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The Ca2+ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO3-based tumor microenvironment (TME) responsive nanoplatform (CaNPCAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca2+-overloading synergistic therapy. In acidic TME, CaCO3 decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca2+). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated 1O2 during PDT process not only directly killed cancer cells but also destroyed the Ca2+ buffering capacity, leading to the mitochondrial Ca2+-overloading. The increased Ca2+ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca2+-overloading, the CaNPCAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. STATEMENT OF SIGNIFICANCE: In the manuscript, a CaCO3-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNPCAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca2+ buffering capacity was destroyed which led to the mitochondrial Ca2+-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca2+-overloading made the CaNPCAT+BSO@Ce6-PEG NPs present remarkable antitumor performance.

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs’ recapitulation of human tumors., Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

Multifocal electroretinogram (mfERG) is an important diagnostic tool in the clinical evaluation of central electro-retinal function of the macula. To enhance the diagnostic values and to improve its accuracy and internal consistency, it is crucial to examine carefully the endogenous and exogenous factors that affect mfERG recordings and clinical interpretations. This mini review focuses on three aspects of exogenous factors including (1) physiological variations pertaining to age and gender; (2) systemic changes owing to oxygen, blood pressure and glucose levels; (3) individual variables due to refractive status, pupil size, luminance and viewing condition.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, and its etiology and risk factors remain uncertain. AIM: To investigate the possible influence of Chinese herbal liquid containing geniposide on IMP. METHODS: The detailed formula of herbal liquid prescriptions of all patients was studied, and the herbal ingredients were compared to identify the toxic agent as a possible etiological factor. Abdominal computed tomography (CT) and colonoscopy images were reviewed to determine the extent and severity of mesenteric phlebosclerosis and the presence of findings regarding colitis. The disease CT score was determined by the distribution of mesenteric vein calcification and colon wall thickening on CT images. The drinking index of medicinal liquor was calculated from the daily quantity and drinking years of Chinese medicinal liquor. Subsequently, Spearman's correlation analysis was conducted to evaluate the correlation between the drinking index and the CT disease score. RESULTS: The mean age of the 8 enrolled patients was 75.7 years and male predominance was found (all 8 patients were men). The patients had histories of 5-40 years of oral Chinese herbal liquids containing geniposide and exhibited typical imaging characteristics (e.g., threadlike calcifications along the colonic and mesenteric vessels or associated with a thickened colonic wall in CT images). Calcifications were confined to the right-side mesenteric vein in 6 of the 8 patients (75%) and involved the left-side mesenteric vein of 2 cases (25%) and the calcifications extended to the mesorectum in 1 of them. The thickening of colon wall mainly occurred in the right colon and the transverse colon. The median disease CT score was 4.88 (n = 7) and the median drinking index was 5680 (n = 7). After Spearman's correlation analysis, the median CT score of the disease showed a significant positive correlation with the median drinking index (r = 0.842, P < 0.05). CONCLUSION: Long-term oral intake of Chinese herbal liquid containing geniposide may play a role in the pathogenesis of IMP.

At diagnosis, more than 70% of bladder cancers (BCs) are at the non-muscle-invasive bladder cancer (NMIBC) stages, which are usually treated with transurethral resection followed by intravesical instillation. For the remaining advanced cancers, systemic therapy is the standard of care, with addition of radical cystectomy in cases of locally advanced cancer. Because of the difference in treatment modalities, different models are needed to advance the care of NMIBC and advanced BC. This article gives a comprehensive review of both in vitro and in vivo BC models and compares the advantages and drawbacks of these preclinical systems in BC research.

Rationale: Zearalenone (ZEN), a pollutant in our daily diet, seriously threatens the reproductive health of humans and animals. The primordial follicle (PF) assembly in the mouse occurs during the perinatal period, which determines the whole ovarian reserve in reproductive lifespan. In the current investigation, we administered ZEN orally to perinatal mice from 16.5 days post coitum (dpc) to postnatal day 3 (PD3), and single-cell RNA sequencing (scRNA-seq) was performed on PD0 and PD3 ovarian tissues in the offspring to check ZEN toxic to primordial follicle formation at the single cell level. Methods: Ovarian tissues (in vivo) were examined by single cell RNA sequencing analysis, Immunostaining, and Western blotting. Ovarian tissues (in vitro) were examined by qRT-PCR, Immunostaining, and Western blotting. Results: We found that ZEN exposure altered the developmental trajectory of both germ cells and granulosa cells. Furthermore, after establishing the cell-cell communication network between germ cells and granulosa cells, we found that this was perturbed by ZEN exposure, especially during the Hippo signaling pathway. Conclusions: This study showed that ZEN affected the status of germ cells and granulosa cells through the Hippo signaling pathway and blocked the assembly of PFs. This research contributes to our deeper understanding of the mechanisms of toxicity in different cell types and the disruption of normal intercellular signaling by ZEN exposure.

