Targeting PRL phosphatases in hematological malignancies.

INTRODUCTION: Phosphatase of regenerating liver (PRL) family proteins, also known as protein tyrosine phosphatase 4A (PTP4A), have been implicated in many types of cancers. The PRL family of phosphatases consists of three members, PRL1, PRL2, and PRL3. PRLs have been shown to harbor oncogenic potentials and are highly expressed in a variety of cancers. Given their roles in cancer progression and metastasis, PRLs are potential targets for anticancer therapies. However, additional studies are needed to be performed to fully understand the roles of PRLs in blood cancers. AREAS COVERED: In this review, we will summarize recent studies of PRLs in normal and malignant hematopoiesis, the role of PRLs in regulating various signaling pathways, and the therapeutic potentials of targeting PRLs in hematological malignancies. We will also discuss how to improve current PRL inhibitors for cancer treatment. EXPERT OPINION: Although PRL inhibitors show promising therapeutic effects in preclinical studies of different types of cancers, moving PRL inhibitors from bench to bedside is still challenging. More potent and selective PRL inhibitors are needed to target PRLs in hematological malignancies and improve treatment outcomes.

Association between disease-modifying antirheumatic drugs for rheumatoid arthritis and risk of incident dementia: a systematic review with meta-analysis.

BACKGROUND: Dysregulation of several inflammatory cytokines including tumour necrosis factor (TNF) in dementia patients has also been identified as a key factor in the pathogenesis of rheumatoid arthritis (RA). We aimed to investigate the association of disease-modifying antirheumatic drugs (DMARDs) therapy for RA with risk of incident dementia. METHODS: Electronic database searches of PubMed, EMBASE and Cochrane Library were performed. Observational studies that assessed the association of dementia with DMARDs in RA were included. Pooled risk ratios (RRs) with 95% CIs were used as summary statistic. The certainty of evidence was judged by using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Overall, 14 studies involving 940 442 patients with RA were included. Pooled RR for developing dementia was 0.76 (95% CI 0.72 to 0.80) in patients taking biological DMARDs overall versus those taking conventional synthetic DMARDs, with 24% for TNF inhibitors (RR 0.76, 95% CI 0.71 to 0.82), 24% for non-TNF biologics (RR 0.76, 95% CI 0.70 to 0.83), separately. There was a significant subgroup effect among different types of TNF inhibitors (RR 0.58 [95%CI 0.53 to 0.65], 0.65 [95% CI 0.59 to 0.72], 0.80 [95% CI 0.72 to 0.88] for etanercept, adalimumab, infliximab, respectively; p value between groups=0.002). However, compared with non-users of DMARDs or investigative treatment, no significant effect on dementia incidence was observed in those receiving conventional synthetic DMARDs overall (RR 0.84, 95% CI 0.59 to 1.20), methotrexate (RR 0.78, 95% CI 0.54 to 1.12), hydroxychloroquine (RR 0.95, 95% CI 0.63 to 1.44), except for sulfasalazine (RR 1.27, 95% CI 1.06 to 1.50). CONCLUSIONS: Biological DMARDs for RA are associated with decreased dementia risk, while protective effect is not observed in conventional synthetic DMARDs. Controlled clinical trials on TNF inhibitors are necessary to test their neuroprotective potentials.

Efficacy of enzyme­induced collagen crosslinking on porcine cornea.

The purpose of the present study was to investigate the effect of a new crosslinking (CXL) method, induced by enzymes, on porcine corneas. Corneal strip (10x3 mm) pairs obtained from 60 fresh porcine eyes were harvested and divided into four groups, Groups A-D. Each pair of corneal strips was incised from the central part of the same cornea; one was incubated in transglutaminase (Tgase) solution (microbial Tgase 2 produced by tissue engineering) and the other remained untreated as a control. CXL strips of Groups A-D were incubated with 2, 1, 0.5 and 0.25 U/ml Tgase solution, respectively at 37˚C for 30 min. After that, tensile strain measurements were performed for all strips. One cornea from each group was chosen randomly for hematoxylin and eosin, and Masson staining to identify histological morphology changes. The elastic modulus of treated corneas of Groups A-D were 6.56±2.93, 4.72±1.29, 5.24±2.13 and 3.48±1.60 MPa (mean ± SD), respectively at a strain of 20%, and had a 66, 43, 36 and -6% increase compared with those of their control strips. Compared with the control strips, the elastic modulus of the treated strips significantly increased in Groups A-C. The central corneal thickness of the treated corneas in Groups A-D were 1.54±0.14, 1.41±0.15, 1.47±0.11 and 1.43±0.13 µm, respectively; however, there was not a statistically significant difference compared with the control group. No reduction in corneal transparency was observed, and no obvious abnormalities were found in corneal morphology. CXL mediated by enzymes can lead to a notable enhancement in the biomechanical characteristics of the cornea while maintaining its structural integrity. Enzyme-induced CXL could be a new generation CXL method for strengthening the cornea.

PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.

Co-occurrence of organophosphate diesters and organophosphate triesters in daily household products: Potential emission and possible human health risk.

Eight paired organophosphate diesters (Di-OPs) and organophosphate triesters (Tri-OPs) were investigated in wipes from analytical instruments and 47 material samples related to household products, including textiles, electrical/electronic devices, building/ decoration materials and children's products. The total concentrations of Di-OPs ranged in 3577-95551 ng/m2 in the wipes and limit of detection-23002 ng/g in the materials. The Tri-OPs concentrations varied significantly in the ranges of 107218-1756892 ng/m2 and 2.13-503149 ng/g, respectively. Four industrial Di-OPs were detected in > 65% of the studied samples suggesting their direct application in the studied materials. Furthermore, we demonstrated for the first time that four non-industrial Di-OPs, e.g., bis(2-chloroethyl) phosphate, bis(1-chloro-2-propyl) phosphate, bis(1,3-dichloro-2-propyl) phosphate, and bis(butoxyethyl) phosphate, identified as degradation products of their respective Tri-OPs were also detected in these studied samples, which might act as important emission sources of Di-OPs in indoor environments. We estimated the burden of Di-OPs and Tri-OPs in a typical residential house and instrumental room, which both exhibited important contributions from furniture, building and decoration materials, and electrical/electronic devices. Limit health risk was posed to local people via air inhalation.

Changing epidemiology of cirrhosis from 2010 to 2019: results from the Global Burden Disease study 2019.

BACKGROUND: Liver cirrhosis is a significant yet largely preventable and underappreciated cause of global health loss. This study aimed to profile the global and regional burdens of liver cirrhosis between 2010 and 2019 and the contributions of various aetiologies. METHOD: Data on the incidence, mortality, and disability-adjusted life years (DALYs) of cirrhosis were obtained from the Global Burden of Disease 2019 study. The burden of cirrhosis was estimated by age, sex, region, aetiology, and socio-demographic index (SDI). The temporal trend was quantified using the annual percentage changes (APC.). RESULTS: Globally, there were 2.05 million new cases and 1.47 million deaths due to cirrhosis in 2019. From 2010 to 2019, the age-standardized incidence rate (ASIR) for cirrhosis increased slightly from 25.19 to 25.35 worldwide, while the age-standardized death rate (ASDR) and age-standardized DALYs (ASDALYs) decreased from 20.37 to 18.00 and 639.86 to 560.43, respectively. Cirrhosis incidence, mortality and DALYs were consistently higher in males than females. Stratification according to the socio-demographic index (SDI) revealed that low SDI countries had the highest ASDR and ASDALYs in 2019, while middle SDI countries had the highest ASIR. Regarding the aetiology of cirrhosis, hepatitis C accounted for the largest proportion of cirrhosis-related incidence (26.9%), death (26.8%) and DALYs (26.3%); however, non-alcoholic fatty liver disease (NAFLD) exhibited a rapidly growing cause of incident cirrhosis (+26.7%), cirrhosis-related death (+25.1%), and DALYs (+21.0%) worldwide during this period. The ASIR for NAFLD also significantly increased with APC 1.080 over the study period. CONCLUSIONS: Albeit the global burden of cirrhosis incidence increased from 2010 to 2019, cirrhosis-associated deaths and DALYs declined significantly. Notably, NAFLD exhibited the most significant increase as a contributor to cirrhosis worldwide.

Global burden of cirrhosis incidence increased from 2010 to 2019.Cirrhosis-associated death and DALYs declined significantly during this period.Non-alcoholic fatty liver disease (NAFLD) exhibited the most significant increase as a contributor to cirrhosis worldwide.

