gy), and conventional (Hyper-fractionated) RT (10*3 Gy). PD-L1 expression was analyzed with immunohistochemical staining on days 2 and 20 and when the size of tumors had reached 2 cm2 after RT. All treated groups expressed PD-L1, but the group receiving single ablative high-dose RT showed higher expression compared to the other groups. No significant differences in PD-L1 expression were observed at different times in the same group. These findings showed that different regimens of RT have different effects on the TME, so a combination of RT and immune checkpoint blockade could be clinically used in cancer patients.

Polarimetric imaging-based cancer bladder tissue's detection: A comparative study of bulk and formalin-fixed paraffin-embedded samples.

The polarimetry imaging technique as a promising technique for pathological diagnosis provides a handy tool for identifying and discriminating cancerous tissues. In this paper, the optical polarization properties of bulk bladder tissues without any further processing and Formalin-Fixed Paraffin-Embedded (FFPE) blocks of bladder tissues have been measured. The images of the Muller matrix for both normal and cancerous samples have been obtained and for quantitative analysis and to provide a more precise comparison, two methods have been applied; the Mueller matrix polar decomposition (MMPD), and the Mueller matrix transformation (MMT). The results have shown that some of the extracted parameters from these methods can be used to identify the microstructural differentiations between normal and cancerous tissues. The results revealed a good accord between the obtained optical parameters for bulk and FFPE bladder tissues. By measuring the polarimetric properties of the tissue right after resection, and also in the early stages of pathology (FFPE tissues), this method can be applied in vivo to perform an optical biopsy; Furthermore, this method has the potential to significantly shortens the duration of pathological diagnosis. The approach seems remarkable, simple, precise, and economical compared to the existing techniques for the detection of cancerous samples.

Evaluation of GATA3 and GCDFP15 Expression in Triple Negative Breast Cancers.

Background & Objective: Breast cancer is one of the most common cancers in the world. There are some different types of breast cancer and triple-negative breast cancer is the type in which no receptors for estrogen, progesterone, and human epidermal growth factor receptor-2 are expressed. Identifying factors that can facilitate the diagnosis of triple-negative breast cancer is important. In this study, we decided to investigate the expression of GATA3 and GCDFP15 genes in triple-negative breast cancers. Methods: This is a retrospective descriptive-analytical study that was performed on 50 specimens of samples of triple-negative breast cancer. Data including age and sex, tumor grade, tumor size, types of invasion, GATA-3, and GCDFP-15 were assessed. Results: The mean age of the patients was 48.3±14.17 years. Of the total specimens, 46% were positive for GCDFP15 and 90% were positive for GATA-3. The intensity of GATA3 was evaluated and it was observed that 33(73.3%) of the cells were strongly stained and 12(26.7%) were weakly stained. There were no relationships between GATA-3 and GCDFP-15 with tumor characteristics. Conclusion: GATA-3 and GCDFP-15 may serve as diagnostic markers for triple-negative breast cancers and GATA-3 seems to be more reliable.

Epidemiology and survival of cervical cancer in Iran based on national cancer registry data (2008-2014).

Background: Cervical cancer (CC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide, associated with the incidence of human papillomavirus (HPV) infection. The CC incidence is low in Iran, ranking 11th among cancers. This study aimed to estimate the survival rate of CC and the reasons for its low survival rate based on the data retrieved from the Iranian National Cancer Registry System. Methods: In this retrospective cohort study, data for patients diagnosed with CC from 2008 to 2014 were collected and analyzed. The Kaplan-Meier method was used for survival analysis based on epidemiological and clinical factors. Results: A total of 5,304 women were diagnosed from March 10, 2008 to March 9, 2014 and 2,423 patients were followed. The mean age of the cases was 51.91 years, and 65.91% were alive. The 5- and 10-year survival rates were 58% and 50%, respectively, with no difference between younger cases with SCC or AC but better survival rates for older patients with SCC. Conclusions: As a preventable disease, CC is related to biological factors and geographical and sociodemographic indices. Geographical, cultural, and religious behaviors affect the CC incidence and survival. In Iran, the 5-year survival rate ranges from 34% to 70% among different geographic regions. Hence, effective screening based on cultural and sociodemographic issues is recommended.

Intraoperative Assessment of High-Risk Thyroid Nodules Based on Electrical Impedance Measurements: A Feasibility Study.