Background lncRNAs and VEGF have been shown to have close connections with oral squamous cell carcinoma (OSCC). We explored the interaction between lncRNA NEAT1 and VEGF-A in OSCC. Methods RT-qPCR was implemented to measure levels of lncRNA NEAT1 and VEGF-A in OSCC cell lines and normal cell lines. Cell functions then were checked after regulating the expressions of lncRNA NEAT1 and VEGF-A separately. Cell viabilities were examined with CCK-8 and apoptosis rate was checked with flow cytometry. Meanwhile, EMT-related genes E-cadherin, N-cadherin, Vimentin, and Snail and Notch signaling genes Notch1, Notch2, and Jagged were evaluated by RT-qPCR. IMR-1 was applied for impeding Notch signaling pathway. Later, cell viabilities, apoptosis, and EMT were assessed. Results Expressions of lncRNA NEAT1 and VEGF-A were both increased significantly in OSCC cell lines especially in TSCC1 cell line. Suppression of lncNRA NEAT1 was associated with lower cell viabilities and EMT and higher apoptosis rate in the TSCC1 cell line. Meanwhile, knockdown of VEGF-A significantly repressed cell viabilities and EMT in the TSCC1 cell line. Magnifying functions of inhibited lncRNA NEAT1 Notch signaling pathway was obviously activated with overexpressions of lncRNA NEAT1 and VEGF-A. Adding IMR-1 significantly downregulated cell viabilities and EMT and sharply increased apoptosis in the context of lncRNA NEAT1 and VEGF-A overexpression. Conclusion LncRNA NEAT1 may upregulate proliferation and EMT and repress apoptosis through activating VEGF-A and Notch signaling pathway in vitro, suggesting an underlying regulatory factor in OSCC. Nevertheless, further research is necessary to gain a greater understanding of lncRNA NEAT1 and connections with VEGF-A in vivo and in clinical study.

OBJECTIVE To evaluate the ability of macular ganglion cell and inner plexiform layer (mGCIPL) and retinal nerve fiber layer (RNFL) thickness measurements by long-wavelength swept-source optical coherence tomography (SS-OCT) to assess retinal ganglion cell (RGC) damage in nonarteritic anterior ischemic optic neuropathy (NAION). METHODS A retrospective study of 20 patients with unilateral NAION was performed. SS-OCT scanning of the macular and peripapillary areas was performed to measure the total and six-sector thicknesses of macular RNFL (mRNFL) and mGCIPL, as well as peripapillary RNFL (pRNFL) thicknesses in global and 12 clock-hour sectors. Further comparison of these thicknesses between NAION involved eyes and uninvolved counterparts was performed in 12 of the 20 patients at 4 visits. The thickness map and en face images generated by volume data of the posterior pole over a 12 × 9-mm area were used for RNFL analysis. RESULTS Median time intervals between the visual symptom onset and first thinning occurrences of mGCIPL, mRNFL, and pRNFL were 17 days (95% Confidence Interval [CI] 14-18 days), 43 days (95% CI 32-48 days), and 70 days (95% CI 62-80 days), respectively. The thickness map indicated a significantly reduced pRNFL in the superior temporal sectors or temporal sectors after 9 weeks, and retinal damage corresponded to the superior hemisphere's mRNFL and mGCIPL. En face images showed that the RNFL thinning area gradually expanded along the retinal nerve fiber direction and progressed toward the optic nerve head. CONCLUSIONS The patterns of RGC damage in the macular and peripapillary areas of NAION eyes can be revealed by SS-OCT. Objective measurement of SS-OCT is valuable in characterizing NAION.

