Insights into adeno-associated virus-based ocular gene therapy: A bibliometric and visual analysis.

BACKGROUND: Adeno-associated virus (AAV) plays a vital role in ocular gene therapy and has been widely studied since 1996. This study summarizes and explores the publication outputs and future research trends of AAV-based ocular gene therapy. METHODS: Publications and data about AAV-based ocular gene therapy were downloaded from the Web of Science Core Collection or ClinicalTrials.gov database. The publications and data were analyzed by Microsoft Excel, CiteSpace, VOS viewer, and a free online platform (http://bibliometric.com). RESULTS: Totally 832 publications from the Web of Science Core Collection relevant to AAV-based ocular gene therapy were published from 1996 to 2022. These publications were contributed by research institutes from 42 countries or regions. The US contributed the most publications among these countries or regions, notably the University of Florida. Hauswirth WW was the most productive author. "Efficacy" and "safety" are the main focus areas for future research according to the references and keywords analysis. Eighty clinical trials examined AAV-based ocular gene therapy were registered on ClinicalTrials.Gov. Institutes from the US and European did the dominant number or the large proportion of the trials. CONCLUSIONS: The research focus of the AAV-based ocular gene therapy has transitioned from the study in biological theory to clinical trialing. The AAV-based gene therapy is not limited to inherited retinal diseases but various ocular diseases.

Estrogens revert neutrophil hyperplasia by inhibiting Hif1α-cMyb pathway in zebrafish myelodysplastic syndromes models.

Myelodysplastic syndromes (MDS) are characterized by daunting genetic heterogeneity and a high risk of leukemic transformation, which presents great challenges for clinical treatment. To identify new chemicals for MDS, we screened a panel of FDA-approved drugs and verified the neutrophil hyperplasia inhibiting role of 17ß-estradiol (E2, a natural estrogen) in several zebrafish MDS models (pu.1G242D/G242D, irf8Δ57Δ/57 and c-mybhyper). However, the protective mechanism of estrogen in the development of hematological malignancies remains to be explored. Here, analyzing the role of E2 in the development of each hematopoietic lineage, we found that E2 exhibited a specific neutrophil inhibiting function. This neutrophil inhibitory function of E2 is attributed to its down-regulation of c-myb, which leads to accelerated apoptosis and decreased proliferation of neutrophils. We further showed that knockdown of hif1α could mimic the neutrophil inhibiting role of E2, and hif1α overexpression could reverse the protective function of E2. Collectively, our findings highlight the protective role of E2 on MDS by inhibiting hif1α-c-myb pathway, suggesting that E2 is a promising and effective drug for hematopoietic tumors associated with abnormal neutrophil hyperplasia.

High-throughput membrane-anchored proteome screening reveals PIEZO1 as a promising antibody-drug target for human esophageal squamous cell carcinoma.

BACKGROUND: Esophageal carcinoma is one of the most fatal cancers worldwide. In China, over 90% of esophageal cancer patients are diagnosed with esophageal squamous cell carcinoma (ESCC). Currently, the survival and prognosis of ESCC patients are not satisfying because of insufficient early screening and lack of efficacious medication. Accumulating studies have suggested that antibody-drug conjugates (ADC) represent a promising antitumor strategy. METHOD: Here, we carried out a specific membrane proteome screening with ESCC patients' samples using a high-throughput antibody microarray to uncover potential targets for ADC development. Candidates were validated with expression and cytotoxicity evaluation both in vitro and in vivo. RESULTS: Our data have shown that the Piezo-Type Mechanosensitive Ion Channel Component 1 (PIEZO1) is particularly overexpressed in human ESCC tumors and can be efficiently internalized when bound with its monoclonal antibody. Furthermore, the PIEZO1 antibody combined with monomethyl auristatin E (MMAE) can specifically kill PIEZO1 high-expressed ESCC tumor cells by inducing cell cycle arrest and apoptosis. More importantly, the Anti-PIEZO1-MMAE can significantly suppress tumor progression in ESCC xenograft tumor models without any obvious side effects. CONCLUSION: Taken together, our work demonstrates that PIEZO1 is a promising target to develop ADCs for human ESCC treatment, providing a new strategy for ESCC patients' personalized therapy.

