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Kai Dong,1,2 Ying Zhang,2 Hong Rui Ji,2 Ze Lin Guan,2 Dan Yang Wang,2 Zi Yang Guo,2 Shu Jing Deng,2 Bin Yang He,2 Jian Feng Xing,2 Cui Yu You1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Jian Feng Xing, School of Pharmacy, Xi’an Jiaotong University, 76 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of China, Tel +86-29-82655139, Fax +86-29-82655139, Email xajdxjf@mail.xjtu.edu.cn Cui Yu You, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of China, Tel +86-29-85323241, Fax +86-29-85323240, Email ycy720123@163.comBackground: The M1/M2 polarization of intestinal macrophages exerts an essential function in the pathogenesis of ulcerative colitis (UC), which can be adjusted to alleviate the UC symptoms.Purpose: A kind of pH-sensitive lipid calcium phosphate core-shell nanoparticles (NPs), co-loading with dexamethasone (Dex) and its water-soluble salts, dexamethasone sodium phosphate (Dsp), was constructed to comprehensively regulate macrophages in different states towards the M2 phenotype to promote anti-inflammatory effects.Methods: Dex and Dsp were loaded in the outer lipid shell and inner lipid calcium phosphate (Cap) core of the LdCaPd NPs, respectively. Then, the morphology of NPs and methods for determining drug concentration were investigated, followed by in vitro protein adsorption, stability, and release tests. Cell experiments evaluated the cytotoxicity, cellular uptake, and macrophage polarization induction ability of NPs. The in vivo distribution and anti-inflammatory effect of NPs were evaluated through a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced BALB/c mice ulcerative colitis model.Results: The LdCaPd NPs showed a particle size of about 200 nm and achieved considerable loading amounts of Dex and Dsp. The in vitro and in vivo studies revealed that in the acidic UC microenvironment, the cationic lipid shell of LdCaPd underwent protonated dissociation to release Dex first for creating a microenvironment conducive to M2 polarization. Then, the exposed CaP core was further engulfed by M1 macrophages to release Dsp to restrict the pro-inflammatory cytokines production by inhibiting the activation and function of the nuclear factor kappa-B (NF-κB) through activating the GC receptor and the NF kappa B inhibitor α (I-κBα), respectively, ultimately reversing the M1 polarization to promote the anti-inflammatory therapy.Conclusion: The LdCaPd NPs accomplished the sequential release of Dex and Dsp to the UC site and the inflammatory M1 macrophages at this site, promoting the regulation of macrophage polarization to accelerate the remission of UC symptoms. Keywords: ulcerative colitis, calcium phosphate, macrophage polarization, colon targeted delivery system, dexamethasone

Kai Dong,1,2 Shu-Jing Deng,2 Bin-Yang He,2 Zi-Yang Guo,2 Ze-Lin Guan,2 Xue Leng,2 Rui-Rui Ma,2 Dan-Yang Wang,2 Jian-Feng Xing,2 Cui-Yu You1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Jian-Feng Xing, School of Pharmacy, Xi’an Jiaotong University, 76 Yanta West Road, Xi’an, 710061, Shaanxi, People’s Republic of China, Tel +86-29-82655139, Fax +86-29-82655139, Email xajdxjf@mail.xjtu.edu.cn Cui-Yu You, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China, Tel +86-29-85323241, Fax +86-29-85323240, Email ycy720123@163.comBackground: As the first-line drug to treat ulcerative colitis (UC), long-term use of glucocorticoids (GCs) produces severe toxic and side effects. Local administration as enema can increase the local GCs concentrations and reduce systemic exposure to high oral doses by directly delivering GCs to the inflammation site in the distal colorectum. However, UC patients are often accompanied by diarrhea, leading to the short colonic residence time of GCs and failure to exert their function fully.Purpose: A kind of mucoadhesive nanoparticles (NPs) loading different dexamethasone derivatives (DDs) were developed, which could attach to the positively charged inflammatory colonic mucosa through electrostatic adsorption after administered by enema, thereby improving the local concentration and achieving effective targeted therapy for UC.Methods: Two DDs, dexamethasone hemisuccinate and dexamethasone phosphate, were synthesized. In NPs preparation, The core PEI-DDs NPs were built by the electrostatic adsorption of DDs and the cationic polymer polyethyleneimine (PEI). Then, the natural polyanionic polysaccharide sodium alginate (SA) was electronically coated around NPs to construct the final SA-PEI-DDs NPs, followed by the in vitro stability and release tests, in vitro and in vivo colonic mucosal adhesion tests. In the in vivo anti-UC test, the experimental colitis mice were induced by 2,4,6-trinitrobenzenesulfonic acid. The body weight and disease activity index changes were measured, and the myeloperoxidase activity, pro-inflammatory cytokines concentration, and hematoxylin and eosin staining were also investigated to evaluate the therapeutic effect of NPs.Results: The structures of two DDs were demonstrated by 1H-NMR and MS. Both NPs were negatively charged and achieved high loading efficiency of DDs, while their particle sizes were significantly different. NPs showed good stability and sustained release properties in the simulated colonic environment. Moreover, the negative charge on the of NPs surface made them easier to adhere to the positively charged inflammatory colonic mucosa, thereby enhancing the enrichment and retention of DDS in the colitis site. Furthermore, the NPs exhibited better therapeutic effects than free Dex on the experimental colitis mice induced by TNBS through the enema rectal.Conclusion: These results indicated the mucoadhesive NPs as a kind of novel nano-enema showed great potential to achieve efficient treatment on UC.Keywords: ulcerative colitis, glucocorticoids, mucoadhesive, polyethyleneimine, sodium alginate

Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next-generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26-2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67-4.50) and in a biobank meta-analysis (OR, 1.16; 95% CI, 1.04-1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9-edited HEK293T cell lines show that loss-of-function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a +/- mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a +/+ , are further generated. In cerulein-stimulated pancreatitis models, Sec16a +/- mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

A 40-year-old man presented with recurrent ocular surface masses in his left eye persisting for over a year. Despite undergoing resection of the conjunctival mass and receiving anti-inflammatory treatment at another hospital, the mass reappeared within a week post-surgery. Over the past 6 months, the mass gradually increased in size, accompanied by a decline in vision. Following conjunctival mass excision combined with amniotic membrane transplantation at Beijing Tongren Hospital, Capital Medical University, histopathological examination revealed a fungal infection of the conjunctiva, resulting in a diagnosis of fungal conjunctivitis and conjunctival granuloma in the left eye. The patient received systemic antifungal medications and local therapy, resulting in a stable condition with no recurrence of the mass.

Background & Aims: Protease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP., Methods: All coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control., Results: We identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress., Conclusions: Our genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Older adults with asthma have the greatest burden and worst outcomes, and there is increasing evidence that chronic cough (CC) is associated with asthma severity and poor prognosis. However, the clinical characteristics of older adult patients with both asthma and CC remain largely unknown., Methods: Participants with stable asthma underwent two cough assessments within 3 months to define the presence of CC. Patients were divided into four groups based on CC and age (cut-off ≥60 years). Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to investigate asthma exacerbations. Logistic regression models were used to explore the interaction effect of CC and age on asthma control and exacerbations., Results: In total, 310 adult patients were prospectively recruited and divided into four groups: older CC group (n=46), older non-CC group (n=20), younger CC group (n=112) and younger non-CC group (n=132). Compared with the younger non-CC group, the older CC group had worse asthma control and quality of life and increased airflow obstruction. The older CC group showed an increase in moderate-to-severe exacerbations during the 12-month follow-up. There was a significant interaction effect of CC and ageing on the increased moderate-to-severe exacerbations (adjusted risk ratio 2.36, 95% CI 1.47-3.30)., Conclusion: Older asthma patients with CC have worse clinical outcomes, including worse asthma control and quality of life, increased airway obstruction and more frequent moderate-to-severe exacerbations, which can be partly explained by the interaction between CC and ageing., Competing Interests: Conflict of interest: W-J. Song is Deputy Chief Editor of this journal. The other authors declare that they have no relevant conflicts of interest., (Copyright ©The authors 2023.)