[Chemical constituents of roots of Rodgersia aesculifolia].

The chemical compositions of Rodgersia aesculifolia were isolated and purified using a combination of silica gel, reverse phase silica gel, Sephadex LH-20 column chromatography, and semi-preparative HPLC. The structures were determined according to the physicochemical properties and spectroscopic data. The MTT method and the ABTS kit were used to measure the cytotoxicity and antioxidant capacity of all isolates, respectively. Thirty-four compounds were isolated from R. aesculifolia and elucidated as stigmastane-6ß-methoxy-3ß,5α-diol(1), stigmastane-3ß,5α,6ß triol(2), ß-sitosterol(3), ß-daucosterol(4), stigmast-4-en-3-one(5), bergenin(6), 11-ß-D-glucopyranosyl-bergenin(7), 11-O-galloybergenin(8), 1,4,6-tri-O-galloyl-ß-D-glucose(9), gallic acid(10), 3,4-dihydroxybenzoic acid methyl ester(11), ethyl gallate(12), ethyl 3,4-dihydroxybenzoate(13), caffeic acid ethyl ester(14), p-hydroxybenzeneacetic acid(15), 4-hydroxybenzoic acid(16), 2,3-dihydroxy-1-(4-hydroxy-3-methoxyphenyl)-propan-1-one(17), 3,7-dimethyl-2-octene-1,7-diol(18), crocusatin-B(19), neroplomacrol(20), geniposide(21), 3-hydroxyurs-12-en-27-oic acid(22), 3ß-trans-p-coumaroyloxy-olean-12-en-27-oic acid(23), aceriphyllic acid G(24), isolariciresinol(25), trans-rodgersinine B(26), cis-rodgersinine A(27), neo-olivil(28),(7S,8R)-dihydro-3'-hydroxy-8-hydroxy-methyl-7-(4-hydroxy-3-methoxy phenyl)-1'-benzofuranpropanol(29), 5,3',4'-trihydroxy-7-methoxyflavanone(30), quercetin 3-rutinoside(31), catechin-[8,7-e]-4ß-(3,4-dihydroxy-phenyl)-dihydro-2(3H)-pyranone(32), ethyl α-L-arabino-furanoside(33), and l-linoleoylglycerol(34). One new compound was discovered(compound 1), 25 compounds were first isolated from R. aesculifolia, and 22 compounds were first isolated from the Rodgersia plant. The results indicated that compounds 22-24 possessed cytotoxicity for HepG2, MCF-7, HCT-116, BGC-823, and RAFLS cell lines(IC_(50) ranged from 5.89 µmol·L~(-1) to 20.5 µmol·L~(-1)). Compounds 8-14 and 30-32 showed good antioxidant capacity, and compound 9 showed the strongest antioxidant activity with IC_(50) of(2.00±0.12) µmol·L~(-1).

Incidence, mortality, and risk factors of acute kidney injury after immune checkpoint inhibitors: Systematic review and meta-analysis of real-world evidence.

BACKGROUND: To precisely quantify the incidence, mortality, and risk factors for acute kidney injury (AKI) following immune checkpoint inhibitor (ICI) treatment for cancer in real-world scenarios. METHODS: Comprehensive searches were performed on PubMed, EMBASE and the Cochrane library. Real-world observational studies reporting incidence, mortality and/or factors for AKI in ICI-treated patients were eligible. Odds ratio (OR) with 95% CI for potential predictors and hazard ratio (HR) with 95% CI for mortality risk associated with AKI were calculated using the random-effect model. RESULTS: Eighteen articles comprising 12,111 patients receiving ICI were finally eligible. The pooled incidence was 16.0% (95% CI 11.2%-20.8%; n = 15) for AKI following ICI therapies overall and 3.5% (95% CI 2.1%-4.9%; n = 8) for ICI-induced AKI. Patients who developed AKI during ICI therapies had 51% increased risk of death compared with those without (HR 1.51, 95% CI 1.07-2.14). Regarding risk factors, statistically increased risk for AKI during ICI therapies was observed with preexisting chronic kidney diseases (OR 1.86, 1.25-2.78), diabetes (OR 1.26, 1.04-1.53), and concomitant extrarenal immune-related adverse events (OR 2.53, 1.79-3.56). Ipilimumab (OR 2.18, 1.43-3.32), combined ICI therapies (OR 1.80, 1.14-2.83) and concomitant use of proton pump inhibitors (OR 1.97, 1.56-2.49), renin-angiotensin system inhibitors (OR 1.50, 1.05-2.14), diuretics (OR 1.69, 1.27-2.26) also significantly predicted the incident AKI. CONCLUSIONS: AKI episode is frequently observed during ICI exposure for cancer treatment, but ICI induced nephrotoxicity is only occasionally. Higher risk of AKI during ICI therapies was significantly associated with specific comorbidities, concomitant of certain drugs, ipilimumab and ICI combination therapies.