Association Between Urinary Protein-to-Creatinine Ratio and Chronic Kidney Disease Progression: A Secondary Analysis of a Prospective Cohort Study.

Objective: Studies on the association between urinary protein-to-creatinine ratio (UPCR) and chronic kidney disease (CKD) progression are limited. This study aimed to investigate the relationship between UPCR and CKD progression in a Japanese population. Methods: The present research was a secondary analysis of a prospective cohort study. Eight hundred and ninety-six subjects from the research of CKD-ROUTE in Japan were included. All the patients were new visitors or first referred to the participating centers of nephrology between October 2010 and December 2011. The target-independent variable was UPCR measured at baseline. The dependent variable was CKD progression and the estimated glomerular filtration rate (eGFR) changes during follow-up. We used Cox proportional hazards regression to investigate the association between UPCR and CKD progression risk. To address UPCR and CKD progression's non-linearity, a multivariate Cox proportional hazards regression analysis with cubic spline functions model and smooth curve fitting (penalized spline method) were conducted. We further used a generalized linear mixed model to explore the relationship between UPCR and the changes of eGFR. Result: The mean age of the included patients was 67.2 ± 13.4 years old. Two hundred and thirty-four people occurred CKD progression during follow-up. The present study showed that UPCR was independently associated with CKD progression in the multivariate analysis [HR = 1.164, 95% CI (1.116, 1.215)]. The non-linear relationship between UPCR and CKD progression was explored in a dose-dependent manner, with an obvious inflection point of 1.699. Furthermore, our findings indicated that the tendency of the effect sizes on both the left and right sides of the inflection point was not consistent [left HR: 4.377, 95% CI (2.956, 6.483); right HR: 1.100, 95% CI (1.049-1.153)]. Using the linear mixed-effects regression model, we found that UPCR was an independent predictor of the longitudinal changes in eGFR (p < 0.001 for the interaction term with time). Conclusion: This study demonstrates a nonlinear positive relationship between UPCR and CKD progression in the Japanese population. UPCR is also an independent predictor of the longitudinal changes in eGFR.

Non-linear relationship between albumin-corrected calcium and 30-day in-hospital mortality in ICU patients: A multicenter retrospective cohort study.

Objective: Albumin-corrected calcium is usually calculated to reflect the real serum calcium level of the whole body by physicians. However, studies on the association between albumin-corrected calcium and 30-day in-hospital mortality in Intensive Care Unit (ICU) patients are rare. The purpose of our study was to explore the association between baseline albumin-corrected calcium and 30-day in-hospital mortality in the American ICU population. Methods: A multicenter retrospective cohort study of 102,245 ICU patients in the eICU-CRD v2.0 from the USA during 2014-2015 was performed. The average age was 63.7 ± 16.9 years, of which 55,313 (53.7%) were men and 47,758 (46.3%) were women. The association between albumin-corrected calcium and 30-day in-hospital mortality was analyzed by Cox proportional-hazards regression, smooth curve fitting, piecewise linear regression, subgroup analyses, and a series of sensitivity analyses. Results: We found that among ICU patients with calcium abnormalities, more than 95% were mild hypocalcemia or mild hypercalcemia. The risk of 30-day in-hospital mortality will increase by 10% in the ≥7.5-< 8.5 mg/dl subgroup (OR=1.1, 95% CI 1.0-1.3) or 20% in the ≥10.3-<12 mg/dl subgroup (OR=1.2, 95% CI 1.1-1.3) when the albumin-corrected calcium level increases by 1 mg/dl. Additionally, the relationship between albumin-corrected calcium and 30-day in-hospital mortality was U shaped; the inflection point was 8.9 mg/dl (log likelihood ratio test P = 0.005). Finally, after a series of sensitivity analyses, we found that the relationship between albumin-corrected calcium and 30-day in-hospital mortality remained significant. Conclusion: In a large nationally representative cohort of ICU patients, abnormalities in albumin-corrected calcium, particularly slight hypocalcemia or slight hypercalcemia, were associated with an increased 30-day in-hospital mortality risk, and yet the findings in this study need to be further confirmed by prospective studies.