Objective: To analyze the clinical features of corneal interface infection. Methods: A retrospective case series study was conducted to explore the clinical features of interstitial corneal infection. The data of eight patients (eight eyes) who were diagnosed with interstitial corneal infection after undergoing corneal transplant or corneal refractive surgery and visited Beijing Tongren Eye Center from January to December 2018 were collected, including two male and six female patients aged between 18 and 55 years (median age, 27 years). The patients' general information, surgical type, onset time, and clinical manifestations were recorded. The lesions were examined by in vivo corneal laser confocal microscopy (IVCM), and microbial cultures and drug sensitivity tests were performed. Results: Among the 8 patients, 4 had undergone small-incision lenticule extraction (SMILE), 2 had undergone lamellar keratoplasty, and 2 had undergone endothelial keratoplasty. The onset of infection occurred between 2 and 30 days after surgery, with a mean of 9.8 days. Among the 3 patients who had undergone SMILE, the treatment outcome was corneal haze or opacity, while the remaining 5 cases required corneal transplantation for interstitial infections. The pathogens of the 4 cases of interstitial infection after corneal transplantation were all Candida species. Under the IVCM, patients with corneal interstitial bacterial infections showed a large amount of necrotic tissue with no normal tissue structure in the corneal stroma, with infiltration of inflammatory cells and local aggregation of inflammatory cells, but no typical pathogen was observed. Patients with fungal infections showed fungal hyphae under the corneal cap (filamentous fungal infection) or dense, punctate, high-reflection structures in the corneal interstitial space (yeast-like fungal infection). Conclusions: Corneal interlayer infection is difficult to diagnose early and has a poor prognosis. IVCM can assist in early diagnosis. The pathogen spectrum of corneal interlayer infection may differ from that of corneal infection caused by trauma.

Objective: To explore the demographic distribution, clinical signs, and clinical types of herpes simplex virus keratitis (HSK). Methods: Retrospective case series. The data of 1 015 cases of HSK (1 054 eyes) diagnosed in Beijing Tongren Eye Center, Beijing Tongren Hospital of Capital Medical University from January 2010 to June 2019 were collected. The patients included 613 males and 402 females, and the age was 47.43±16.79 years. Information of the patients such as age, sex, the season of onset, eye laterality, and clinical signs was assessed. Slit-lamp microscopy and corneal fluorescein staining were used to locate the anatomical position of lesions. HSK was classified into epithelial type, neurotrophic type, stromal type, endothelial type, and mixed type. The distribution data was compared by the Chi-square test or Fisher's exact test. Results: There were 41 children (≤14 years old; 4.04%), 338 youth (15-44 years old; 33.30%), 374 middle-aged (45-59 years old; 36.85%), and 262 elderly (≥60 years old; 25.81%) patients. The type was epithelial in 246 cases (24.24%), neurotrophic in 27 cases (2.66%), stromal in 372 cases (36.65%), endothelial in 274 cases (26.99%), and mixed in 96 cases (9.46%). There was statistically significant difference in clinical typing among the different age groups ( χ 2 =30.197, P =0.003). Epithelial HSK was found in 141 males (57.32%) and 105 females (42.68%), neurotrophic HSK in 16 males (59.26%) and 11 females (40.74%), stromal HSK in 226 males (60.75%) and 146 females (39.25%), endothelial HSK in 171 males (62.41%) and 103 females (37.59%), and mixed HSK in 59 males (61.46%) and 37 females (38.54%). There was no statistically significant difference in clinical classification of keratitis between genders ( χ 2 =1.519, P =0.823). Among the cases of mixed type, there were 21 cases of epithelial-stromal type (21.88%), 30 cases of epithelial-endothelial type (31.25%), 37 cases of stromal-endothelial type (38.54%), 1 case of epithelial-neurotrophic type (1.04%), and 7 cases of neurotrophic-stromal type (7.29%). Conclusions: HSK occurs mainly in middle-aged and young adults, but rarely in children. The proportion of males is higher than that of females. The proportion of stromal HSK is highest, and 9.46% of patients present mixed HSK.

The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to efficiently inhibit Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle, which could have important implications in establishing an effective strategy for combating SARS-CoV-2 viral infections., (© 2022. The Author(s).)

Introduction: South Sudan is facing a protracted humanitarian crisis with increasing population vulnerability. The study aimed to describe the epidemiology of COVID-19 in displaced populations in South Sudan., Methods: the study involved the internally displaced populations (IDP) in Bentiu IDP camp, South Sudan. This was a descriptive cross-sectional study involving individuals that met the COVID-19 probable and confirmed case definitions from May 2020 to November 2021. Case data were managed using Microsoft Excel databases., Results: the initial COVID-19 case in Bentiu IDP camp was reported on 2 May 2020. The overall cumulative attack rate (cases per million) was 3,230 for Bentiu IDP and 1,038 at the national level. The COVID-19 Case Fatality Ratio (CFR) among the IDPs was 19.08% among confirmed and 1.06% at the national level. There was one wave of COVID-19 transmission in the IDPs that coincided with the second COVID-19 wave in South Sudan for the period May 2020 to November 2021. Adult males aged 20-49 years were the most affected and constituted 47.1% of COVID-19 cases. Most severe cases were reported among adults 60-69 years (53%) and ≥ 70 years (80%). The risk of COVID-19 death (deaths per 10,000) increased with age and was highest in patients aged ≥ 60 years at 64.1. The commonest underlying illnesses among COVID-19 deaths was HIV-related illness, heart disease, and tuberculosis., Conclusion: COVID-19 constitutes a significant impact on internally displaced populations of South Sudan. The COVID-19 response in displaced populations and the high-risk groups therein should be optimized., Competing Interests: The authors declare no competing interests., (©Joseph Francis Wamala et al.)

In eutrophic water, attached bacteria of Microcystis play an important role in the formation, development, and degradation of Microcystis blooms. A novel actinobacterium, designated as JXJ CY 35 T , was isolated from the culture mass of Microcystis aeruginosa FACHB-905 (Maf) collected from Lake Dianchi, Yunnan Province, China. Strain JXJ CY 35 T was gram-positive, acid-fast staining, aerobic, with short rod-shaped cells, positive for catalase, and negative for oxidase. The isolate was able to grow at 10.0-36.0°C, pH 4.0-10.0, and tolerate up to 5.0% (w/v) NaCl, with optimal growth at 28°C, pH 7.0-8.0, and 0% (w/v) NaCl. Cell-wall peptidoglycan contains aspartic acid, glutamic acid, glycine, and alanine, with mannose, ribose, galactose, and arabinose as whole-cell sugars. Polar lipids consist of diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), glycolipid (GL1-3), phosphoglycolipid (PGL), phosphatidylinositol (PI), and unidentified lipid (L1). The predominant menaquinone was MK-9. Major fatty acids (>10%) were C 17:1 ω7c (37.0%) and C 18:1 ω9c (18.9%). The complete genome sequence of strain JXJ CY 35 T was 6,138,096 bp in size with a DNA G + C content of 68.3%. Based on 16S rRNA gene sequences, it has 98.2% similarity to Mycolicibacterium arabiense JCM 18538 T . The digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) values between strain JXJ CY 35 T and the closest five type strains M. arabiense JCM 18538 T , M. goodii ATCC 700504 T , M. mageritense DSM 44476 T , M. austroafricanum DSM 44191 T , and Mycobacterium neglectum CECT 8778 T were 52.1, 20.3, 20.3, 20.6, and 19.8%, and 92.7, 75.5, 75.6, 76.0, and 75.2%, respectively. On the basis of the above taxonomic data and differences in physiological characteristics from the closely related type strain, strain JXJ CY 35 T was determined to represent a novel species of genus Mycolicibacterium , for which the name Mycolicibacterium lacusdiani sp. nov., is proposed. The type strain is JXJ CY 35 T (=KCTC 49379 T = CGMCC 1.17501 T ). Different inoculation dosages of the type strain JXJ CY 35 T could exhibit different effects on the growth of Maf and its toxin synthesis and release. Strain JXJ CY 35 T could promote the growth of Maf by providing it with available phosphorus, nitrogen, probably vitamins, and plant growth hormones., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xiao, Chen, Chen, Deng, Xiong, Tian and Zhang.)

