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.

LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses.

LRRC8 family proteins on the plasma membrane play a critical role in cellular osmoregulation by forming volume-regulated anion channels (VRACs) necessary to prevent necrotic cell death. We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. LRRC8 proteins on lysosome membranes generate large lysosomal volume-regulated anion channel (Lyso-VRAC) currents in response to low cytoplasmic ionic strength conditions. When a double-leucine L706L707 motif at the C terminus of LRRC8A was mutated to alanines, normal plasma membrane VRAC currents were still observed, but Lyso-VRAC currents were absent. We used this targeting mutant, as well as pharmacological tools, to demonstrate that Lyso-VRAC currents are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis. Thus, Lyso-VRACs allow lysosomes of mammalian cells to act as the cell`s "bladder." When Lyso-VRAC current was selectively eliminated, the extent of necrotic cell death to sustained stress was greatly increased, not only in response to hypoosmotic stress, but also to hypoxic and hypothermic stresses. Thus Lyso-VRACs play an essential role in enabling cells to mount successful homeostatic responses to multiple stressors.

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.

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.

[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).

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.

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.

Mucosal chemokine CXCL17: What is known and not known.

CXCL17, the last described chemokine, has recently been found to be abundantly and specifically expressed in mucosal sites, while its receptor is still not well determined. Accumulative studies indicate that CXCL17 could potentially exhibit chemotactic, anti-inflammatory, antimicrobial activities under multiple biological conditions. However, the mechanism by which it contributes to the physiological and pathological processes within specific mucosal tissues is still far from being fully elucidated. In this present review, we therefore summarize the current available evidence of CXCL17 with specific emphasis on its biological role and pathophysiological significance, in order to aid in the advancement of CXCL17-related studies.

Integrative proteomic and metabolomic analyses reveal the mechanism by which bismuth enables Helicobacter pylori eradication.

BACKGROUND: Bismuth-based drugs are used to treat Helicobacter pylori infection; however, the antibacterial activity of bismuth, especially against H. pylori, has not been fully elucidated. In this study, the mechanisms by which bismuth exerts its detrimental effects on H. pylori were evaluated. Methods Six H. pylori strains isolated from different patients were cultured with or without bismuth; proteins and metabolites differentially expressed in these two sets of bacteria were detected via data independent acquisition proteomic and gas chromatography-mass spectrometry metabolic approaches, respectively. Gene ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes database were used to identity pathway enrichment. RESULTS: Bismuth inhibited H. pylori growth in vitro via the following mechanisms: downregulation of virulence proteins CagA and VacA; disruption of flagella assembly responsible for bacterial colonization; and inhibition of antioxidant enzymes, including catalase, catalase-related peroxidase, and superoxide dismutase. Diverse metabolic pathways related to growth and RNA translation in H. pylori were disrupted by bismuth. Bismuth treatment impaired many biological processes in H. pylori, including antioxidant response and purine, pyrimidine, amino acid, and carbon metabolism. Conclusions The findings of this study suggest that motility, virulence factors CagA and VacA, antioxidant defense system, and many important metabolic pathways associated with bacterial growth, including nucleotide and amino acid metabolism and translation in H. pylori, are inhibited by bismuth. This study provides novel insights into the mechanism by which bismuth eradicates H. pylori upon being incorporated into quadruple therapy.

The impact of Helicobacter pylori infection, eradication therapy, and probiotics intervention on gastric microbiota in young adults.

BACKGROUND: The impact of probiotics on non-Helicobacter pylori gastric microbiota and its role in microbial restoration after eradication were relatively unknown. We aimed to explore the effect of H. pylori eradication and probiotic intervention on gastric microbiota in young adults. METHODS: Fifty-six H. pylori-negative and 95 H. pylori-positive subjects aged 19-30 were included in this study. H. pylori-infected individuals were randomly assigned to quadruple therapy, probiotics supplemented quadruple therapy, or probiotics monotherapy group. Gastric mucosa and gastric juice samples were collected before and 2 months after treatment for 16SrRNA gene sequencing. RESULTS: The gastric microbial community structure and composition differed from H. pylori-negative subjects 2 months after successful H. pylori eradication. The α diversity of gastric mucosal microbiota significantly increased and was higher than H. pylori-negative subjects, while the α diversity of gastric juice microbiota decreased and was lower than the H. pylori-negative. After probiotics supplemented eradication treatment, Bifidobacterium was enriched in gastric mucosa, Lactobacillus was enriched in gastric juice, potentially pathogenic bacteria such as Fusobacterium and Campylobacter decreased, and the microbial diversity was closer to that of H. pylori-negative subjects compared to quadruple therapy group. Probiotics monotherapy significantly altered the diversity, community structure, and composition of gastric microbiota but showed no advantage in H. pylori inhibition and upregulating beneficial bacteria such as Bifidobacterium and Lactobacillus and related metabolism pathways. Certain potentially pathogenic bacteria such as Fusobacterium increased after probiotic monotherapy. CONCLUSION: H. pylori eradication significantly disrupted gastric microbiota in young adults and could not be restored in a short time. Probiotics supplementation partially helped restore the gastric dysbiosis caused by eradication therapy, but it might be unnecessary for H. pylori-infected young adults to take probiotics alone.