Multifocal glioblastoma-two case reports and literature review.

BACKGROUND: Multifocal glioblastoma is a rare type of glioblastoma with worse prognosis. In this article, we aimed to report two cases of classical multifocal glioblastoma. CASE PRESENTATION: In case 1, a 47-year-old male presented with dizziness, and once had a sudden loss of consciousness accompanied by convulsion of limbs. Contrast-enhanced MRI showed multiple lesions with heterogeneously ring-enhanced characters in the left hemisphere, diagnosed as multifocal glioblastoma. He underwent a craniotomy of all lesions, concurrent radiotherapy and chemotherapy as well as additional chemotherapy of temozolomide. After 2 cycles, repeat MRI showed that the new lesions already occurred and progressed. Eventually, he abandoned the chemotherapy after the 2 cycles and died 1 year later. In case 2, a 71-year-old male presented with a history of headache, left limb weakness, and numbness. Discontinuous convulsion of limbs once occurred. Contrast-enhanced MRI showed multiple lesions located in the right hemisphere, diagnosed as multifocal glioblastoma. He underwent a right frontoparietal craniotomy of the main lesion. Hemorrhage of the residual tumor and pulmonary artery embolism occurred synchronously. Eventually, his family decided not to pursue any further treatment and opted for hospice care and he passed away within 11 days of surgery. CONCLUSIONS: We reported two cases of typical multifocal glioblastoma. Valid diagnosis is crucial; then, resection of multiple lesions and canonical radio-chemotherapy probably bring survival benefits.

Report Quality of Clinical Practice Guidelines of Rehabilitation Based on RIGHT / 中国康复理论与实践

@#Objective To evaluate the quality of reporting of clinical practice guidelines of rehabilitation.Methods A comprehensive retrieve was performed in electronic databases of PubMed, EMBASE, CNKI, China Biology Medicine disc, Wanfang data, etc., from January 1, 2017 to January 11, 2020. Supplementary searches had been done on relevant websites. Two researchers reviewed literatures and assessed the reporting quality independently by using Reporting Items for Practice Guidelines in Healthcare (RIGHT), and any disagreements needed to be discussed in a consensus meeting.Results A total of 16 guidelines were included, with an average reporting rate of (44.8±27.9)%. Among the seven domains of RIGHT, basic information was reported the highest (57.3%), and evidence (31.3%) and other information (31.3%) was the lowest. The reporting rate was less as the guidelines published in China than in foreign contries (OR = 0.80, 95%CI 0.56-1.16), in original version than in update version (OR = 0.79, 95%CI 0.54-1.16); and higher as developed by various societies or associations than developed by non-societies or associations (OR = 1.15, 95%CI 0.82-1.61), however, no statistically significant difference was found in above comparisons.Conclusion Current clinical practice guidelines of rehabilitation reported with low quality. It is proposed that future guideline developers should report guidelines after RIGHT statements, including key information and content, in order to improve the quality of reporting guidelines.

Nicotine exposure impairs germ cell development in human fetal ovaries cultured in vitro.

In the present paper, we found that human fetal ovaries (at ~16 weeks) express the transcripts for several subunits of the nicotinic acetylcholine receptor (nAChR). Exposure to the drug in vitro resulted in the marked increase of apoptosis in the ovaries in a time and dose-dependent manner. Evidence that adverse nicotine effects are potentially due to an increased level of reactive oxygen species (ROS) and consequent DNA damage, both in the ovarian somatic cells and germ cells, are reported. After 4 days of culture, exposure to 1 mM and 10 mM nicotine caused a 50% and 75% decrease, respectively, in the number of oogonia/oocytes present in the fetal ovaries. These results represent the first indication that nicotine may directly cause apoptosis in cells of the fetal human ovary and may lead to a reduction of the ovarian reserve oocytes and consequent precocious menopause in mothers smoking during pregnancy.