Background: Cough is often the most prominent and intractable symptom reported by patients with asthma, but few studies have explored the characteristics of patients with asthma and with chronic cough (CC) in a real-world setting. Methods: In a prospective cohort study, patients ages ≥ 18 years with stable asthma were consecutively recruited at the West China Hospital, Sichuan University. The patients were classified as having asthma with CC (the CC group) or asthma with non-CC (the non-CC group) after 3 months of optimized asthma therapy according to standard guidelines. Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to assess asthma exacerbations. Results: Of 323 patients with asthma, 127 patients were assigned to the CC group and 196 patients were assigned to the non-CC group. The participants with CC were older and had more airflow obstruction; worse asthma control and quality of life; increased airway inflammation; upper respiratory tract infection as a trigger; and more comorbidities, such as psychological dysfunction, rhinitis, chronic obstructive pulmonary disease, and bronchiectasis. They reported greater work productivity loss and daily activity impairment, and increased moderate-to-severe exacerbations. Conclusion: The participants with asthma and with CC had a significant disease burden, with increased exacerbations, health-care utilization, and impaired work productivity and daily activity. These observations indicated potential clinical implications in patients with asthma and with CC, and call for more attention to this aspect of asthma.

Background: A hormonal role in the development of non-small cell lung cancer (NSCLC) has been well documented, and the classic estrogen receptors (ERs)-ERα and ERβ have been extensively investigated over the past decade. The expression of ERβ was found to be high and display biological activity in NSCLC, but anti-estrogen therapy targeting this receptor has shown limited efficacy for the disease. The third estrogen receptor, G protein-coupled estrogen receptor 1 (GPER1/GPR30), was recently found to be highly expressed in NSCLC. Herein, we aimed to investigate the expression profile of GPER1 and correlate it with clinicopathological factors as well as postoperative prognosis in NSCLC., Methods: We examined GPER1 and ERβ expression using immunohistochemistry among 183 NSCLC cases, including 132 lung adenocarcinoma (LUAD) with identified epidermal growth factor receptor (EGFR) mutation status and 51 squamous cell carcinoma (SCC) patients. We then conducted correlation analysis between the expression of GPER1 and clinicopathological factors and patients' postoperative prognosis., Results: Positive expression of GPER1 was categorized into 2 main classes: nuclei-GPER1 (nGPER1) and concurrent nuclei-and cytoplasm-GPER1 (n/cGPER1), according to its subcellular localization. The LUAD with wild-type EGFR (wt-EGFR) had a higher frequency of n/cGPER1 (50%) but a lower frequency of nGPER1 (31%) when compared with those with mutated EGFR (n/cGPER1: 31%, nGPER1: 41%, respectively). The expression of GPER1, regardless of subcellular localization, was positively correlated with tumor stage and lymph node metastasis. The median recurrence-free survival (mRFS) and overall survival (OS) were significantly worse in participants with n/cGPER1 expression than in those with nGPER1 or without GPER1 expression., Conclusions: This study revealed that GPER1 is aberrantly highly expressed and presents a unique GPER1 expression profile in NSCLC. The n/cGPER1 expression was significantly associated with EGFR mutation status, tumor stage, lymph node metastasis, and poor postoperative prognosis in NSCLC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-29/coif). The authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Background: Neuroinflammation, which is mainly mediated by excessive microglia activation, plays a major role in ischemic stroke. Overactivated microglia secrete numerous inflammatory cytokines, causing excessive inflammatory responses and ultimately exacerbating ischemic brain injury. Hence, compounds that attenuate neuroinflammation could become promising drug candidates for ischemic stroke. Fraxetin has an anti-inflammatory effect in many inflammatory diseases. However, whether it possesses an anti-inflammatory capacity in microglia-mediated neuroinflammation after ischemic brain injury is unknown. Our study aimed to investigate the suppression effect of fraxetin on neuroinflammation in lipopolysaccharide (LPS)-activated microglia and establish whether fraxetin could alleviate ischemic brain injury in a rodent model of ischemic stroke., Methods: For the in vitro experiment, primary microglia were obtained from 1-day-old C57/BL6J mice. The cells were activated with LPS and treated with fraxetin at a non-cytotoxic concentration. Real-time PCR, enzyme-linked immunosorbent assays, and immunofluorescence staining were used to evaluate the anti-inflammatory effects of fraxetin. The potential molecular mechanisms were explored and verified through RNA-sequencing analysis, western blotting and real-time PCR. For the in vivo experiment, focal ischemia was induced by middle cerebral artery occlusion (MCAO) in 8-week-old male C57/BL6J mice. Fraxetin (5 mg/kg) or an equal volume of saline was injected into mice intraperitoneally after MCAO, and 2% 2,3,5-triphenyltetrazolium chloride staining was applied to measure infarct volume. Behavioral tests were conducted to measure neurological deficits in the mice. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the expression of inflammatory cytokines and microglia activation in the ischemic penumbra., Results: Fraxetin effectively inhibited the expression of proinflammatory cytokines including inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1 beta, and interleukin-6 in LPS-activated microglia. Fraxetin also suppressed the PI3K/Akt/NF-κB signaling pathway in activated microglia, which contributed to its anti-inflammatory effects. Furthermore, the administration of fraxetin attenuated ischemic brain injury and behavioral deficits after stroke. Finally, fraxetin was found to attenuate the activation of microglia both in vitro and in vivo ., Conclusions: Our results suggest that fraxetin has a suppression effect on microglia-mediated neuroinflammation, and this effect is associated with the PI3K/Akt/NF-κB signaling pathway. Fraxetin may therefore have potential neuroprotective properties for ischemic stroke., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-4636/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own and in complex with angiotensin-converting enzyme 2 (ACE2) or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein and change binding epitopes to many current antibodies. In the ACE2-binding site, compensating mutations strengthen receptor binding domain (RBD) binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.

Chemotherapeutic agents and photosensitizers often suffer from poor tumor selectivity, high side toxicity, or low water solubility. To address these problems, various drug delivery systems (DDS) have been explored but most of them are toxic, difficult to synthesize, or of single function. In order to design a highly biocompatible, conveniently prepared, multi-functional drug delivery system, herein, an aptamer of vascular endothelial growth factor (VEGF) and a cytosine (C)-DNA fragment were grafted on the surface of superparamagnetic iron oxide nanoparticles (SPION), and then a chemotherapeutic agent daunomycin (DNM) and a photosensitizer 5, 10, 15, 20-tetra (phenyl-4-N-methyl-4-pyridyl) porphyrin (TMPyP) were self-assembled with the hybridized VEGF-based DNA structure. By loading DNM and TMPyP, the DDS displayed strong chemotherapeutic/phototherapeutic capability against cancer cells via mechanisms such as mitochondrial dysfunction and ROS elevation, which triggered the apoptosis of the tumor cells. The dual delivery of chemotherapeutical agents and photosensitizers with aptamer/C-rich DNA successfully integrated the functions of pH stimuli-responsive drug release and chemotherapeutic/phototherapeutic modalities into one single system and thus could be considered as an ideal drug delivery vehicle with great potential in clinic.