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer was first analyzed with The Cancer Genome Atlas (TCGA) database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anti-cancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD-1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 days to 32 days compared to vehicle only controls (p=0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI >3) and in vivo, but significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

Background Parents play important role in providing information regarding their children’s health status to healthcare providers. However, parents’ ability in reporting signs and symptoms of eye problems among their children required more in-depth investigation. Our study aimed to compare the differences of parental report regarding eye problems among their children using two different question approaches. Methods A total of 416 parents with children aged between two months old and 17 years old were participated in this cross-sectional survey. The responses of parents’ observation on signs and symptoms of eye problems were compared between one open-ended question and ten close-ended questions. We also examined the demographic contributing factors that could influence parental responses. Results The total count of reported signs and symptoms through open-ended and close-ended question was 164 and 529 reports, respectively. Parents reported more diverse (70% higher) categories of signs and symptoms in open-ended compared to close-ended questions. Parent’s ability to report eye problems using open-ended question was associated with their gender (p

To compare the thoracic magnetic resonance imaging (TMRI) features between peripheral lung cancer (PLC) and progressive massive fibrosis (PMF) of coal silicosis (CS), and to excavate information of differential diagnostic value. 68 patients with PLC (68 lesions) were selected as lung cancer group (LCG), and 50 patients with PMF of CS (78 lesions) were selected as coal silicosis group (CSG). TMRI was performed in both groups, and T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) and Spectral pre-saturated inversion recovery (SPIR) were used. The differences and characteristics of TMRI between the two groups were analyzed. 55 cases of pulmonary masses (PM) in LCG showed iso-signal intensity on T1WI (80.9%), and 63 cases showed high-signal intensity on T2WI and SPIR (92.6%); 65 cases of PMF in CSG showed iso-signal intensity on T1WI (83.5%), and high-signal intensity on T2WI and SPIR was found in 4 cases (5.1%), but 67 cases showed low-signal intensity (85.9%). PMF in CSG with high-signal intensity on T2WI and SPIR were significantly lower than PM in LCG(P < 0.1). Compared with TMRI of PLC showed high-signal intensity on T2WI and SPIR, PMF in CS showed low-signal intensity on T2WI and SPIR. This feature is of important significance in differential diagnosis.

AIM: To evaluate the quality of life of recruits after refractive surgery. METHODS: Population-based, cross-sectional study. Using the Quality of Life Impact of Refractive Correction (QIRC) questionnaire, the quality of life in 615 recruits underwent refractive surgery was evaluated. The overall score and each question score of QIRC were compared between subgroups of different strength of preoperative refractive error, postoperative interval, type of surgical procedure and postoperative recovery. RESULTS: The mean overall QIRC score of recruits underwent refractive surgery was 49.15±7.89. Significant difference was found for strength of preoperative refractive error (F=4.16, P0.05). Scores of recruits underwent mechanical microkeratome laser in situ keratomileusis (MK-LASIK), Sub-Bowman’s keratomileusis (SBK), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK), femtosecond lenticule extraction (ReLEx flex) or small-incision lenticule extraction (ReLEx SMILE) procedure showed no significant difference too. Recruits had adverse complaints postoperatively (45.85±6.66) scored lower when compared with all underwent refractive surgery (t=5.28, P

To observe the effects of electroacupuncture (EA) on the protein and gene expressions of Bax, Caspase-3 and Bcl-2 in cerebral cortex of type 2 diabetic rats with cognitive impairment (CI), and to explore the mechanism of EA in improving the learning and memory abilities. A total of 100 Sprague-Dawley (SD) rats were divided into a normal group (n=10) and a model group (n=90) by random number table method. Rats in the model group were intraperitoneally injected with a small dose of streptozotocin (STZ) to establish the type 2 diabetic models, after being fed with high-fat and high-sugar diet for 1 month. Twenty CI rats were selected from the 50 successful model rats by the Morris water maze (MWM) test and randomly divided into a model group and an EA group according to the blood glucose level and MWM data (n=10). Rats in the EA group received acupuncture at Zusanli (ST 36), Neiting (ST 44) and Yishu (Extra), of which Zusanli (ST 36) and Neiting (ST 44) were stimulated by EA apparatus, 20 min/time, once a day for 6 d a week and 4 consecutive weeks. The rats in the model and the normal groups were fixed without treatment. After 4-week treatment, the random blood glucose level of the rats was measured; the learning and memory abilities of rats were measured by MWM; terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect apoptotic cells; Western blot (WB) and real-time quantitative polymerase chain reaction (RT-qPCR) were used to detect the protein and gene expressions of Bax, Caspase-3 and Bcl-2 in cerebral cortex. After modeling, the random blood glucose level and the escape latency tested by MWM were significantly increased, and the number of crossing the platform tested by the MWM was decreased in the EA and model groups, and were significantly different from those in the normal group (P 0.05). After 4-week treatment, the random glucose level and the escape latency tested by MWM were significantly increased (both P

