重症真菌性角膜炎患者的临床特征分析

目的:探讨重症真菌性角膜炎病因、人群特征及临床特点。方法:搜集2008-01/2013-11就诊于我院眼科的233例233眼重症真菌性角膜炎患者的临床资料,回顾性分析其病因、人群特征、临床特点等情况。结果:重症真菌性角膜炎233例患者中,男153例(65.7%),男女比例约为1.9∶1;年龄分布中,中老年龄段人数居多,平均年龄52.7±11.3岁;居住地多为农村(78.1%);并且其职业以农民为主(66.1%),发病患者文化程度普遍较低(59.7%);重症患者中,188例(80.7%)患者具有明确的眼部外伤史,以植物性外伤为主(60.9%)。主要致病菌属为镰刀菌属,为90例(57.3%),其次为曲霉菌属47例(29.9%);治疗中手术率为87.9%。其中多数行穿透性角膜移植术,为83例(52.9%),在镰刀菌及曲霉菌感染的重症角膜炎患者中,行穿透性角膜移植术者比例较高,为58.4%(80/137);行眼内容剜除术或眼球摘除术的重症患者中,68.4%(13/19)的患者为镰刀菌属感染。结论:我院重症真菌性角膜炎患者多为农村居住的中老年男性农民,可能与其经济条件及诊疗意识差有关。其主要致病菌为镰刀菌及曲霉菌属,穿透性角膜移植手术为主要治疗手段,且预后差的重症患者多为镰刀菌感染。     

Dectin-1 agonist curdlan modulates innate immunity to Aspergillus fumigatus in human corneal epithelial cells

AIM: To explore the immunomodulatory effects of curdlan on innate immune responses against Aspergillus fumigatus (A. fumigatus) in cultured human corneal epithelial cells (HCECs), and whether C-type lectin receptor Dectin-1 mediates the immunomodulatory effects of curdlan.METHODS:The HCECs were stimulated by curdlan in different concentrations (50, 100, 200, 400 μg/mL) for various time. Then HCECs pretreated with or without laminarin (Dectin-1 blocker, 0.3 mg/mL) and curdlan were stimulated by A. fumigatus hyphae. The mRNA and protein production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined by real-timequantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The protein level of Dectin-1 was measured by Western blot.RESULTS: Curdlan stimulated mRNA expression of TNF-α and IL-6 in a dose and time dependent manner in HCECs. Curdlan pretreatment before A. fumigatus hyphae stimulation significantly enhanced the expression of TNF-α and IL-6 at mRNA and protein levels compared with A. fumigatus hyphae stimulation group (P<0.05). Both curdlan and A. fumigatus hyphae up-regulated Dectin-1 protein expression in HCECs, and Dectin-1 expression was elevated to 1.5- to 2-fold by curdlan pretreatment followed hyphaestimulation. The Dectin-1 blocker laminarin suppressed the mRNA expression and protein production of TNF-α and IL-6 induced by curdlan and hyphae (P<0.05).CONCLUSION:These findings demonstrated that curdlan pretreatment enhanced the inflammatory response induced by A. fumigatus hyphae in HCECs. Dectin-1 is essential for the immunomodulatory effects of curdlan. Curdlan may have high clinical application values in fungal keratitis treatment.     

Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges

Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.     

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

Background:

Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.

Methods:

Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).

Results:

Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C_max), 91.43 ± 30.82 μg·h⁻¹ ·ml⁻¹, 55.49 ± 37.58 μg·h⁻¹ ·ml⁻¹, 96.50 ± 47.24 μg·h⁻¹ ·ml⁻¹, 101.47 ± 33.07 μg·h⁻¹ ·ml⁻¹, respectively, for area under the concentration-time curve (AUC_{0−24 h}).

Conclusions:

Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).     

Low plasma DHEA-S increases mortality risk among male hemodialysis patients

Objective

The incidence of chronic kidney disease (CKD) is on the rise. CKD patients are at high risk of cardiovascular (CVD) and all-cause mortality. CKD patients have several endocrine disorders, including low levels of dehydroepiandrosterone sulfate (DHEA-S). In the general population, low levels of DHEA-S are associated with high CVD and all-cause mortality. The aim of this study was to analyze the prognostic value of plasma DHEA-S on the survival of CKD patients on hemodialysis.

Method

This was a single-center prospective cohort study on two hundred CKD patients on hemodialysis, which assessed the prognostic value of plasma DHEA-S on their survival.