Aims: Microglia-mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post-stroke neuroinflammation is not fully understood., Methods: Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT-PCR, ELISA, and Western blot. The activation of MAPK and NF-κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume., Results: Imperatorin suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF-κB pathways might contribute to the protective effects of imperatorin., Conclusions: Imperatorin downregulated MAPK and NF-κB signaling pathways and exerted anti-inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke., (© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background & Aims: A hybrid allele that originated from homologous recombination between CEL and its pseudogene (CELP), CEL-HYB1 increases the risk of chronic pancreatitis (CP). Although suggested to cause digestive enzyme misfolding, definitive in vivo evidence for this postulate has been lacking., Methods: CRISPR-Cas9 was used to generate humanized mice harboring the CEL-HYB1 allele on a C57BL/6J background. Humanized CEL mice and C57BL/6J mice were used as controls. Pancreata were collected and analyzed by histology, immunohistochemistry, immunoblotting, and transcriptomics. Isolated pancreatic acini were cultured in vitro to measure the secretion and aggregation of CEL-HYB1 protein. Mice were given caerulein injections to induce acute pancreatitis (AP) and CP., Results: Pancreata from mice expressing CEL-HYB1 developed pathological features characteristic of focal pancreatitis that included acinar atrophy and vacuolization, inflammatory infiltrates, and fibrosis in a time-dependent manner. CEL-HYB1 expression in pancreatic acini led to decreased secretion and increased intracellular aggregation and triggered endoplasmic reticulum stress compared with CEL. The autophagy levels of pancreata from mice expressing CEL-HYB1 changed at different developmental stages; some aged CEL-HYB1 mice exhibited an accumulation of large autophagic vesicles and impaired autophagy in acinar cells. Administration of caerulein increased the severity of AP/CP in mice expressing CEL-HYB1 compared with control mice, accompanied by higher levels of endoplasmic reticulum stress., Conclusions: Expression of a humanized form of CEL-HYB1 in mice promotes endoplasmic reticulum stress and pancreatitis through a misfolding-dependent pathway. Impaired autophagy appears to be involved in the pancreatic injury in aged CEL-HYB1 mice. These mice have the potential to be used as a model to identify therapeutic targets for CP., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The carboxyl-ester lipase (CEL) gene contains a variable number of tandem repeats (VNTR) region. It remains unclear whether the number of repeats in the CEL VNTR is related to the risk of pancreatic diseases. The aim of this study was to investigate whether CEL VNTR length is associated with idiopathic chronic pancreatitis (ICP), alcoholic chronic pancreatitis (ACP), or pancreatic cancer in a cohort of Chinese patients., Methods: CEL VNTRs were genotyped in patients diagnosed with ICP (n = 771), ACP (n = 222), or pancreatic cancer (n = 263), and in healthy controls (n = 927). CEL VNTR lengths were determined using a screening method combining PCR and DNA fragment analysis., Results: Overall, the CEL VNTR lengths ranged from 5 to 22 repeats, with the 16-repeat allele ('normal' size, N) accounting for 73.82% of all observed alleles. The VNTR allele frequencies and genotype distributions were not significantly different between healthy controls and patients with ACP or pancreatic cancer. For the ICP group, allele frequencies did not differ significantly from the controls, while the frequency of the SS genotype (homozygosity for 5-15 repeats) was significantly higher in the patients (4.67%) than in the controls (1.94%) (p = 0.0014; OR = 2.47; 95% CI = 1.39-4.39)., Conclusions: There were no associations between the CEL VNTR length and ACP or pancreatic cancer. However, homozygosity for short VNTR lengths may confer susceptibility to ICP., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Thyroid cancer is the most common malignancy in human endocrine system. Increasing evidence has indicated that p62 plays a key role in tumorigenesis. The roles and underlying molecular mechanisms of P62 in thyroid cancer, however, remain to be elucidated., Methods: The expression levels of P62 in thyroid tumor tissues and thyroid cancer cells were detected by western blotting and qRT-PCR. Then, the effects of up-regulation or down-regulation of P62 on thyroid cancer cell proliferation, migration, invasion, cell cycle and apoptosis were measured by CCK-8 assay, transwell assay, flow cytometry and transwell assay, respectively. In terms of the mechanism, P62 could stimulate thyroid cancer progression by the activation of nuclear factor-kappa B (NF-κB) signaling pathway., Results: P62 was highly expressed in thyroid tumor tissues. Furthermore, high expression of p62 was observed in PTC cell lines, and especially in the K1 and TPC-1 cells. In vitro, the up-regulation of p62 promoted cell proliferation, migration, and invasion of thyroid cancer cells, whereas the knockdown of p62 resulted in the opposite effect. Knock-down of P62 increased the number of cells in the G0/G1 phase but reduced it in the S and G2/M phase. Moreover, we confirmed that overexpression of p62 inactivated NF-κB pathway with sequencing analysis and bioinformatics analysis., Conclusion: This research work suggested that p62 could promote PTC cell proliferation, migration, and invasion via NF-κB signaling pathway. Furthermore, p62 is a potential biomarker which might be closely related to the tumorigenesis in PTC. Its potential role as a therapeutic target for PTC is worthy of further study., Competing Interests: Declaration of Competing Interests The authors declare that this research has no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

TLRs recognizing PAMPS play a role in local immunity and participate in implant-associated loosening. TLR-mediated signaling is primarily regulated by IL-1 receptor associated kinase-M (IRAK-M) negatively and IRAK-4 positively. Our previous studies have proved that wear particles promote endotoxin tolerance in macrophages by inducing IRAK-M. However, whether IRAK-4 is involved in inflammatory osteolysis of wear particles basically, and the specific mechanism of IRAK-4 around loosened hip implants, is still unclear. IRAK-4 was studied in the interface membranes from patients in vivo and in particle-stimulated macrophages to clarify its role. Also, IL-1β and TNF-α levels were measured after particle and LPS stimulation in macrophages with or without IRAK-4 silenced by siRNA. Our results showed that the interface membranes around aseptic and septic loosened prosthesis expressed more IRAK-4 compared with membranes from osteoarthritic patients. IRAK-4 in macrophages increased upon particle and LPS stimulation. In the former, IL-1β and TNF-α levels were lower compared with those of LPS stimulation, and IRAK-4 siRNA could suppress production of pro-inflammatory cytokines. These findings suggest that besides IRAK-M, IRAK-4 also plays an important role in the local inflammatory reaction and contributes to prosthesis loosening.

Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.