Micro- and Nanostructure Analysis of Vapor-Phase-Grown AlN on Face-to-Face Annealed Sputtered AlN/Nanopatterned Sapphire Substrate Templates.

Micro- and nanostructures in vapor-phase-grown AlN on face-to-face annealed sputtered AlN (FFA Sp-AlN) templates formed on nanopatterned sapphire substrates (NPSS) were comprehensively analyzed using transmission electron microscopy. The comparison between metal-organic vapor-phase epitaxy-grown AlN/FFA Sp-AlN/hole-type NPSS (Sample MOH) and hydride vapor-phase epitaxy-grown AlN/FFA Sp-AlN/cone-type NPSS (Sample HVC) showed apparent differences in the morphology of dislocation propagation, presence of voids, shape of polarity inversion boundaries, and crystal structure on the slope region of NPSS. Notably, cross-sectional and plan-view observations revealed that the quality of FFA Sp-AlN significantly affects the threading dislocation density in the vapor-phase-grown layer. At the slope region of the AlN/NPSS interface, γ-AlON was observed in the MOH sample, while highly misaligned AlN grains were observed in the HVC sample. These characteristic crystal structures affect the occurrence of dislocations via different mechanisms in each sample. This study provides practical information for strategically controlling the micro- and nanostructures formed in AlN/NPSS structures for high-performance AlGaN-based deep-ultraviolet emitters. Supplementary Information: The online version contains supplementary material available at 10.1007/s11664-023-10348-3.

The Immune Landscape and Molecular Subtypes of Pediatric Crohn's Disease: Results from In Silico Analysis.

Pediatric Crohn's disease (CD) presents a distinct phenotype from adult-onset disease. A dysregulated immune response is critical in CD pathogenesis; thus, it is clinically important to describe immune cell alterations and to identify a new molecular classification for pediatric CD. To this end, in this study, a RNA-seq derived dataset GSE101794-which contains the expression profiles of 254 treatment-naïve pediatric CD samples, including CIBERSORTx and weighted gene-co-expression network analysis (WGCNA)-were performed to estimate the ratio of immune cells and to identify modules and genes related to specific immune cell infiltration, respectively. Hub genes derived from WGCNA were further employed to create a molecular classification using unsupervised K-means clustering. In the pediatric CD samples, it was found that M2 macrophages, CD4+ memory resting T cells, CD8+ T cells, and resting mast cells were the most prominent immune cells in intestinal tissues. Then, 985 up-regulated genes and 860 down-regulated genes were identified in samples with high immune cell infiltration. Of these differential genes, 10 hub genes (APOA1, CYB5A, XPNPEP2, SLC1A7, SLC4A6, LIPE, G6PC, AGXT2, SLC13A1, and SOAT2) were associated with CD8+T cell infiltration. Clinically, the higher expression of these 10 hub genes was strongly associated with an earlier age of CD onset and colonic-type CD. Furthermore, based on these key genes, pediatric CD could be classified into three molecular subtypes, displaying a different immune landscape. Altogether, this in silico analysis provides a novel insight into the immune signature of pediatric CD, and a new classification of pediatric CD is presented, which may help us develop more personalized disease management and treatments for pediatric CD.

p53 directly downregulates the expression of CDC20 to exert anti-tumor activity in mantle cell lymphoma.