Purpose Incorporating mass pediatric vision screening programs as part of a national agenda can be challenging. This review assessed the implementation strategy of the existing pediatric vision screening program. Methods A search was performed on PubMed, EBSCO host MEDLINE Complete, and Scopus databases encompassing the past ten years for mass pediatric screening practice patterns that met the selection criteria regarding their objectives and implementation. Results were analyzed from 18 countries across five continents. Results Eight countries (44%) offered screening for distance visual acuity only, where the majority of the countries (88%) used either Snellen or Tumbling E chart. High-income countries initiated screening earlier and applied a more comprehensive approach, targeting conditions other than reduced vision only, compared with middle-income countries. Chart-based testing was most commonly performed, with only three countries incorporating an instrument-based approach. Lack of eyecare and healthcare practitioners frequently necessitated the involvement of non-eyecare personnel (94%) as a vision screener including parent, trained staff, and nurse. Conclusions Implementation of a vision screening program was diverse within countries preceded by limited resources issues. Lack of professional eyecare practitioners implied the need to engage a lay screener. The limitation of existing tests to detect a broader range of visual problems at affordable cost advocated the urgent need for the development of an inexpensive and comprehensive screening tool.

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective homing of T effector (Teff) cells to tumours and the immunosuppressive tumour microenvironment (TME). Here, we report a programmable tumour cells/Teff cells bispecific nano-immuno-engager (NIE) that can circumvent these limitations to improve ICB therapy. We have developed 28 nm non-toxic peptidic micellar nanoparticles (NIE-NPs) that bind α3β1 integrin on tumour cells membrane and undergo in situ transformation on surface of tumour cells into nanofibrillar network (NIE-NFs). The nanofibrillar network persistently facilitates cytotoxic T cells’ homing to the proximity of tumour cells via activatable α4β1 integrin ligands, and also allows sustained release of resiquimod to reprogram the TME. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Atherosclerosis is the main pathological basis of cardiovascular diseases and it is closely associated with hyperlipidemia, endothelial injury, macrophage-derived foam cells formation, proliferation and migration of vascular smooth muscle cells (VSMCs), platelet aggregation, and altered gut microbiota. Various symptomatic treatments, that are currently used to inhibit atherosclerosis, need to be administered in long term and their adverse effects cannot be ignored. Berberine (BBR) has beneficial effects on atherosclerosis through regulating multiple aspects of its progression. This review highlights the recent advances in understanding the anti-atherosclerosis mechanism of BBR. BBR alleviated atherosclerosis by attenuation of dyslipidemia, correction of endothelial dysfunction, inhibition of macrophage inflammation and foam cell formation, activation of macrophage autophagy, regulation of the proliferation and migration of VSMCs, attenuation of platelet aggregation, and modulation of gut microbiota. This review would provide a modern scientific perspective to further understanding the molecular mechanism of BBR attenuating atherosclerosis and supply new ideas for atherosclerosis management.

Background: Several echocardiographic methods to estimate pulmonary vascular resistance (PVR) in patients with pulmonary hypertension (PH) have been proposed. So far, most studies have focused on relatively low PVR. We aimed to clarify the clinical usefulness of our new echocardiographic index of evaluating markedly elevated PVR in pre-capillary PH patients. Methods: We studied 129 consecutive patients with pre-capillary PH. We estimated the mean pulmonary artery pressure using echocardiography (mPAPEcho) and measured LV internal diameter at end diastole (LVIDd). The ratio of mPAPEcho / LVIDd was then correlated with invasive PVR. Using receiver operating characteristic curve analysis, a cutoff value for the index was generated to identify patients with PVR > 15 Wood units (WU). Results: mPAPEcho / LVIDd correlated well with PVR (r = 0.70, P < 0.0001). There was a better correlation between PVR and mPAPEcho / LVIDd in patients with PVR > 15 WU compared with TRV2 /TVIRVOT and sPAPEcho / LVIDd. A cut-off value of 1.14 had an 80.0% sensitivity and 74.7% specificity to determine PVR > 15 WU (AUC=0.840, pConclusions: The index of mPAPEcho / LVIDd could be a valuable noninvasive and simple method of estimating markedly elevated PVR in pre-capillary PH patients.