Background: Compound sophorae decoction (CSD), a Chinese Herbal decoction, is frequently clinically prescribed for patients suffered from ulcerative colitis (UC) characterized by bloody diarrhea. Yet, the underlying mechanism about how this formulae works is remain elusive., Methods: In the present study, the experimental colitis in C57BL/6 J mice was induced by oral administration of standard diets containing 3% dextran sodium sulfate (DSS), and CSD was given orally for treatment at the same time. The clinical symptoms including stool and body weight were recorded each day, and colon length and its histopathological changes were observed. Apoptosis of colonic epithelium was studied by detecting protein expression of cleaved caspase-3, and cell proliferation by Ki-67 immunohistochemistry. Tight junction complex like ZO-1 and occludin were also determined by transmission electron microscope and immunofluorescence. The concentration of FITC-dextran 4000 was measured to evaluate intestinal barrier permeability and possible signaling pathway was investigated. Mucin2 (MUC2) and notch pathway were tested through western blot. The M1/M2 ratio in spleen and mesenteric lymph nodes were detected by flow cytometry. And the mRNA levels of iNOS and Arg1 were examined by qRT-PCR., Results: CSD could significantly alleviate the clinical manifestations and pathological damage. Body weight loss and DAI score of mice with colitis were improved and shortening of colon was inhibited. The administration of CSD was able to reduce apoptotic epithelial cells and facilitate epithelial cell regeneration. Increased intestinal permeability was reduced in DSS-induced colitis mice. In addition, CSD treatment obviously up-regulated the expression of ZO-1 and occludin and the secretion of MUC2, regulated notch signaling, and decreased the ratio of M1/M2., Conclusions: These data together suggest that CSD can effectively mitigate intestinal inflammation, promote phenotypic change in macrophage phenotype and enhance colonic mucosal barrier function by, at least in part, regulating notch signaling in mice affected by DSS-induced colitis., (Copyright © 2020. Published by Elsevier Masson SAS.)

The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate's stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro , prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases., Competing Interests: PL, ZP, CG, XC, XL, JZ, ZX, XW, HG, and S-JD were employed by Shanghai Jemincare Pharmaceuticals Co., Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Liu, Pan, Gu, Cao, Liu, Zhang, Xiao, Wang, Guo, Ju and Deng.)

Background: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies., Methods: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis., Results: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10 -5 ) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis., Conclusions: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Chronic pancreatitis (CP) is a progressive fibroinflammatory syndrome of the pancreatic tissue caused by genetic and environmental factors. Previously reported susceptibility genes in CP explain less than half of the apparent heritability. To uncover novel pathogenic mechanisms, we initially performed low-coverage whole-genome sequencing on 464 Chinese CP patients and 504 controls. The transient receptor potential cation channel, Subfamily V, Member 6 (TRPV6) gene was found to be significantly associated with CP after a burden test of aggregated rare nonsynonymous variants with a combined annotation dependent depletion score > 20 (p = .020). In the replication stage, we analyzed the entire coding sequence and exon/intron boundaries of the TPRV6 gene by Sanger sequencing in another 205 patients with CP and 105 controls. Integration of the findings from the two stages resulted in the identification of 25 TRPV6 variants: 1 rare nonsense variant, 20 rare missense variants, and 4 common missense variants. Loss-of-function variants, as determined by intracellular Ca 2+ concentration in transfected HEK293T cells, were significantly overrepresented in patients as compared to controls (9/669 [1.35%] vs. 1/609 [0.16%]; odds ratio = 8.29; p = .022). This study provides evidence suggesting that TRPV6 is a novel susceptibility gene for CP., (© 2020 Wiley Periodicals LLC.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory protein that promotes low-density lipoprotein receptor (LDLR) degradation and thereby regulating plasma levels of LDL cholesterol. Previous studies have revealed the role of the C-terminal domain (CTD) of PCSK9 in its secretion, however, how CTD regulates PCSK9 secretion is not completely understood. Additionally, SEC24A, the cargo adaptor protein of the coat protein complex II, has been implicated in the secretion of mouse PCSK9. Here, we investigated how CTD and SEC24 regulated PCSK9 secretion in humans. We found that mutant PCSK9 1-528 , in which amino acids from 529 to the end (amino acid 692) were deleted, was maturated and secreted from cells as effectively as the wild-type protein. On the other hand, lacking amino acids 454 to 692 in mutant PCSK9 1-453 significantly reduced its maturation and secretion, but to a lesser extent when compared to mutants PCSK9 1-446 , PCSK9 1-445 and PCSK9 1-444 , that all markedly impaired PCSK9 maturation. However, mutant PCSK9 1-444 virtually eliminated PCSK9 secretion while PCSK9 1-446 and PCSK9 1-445 could still be adequately detected in culture medium. Interestingly, mutation of Pro 445 to other amino acid residues considerably impaired the secretion of mutant PCSK9 1-445 but not the full-length protein. We also found that natural variants in CTD including S462P, S465L, E482G, R495Q and A522T impaired PCSK9 secretion. Further, the knockdown of SEC24A, SEC24B, SEC24C but not SEC24D reduced secretion of the full-length PCSK9 but not mutant PCSK9 1-446 . Therefore, SEC24A, SEC24B, and SEC24C facilitate endogenous PCSK9 secretion from cultured human hepatocytes, that are most likely mediated by the CTD of PCSK9. Our studies also indicate that the CTD of PCSK9 may allosterically and independently modulate the stability of the hinge region. Collectively, these data revealed that the CTD of PCSK9 and the hinge region play a critical role in PCSK9 maturation and secretion., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autotaxin-lysophosphatidic acid (ATX-LPA) axis is closely associated with several inflammation-related diseases. In the colonic mucosa of patients with chronic ulcerative colitis (UC), the expression of ATX and the percentage of Th17 cells are found to increase. However, it is unclear whether ATX-LPA axis affects the differentiation of Th17 cells in chronic UC. To investigate whether ATX-LPA axis contributes to Th17 cell differentiation, a mouse model of chronic UC was established by drinking water with DSS at intervals. ATX inhibitor was used as an intervention. The disease active index (DAI), colonic weight to length ratio, colon length, colon histopathology, and MAdCAM-1 were observed. Additionally, the expression of ATX, LPA receptor, CD34, IL-17A, IL-21, IL-6, ROR-γt, STAT3 in colonic tissue, and the percentage of Th17 cells in spleens and mesenteric lymph nodes (MLNs) were measured using different methods. ATX blockade was able to relieve symptoms and inflammatory response of DSS-induced chronic colitis. The DAI and colonic weight to length ratio were apparently decreased, while the colon length was increased. The pathological damage and colitis severity were lighter in the inhibitor group than that in the DSS group. Inhibiting ATX reduced the expression of ATX, LPA receptor, and CD34 and also decreased the percentages of Th17 cells in spleens and MLNs and the expressions of IL-17A and IL-21, as well as the factors in Th17 cell signaling pathway including IL-6, ROR-γt, and STAT3 in colonic tissue. ATX-LPA axis blockade could alleviate inflammation by suppressing Th17 cell differentiation in chronic UC.

It has long been known that canonical 5' splice site (5'SS) GT>GC variants may be compatible with normal splicing. However, to date, the actual scale of canonical 5'SSs capable of generating wild-type transcripts in the case of GT>GC substitutions remains unknown. Herein, combining data derived from a meta-analysis of 45 human disease-causing 5'SS GT>GC variants and a cell culture-based full-length gene splicing assay of 103 5'SS GT>GC substitutions, we estimate that ~15-18% of canonical GT 5'SSs retain their capacity to generate between 1% and 84% normal transcripts when GT is substituted by GC. We further demonstrate that the canonical 5'SSs in which substitution of GT by GC-generated normal transcripts exhibit stronger complementarity to the 5' end of U1 snRNA than those sites whose substitutions of GT by GC did not lead to the generation of normal transcripts. We also observed a correlation between the generation of wild-type transcripts and a milder than expected clinical phenotype but found that none of the available splicing prediction tools were capable of reliably distinguishing 5'SS GT>GC variants that generated wild-type transcripts from those that did not. Our findings imply that 5'SS GT>GC variants in human disease genes may not invariably be pathogenic., (© 2019 Wiley Periodicals, Inc.)