BACKGROUND: Cell cycle dysregulation characterized by cyclin D1 overexpression is common in mantle cell lymphoma (MCL), while mitotic disorder was less studied. Cell division cycle 20 homologue (CDC20), an essential mitotic regulator, was highly expressed in various tumors. Another common abnormality in MCL is p53 inactivation. Little was known about the role of CDC20 in MCL tumorigenesis and the regulatory relationship between p53 and CDC20 in MCL. METHODS: CDC20 expression was detected in MCL patients and MCL cell lines harboring mutant p53 (Jeko and Mino cells) and wild-type p53 (Z138 and JVM2 cells). Z138 and JVM2 cells were treated with CDC20 inhibitor apcin, p53 agonist nutlin-3a, or in combination, and then cell proliferation, cell apoptosis, cell cycle, cell migration and invasion were determined by CCK-8, flow cytometry and Transwell assays. The regulatory mechanism between p53 and CDC20 was revealed by dual-luciferase reporter gene assay and CUT&Tag technology. The anti-tumor effect, safety and tolerability of nutlin-3a and apcin were investigated in vivo in the Z138-driven xenograft tumor model. RESULTS: CDC20 was overexpressed in MCL patients and cell lines compared with their respective controls. The typical immunohistochemical marker of MCL patients, cyclin D1, was positively correlated with CDC20 expression. CDC20 high expression indicated unfavorable clinicopathological features and poor prognosis in MCL patients. In Z138 and JVM2 cells, either apcin or nutlin-3a treatment could inhibit cell proliferation, migration and invasion, and induce cell apoptosis and cell cycle arrest. GEO analysis, RT-qPCR and WB results showed that p53 expression was negatively correlated with CDC20 expression in MCL patients, Z138 and JVM2 cells, while this relationship was not observed in p53-mutant cells. Dual-luciferase reporter gene assay and CUT&Tag assay revealed mechanistically that CDC20 was transcriptionally repressed by p53 through directly binding p53 to CDC20 promoter from - 492 to + 101 bp. Moreover, combined treatment of nutlin-3a and apcin showed better anti-tumor effect than single treatment in Z138 and JVM2 cells. Administration of nutlin-3a/apcin alone or in combination confirmed their efficacy and safety in tumor-bearing mice. CONCLUSIONS: Our study validates the essential role of p53 and CDC20 in MCL tumorigenesis, and provides a new insight for MCL therapeutics through dual-targeting p53 and CDC20.

CTD Sensors for Ocean Investigation Including State of Art and Commercially Available.

Over 70% of the earth's surface is covered by oceans; globally, oceans provides a huge source of wealth to humans. In the literature, several sensors have been developed to investigate oceans. Electrical conductivity temperature depth (CTD) sensors were used frequently and extensively. Long-term accurate CTD data is important for the study and utilization of oceans, e.g., for weather forecasting, ecological evolution, fishery, and shipping. Several kinds of CTD sensors based on electrics, optical, acoustic wave and radio waves have been developed. CTD sensors are often utilized by measuring electrical signals. The latest progress of CTD sensors will be presented in order of performance. The principles, structure, materials and properties of many CTD sensors were discussed in detail. The commercially available CTD sensors were involved and their respective performances were compared. Some possible development directions of CTD sensors for ocean investigation are proposed.

PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.

Association of gestational diabetes mellitus with overall and type specific cardiovascular and cerebrovascular diseases: systematic review and meta-analysis.