Precise diagnosis of thyroid nodules is challenging due to non-diagnostic/inconclusive results and uncertainties about the malignancy of follicular neoplasms (FNs), even in frozen-section pathology. Therefore, surgical management, especially in Bethesda III and IV categories, may be complicated, and sometimes a second surgery may be required. The Thyroid Nodule Impedance Measurement System (TN-IMS) consists of a metallic patch attached to submental skin and a G20 I.V. cannula inserted into the targeted nodules. Two impedance-based parameters named Z1kHz and impedance phase slope (IPS) in 100 kHz to 500 kHz of the thyroid nodules are recorded and compared with their histopathological results as the gold standard. TN-IMS was intra-surgically applied to 103 human thyroid nodules and normal thyroid tissues. A remarkable consistency between defined co-ranges of Z1kHz/IPS and the histopathological status of specimens was achieved (p < 0.001). Based on these measurements, it was concluded that intraoperative bioelectrical impedance scanning of thyroid nodules would be a helpful complementary approach to detecting high-risk excision-required thyroid nodules.

Expression of tolerogenic dendritic cells in the small intestinal tissue of patients with celiac disease.

Tolerogenic dendritic cells (tolCDs) play an important role in the regulation of inflammation in autoimmune diseases such as celiac disease (CeD). Dendritic cells express CD207, CD11c, and CD103 on their surface. In addition to the receptors mentioned above, tolCDs can express the immune-regulating enzyme indoleamine 2,3-dioxygenase (IDO). This study aimed to determine the mRNA and protein expression of CD11c, CD103 and CD207 markers, and also IDO gene expression in intestinal tissues of CeD patients in comparison to the healthy individuals. Duodenal biopsies were collected from 60 CeD patients and 60 controls. Total RNA was extracted and gene expression analysis was performed using Real-time PCR SYBR® Green method. Additionally, biopsy specimens were paraffinized and protein expression was evaluated using immunohistochemistry (IHC) for expression of CD11c+, CD207+and CD103+. Gene expression levels of CD11c (P = 0.045), CD103 (P < 0.001), CD207 (P < 0.001) and IDO (P = 0.01) were significantly increased in CeD patients compared to the control group. However, only CD103 protein expression was found to be significantly higher in CeD patients in comparison to the control group (P < 0.001). The result of this study showed that the expresion levels of CD11c, CD103, CD207 and IDO markers were higher in CeD patients compared to the controls, indicating the effort of dendritic cells to counterbalance the gliadin-triggered abnormal immune responses in CeD patients.

High expression of ZEB1 is associated with EMAST & metastasis in colorectal cancer patients.

Background & objectives: Transforming growth factor-beta (TGF-ß) signalling pathway has been reported to be involved in metastasis and at the same time has been considered compellingly an important mediator of epithelial-to-mesenchymal transition (EMT). Besides, EMT process is maintained by zinc-finger E-box-binding homeobox 1 (ZEB1) gene which is induced by TGF-ß pathway. TGF-ß has been shown to be associated with elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) phenomenon, which is one of the prognostic biomarkers of colorectal cancer (CRC). This study was conducted to determine the link among ZEB1-induced TGF-ß, EMAST status and metastasis. Methods: The expression level of ZEB1 was evaluated using quantitative reverse transcription (qRT) real-time PCR in 122 formalin fixed paraffin-embedded tissues of CRC sample with known EMAST status and TGF-ß/Smad-dependent pathways. The association among ZEB1 expression, TGF-ß signalling pathway, EMAST status and metastatic behaviour was examined. Results: ZEB1 gene expression level was higher in tumour tissues as compared to normal samples (P<0.045). In addition, ZEB1 positive expression level was associated significantly with metastasis (P=0.05), EMAST+ status (P=0.052) and activated TGF-ß signalling pathway (P=0.002). Interpretation & conclusions: Our results validated significant association between activated TGF-ß signalling pathway and EMAST+ phenotype with higher expression of ZEB1 and higher level of metastasis.

Algorithmic Approach to Inflammatory Disorders of Ileum.

The ileum has been candidate more frequently for endoscopic biopsy compared to the past. Most of those biopsies show either completely normal tissue or non-specific changes. Nevertheless, in some diseases, ileal biopsy would be diagnostic, and in some cases, it may be the only anatomical involved location by the disease. Endoscopically, normal mucosal biopsy is unlikely to provide useful diagnostic information and is not routinely recommended. However, in the presence of ileitis, ulcers, or erosions, biopsies can be very helpful. Ileitis might be induced by various conditions including infectious diseases, vasculitis, medication-induced, ischemia, eosinophilic enteritis, tumors etc. The conclusive cause of the condition is proposed by a comprehensive clinical background and physical examination, laboratory investigations, ileocolonoscopy, and imaging findings. Ileoscopy and biopsy are mainly useful in correctly selected cases such as patients who present with inflammatory diarrhea and endoscopic lesions. The purpose of this review article is to provide a simple algorithmic approach to the ileal biopsy samples through several boxes that give diagnostic clues and an idea behind the categories of ileal disorders. This review is written based on those that were previously reported in the literature as well as the authors' experiences. We have summarized different histological patterns in the ileal biopsy specimens that can be used in the diagnosis of inflammatory disorders of the ileum. This review provides an algorithmic approach to the clinicopathological features of inflammatory disorders of the ileum with a brief discussion of some important related issues.