Objective: To analyze the sensitivity and specificity of fungal fluorescent staining in the diagnosis of fungal keratitis, and to compare it with conventional fungal culture, in vivo confocal microscopy (IVCM) and Giemsa staining. To explore its value of clinical application. Methods: Prospective case-control study. A total of 105 consecutive patients (105 eyes) diagnosed with infectious keratitis at Beijing Tongren Hospital from August 2017 to April 2018 were included. Patients with infectious keratitis were divided into fungal keratitis (FK) group and non-fungal keratitis (NFK) group by slit lamp microscopy, corneal in vivo confocal microscopy (IVCM) examination, and the results of Giemsa staining, fluorescent staining and pathogenic culture of corneal scraping from ulcer. The sensitivity and specificity of the above-mentioned examination methods for the diagnosis of fungal keratitis were analyzed. The receiver operating characteristic curve (ROC curve) and Area Under Curve (AUC) values were calculated to determine the diagnostic value of fungal fluorescent staining for fungal keratitis. Results: Among the 105 patients with infectious keratitis, 66 were fungal keratitis, 39 were non-fungal keratitis (29 cases of bacterial keratitis and 10 cases of acanthamoeba keratitis). Isolation from fungal keratitis were mainly Fusarium spp . (43.5%), followed by Alternaria spp . (21.7%) and Aspergillus spp. (19.6%). After fluorescent staining of the ulcer smear, the background of tissue demonstrated homogeneous black or weak blue fluorescence. The cell wall of fungi showed bright blue-violet to blue fluorescence, and the morphology, structure and hyphal density were easily recognized. The sensitivity of different methods for the diagnosis of corneal fungal infection were smear fluorescence staining (97.0%), IVCM (87.9%) , Giemsa staining (86.7%), and fungal culture (69.7%); the specificity of fungal culture was the highest (100%), followed by IVCM and Giemsa staining (94.9%), and fluorescent staining (87.2%). The ascending order of AUC values was: fungal culture (0.848)

Rationale : Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood. The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis. Methods : A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients. The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected. Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed. We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes. Results : We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues. Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo. We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2. Consequentially, MTA2 can stabilize the HIF-1α protein via deacetylation, which further activates HIF-1α transcriptional activity. Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1α under hypoxic conditions. Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients. Conclusions : These results suggest that feedback between MTA2TR and HIF-1α may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

To investigate the hydrochemical variation of karstic groundwaters in a vertically zoned climate region affected by human activity, Shuifang Spring and Bitan Spring in the Jinfo Mountain area of Chongqing were selected as a study site. Based on the differences between the natural state and intensity of human activity of these two springs, their hydrogeochemical characteristics and the controlling factors on karstic groundwaters were analyzed by means of independent sample t tests, the Gibbs graphic method, principle component analysis (PCA), and geochemical susceptivity analysis. The results show that differences in karst development in the vertical climatic zone leads to higher total ion concentrations in Bitan Spring than in Shuifang Spring. The hydrochemical types of Shuifang Spring and Bitan Spring are HCO 3 -Ca and HCO 3 -Ca·Mg, respectively, which reflect the lithology of their different elevations. Carbonate rock dissolution is the main source of Ca 2+ , Mg 2+ , and HCO 3 - in karstic groundwaters. Hotel sewage discharge supplies SO 4 2- , NO 3 - , PO 4 3- , K + , and Na + in Shuifang Spring, which peaked in winter and summer, while hydrochemical parameters of Bitan Spring changed smoothly throughout the year. The water quality of Bitan Spring is better than Shuifang Spring (Shuifang Spring water is classified as Class Ⅳ). PCA shows that the water-rock interaction was the first controlling factor. Hotel sewage discharge and ions from precipitation had important effects on Shuifang Spring and Bitan Spring, respectively. In addition, the effects of soil erosion and leaching caused by precipitation also impact on the water quality of two springs to some extent. The geochemical susceptibility of Shuifang Spring was greater than that of Bitan Spring; therefore, corresponding measures should be formulated according to the characteristics of these differently elevated karst systems when exploiting groundwater resources. This is especially the case for the treatment of hotel sewage.

Hair-coloring products include permanent, semi-permanent and temporary dyes that vary by chemical formulation and are distinguished mainly by how long they last. Domestic temporary hair dyes, such as fuchsin basic, basic red 2 and Victoria blue B, are especially popular because of their cheapness and facile applications. Despite numerous studies on the relationship between permanent hair dyes and disease, there are few studies addressing whether these domestic temporary hair dyes are associated with an increased cancer risk. Herein, to ascertain the bio-safety of these temporary hair dyes, we comparatively studied their percutaneous absorption, hemolytic effect and cytotoxic effects in this paper. Furthermore, to better understand the risk of these dyes after penetrating the skin, experimental and theoretical studies were carried out examining the interactions between the dyes and serum albumins as well as calf thymus (CT)-DNA. The results showed that these domestic temporary hair dyes are cytotoxic with regard to human red blood cells and NIH/3T3 cell lines, due to intense interactions with bovine serum albumin (BSA)/DNA. We conclude that the temporary hair dyes may have risk to human health, and those who use them should be aware of their potential toxic effects.

Cancer cells are known to undergo metabolic reprogramming, such as glycolysis and glutamine addiction, to sustain rapid proliferation and metastasis. It remains undefined whether long noncoding RNAs (lncRNA) coordinate the metabolic switch in pancreatic cancer. Here we identify a nuclear-enriched antisense lncRNA of glutaminase (GLS-AS) as a critical regulator involved in pancreatic cancer metabolism. GLS-AS was downregulated in pancreatic cancer tissues compared with noncancerous peritumor tissues. Depletion of GLS-AS promoted proliferation and invasion of pancreatic cancer cells both in vitro and in xenograft tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via formation of double stranded RNA with GLS pre-mRNA through ADAR/Dicer-dependent RNA interference. GLS-AS expression was transcriptionally downregulated by nutrient stress-induced Myc. Conversely, GLS-AS decreased Myc expression by impairing the GLS-mediated stability of Myc protein. These results imply a reciprocal feedback loop wherein Myc and GLS-AS regulate GLS overexpression during nutrient stress. Ectopic overexpression of GLS-AS inhibited proliferation and invasion of pancreatic cancer cells by repressing the Myc/GLS pathway. Moreover, expression of GLS-AS and GLS was inversely correlated in clinical samples of pancreatic cancer, while low expression of GLS-AS was associated with poor clinical outcomes. Collectively, our study implicates a novel lncRNA-mediated Myc/GLS pathway, which may serve as a metabolic target for pancreatic cancer therapy, and advances our understanding of the coupling role of lncRNA in nutrition stress and tumorigenesis. Significance: These findings show that lncRNA GLS-AS mediates a feedback loop of Myc and GLS, providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1.large.jpg. See related commentary by Mafra and Dias, p. 1302 ., (©2018 American Association for Cancer Research.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes LDL receptor (LDLR) degradation, increasing plasma levels of LDL cholesterol and the risk of cardiovascular disease. We have previously shown that, in addition to the epidermal growth factor precursor homology repeat-A of LDLR, at least three ligand-binding repeats (LRs) of LDLR are required for PCSK9-promoted LDLR degradation. However, how exactly the LRs contribute to PCSK9's action on the receptor is not completely understood. Here, we found that substitution of Asp at position 172 in the linker between the LR4 and LR5 of full-length LDLR with Asn (D172N) reduced PCSK9 binding at pH 7.4 (mimic cell surface), but not at pH 6.0 (mimic endosomal environment). On the other hand, mutation of Asp at position 203 in the LR5 of full-length LDLR to Asn (D203N) significantly reduced PCSK9 binding at both pH 7.4 and pH 6.0. D203N also significantly reduced the ability of LDLR to mediate cellular LDL uptake, whereas D172N had no detectable effect. These findings indicate that amino acid residues in the LRs of LDLR play an important role in PCSK9 binding to the receptor., (Copyright © 2019 Deng et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: The clinical significance of SPINK1 intronic variants in chronic pancreatitis has been previously assessed by various approaches including a cell culture-based full-length gene assay. A close correlation between the results of this assay and in silico splicing prediction was apparent. However, until now, a clinical diagnostic pipeline specifically designed to classify SPINK1 intronic variants accurately and efficiently has been lacking. Herein, we present just such a pipeline and explore its efficacy and potential utility in potentiating the classification of newly described SPINK1 intronic variants., Results: We confirm a close correlation between in silico splicing prediction and results from the cell culture-based full-length gene assay in the context of three recently reported pathogenic SPINK1 intronic variants. We then integrated in silico splicing prediction and the full-length gene assay into a stepwise approach and tested its utility in the classification of two novel datasets of SPINK1 intronic variants. The first dataset comprised 16 deep intronic variants identified in 52 genetically unexplained Chinese chronic pancreatitis patients by sequencing the entire intronic sequence of the SPINK1 gene. The second dataset comprised five novel rare proximal intronic variants identified through the routine analysis of the SPINK1 gene in French pancreatitis patients. Employing a minor allele frequency of > 5% as a population frequency filter, 6 of the 16 deep intronic variants were immediately classified as benign. In silico prediction of the remaining ten deep intronic variants and the five rare proximal intronic variants with respect to their likely impact on splice site selection suggested that only one proximal intronic variant, c.194 + 5G > A, was likely to be of functional significance. Employing the cell culture-based full-length gene assay, we functionally analyzed c.194 + 5G > A, together with seven predicted non-functional variants, thereby validating their predicted effects on splicing in all cases., Conclusions: We demonstrated the accuracy and efficiency of in silico prediction in combination with the cell culture-based full-length gene assay for the classification of SPINK1 intronic variants. Based upon these findings, we propose an operational pipeline for classifying SPINK1 intronic variants in the clinical diagnostic setting.