OBJECTIVE: To quantify the risk of overall and type specific cardiovascular and cerebrovascular diseases as well as venous thromboembolism in women with a history of gestational diabetes mellitus. DESIGN: Systematic review and meta-analyses. DATA SOURCES: PubMed, Embase, and the Cochrane Library from inception to 1 November 2021 and updated on 26 May 2022. REVIEW METHODS: Observational studies reporting the association between gestational diabetes mellitus and incident cardiovascular and cerebrovascular diseases were eligible. Data, pooled by random effects models, are presented as risk ratios (95% confidence intervals). Certainty of evidence was appraised by the Grading of Recommendations, Assessment, Development, and Evaluations. RESULTS: 15 studies rated as moderate or serious risk of bias were included. Of 513 324 women with gestational diabetes mellitus, 9507 had cardiovascular and cerebrovascular disease. Of more than eight million control women without gestational diabetes, 78 895 had cardiovascular and cerebrovascular disease. Compared with women without gestational diabetes mellitus, women with a history of gestational diabetes mellitus showed a 45% increased risk of overall cardiovascular and cerebrovascular diseases (risk ratio 1.45, 95% confidence interval 1.36 to 1.53), 72% for cardiovascular diseases (1.72, 1.40 to 2.11), and 40% for cerebrovascular diseases (1.40, 1.29 to 1.51). Women with gestational diabetes mellitus showed increased risks of incident coronary artery diseases (1.40, 1.18 to 1.65), myocardial infarction (1.74, 1.37 to 2.20), heart failure (1.62, 1.29 to 2.05), angina pectoris (2.27, 1.79 to 2.87), cardiovascular procedures (1.87, 1.34 to 2.62), stroke (1.45, 1.29 to 1.63), and ischaemic stroke (1.49, 1.29 to 1.71). The risk of venous thromboembolism was observed to increase by 28% in women with previous gestational diabetes mellitus (1.28, 1.13 to 1.46). Subgroup analyses of cardiovascular and cerebrovascular disease outcomes stratified by study characteristics and adjustments showed significant differences by region (P=0.078), study design (P=0.02), source of data (P=0.005), and study quality (P=0.04), adjustment for smoking (P=0.03), body mass index (P=0.01), and socioeconomic status (P=0.006), and comorbidities (P=0.05). The risk of cardiovascular and cerebrovascular diseases was, however, attenuated but remained significant when restricted to women who did not develop subsequent overt diabetes (all gestational diabetes mellitus: 1.45, 1.33 to 1.59, gestational diabetes mellitus without subsequent diabetes: 1.09, 1.06 to 1.13). Certainty of evidence was judged as low or very low quality. CONCLUSIONS: Gestational diabetes mellitus is associated with increased risks of overall and type specific cardiovascular and cerebrovascular diseases that cannot be solely attributed to conventional cardiovascular risk factors or subsequent diabetes.

Comparison of hyperreflective foci in macular edema secondary to multiple etiologies with spectral-domain optical coherence tomography: An observational study.

BACKGROUND: Hyperreflective foci (HRF) features in macular edema associated with different etiologies may indicate the disease pathogenesis and help to choose proper treatment. The goal of this study is to investigate the retinal microstructural features of macular edema (ME) secondary to multiple etiologies with spectral-domain optical coherence tomography (SD-OCT) and analyze the origin of HRF in ME. METHODS: This was a retrospective study. SD-OCT images were reviewed to investigate macular microstructural features such as the number and distribution of HRF and hard exudates and the internal reflectivity of the cysts. The differences in microstructural features between groups and the correlations between the number of HRF and other parameters were analyzed. RESULTS: A total of 101 eyes with ME from 86 diabetic (diabetic macular edema, DME) patients, 51 eyes from 51 patients with ME secondary to branch retinal vein occlusion (branch retinal vein occlusion-macular edema, BRVO-ME), 59 eyes from 58 central retinal vein occlusion (central retinal vein occlusion-macular edema, CRVO-ME) patients, and 26 eyes from 22 uveitis (uveitic macular edema, UME) patients were included in this study. The number of HRF, the frequency of hard exudates and the enhanced internal reflectivity of the cysts were significantly different among the groups. The number of HRF in the DME group was significantly higher than that in the other groups (all P < 0.05). The frequency of hard exudates and enhanced internal reflectivity of the cysts in the DME group were significantly higher than ME secondary to other etiologies (all P < 0.001). Within the DME group, the number of HRF in the patients with hard exudates was significantly higher than that in the patients without hard exudates (P < 0.001). CONCLUSION: HRF detected with SD-OCT were more frequent in DME patients than in BRVO-ME, CRVO-ME, or UME patients. The occurrence of HRF was correlated with the frequency of hard exudates. HRF may result from the deposition of macromolecular exudates in the retina, which is speculated to be a precursor of hard exudates.

Epigenetic modification facilitates proline synthase PYCR1 aberrant expression in gastric cancer.