[Seasonal Variation of Carbon Fractions in PM2.5 in Heze].

PM2.5 samples were collected in Heze from August 2015 to April 2016. Eight carbon fractions were analyzed by a thermal/optical carbon analyzer, and organic carbon (OC) and elemental carbon (EC) analyses were obtained. The OC/EC ratio and the correlation between OC and EC were analyzed. Secondary organic carbon (SOC) mass concentration was estimated by the OC/EC ratio method; and eight carbon fractions were analyzed using a principal component analysis. The results showed that:① The annual average mass concentrations of OC and EC were 1.2-60.6 µg·m-3 and 0.6-24.8 µg·m-3, respectively; and the characterization of OC and EC percentages in PM2.5 during different seasons were similar with winter > spring > autumn > summer. ② The annual average OC/EC ratio was 2.6±1.0, and the correlations between OC and EC during spring, summer, autumn, and winter were 0.91, 0.56, 0.86, and 0.75, respectively, and the estimated mass concentration of SOC was (4.7±5.0) µg·m-3. ③ The characterization of eight carbon fractions percentages in PM2.5 in the different seasons demonstrated similar seasonal variations, with EC1 having the highest percentage and EC3 having the lowest percentage. The result of the principal component analysis showed that coal burning, motor vehicle emissions, and biomass burning were the major sources of carbon.

Di-(2-ethylhexyl) phthalate and bisphenol A exposure impairs mouse primordial follicle assembly in vitro.

Bisphenol-A (BPA) and diethylhexyl phthalate (DEHP) are estrogenic compounds widely used in commercial plastic products. Previous studies have shown that exposure to such compounds have adverse effects on various aspects of mammalian reproduction including folliculogenesis. The objective of this study was to examine the effects of BPA and DEHP exposure on primordial follicle formation. We found that germ cell nest breakdown and primordial follicle assembly were significantly reduced when newborn mouse ovaries were exposed to 10 or 100 µM BPA and DEHP in vitro. Moreover, BPA and DEHP exposure increased the number of TUNEL positive oocytes and the mRNA level of the pro-apoptotic gene Bax in oocytes. These effects were associated with decreased expression of oocyte specific genes such as LIM homeobox 8 (Lhx8), factor in the germline alpha (Figla), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and newborn ovary homeobox (Nobox). Interestingly, BPA and DEHP exposure also prevented DNA demethylation of CpG sites of the Lhx8 gene in oocytes, a process normally associated with folliculogenesis. Finally, folliculogenesis was severely impaired in BPA and DEHP exposed ovaries after transplantation into the kidney capsules of immunodeficient mice. In conclusion, BPA and DEHP exposures impair mouse primordial follicle assembly in vitro.

Exposure to diethylhexyl phthalate (DEHP) results in a heritable modification of imprint genes DNA methylation in mouse oocytes.

Diethylhexyl phthalate (DEHP) is an estrogen-like compound widely used as a plasticizer in commercial products and is present in medical devices, and common household items. It is considered an endocrine disruptor since studies on experimental animals clearly show that exposure to DEHP can alter epigenetics of germ cells. This study was designed to assess the effects of DEHP on DNA methylation of imprinting genes in germ cells from fetal and adult mouse. Pregnant mice were treated with DEHP at doses of 0 and 40 µg DEHP/kg body weight/day from 0.5 to 18.5 day post coitum. The data revealed DEHP exposure significantly reduced the percentage of methylated CpG sites in Igf2r and Peg3 differentially methylated regions (DMRs) in primordial germ cells from female and male fetal mouse, particularly, in the oocytes of 21 dpp mice (F1), which were produced by the pregnant micetreated with DEHP. More surprisingly, the modification of the DNA methylation of imprinted genes in F1 mouse oocytes was heritable to F2 offspring which exhibit lower percentages of methylated CpG sites in imprinted genes DMRs. In conclusion, DEHP exposure can affect the DNA methylation of imprinting genes not only in fetal mouse germ cells and growing oocytes, but also in offspring's oocytes.