Objective: Compound sophorae decoction, a Chinese medicinal formulae composed of six Chinese herbs, is effective for the clinical treatment of ulcerative colitis (UC). Some of its effective monomers had been proven to have suppressive effect on UC models. The aim of this study is to further explore the mechanism whether compound sophorae decoction ameliorates dextran sodium sulfate (DSS)-induced mice colitis by regulating the balance between T helper (Th) 17 and regulatory T (Treg) cells., Methods: Experimental model of UC, established by drinking water with DSS, was treated with compound sophorae decoction and mesalazine. The stool, activity, body weight of the mice, colon length and colon histopathology were observed to evaluate severity of colitis. The concentration of cytokines in colonic tissues were detected by ELISA. The expression of phosphorylated nuclear factor-kappaB (NF-κB) p65, STAT3 and phosphorylated STAT3 in colonic tissues were determined by western blotting and immunohistochemistry. The percentage of Th17 and Treg cells in spleen and mesenteric lymph nodes (MLNs) were detected by flow cytometry. The levels of transcription factor ROR-γt and FOXP3 in colon tissues were detected by qRT-PCR and immunohistochemistry., Results: The aqueous extract of compound sophorae decoction was able to improve the symptoms and pathological damage of mice. The body weight of mice were increased and DAI were significantly decreased; ulcers were slighter than DSS group. The administration of compound sophorae decoction reduced the level of inflammatory factors interleukin (IL)-1β, tumor necrosis factor (TNF)-α and phospho-NF-κB p65, and also decreased the proportions of Th17 cells in spleen and MLNs and the expression of ROR-γt, IL-17A, STAT3, IL-6 in colonic tissues; while the percentage of Treg cells in spleen and MLNs and the expression of FOXP3, transforming growth factor (TGF)-β1, IL-10 in colonic tissues were upregulated., Conclusion: Overall, this study suggested that compound sophorae decoction significantly improves the symptoms and the pathological damage of mice with colitis and influences the immune function by regulating Th17/Treg cell balance in DSS-induced colitis in mice., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: Rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort., Methods: We performed targeted next-generation sequencing of the four CP-associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model., Results: We identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P < 0.001). Mutation-positive patients had significantly earlier median ages at disease onset and at diagnosis of pancreatic stones, diabetes mellitus and steatorrhea than mutation-negative ICP patients. Pathogenic genotypes were present in 57.1, 39.8, and 32.1% of the ICP, ACP, and SCP patients, respectively, and influenced age at disease onset and clinical outcomes in all subgroups., Conclusions: We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified.

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.

Objective: To explore the effects of icariin on the proliferation and apoptosis abilities of human ovarian cancer cells SKOV3 and multi-drug resistant SKVCR cells., Methods: Human ovarian cancer cells SKOV3 and multi-drug resistant SKVCR cells were treated with various concentrations of icariin. The inhibitory concentration and the half maximal inhibitory concentration were detected by CCK8 kit. The proliferation and apoptosis abilities of SKOV3 and SKVCR cells were measured by flow cytometry. The migration and invasion abilities of SKOV3 and SKVCR cells were evaluated by Transwell assays. The protein expression level of Caspase-3 was detected by Western blot analysis., Results: Icariin significantly suppressed the proliferation abilities of SKOV3 and SKVCR cells in a dose-dependent manner at variant levels from 5-100 μg/mL. SKOV3 and SKVCR cells were treated with 19.5 μg/mL icariin and 48.4 μg/mL icariin (0.8×IC 50 ) for 48 h, respectively. The results showed that the cell proliferation, migration and invasion abilities were markedly decreased comparing with control group, and the apoptosis rate was significantly increased as compared with control group ( P <0.05). Western blot results indicated that icariin significantly increased the protein expression level of caspase-3 in SKOV3 and SKVCR cells ( P <0.05)., Conclusion: Icariin suppressed the proliferation, migration and invasion abilities of human ovarian cancer cells. Increasing expression of Caspase-3 might be the mechanism of its enhancement of apoptosis., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.

Objective: To analyze the etiology and drug sensitivity of lacrimal canaliculitis. Methods: Retrospective study of case series. The general information, culture results and drug sensitivity results of 52 patients (including 10 males and 42 females with an average age of 60.3 years) clinically diagnosed with lacrimal canaliculitis during 2011 and 2016 at Beijing Tongren Hospital of Capital Medical University have been analyzed. The enumeration data have been tested with Chi-square method. Results: The positive rate of bacterial culture was 78.8%, and the fungal culture tests of all cases showed negative results. Sixty strains of bacteria were isolated from 41 patients whose bacterial culture tests showed positive results, Gram-positive bacteria have been confirmed as the main among the isolated bacteria with Streptococcus (18.3%), Propionibacterium (18.3%), and Streptococcus (15.0%) identified as the three common genera. Thirteen cases (25.0%, all the 13 patients were female) involved with mixed infection, 13.3% (8/60) of the isolated strains were multi-drug resistant bacteria. The drug sensitive rate of the bacteria to fluoroquinolones antibiotics(79.3%, 230/290) was higher than that to cephalosporins(62.1%, 36/58) and aminoglycoside antibiotics(56.3%, 98/174), and such differences are of statistical significance (χ(2)=7.977, 27.738, P< 0.05). Except for the fact that gram-positive bacteria are mostly sensitive to vancomycin, the sensitive rate of the bacteria to gatifloxacin was the highest and that to tobramycin was the lowest. Conclusion: Lacrimal canaliculitis tend to affect women and elderly patients. Staphylococcus, Propionibacterium, and Streptococcus are the three most common genera. Gatifloxacin may be the preferred antibiotic. Antibiotics combination therapy should be applied for multi-drug resistant bacteria. (Chin J Ophthalmol, 2018, 54: 111-114) .

