Vasomotion heterogeneity and spectral characteristics in diabetic and hypertensive patients.

Vasomotion refers to the spontaneous oscillation of blood vessels within a frequency range of 0.01 to 1.6 Hz. Various disease states, including hypertension and diabetes, have been associated with alterations in vasomotion at the finger, indicating potential impairment of skin microcirculation. Due to the non-linear nature of human vasculature, the modification of vasomotion may vary across different locations for different diseases. In this study, Laser Doppler Flowmetry was used to measure blood flow motion at acupoints LU8, LU5, SP6, and PC3 among 49 participants with or without diabetes and/or hypertension. Fast Fourier Transformation was used to analyze noise type while Hilbert-Huang Transformation and wavelet analysis were applied to assess Signal Noise Ratio (SNR) results. Statistical analysis revealed that different acupoints exhibit distinct spectral characteristics of vasomotion not only among healthy individuals but also among patients with diabetes and/or hypertension. The results showed strong heterogeneity of vasomotion among blood vessels, indicating that the vasomotion measured at a certain point may not reflect the real status of microcirculation.

An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial.

BACKGROUND AND AIMS: The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS: A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS: Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS: Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).

Selective α-oxidation of amides via visible-light-driven iron catalysis.

Hydroxyl radicals (˙OH) as one of the highly reactive species can react unselectively with a wide range of chemicals. The ˙OH radicals are typically generated under harsh conditions. Herein, we report hydroxyl radical-induced selective N-α C(sp3)-H bond oxidation of amides under greener and mild conditions via an Fe(NO3)3·9H2O catalyst inner sphere pathway upon irradiation with a 30 W blue LED light strip (λ = 455 nm) using NaBrO3 as the oxidant. This protocol exhibited high chemoselectivity and excellent functional group tolerance. A preliminary mechanism investigation demonstrated that the iron catalyst afforded hydroxyl radicals via the visible-light-induced homolysis (VLIH) of iron complexes followed by a hydrogen atom transfer (HAT) process to realize this transformation.

Lactococcus garvieae exerts a critical role in inducing inflammation in dairy mastitis by triggering NLRP3 inflammasome-mediated pyroptosis in MAC-T cells.

Lactococcus garvieae (L. garvieae) is a pathogenic bacterium that is Gram-positive and catalase-negative (GPCN), and it is capable of growing in a wide range of environmental conditions. This bacterium is associated with significant mortality and losses in fisheries, and there are concerns regarding its potential as a zoonotic pathogen, given its presence in cattle and dairy products. While we have identified and characterized virulent strains of L. garvieae through phenotyping and molecular typing studies, their impact on mammary tissue remains unknown. This study aims to investigate the pathogenicity of strong and weak virulent strains of L. garvieae using in vivo mouse models. We aim to establish MAC-T cell model to examine potential injury caused by the strong virulent strain LG41 through the TLR2/NLRP3/NF-kB pathway. Furthermore, we assess the involvement of NLRP3 inflammasome-mediated pyroptosis in dairy mastitis by silencing NLRP3. The outcomes of this study will yield crucial theoretical insights into the potential mechanisms involved in mastitis in cows caused by the L. garvieae-induced inflammatory response in MAC-T cells.

Hepatocyte proliferation favours viral clearance in young children with chronic hepatitis B virus infection.

AIM: The aim of this study is to explore the correlation between hepatocyte proliferation and hepatitis B virus (HBV) clearance in young children with chronic HBV infection. METHODS: We collected liver biopsy samples and clinical data corresponding to paediatric patients with chronic HBV infection. Ki-67 expression in liver tissues was evaluated by immunohistochemical staining. RESULTS: Eighteen patients were included and were divided into two groups based on different antiviral outcomes. Group I achieved hepatitis B surface antigen (HBsAg) loss within 48 weeks. Group II did not develop seroconversion from hepatitis B e (HBe) antigen to anti-HBe after 48 weeks. There were 10 patients in Group I and 8 in Group II, respectively. Demographical data and baseline virological and biochemical characteristics in serum across Group I and Group II were not statistically different. Histologically, mean Ki-67 expression index in Group I was 15%, while the mean index in Group II was 5%. There was a significant difference between the two groups (p < 0.01). CONCLUSION: High Ki-67 expression can contribute to viral clearance in young children with chronic HBV infection. This is the first confirmation of the association between hepatocyte proliferation and HBV clearance in vivo and has implications for novel therapeutic strategies against hepatitis B.