Result

We found that plasma DHEA-S levels were negatively associated with age, and positively associated with dialysis duration and plasma creatinine, albumin, and phosphate levels in hemodialysis men. Elderly patients with co-morbidities (i.e. diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease), poorer fluid control which was evaluated by higher cardiothoracic ratio, and low plasma creatinine and albumin levels seemed to have poor prognosis in hemodialysis men. Furthermore, low plasma DHEA-S levels were significantly associated with CVD-related [hazard ratio (HR) = 3.877; P = 0.021], non-CVD-related (HR = 3.522; P = 0.016), and all-cause mortality (HR = 3.667; P = 0.001) in hemodialysis men. But low plasma DHEA-S levels were not significantly associated with CVD-related, non-CVD-related, and all-cause mortality in hemodialysis women. Multivariate Cox regression analysis suggested that low plasma DHEA-S levels are significantly and independently associated with all-cause mortality in hemodialysis men (HR = 2.933; P = 0.033).

Conclusion

The study suggested that low plasma DHEA-S was independently and significantly associated with all-cause mortality in CKD hemodialysis men.     

The rapid effects of eicosapentaenoic acid (EPA) enriched phospholipids on alleviating exercise fatigue in mice

It has been reported that docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) and phospholipids (PLs) play an important role in alleviating exercise fatigue. However, the difference of DHA and EPA in ameliorating exercise fatigue is still unclear. Furthermore, the comparative study about DHA/EPA-PLs and nonpolar DHA/EPA on exercise fatigue has not been reported. In the present study, the effects of DHA and EPA on exercise fatigue was firstly compared by conducting an exhaustion test, and the results showed that triglyceride (TG) with high ratio of EPA had a more significant effect on alleviating exercise fatigue than TG with a low ratio of EPA in mice. Therefore, eicosapentaenoic acid–ethyl ester (EPA–EE) and EPA–PL were then selected to compare the rapid effects of polar and nonpolar DHA/EPA on exercise fatigue in mice by a weight-loaded swimming exhaustion test. A single intake of EPA–PL but not EPA–EE significantly alleviated exercise fatigue in mice by increasing the lactic acid recycling rate as well as inhibiting glycogen consumption and muscle injury, suggesting that EPA–PL exhibited a rapid effect on alleviating exercise fatigue. The study might represent a potential novel candidate or targeted dietary pattern for alleviating exercise fatigue.

EPA-PL has rapid effects on alleviating exercise fatigue by inhibiting lactic acid accumulation, glycogen consumption and muscle injury.     

CEACAM5 has different expression patterns in gastric non-neoplastic and neoplastic lesions and cytoplasmic staining is a marker for evaluation of tumor progression in gastric adenocarcinoma

Objective

The aim of this study was to investigate the expression patterns of CEACAM5 in non-neoplastic and neoplastic gastric lesions, as well as its application in the differential diagnosis and its relationship with tumor progression.

Methods

CEACAM5 expression was detected by immunohistochemical staining in the serial sections of the gastric neoplastic and non-neoplastic lesions. The impacts of CEACAM5 expression patterns on tumor progression were evaluated by statistics, the clinical and pathological data included sex, age, tumor extension, lymph node involvement and tumor staging.

Results

There was no CEACAM5 expression in normal gastric epithelial cells. In hyperplastic polyps, CEACAM5 was expressed with apical membranous staining in the hyperplastic and prolonged gastric pit adjacent to the surface. Intestinal metaplasia (IM) expressed CEACAM5 mainly with membranous pattern, and some cases showed membranous staining mixed with cytoplasmic staining. GIN expressed CEACAM5 mainly with membranous staining, but the mixed staining of cytoplasmic and membranous patterns increased, and especially in the high grade GIN, cytoplasmic staining of CEACAM5 began to occur. Compared with IM and GIN, CEACAM5 expression patterns of hyperplastic polyp showed a significant difference (P = 0.000). IM, low grade GIN and the whole GIN showed no significant difference in CEACAM5 expression patterns (P = 0.355), but IM and high grade GIN showed a significant difference (P = 0.027). There was a significant difference between low and high grade GIN (P = 0.002). GIN and well-differentiated carcinomas showed no significant difference (P = 0.070), but low grade GIN and well differentiated carcinomas showed a significant difference (P = 0.006). In gastric adenocarcinomas, CEACAM5 expression patterns showed a significant difference in tumor grading (P = 0.010) and Laurén classification (P = 0.001). In histological grading, well differentiated carcinomas showed more membranous staining than moderately and poorly differentiated, and more cytoplasmic CEACAM5 staining was detected in moderately and poorly differentiated carcinomas. Similar to that, in Laurén classification, intestinal carcinomas showed more membranous staining, and diffuse carcinomas showed more cytoplasmic staining. Moreover, CEACAM5 expression patterns showed a significant difference in tumor extension (P = 0.012), lymph node involvement (P = 0.015) and tumor staging (P = 0.002), suggesting that CEACAM5 should be involved in tumor progression. In advanced carcinomas, CEACAM5 was expressed with more cytoplasmic staining regardless of the histological classification.