Identification of Candidate mRNA Isoforms for Prostate Cancer-Risk SNPs Utilizing Iso-eQTL and sQTL Methods.

Single nucleotide polymorphisms (SNPs) impacting the alternative splicing (AS) process (sQTLs) or isoform expression (iso-eQTL) are implicated as important cancer regulatory elements. To find the sQTL and iso-eQTL, we retrieved prostate cancer (PrCa) tissue RNA-seq and genotype data originating from 385 PrCa European patients from The Cancer Genome Atlas. We conducted RNA-seq analysis with isoform-based and splice event-based approaches. The MatrixEQTL was used to identify PrCa-associated sQTLs and iso-eQTLs. The overlap between sQTL and iso-eQTL with GWAS loci and those that are differentially expressed between cancer and normal tissue were identified. The cis-acting associations (FDR < 0.05) for PrCa-risk SNPs identified 42, 123, and 90 PrCa-associated cassette exons, intron retention, and mRNA isoforms belonging to 25, 95, and 83 genes, respectively; while assessment of trans-acting association (FDR < 0.05) yielded 59, 65, and 196 PrCa-associated cassette exons, intron retention and mRNA isoforms belonging to 35, 55, and 181 genes, respectively. The results suggest that functional PrCa-associated SNPs can play a role in PrCa genesis by making an important contribution to the dysregulation of AS and, consequently, impacting the expression of the mRNA isoforms.

IsomiR-eQTL: A Cancer-Specific Expression Quantitative Trait Loci Database of miRNAs and Their Isoforms.

The identification of expression quantitative trait loci (eQTL) is an important component in efforts to understand how genetic variants influence disease risk. MicroRNAs (miRNAs) are short noncoding RNA molecules capable of regulating the expression of several genes simultaneously. Recently, several novel isomers of miRNAs (isomiRs) that differ slightly in length and sequence composition compared to their canonical miRNAs have been reported. Here we present isomiR-eQTL, a user-friendly database designed to help researchers find single nucleotide polymorphisms (SNPs) that can impact miRNA (miR-eQTL) and isomiR expression (isomiR-eQTL) in 30 cancer types. The isomiR-eQTL includes a total of 152,671 miR-eQTLs and 2,390,805 isomiR-eQTLs at a false discovery rate (FDR) of 0.05. It also includes 65,733 miR-eQTLs overlapping known cancer-associated loci identified through genome-wide association studies (GWAS). To the best of our knowledge, this is the first study investigating the impact of SNPs on isomiR expression at the genome-wide level. This database may pave the way for researchers toward finding a model for personalised medicine in which miRNAs, isomiRs, and genotypes are utilised.

Accuracy of Paris 2016 System for Non-invasive Diagnosis Bladder Malignancy.

Background & Objective: The Paris System for Reporting Urinary Cytology (TPS) is a new method for evaluating urinary cytology designed to reduce unreproducible reports. The aim of this study was to reclassify and compare urinary cytology reports with TPS criteria to determine the frequency of unreproducible reports compared to the previous system. Methods: In this study, the laboratory electronic registration system analyzed patients' urine samples taken by voided or washing and brushing methods. The cytological evaluation was performed considering the previous system and TPS by a pathologist. The results of the two systems were compared, and the sensitivity and specificity of TPS were calculated. Results: Urine samples were taken from 876 patients. The mean age of patients was 63.36 ± 12.62. Comparing the routine classification system and TPS, it was observed that the number of atypical reports in the TPS system decreased by 12%, and all of these cases were downgraded to the negative group in the new classification. The sensitivity and specificity of TPS were 29.4% and 95.1%, respectively, if suspected malignancy and positive reports for malignancy were considered. Finally, if positive reports for malignancy were selected, sensitivity and specificity changed to 11.8% and 100%, respectively. Conclusion: Although the TPS system has low sensitivity for the diagnosis of urothelial malignancies, due to its high specificity, it is possible to consider and use this classification for screening patients.

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Electromagnetic energy density in hyperbolic metamaterials.

We present the theory of electromagnetic energy propagation through a dispersive and absorbing hyperbolic metamaterial (HMM). In this way, the permittivity tensor components of HMM (especially, nanowire HMM) may appear to be hopeless, but as a non-trivial step, we find that they can be cast into more transparent forms. We find under the influence of an electromagnetic wave, the responses of nanowire HMM (multilayer HMM) in the directions perpendicular to and parallel to the optical axis are similar to those of Lorentz (Drude) and Drude (Lorentz) media, respectively. We obtain simple expressions for the electromagnetic energy density formula of both typical structures of HMMs, i.e., nanowire and multilayer HMMs. Numerical examples reveal the general characteristics of the direction-dependent energy storage capacity of both nanowire and multilayer HMMs. The results of this study may shed more physical insight into the optical characteristics of HMMs.