Mosaic Evolution of Beta-Barrel-Porin-Encoding Genes in Escherichia coli.

Bacterial porin-encoding genes are often found under positive selection. Local recombination has also been identified in a few of them to facilitate bacterial rapid adaptation, although it remains unknown whether it is a common evolutionary mechanism for the porins or outer membrane proteins in Gram-negative bacteria. In this study, we investigated the beta-barrel (ß-barrel) porin-encoding genes in Escherichia coli that were reported under positive Darwinian selection. Besides fhuA that was found with ingenic local recombination previously, we identified four other genes, i.e., lamB, ompA, ompC, and ompF, all showing the similar mosaic evolution patterns. Comparative analysis of the protein sequences disclosed a list of highly variable regions in each family, which are mostly located in the convex of extracellular loops and coinciding with the binding sites of bacteriophages. For each of the porin families, mosaic recombination leads to unique combinations of the variable regions with different sequence patterns, generating diverse protein groups. Structural modeling indicated a conserved global topology among the different porins, with the extracellular surface varying a lot due to individual or combinatorial variable regions. The conservation of global tertiary structure would ensure the channel activity, while the wide diversity of variable regions may represent selection to avoid the invasion of phages, antibiotics or immune surveillance factors. Our study identified multiple bacterial porin genes with mosaic evolution. We hypothesize that this could be generalized strategy for outer membrane proteins to both maintain normal life processes and evade the attack of unfavored factors rapidly. IMPORTANCE Microevolution studies can disclose more elaborate evolutionary mechanisms of genes, appearing especially important for genes with multifaceted function such as those encoding outer membrane proteins. However, in most cases, the gene is considered as a whole unit, and the evolutionary patterns are disclosed. Here, we report that multiple bacterial porin proteins follow mosaic evolution, with local ingenic recombination combined with spontaneous mutations based on positive Darwinian selection, and conservation for most structural regions. This could represent a common mechanism for bacterial outer membrane proteins. The variable regions within each porin family showed large coincidence with the binding sites of bacteriophages, antibiotics, and immune factors and therefore would represent effective targets for the development of new antibacterial agents or vaccines.

Particulate Projectiles Driven by Cavitation Bubbles.

The removal of surface-attached particles with cavitation bubbles is usually attributed to the jetting or shear stresses when bubbles collapse. In this Letter, we report an unexpected phenomenon that millimeter-sized spherical particles made of heavy metals (e.g., stainless steel), when initially resting on a fixed rigid substrate, are suddenly accelerated like projectiles through the production of nearby laser-induced cavitation bubbles of similar sizes. We show experimentally and theoretically that the motion of a particle with radius R_{p} is determined by the maximum bubble radius R_{b,max}, the initial distance from the laser focus to the center of the particle L_{0}, and the initial azimuth angle φ_{0}. We identify two dominant regimes for the particle's sudden acceleration, namely, the unsteady liquid inertia dominated regime and the bubble contact dominated regime, determined by R_{b,max}R_{p}/L_{0}^{2}. We find the nondimensional maximum vertical displacement of the particle follows the fourth power and the square power scaling laws for respective regimes, which is consistent with the experimental results. Our findings can be applied to nonintrusive particle manipulation from solid substrates in a liquid.

Prognostic and Theranostic Biomarkers in Ovarian Clear Cell Carcinoma.