Conclusion

CEACAM5 had different expression patterns in gastric non-neoplastic and neoplastic lesions. The CEACAM5 expression patterns were associated with tumor progression. Membranous staining of CEACAM5 might be a marker of premalignancy in gastric lesions, and cytoplasmic CEACAM5 might enhance tumor invasion and migration and be an evaluated marker for progressive and advanced gastric cancer. Also, it might be useful for the differential diagnosis of gastric premalignant lesions.     

Inhibition of human thrombin by the constituents of licorice: inhibition kinetics and mechanistic insights through in vitro and in silico studies

Thrombin inhibition therapy is a practical strategy to reduce thrombotic and cardiovascular risks via blocking the formation of blood clots. This study aimed to identify naturally occurring thrombin inhibitors from licorice (one of the most popular edible herbs), as well as to investigate their inhibitory mechanisms. Among all tested licorice constituents, licochalcone A was found as the most efficacious agent against human thrombin (IC₅₀ = 7.96 μM). Inhibition kinetic analyses demonstrated that licochalcone A was a mixed inhibitor against thrombin-mediated Z-Gly-Gly-Arg-AMC acetate hydrolysis, with a K_i value of 12.23 μM. Furthermore, mass spectrometry-based chemoproteomic assays and molecular docking simulations revealed that licochalcone A could bind to human thrombin at both exosite I and the catalytic site. In summary, our findings demonstrated that the chalcones isolated from licorice were a new class of direct thrombin inhibitors, also suggesting that licochalcone A was a promising lead compound for developing novel anti-thrombotic agents.

Licochalcone A, a bioactive compound from licorice, displayed strong inhibition of thrombin.     

Primary myelofibrosis with concurrent CALR and MPL mutations: A case report

BACKGROUNDPrimary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by recurrent mutations in the JAK2, CALR, and MPL genes. The CALR and MPL co-mutation is very rare. To our knowledge, no more than five cases have been reported. Here, we report a case of PMF in which a CALR and MPL co-mutation was detected by next-generation sequencing (NGS) technology, and a literature review was performed.CASE SUMMARYA 73-year-old woman was admitted to our hospital in 2018 due to abdominal distension. The patient had splenomegaly, lymphadenopathy, leukopenia, anemia, and immature granulocytes in peripheral blood. There were dacrocytes and atypical megakaryocytes in bone marrow, and megakaryocytic proliferation was very active, accompanied by reticulin fibrosis grade 2. By NGS analysis of the bone marrow sample, we detected mutations in CALR, MPL, and PIK3RI, while JAK2 V617F and BCR-ABL were negative. Therefore, the patient was diagnosed with PMF and received oral ruxolitinib. However, the spleen and hematologic responses were poor. We review the literature, analyze previous reports of the mutation sites in our patient and differences between our patient and other reported cases of co-mutated CALR and MPL genes, and discuss the reason why the CALR and MPL co-mutations are rare and possible mechanisms and their impact on the prognosis of patients.CONCLUSIONCALR and MPL mutations can be concurrent in MPN, but they are rare. The use of NGS may help to identify more patients with co-mutated CALR and MPL genes. This will help to further explore the mechanism and its impact on these patients to develop appropriate treatment strategies.     

罕见表型的8p11骨髓增殖综合征的特征

目的:提高对罕见表型的8p11骨髓增殖综合征(eight p11 myeloproliferative syndrome,EMS)临床表现、实验室检查特征、诊断及治疗的认识.方法:总结1例罕见累及T/B/髓三系的EMS病例临床、实验室特征及接受异基因造血干细胞移植治疗过程,同时结合既往文献报道的2例类似病例进行讨论.结...