Notch pathway regulates female germ cell meiosis progression and early oogenesis events in fetal mouse.

A critical process of early oogenesis is the entry of mitotic oogonia into meiosis, a cell cycle switch regulated by a complex gene regulatory network. Although Notch pathway is involved in numerous important aspects of oogenesis in invertebrate species, whether it plays roles in early oogenesis events in mammals is unknown. Therefore, the rationale of the present study was to investigate the roles of Notch signaling in crucial processes of early oogenesis, such as meiosis entry and early oocyte growth. Notch receptors and ligands were localized in mouse embryonic female gonads and 2 Notch inhibitors, namely DAPT and L-685,458, were used to attenuate its signaling in an in vitro culture system of ovarian tissues from 12.5 days post coitum (dpc) fetus. The results demonstrated that the expression of Stra8, a master gene for germ cell meiosis, and its stimulation by retinoic acid (RA) were reduced after suppression of Notch signaling, and the other meiotic genes, Dazl, Dmc1, and Rec8, were abolished or markedly decreased. Furthermore, RNAi of Notch1 also markedly inhibited the expression of Stra8 and SCP3 in cultured female germ cells. The increased methylation status of CpG islands within the Stra8 promoter of the oocytes was observed in the presence of DAPT, indicating that Notch signaling is probably necessary for maintaining the epigenetic state of this gene in a way suitable for RA stimulation. Furthermore, in the presence of Notch inhibitors, progression of oocytes through meiosis I was markedly delayed. At later culture periods, the rate of oocyte growth was decreased, which impaired subsequent primordial follicle assembly in cultured ovarian tissues. Taken together, these results suggested new roles of the Notch signaling pathway in female germ cell meiosis progression and early oogenesis events in mammals.

Effects of diethylhexyl phthalate (DEHP) given neonatally on spermatogenesis of mice.

We previously demonstrated that the effects of diethylhexyl phthalate (DEHP) alter reproduction function on male mice. Immature male mice were treated daily with DEHP from postnatal day 7-21, 7-35, 7-49, in a dose-dependent manner. As results, both the quality and quantity of spermatozoa were decreased in 60-day-old mice. The results by RT-PCR analysis indicated that DDx3Y, Usp9Y, RBM, E1F1AY, EGF, FSHR and EGFR genes were down-regulated, and LHR, Cyp17a1 and Cyp19a1 were down-regulated in response to DEHP. These genes were selected based on their markedly increased or decreased expression levels. However, DEHP had no effect on the meiotic process and recombination levels in male mouse germ cells. Treatment with DEHP induced histopathological changes in the testes. Taken together, these results provide a new insight into the molecular mechanisms underlying the detrimental impacts of DEHP in humans and wildlife.

The analyses on dust pollution of one underground iron mine from 1991 to 2010 / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>The main purpose of this work was to give the evidence of reasonable and feasible dust control measures which will be taken in the future by analyzing the trend of dust concentration from 1991 to 2010 and identifying working faces with the severe dust contamination in one underground iron mine.</p><p><b>METHODS</b>The data was from routine monitoring between the years 1991 and 2010, which enclosed the total dust concentrations and silica contents. China National Standard of Occupational exposure limits for hazardous agents in the workplace used to judge whether the dust concentration exceeded the National Standard.</p><p><b>RESULTS</b>The general trend of total dust concentration from 1991 to 2010 was decreased, especially maximum and average levels. The highest exceeding rate was 43.16% in 1993 and the best years were 2009 and 2010, but the exceeding rates were still over 30%. The dust exposure levels varied with different work faces. The mining and supporting were the most severe dust pollution faces which the highest ultra exceeding rates were 51.61% and 51.48% and the maximum exceeding times were 64.6 and 16.4 respectively. The next was constructing face with 40.23% exceeding rate and 24.6 times more than standard.</p><p><b>CONCLUSION</b>The trend of total dust concentration from 1991 to 2010 was decreased, but the dust exceeding rate was still high. The strong measures should be taken to control the dust pollution in this iron mine, especially mining and supporting faces.</p>