In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theranostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 samples of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theranostic biomarkers (ALK, BRAF V600E, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-yr ovarian cancer-specific survival of 33.3%, compared with 91.5% in the other stage I cases). Among theranostic targets, ERBB2 amplification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. In addition, OCCC could be tested for ERBB2 amplification for inclusion in gynecological basket trials targeting this alteration.

Nano-crystal melting calculation for Al, Cu and Ag considering macro-crystal surface melting.

The surface melting of macro-crystals and melting of nano-crystals for Al, Cu and Ag pure components are modeled in comparison with literature data. The relevant temperatures of surface premelting and melting are calculated. The corresponding temperature-dependent equilibrium thickness of the liquid melted layer is obtained as well, which tends to infinity when the temperature is at the bulk melting point. Furthermore, the size-dependent melting behaviors for Al, Cu and Ag are investigated and the corresponding critical size is determined using a home-made code. The melting point depression with particle size is also demonstrated in the present work. As illustrated in the size-dependent phase diagram, the temperatures of both the solidus and liquidus decrease and they merge with the decrease in the radius.

Experimental investigation and thermodynamic modeling of phase equilibria in the Ag-Ni-Zr ternary system.

The phase equilibria of the Ag-Ni-Zr ternary system were investigated based on the key experiments coupled with thermodynamic modeling. Thirty ternary alloys were prepared to determine the isothermal sections of the Ag-Ni-Zr system at 500, 700 and 900 °C, respectively, by means of X-ray diffraction (XRD) and scanning electron microscopy equipped with energy dispersive X-ray spectroscopy (SEM/EDS). Based on the thermodynamic descriptions of three binary systems available in the literature as well as the experimental phase equilibrium data obtained from the present work, ten three-phase regions were determined. No ternary compound was found. The maximum solubilities of Ag in the Ni-Zr binary compounds and Ni in the Ag-Zr binary compounds were measured. The substitutional model and sublattice model were used to describe the solution phases and intermediate phases, respectively. Based on the thermodynamic descriptions of three constituent binary systems as well as the experimental phase equilibrium data obtained from the present work, a thermodynamic assessment of the Ag-Ni-Zr system was carried out using the CALPHAD (CALculation of PHAse Diagrams) approach. A set of thermodynamic parameters were obtained and the isothermal sections of the Ag-Ni-Zr system were calculated. The calculated results agree well with the experimental data.

Reappraisal of the diagnostic value of alpha-fetoprotein for surveillance of HBV-related hepatocellular carcinoma in the era of antiviral therapy.

This study was designed to explore if antiviral treatment influences the performance of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high-risk chronic HBV-infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non-antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non-antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut-off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high-risk population of CHB and LC patients.

Hepatic Histopathology Among Excessive Drinkers Without Advanced Liver Disease.

AIMS: Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. METHODS: We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. RESULTS: Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. CONCLUSION: Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.

Emperipolesis mediated by CD8+ T cells correlates with biliary epithelia cell injury in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by chronic destruction of the bile ducts. A major unanswered question regarding the pathogenesis of PBC is the precise mechanisms of small bile duct injury. Emperipolesis is one of cell-in-cell structures that is a potential histological hallmark associated with chronic hepatitis B. This study aimed to clarify the pathogenesis and characteristics of emperipolesis in PBC liver injury. Sixty-six PBC patients, diagnosed by liver biopsy combined with laboratory test, were divided into early-stage PBC (stages I and II, n = 39) and late-stage PBC (stages III and IV, n = 27). Emperipolesis was measured in liver sections stained with haematoxylin-eosin. The expressions of CK19, CD3, CD4, CD8, CD20, Ki67 and apoptosis of BECs were evaluated by immunohistochemistry or immunofluorescence double labelling. Emperipolesis was observed in 62.1% of patients with PBC, and BECs were predominantly host cells. The number of infiltrating CD3+ and CD8+ T cells correlated with the advancement of emperipolesis (R2  = 0.318, P < .001; R2  = 0.060, P < .05). The cell numbers of TUNEL-positive BECs and double staining for CK19 and Ki67 showed a significant positive correlation with emperipolesis degree (R2  = 0.236, P < .001; R2  = 0.267, P < .001). We conclude that emperipolesis mediated by CD8+ T cells appears to be relevant to apoptosis of BEC and thus may aggravate the further injury of interlobular bile ducts.