Endoscopic grading of gastric atrophy on risk assessment of gastric neoplasia: A systematic review and meta-analysis.

BACKGROUND AND AIM: Endoscopic examination of gastric atrophy has been developed to determine the extent of atrophy by identifying the atrophic border of gastric mucosa, but its value in predicting the risk of developing gastric neoplasms is not quantified. Thus, this systematic review and meta-analysis aim to assess the incidence risk of gastric neoplasms on the basis of endoscopic grading of gastric atrophy. METHODS: Two authors independently searched the electronic databases (PubMed, Embase, and the Cochrane Library) from inception through December 31, 2019, without language restriction. The effect size on study outcomes is calculated using random-effects model and presented as risk ratio (RR) with 95% confidence interval (CI). Heterogeneity, publication bias, and quality of included studies were also assessed. RESULTS: Fourteen retrospective studies are identified to perform systematic review and meta-analysis, 11 were cohort studies, and three were cross-sectional research. The pooled RR for developing gastric neoplasms is 3.89 (95% CI 2.92-5.17) among general patients with severe endoscopic atrophy. For patients who underwent endoscopic resection for early gastric neoplasms, nearly two times increased risk of synchronous or metachronous neoplasms is pooled (RR = 1.96, 95% CI 1.39-2.75). In terms of the type of endoscopic atrophy, patients with open-type endoscopic atrophy have a higher risk of gastric cancer development (RR 8.02; 95% CI 2.39-26.88) than those with close type. [Correction added on 22 December 2020, after first online publication: '(RR = 7.27; 95% CI 1.64-32.33)' has been corrected to '(RR 8.02; 95% CI 2.39-26.88)'] CONCLUSIONS: Grading endoscopic atrophy according to the Kimura-Takemoto classification can assess the risk of gastric neoplasia development. Patients with severe or open-type endoscopic gastric atrophy at baseline should undergo rigorous surveillance to early detect premalignant lesions and cancer.

A meta-analysis of biologic therapies on risk of new or recurrent cancer in patients with rheumatoid arthritis and a prior malignancy.

OBJECTIVES: To explore the risk of new and recurrent cancer in adult RA patients with prior malignancy and subsequently exposed to biologic therapies. METHODS: Separate searches were performed of PubMed, EMBASE and Cochrane Library and conference proceedings for observational studies reporting cancer incidence or recurrence in patients with RA and prior malignancy treated with biologics and conventional synthetic DMARDs (csDMARDs). Mantel-Haenszel fixed-effects method was conducted to calculate relative risk and 95% CI. RESULTS: A total of 12 studies involving 13 598 patients and 32 473 patient-years of follow-up were included (10, 3 and 1 studies for TNF inhibitors [TNFi], rituximab and anakinra, respectively). The crude incidence of new and recurrent cancer per 1000 patient-years were 34.4 for TNFi, 32.3 for rituximab, 32.3 for anakinra and 31.8 for csDMARDs. In the quantitative meta-analysis, biologics were not associated with an increased risk of new or recurrent cancer compared with csDMARDs in patients with RA and prior cancer (TNFi: relative risk = 0.95, 95% CI = 0.83, 1.09; rituximab: relative risk = 0.89, 95% CI = 0.52, 1.53). Secondary analyses of stratification of cancer types, the interval between initiation of TNFi and prior cancer diagnosis, and duration of TNFi exposure, found similar results. CONCLUSION: Compared with csDMARDs, there is no increased risk of developing cancer overall or some specific subtypes in RA patients with a prior cancer receiving biologics. More investigations are warranted to explore the risk of cancer development in individual cancer as well as to determine optimal time to initiate biologic therapy after the diagnosis of cancer or completion of cancer treatment.