Extracellular acid can have important effects on cancer cells. Acid-sensing ion channels (ASICs), which emerged as key receptors for extracellular acidic pH, are differently expressed during various diseases and have been implicated in underlying pathogenesis. This study reports that ASIC1 and ASIC3 are mainly expressed on membrane of pancreatic cancer cells and upregulated in pancreatic cancer tissues. ASIC1 and ASIC3 are responsible for an acidity-induced inward current, which is required for elevation of intracellular Ca 2+ concentration ([Ca 2+ ]i). Inhibition of ASIC1 and ASIC3 with siRNA or pharmacological inhibitor significantly decreased [Ca 2+ ]i and its downstream RhoA during acidity and, thus, suppressed acidity-induced epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. Meanwhile, downregulating [Ca 2+ ]i with calcium chelating agent BAPTA-AM or knockdown of RhoA with siRNA also significantly repressed acidity-induced EMT of pancreatic cancer cells. Significantly, although without obvious effect on proliferation, knockdown of ASIC1 and ASIC3 in pancreatic cancer cells significantly suppresses liver and lung metastasis in xenograft model. In addition, ASIC1 and ASIC3 are positively correlated with expression of mesenchymal marker vimentin, but inversely correlated with epithelial marker E-cadherin in pancreatic cancer cells. In conclusion, this study indicates that ASICs are master regulator of acidity-induced EMT. In addition, the data demonstrate a functional link between ASICs and [Ca 2+ ]i/RhoA pathway, which contributes to the acidity-induced EMT.

Aim: Recently, several studies have reported that thrombocytosis may be associated with the poor prognosis of colorectal cancer (CRC). Nevertheless, their conclusions were still controversial. Results & methodology: We searched PubMed, Embase, Cochrane Library and Web of Science up to April 2016. A total of 30 studies including 9129 patients were included in this meta-analysis. Thrombocytosis had a close relationship with the poor overall survival of CRC compared with normal platelet counts, with the pooled hazard ratios being 1.89 (95% CI: 1.45-2.47; p < 0.00001) and 1.83 (95% CI: 1.33-2.53; p = 0.0002), with univariate and multivariate analyses, respectively., Discussion & Conclusion: This meta-analysis indicated that thrombocytosis may be a cost-effective and noninvasive indicator for poor prognosis of patients with CRC, especially for overall survival.

Aim: This meta-analysis was designed to analyze and evaluate the prognostic role of preoperative or pretreatment platelet-to-lymphocyte ratio (PLR) in patients with colorectal cancer (CRC)., Method: We searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and WanFang Database up to April 2016., Results: A total of 16 studies (n = 5068 participants) were included for this meta-analysis. Elevated PLR has a close relationship with the poor overall survival of CRC, with the pooled hazard ratio being 1.88 (95% CI: 1.50, 2.36; p < 0.00001)., Conclusion: This meta-analysis indicated that pretreatment PLR may be a cost-effective and noninvasive serum biomarker for poor prognosis for patients with CRC.

Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in numerous cancers, while their function in pancreatic cancer is rarely elucidated. The present study identifies a functional lncRNA and its potential role in tumorigenesis of pancreatic cancer. Microarray co-assay for lncRNAs and mRNAs demonstrates that lncRNA-NUTF2P3-001 is remarkably overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS mRNA expression. After downregulating lncRNA-NUTF2P3-001, the proliferation and invasion of pancreatic cancer cell are significantly inhibited both in vitro and vivo, accompanying with decreased KRAS expression. The dual-luciferase reporter assay further validates that lncRNA-NUTF2P3-001 and 3'UTR of KRAS mRNA competitively bind with miR-3923. Furthermore, miR-3923 overexpression simulates the inhibiting effects of lncRNA-NUTF2P3-001-siRNA on pancreatic cancer cell, which is rescued by miR-3923 inhibitor. Specifically, the present study further reveals that lncRNA-NUTF2P3-001 is upregulated in pancreatic cancer cells under hypoxia and CoCl2 treatment, which is attributed to the binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the upstream of KRAS promoter. Data from pancreatic cancer patients show a positive correlation between lncRNA-NUTF2P3-001 and KRAS, which is associated with advanced tumor stage and worse prognosis. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumor oncogene KRAS and implicate that lncRNA-NUTF2P3-001 and miR-3923 can be applied as novel predictors and therapeutic targets for pancreatic cancer.

The blue sheep (Pseudois nayaur szechuanensis) belongs to the subfamily Caprinae, which distributes in Sichuan, Gansu, Qinghai, southeastern Xinjiang, northern Yunnan and Ningxia-Inner Mongolia border, China. In this study, the complete mitochondrial genome of P. n. szechuanensis was sequenced. The mitogenome was 16,738 bp in length, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and a non-coding control region. As in other mammals, most mitochondrial genes are encoded on the heavy strand, except for ND6 and eight tRNA genes which are encoded on the light strand. The overall base composition of the P. n. szechuanensis is 33.5% A, 26.4% T, 27.0% C, and 13.2% G. The alignment of the Pseudois species control regions exhibited high genetic variability and rich A + T content. The complete mitogenome of P. n. szechuanensis can provide an important data for the studies on phylogenetic relationship and population genetics to further explore the taxonomic status of this species.

A 50-year-old female was administered with left lower lobe lesion for 10 days. A preoperative chest computed tomography (CT) revealed a mass in the left basilar segment of the lung, about 2.1 cm × 1.7 cm in size. Therefore, video-assisted thoracic surgery (VATS) left lower lobectomy was performed. The operation takes 60 minutes. During the operation, the estimated blood loss was 15 mL. The patient was discharged on postoperative day (POD) 6 with no complications. And the pathological results confirmed the diagnosis of adenocarcinoma with no lymph nodes metastasis.

The administration of bone mesenchymal stem cells (BMSCs) could reverse experimental colitis, and the predominant mechanism in tissue repair seems to be related to their paracrine activity. BMSCs derived extracellular vesicles (BMSC-EVs), including mcirovesicles and exosomes, containing diverse proteins, mRNAs and micro-RNAs, mediating various biological functions, might be a main paracrine mechanism for stem cell to injured cell communication. We aimed to investigate the potential alleviating effects of BMSC-EVs in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model. Intravenous injection of BMSC-EVs attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI) and histological colonic damage. In inflammation response, the BMSC-EVs treatment significantly reduced both the mRNA and protein levels of nuclear factor kappaBp65 (NF-κBp65), tumor necrosis factor-alpha (TNF-α), induciblenitric oxidesynthase (iNOS) and cyclooxygenase-2 (COX-2) in injured colon. Additionally, the BMSC-EVs injection resulted in a markedly decrease in interleukin-1β (IL-1β) and an increase in interleukin-10 (IL-10) expression. Therapeutic effect of BMSC-EVs associated with suppression of oxidative perturbations was manifested by a decrease in the activity of myeloperoxidase (MPO) and Malondialdehyde (MDA), as well as an increase in superoxide dismutase (SOD) and glutathione (GSH). BMSC-EVs also suppressed the apoptosis via reducing the cleavage of caspase-3, caspase-8 and caspase-9 in colitis rats. Data obtained indicated that the beneficial effects of BMSC-EVs were due to the down regulation of pro-inflammatory cytokines levels, inhibition of NF-κBp65 signal transduction pathways, modulation of anti-oxidant/ oxidant balance, and moderation of the occurrence of apoptosis.