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19.

Background & Aims: Liver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). Whether or not severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to liver damage per se remains unknown. Herein, we reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with liver enzyme abnormalities. Methods: We analyzed 156 patients diagnosed with COVID-19 from 2 designated centers in China and compared clinical features between patients with or without elevated aminotransferases. Postmortem liver biopsies were obtained from 2 cases who had elevated aminotransferases. We investigated the patterns of liver impairment by electron microscopy, immunohistochemistry, TUNEL assay and pathological studies. Results: Sixty-four out of 156 (41.0%) patients with COVID-19 had elevated aminotransferases. The median levels of alanine aminotransferase were 50 U/L vs. 19 U/L, respectively, aspartate aminotransferase were 45.5 U/L vs. 24 U/L, respectively in abnormal and normal aminotransferase groups. Liver enzyme abnormalities were associated with disease severity, as well as a series of laboratory tests including higher alveolar-arterial oxygen partial pressure difference, higher gamma-glutamyltransferase, lower albumin, decreased CD4+ T cells and B lymphocytes. Ultrastructural examination identified typical coronavirus particles, characterized by spike structures, in the cytoplasm of hepatocytes in 2 COVID-19 cases. SARS-CoV-2-infected hepatocytes displayed conspicuous mitochondrial swelling, endoplasmic reticulum dilatation and glycogen granule decrease. Histologically, massive hepatic apoptosis and some binuclear hepatocytes were observed. Taken together, both ultrastructural and histological evidence indicated a typical lesion of viral infection. Immunohistochemical results showed scarce CD4+ and CD8+ lymphocytes. No obvious eosinophil infiltration, cholestasis, fibrin deposition, granuloma, massive central necrosis, or interface hepatitis were observed. Conclusions: SARS-CoV-2 infection in the liver directly contributes to hepatic impairment in patients with COVID-19. Hence, a surveillance of viral clearance in liver and long-term outcome of COVID-19 is required. Lay summary: Liver enzyme abnormalities are common in patients with coronavirus disease 2019 (COVID-19). We reported the clinical characteristics and liver pathological manifestations of COVID-19 patients with elevated liver enzymes. Our findings suggested that SARS-CoV-2 infection of the liver is a crucial factor contributing to hepatic impairment in patients with COVID-19.

Incidence, predictors and prognosis of genotype 4 hepatitis E related liver failure: A tertiary nested case-control study.

BACKGROUND/AIMS: Hepatitis E virus (HEV) infection has been recognized an important insult of acute or acute-on-chronic liver failure (A(C)LF). This study aimed to identify the incidence, predictors and outcomes of A(C)LF in patients with hepatitis E. METHODS: All patients diagnosed of hepatitis E between 2012 and 2018 in the tertiary hospital were retrospectively and consecutively analysed. Patients with hepatitis E who developed A(C)LF were enrolled as cases (HEV-LF) and controls were randomly selected from those who did not develop liver failure with 1:3 ratio in the same cohort. RESULTS: Eight hundred and nine patients were diagnosed with hepatitis E, among which 80 were identified with HEV-related liver failure (HEV-LF) with HEV as the solely acute aetiology of A(C)LF. Sequencing of HEV genome showed genotype (GT) 4 strains in all available serum samples. Hepatitis E patients with cirrhosis underwent higher risk to develop liver failure, compared to non-cirrhotic patients. Hydrothorax, respiratory infections, lower γ-glutamyl transferase, higher lactate dehydrogenase and alpha-foetoprotein were found to be independent predictors of A(C)LF in patients with hepatitis E. The 28-day and 90-day mortality for HEV-LF was 12.86% and 30.36% respectively. Renal injury and lower triglyceride were independent factors associated with 28-day mortality. Lower alanine aminotransferase and higher International normalized ratio were independent predictors of 90-day mortality. CONCLUSIONS: Patients with GT4 hepatitis E are at high risk to develop A(C)LF. Different CLD status impacted the incidence of HEV-LF distinctively. The identified variables shall help to identify HEV patients with high risk for developing liver failure and the risk for death.