BACKGROUND & AIMS: Pyrroline-5-carboxylate reductase 1 (PYCR1) upregulation contributes to the progression of gastric cancer (GC) and indicates poor survival. However, PYCR1 expression profile in GC subtypes and the mechanism behind its upregulation are not well-studied. METHODS: PYCR1 expression profiles in GC subtypes and different stages of gastric carcinogenesis were assessed in different GC cohorts. Genetic alterations and epigenetic modulation in PYCR1 regulation were further investigated using bioinformatics analysis and in vitro experiments. RESULTS: PYCR1 expression was significantly higher in intestinal-type GC and associated molecular subtypes in TCGA and ACRG GC cohorts. During the cascade of intestinal-type GC, PYCR1 was continuously increased from normal gastric tissues through to atrophic gastritis, to intraepithelial neoplasia, and to GC. Copy number alterations in PYCR1 were associated with PYCR1 transcript expression. One CpG island was observed in PYCR1 promoter region, and the hypomethylation occurred at this region could contribute to PYCR1 transcriptional activation in GC. Besides, H3K27ac combination was found in PYCR1 promoter, and acetyltransferase p300 induced H3K27ac could promote PYCR1 expression in GC. CONCLUSIONS: PYCR1 expression varies across GC subtypes, with intestinal-type GC and associated molecular subtypes having the highest expression. Hypomethylation at CpG sites and p300-induced H3K27ac modification within PYCR1 promoter could contribute to maintaining PYCR1 overexpression in GC. These results provide us with a new insight into epigenetic modulation in mitochondrial proline metabolism.

Incidence of and Risk Factors for Paradoxical Psoriasis or Psoriasiform Lesions in Inflammatory Bowel Disease Patients Receiving Anti-TNF Therapy: Systematic Review With Meta-Analysis.

Background: Paradoxical psoriasis or psoriasiform lesions induced by anti-tumor necrosis factor (anti-TNF) therapies receive increasing attention worldwide. However, no comprehensive meta-analysis investigating the incidence estimates and risk factors for anti-TNF-induced psoriasis is currently available. We aimed to precisely quantify its incidence as well as risk factors in patients with inflammatory bowel disease (IBD). Methods: This study was registered on PROSPERO database under review registration number CRD42021233695. The electronic databases PubMed, EMBASE, and the Cochrane library were comprehensively searched for observational studies published as full-length papers in English and reporting the incidence and/or predictors for psoriasis or psoriasiform lesions in IBD patients. A random-effects meta-analysis was performed to calculate the pooled incidence. Pooled odds ratio (OR) and 95% confidence interval for potential predictors were combined using a fixed-effects or random-effects model. Results: In total, 30 articles comprising 24,547 IBD patients treated by anti-TNF were finally included. The overall pooled incidence of psoriasis and/or psoriasiform lesions following anti-TNF therapy was 6.0% (5.0-7.0%; I2 = 93.9%), with 6.9% (5.1-8.7%; I2 = 92.4%) for psoriasiform lesions and 4.6% (3.6-5.6%; I2 = 93.9%) for psoriasis. Multivariable meta-regression analysis indicated regions and populations that significantly contributed to the heterogeneity. A statistically higher risk for psoriasis or psoriasiform lesions during anti-TNF therapy was observed in female patients (OR 1.46, 1.23-1.73), those who are at a younger age at anti-TNF initiation (OR 1.03, 1.00-1.05), smokers (OR 1.97, 1.56-2.48), ileocolonic Crohn's disease patients (OR 1.48, 1.03-2.13), and those who are using adalimumab or certolizumab (vs. infliximab) (OR: 1.48 and 2.87 respectively). Conclusions: The incidence of psoriasis or psoriasiform lesions was not uncommon in IBD patients following anti-TNF therapy. Female, younger age, smoker, ileocolonic Crohn's disease, and the types of anti-TNF were significantly associated with such risk. These findings may help gastroenterologists to make more individualized decisions and understand the mechanisms of this paradoxical phenomenon. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=233695, identifier CRD42021233695.

The necessity and appropriate range of the diagnostic "gray zone" of 13C-urea breath test.