Effect of statin use on cardiovascular events and all-cause mortality in immune-mediated inflammatory diseases: A systematic review and meta-analysis involving 148,722 participants.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are associated with an increased risk of premature cardiovascular disease and all-cause mortality. Given lipid-lowering and anti-inflammatory properties, statins theoretically provide greater survival benefits for patients with IMIDs. OBJECTIVE: We aimed to evaluate the impact of statin on all-cause mortality and cardiovascular risk in patients with IMIDs, and examine whether the effect varies between primary prevention and secondary prevention. METHODS: We systematically searched PubMed, EMBASE and Cochrane Library to identify eligible studies evaluating the association between statin use and all-cause mortality or cardiovascular events in IMIDs. Data were pooled using fixed-effects or random-effects meta-analysis according to I2 and pooled hazard ratios (HRs) and 95 % confidence intervals (CIs) were used as summary statistic. RESULTS: Our meta-analysis included 12 studies that comprised 148,722 patients with IMIDs (57,670 statin users, 91,052 statin non-users) contributing more than 840,113 patient-years. In pooled analysis, statin initiation was associated with 28 % decreased risk of all-cause mortality (random-effects: meta-HR 0.72, 95 % CI 0.65-0.80), 23 % decreased risk of major adverse cardiovascular events (fixed-effects: meta-HR 0.72, 95 % CI 0.62-0.83). Subgroup analysis of patients with rheumatoid arthritis showed similar results (fixed-effects: meta-HR 0.77, 95 % CI 0.67-0.89 for all-cause mortality; meta-HR 0.75, 95 % CI 0.63-0.88 for major adverse cardiovascular events). Furthermore, the protective role of statin in decreasing mortality was stronger in patients receiving statin for primary prevention of cardiovascular diseases than that for secondary prevention (fixed-effects: meta-HR 0.64, 95 % CI 0.59-0.70; meta-HR 0.84, 95 % CI 0.80-0.89, respectively), although both were statistically significant. Additional analysis yielded similar benefit from statin usage between females and males regarding mortality. CONCLUSION: Statin use was associated with lower risks of mortality and cardiovascular events, with greater benefits for primary prevention in those IMIDs patients without prior cardiovascular disease.

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: To investigate the effect of Janus kinase inhibitors (Jakinibs) on cardiovascular risk in adult patients with rheumatoid arthritis (RA) via a meta-analysis of randomised controlled trials (RCTs). METHODS: PubMed, Embase and Cochrane library were thoroughly searched for RCTs reporting safety issues in patients with RA receiving Jakinibs, from inception to October 2018. The primary and secondary outcomes were all cardiovascular events (CVEs) and major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs). OR and 95% CI were calculated using the Mantel-Haenszel fixed-effect method. RESULTS: 26 RCTs randomising 11 799 patients were included. No significant difference was observed regarding all CVEs risk following Jakinibs usage in general (OR 1.04 (0.61 to 1.76), p = 0.89), tofacitinib (OR 0.63 (0.26 to 1.54), p = 0.31), baricitinib (OR 1.21 (0.51 to 2.83), p = 0.66), upadacitinib (OR 3.29 (0.59 to 18.44), p = 0.18), peficitinib (OR 0.43 (0.07 to 2.54), p = 0.35) or decernotinib (OR 1.12 (0.13 to 10.11), p = 0.92). Likewise, there was no significant difference for Jakinibs treatment overall regarding occurrence of MACEs (OR 0.80 (0.36 to 1.75), p = 0.57) or VTEs (OR 1.16 (0.48 to 2.81), p = 0.74). Dose-dependent impact of Jakinibs on the risks of all CVEs, MACEs and VTEs was not observed in tofacitinib (5 mg vs 10 mg), upadacitinib (15 mg vs 30 mg), whereas baricitinib at 2 mg was found to be safer than 4 mg in all CVEs incidence (OR 0.19 (0.04 to 0.88), p = 0.03). CONCLUSION: The existing evidence from RCTs indicated no significant change in cardiovascular risk for Jakinib-treated patients with RA in a short-term perspective, but postmarketing data are sorely needed to ascertain their cardiovascular safety, especially at the higher dose, due to increased risk of thromboembolism events for both tofacitinib and baricitinib at higher dosage.

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.

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.

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.

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.