Immunohistochemistry is a feasible method to screen BRAF V600E mutation in colorectal and papillary thyroid carcinoma.

AIMS: To investigate whether immunohistochemistry (IHC) could be used to screen BRAF mutation status in formalin-fixed paraffin-embedded (FFPE) colorectal carcinoma (CRC) and papillary thyroid carcinoma (PTC) samples. METHODS: Eight surgical resected samples, including 2 CRCs with mutated BRAF V600E, 2 PTCs with mutated BRAF V600E, 2 CRCs with wild-type BRAF and 2 PTCs with wild-type BRAF, were selected to explore the optimized IHC conditions for BRAF V600E (VE1) immunostaining using BenchmarkXT automated immunostainer VENTANA Medical System. BRAF V600E status was tested by optimized IHC and ARMS-PCR methods in 255 samples (123 CRCs and 132 PTCs). Sanger sequencing was performed to validate the BRAF V600E status if discordant results were found between optimized IHC and ARMS-PCR methods. RESULTS: Antigen retrieval time in 32 min and 64 min showed satisfactory intensity and homogeneity of BRAF V600E staining in CRC and PTC samples, respectively. The concordance between IHC and ARMS/Sanger sequencing was 99.2% (122/123) in CRCs and 96.2% (127/132) in PTCs. In CRCs, the sensitivity of IHC staining for BRAF V600E was 100% (3/3) and the specificity was 99.1% (119/120). In PTCs, the sensitivity was 100% (106/106) and specificity was 80.8% (21/26). The overall concordance across all cases was 97.6% (249/255). CONCLUSION: The appropriate antigen retrieval protocol is critical for accurate analysis of BRAF V600E status by Benchmark XT automated immunostainer. IHC is a suitable method to screen BRAF V600E mutation in FFPE samples of CRCs and PTCs.

Motion of a Free-Settling Spherical Particle Driven by a Laser-Induced Bubble.

We document experimentally four different interactions of a laser-induced bubble and a free-settling particle, with different combinations of the geometric and physical parameters of the system. Our force balance model shows that four nondimensional factors involving the particle radius a, the maximum bubble radius R_{max}, the initial separation distance l_{0} between the particle center and the bubble center, the fluid viscosity µ_{f}, and the particle and fluid densities ρ_{p} and ρ_{f}, respectively, in detail l_{0}/R_{max}, a/R_{max}, ρ_{p}/ρ_{f}, and µ^{*}=µ_{f}T_{c}/ρ_{f}R_{max}^{2}, where T_{c}=0.915R_{max}sqrt[ρ_{f}/(p_{∞}-p_{v})], influence the particle-bubble dynamics, and reasonably predict the maximum particle velocity and the limiting condition when the particle starts to "bounce off" the bubble during bubble growth. In particular, we also discover the high-speed ejection of the particle, and a cavity behind the particle, in cases when initially the particle is in very close proximity to the bubble. These observations offer new insights into the causal mechanism for the enhanced cavitation erosion in silt-laden water.

Immunohistochemical Profiling of Endometrial Serous Carcinoma.