Background: The 13C-urea breath test (13C-UBT) is preferred for non-invasive detection of Helicobacter pylori (H. pylori); however, its accuracy drops when results fall between 2‰ and 6‰ (called the gray zone). This study aimed to evaluate the accuracy of 13C-UBT (cut-off point 4‰) between 2‰ and 6‰, find a more appropriate gray zone, and identify the factors influencing 13C-UBT. Methods: Patients with 13C-UBT results 2‰-6‰, over an eight-year period, were studied. H. pylori infection was diagnosed if patients were positive for either Warthin-Starry staining or quantitative real-time polymerase chain reaction (real-time PCR), and excluded if both were negative. Accuracy of 13C-UBT under different cut-off points was calculated, and the factors affecting 13C-UBT were analyzed. Results: A total of 208 patients were included, of whom 129 were H. pylori-positive. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 13C-UBT were 71.32%, 83.54%, 64.08%, and 87.62%, respectively. When the cut-off point was changed to 2.15‰, the NPV of 13C-UBT reached a maximum (76.47%); when the cut-off point was changed to 4.95‰, PPV reached its maximum (93.22%). Therefore, the original gray zone (2‰-6‰) was adjusted to 2‰-4.95‰. Gastric antral intestinal metaplasia (OR = 3.055, 95% CI: 1.003-9.309) was an independent risk factor for false-negative 13C-UBT. Conclusions: Accuracy of 13C-UBT over 2‰-6‰ was poor, and the gray zone was changed to 2‰-4.95‰. 13C-UBT results over 2‰-4.95‰ should be interpreted with caution during mass screening of H. pylori, especially for patients with gastric antral intestinal metaplasia.

Long-Term Outcome of Gastric Mild-Moderate Dysplasia: A Real-World Clinical Experience.

BACKGROUND & AIMS: The natural course of gastric mild-moderate dysplasia in a country with high incidence of gastric cancer (GC) is relatively unknown. We aimed to determine the long-term cumulative incidence of and risk factors for advanced neoplasia in patients with gastric dysplasia. METHODS: This was a single-center observational study including all consecutive patients diagnosed with gastric mild-moderate dysplasia between 2000 and 2017. Follow-up data were collected until December 2019. We determined the cumulative incidence of advanced neoplasia and identified risk factors with Cox regression. RESULTS: A total of 3489 consecutive participants were followed for a median of 4.19 years from initial mild-moderate dysplasia diagnosis. The median surveillance interval between index endoscopy and next follow-up endoscopy was 1.08 years, and more than half of patients had at least 3 surveillance gastroscopies. During the study period, the majority of participants did not show disease progression, either with dysplasia not detected (51.4%) or with persistent dysplasia (46.1%). There were 88 (2.9%) patients (5.13 per 1000 patient-years) who progressed to advanced neoplasia within a median of 4.3 years. The annual incidence of advanced neoplasia and GC were 0.43% and 0.26%, respectively, within 5 years of mild-moderate dysplasia diagnosis. Increasing age, male sex, moderate dysplasia, dysplasia detected in fundus or cardia at index endoscopy, and persistent Helicobacter pylori infection during follow-up were independent risk factors for developing advanced neoplasia. CONCLUSIONS: Even in a country with high incidence of GC, the majority of patients with gastric mild-moderate dysplasia did not experience disease progression in the long term. Intensified surveillance during the first 5 years after mild-moderate dysplasia detection is suggested.

Timing of Aspirin Use Among Patients With Colorectal Cancer in Relation to Mortality: A Systematic Review and Meta-Analysis.

Background: Exposure of aspirin has been associated with reduced risk of colorectal cancer (CRC) incidence, but aspirin use in relation to CRC patients' mortality remains undetermined. It is necessary to quantify the association between aspirin use and CRC mortality. Methods: Two authors independently searched the electronic databases (PubMed, Embase, and the Cochrane Library) from 1947 through April 25, 2020. All observational studies assessing the association between different timing of aspirin use and CRC mortality were included. The effect size on study outcomes was calculated using random-effect model and presented as risk ratio (RR) with 95% confidence interval (CI). Heterogeneity, publication bias, and quality of included studies were also assessed. Results: A total of 34 studies were included in this systematic review and meta-analysis. Prediagnosis aspirin use was not associated with CRC-specific mortality (RR = 0.91, 95% CI = 0.79 to 1.05) and all-cause mortality (RR = 0.87, 95% CI = 0.57 to 1.31). A statistically significant association between continued aspirin use and improvement in both CRC-specific mortality (RR = 0.76, 95% CI = 0.70 to 0.81) and all-cause mortality (RR = 0.83, 95% CI = 0.74 to 0.93) was observed. Postdiagnosis use of aspirin was associated only with reduced all-cause mortality (RR = 0.80, 95% CI = 0.69 to 0.94). Conclusions: Continued aspirin use before and after CRC diagnosis has the most advantage regarding the improvement of CRC mortality. Nevertheless, further prospective trials and mechanistic studies are highly warranted.