Endometrial serous carcinoma (ESC) is an aggressive neoplasm mainly seen in older women. The objective of this study was to refine immunohistochemical (IHC) panels for the differential diagnoses against endometrial endometrioid grade 3 (EC3), endometrial clear cell, and ovarian high-grade serous carcinoma as well as exploring the prognostic role of selected IHC markers. Fifty-two ESC from a single institution were assessed for 20 IHC markers, including ARID1A, CCNE1, CDKN2A, ERBB2, ESR1, HNF1B, FBXW7, IGF2BP3, MLH1, MSH2, MSH6, NAPSA, PAX8, PGR, PMS2, PTEN, TFF3, TP53, VIM, and WT1. ERBB2 chromogenic in situ hybridization was evaluated on tissue microarrays. Statistical analysis was performed. All ESC showed aberrant TP53, normal mismatch repair protein, and retained ARID1A and PTEN expression. ESR1 expression was present in 80% of ESC. A combination of TP53, PTEN, and CDKN2A had a sensitivity of 93.6% [95% confidence interval (CI), 84%-98%] and specificity of 87.8% (95% CI, 75%-95%) for ESC versus EC3. A combination of NAPSA and ESR1 had a sensitivity of 97.9% (95% CI, 89%-99%) and specificity of 72.2% (95% CI, 46%-90%) for ESC versus clear cell carcinoma. Absence of WT1 alone had a sensitivity of 66.0% (95% CI, 51%-79%) and specificity of 98.0% (95% CI, 94%-99%) for ESC versus ovarian high-grade serous carcinoma. Among all 52 ESCs, ERBB2 amplification was present in 23%, FBXW7 expression was absent in 10%, and CCNE1 was overexpressed in 59%, however, none were associated with prognosis. Our data support the value of IHC marker panels for histotyping of high-grade endometrial carcinomas.

Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria.

BACKGROUND: An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. METHODS: We reviewed 2324 MC cases in Calgary over 14 years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFNγ and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNFα+ cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). RESULTS: IBD transformers had increased IFNγ+, T-bet+, TNF-α+, and GATA-3+ LPMNCs compared to the MC-resolved cases. The LC-to-IBD subgroup had increased IFNγ+ and GATA-3+ cells compared to the LC-resolved subgroup. The CC-to-IBD subgroup had increased T-bet+, TNF-α+, and GATA-3+ cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-α+ and RORc+ cells were seen in LC than in CC. CONCLUSION: Th1/Tc1- and TNFα-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation.

Lactic Dehydrogenase in the In Vitro Evaluation of Hemolytic Properties of Ventricular Assist Device.

Ventricular assist devices (VADs) can effectively improve the survival rate of patients with end-stage heart failure, but the hemolytic complications induced by long-time VAD support have received wide attention recently. The conventional evaluation method of the hemolytic properties of VADs by the indicator of plasma free hemoglobin (PFH) concentration is used but not sensitive enough to meet the needs of the actual examinations. In this study, an experimental method was applied for the evaluation of the injuries and damages caused by VADs to erythrocytes by both indicators of PFH and lactic dehydrogenase (LDH) in the in vitro hemolysis assay of VADs. The changes of LDH and PFH concentrations in plasma with the shear stress and the exposure time under a fixed shear stress were measured and analyzed to investigate the sensitivity and accuracy of the evaluation of erythrocyte damage by LDH. Furthermore, through 24 h in vitro hemolysis tests, the changes of LDH and PFH concentrations in blood samples were measured in combination with the microscopic histological changes and ultrastructural changes of erythrocytes, to assess the possibility of LDH evaluating the hemolysis of VADs. The changes of the concentration of LDH were more sensitive than those of PFH to different shear stress and exposure times, especially lower stress. Meanwhile, in the 24 h in vitro hemolysis assay, the PFH concentration in the blood samples showed no significant changes in the first 8 h, while the LDH concentration increased significantly in the first 3 h, which was consistent with the morphological changes of erythrocytes. Compared with the changes of the PFH concentration, the LDH concentration is sensitive to the damage of erythrocytes caused by VADs. It was considered that LDH could be applied as an additional indicator in the evaluation of erythrocyte damage and hemolytic properties of VADs in combination with the normalized index of hemolysis, for the more accurate assessment of the blood compatibility of VADs.