Bark of Phellodendron chinense Schneid. (Rutaceae), called "Huang Bai" in China, is one of the 50 most used Chinese medicines in clinical practice. In this paper, a new isoquinoline alkaloid glycoside was isolated from P. chinense, and its structure was elucidated using spectroscopic method. The compound was eventually identified as (1S, 3"S)-1, 2, 3, 4-tetrahydro-7-hydroxy-1-[(4-hydroxybenzyl) methyl]-2-methyl-8-O-isoquinolinyl-[3-hydroxy-3-methylglutaryl]-β-D-glucopyranoside and named as Phellodendronoside A (PDA). The results of molecular docking showed that PDA could stably bind to an extracellular signal-regulated kinase (ERK), stress-activated protein kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) proteins that are closely related to inflammation. Further, the anti-inflammatory activity of PDA was evaluated using the lipopolysaccharide (LPS) induced RAW264.7 macrophage model. We observed that PDA can effectively reduce the levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and decrease the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, we found that PDA inhibits the activation of ERK, JNK and p38MAPK proteins in the MAPK signaling pathway. Collectively, the present study demonstrates that PDA has excellent anti-inflammatory effect in vitro by inhibiting the overproduction of pro-inflammatory mediators, and its mechanism of action involves suppressing the activation of MAPK pathways, suggesting that PDA may be a potential agent for the treatment of inflammatory illness.

Highly-ordered inorganic chiral mesoporous silica(HOCMS) has attracted substantial interest in recent decades. High performance liquid chromatography(HPLC) is the most important approach for the separation of enantiomers and herein reported an HPLC chiral stationary phase composed of HOCMS. The column was fabricated by conventional high pressure slurry packing. Eighteen racemates, including alcohols, ketones, amines, aldehydes and organic acids, were resolved on the column. Good chiral separations of hydrobenzoin, metoprolol, propranolol hydrochloride, 4-methyl-2-pentanol, omeprazole, 2,2′-furoin and ketoprofen were obtained. The relative standard devi-ations for five replicate separations of racemates were 0.1%–0.16% for retention time and 1.73%–2.64% for peak areas. The results suggest that HOCMS is a promising candidate for preparation of chiral stationary phases for HPLC.

Allergy is a major public health concern, the main treatment for which is symptomatic relief with anti-inflammatory drugs. A key clinical challenge is to induce specific tolerance in order to control allergen-specific memory B and T cells, and specifically block effector cell responses. Our lab recently developed antigen-specific regulatory T-cell (Treg) therapies as a treatment for adverse responses. Recently, we created a chimeric antigen receptor (CAR) approach in which we engineered a target protein antigen, ovalbumin (OVA), linked with the transmembrane and signal transduction domains, CD28-CD3ζ to directly target B cells and sensitized mast cells in an allergy model. We named this receptor “BAR” for B-cell Antibody Receptor. Murine or human Tregs, transduced with a BAR containing OVA or control Tregs expressing an unrelated antigen, were successfully expanded in vitro and tested in the murine OVA-alum allergy model with measurable titers of anti-OVA IgE. Because BAR Tregs express the target antigen and could interact with specific IgE on sensitized mast cells, we first demonstrated that intravenously injected OVA-BAR Tregs did not directly lead to a drop in temperature or release of mediators in plasma indicative of anaphylaxis. Forty-eight hours later, mice were challenged intraperitoneally with 200 μg OVA to induce an anaphylactic reaction, and temperature immediately measured for 30 min. We found that OVA-BAR Tregs protected mice from hypothermia, whereas mice given control BARs (expressing an unrelated antigen) or PBS showed substantial temperature drops indicative of anaphylaxis when systemically challenged with OVA. Importantly, this effect was also demonstrated in a passive anaphylaxis model in which mice that received anti-OVA IgE antibody were protected from hypothermia when treated with OVA-BAR Tregs prior to systemic OVA challenge. These results provide proof of principle that engineered allergen-specific T-regulatory cells can provide clinical protection against severe allergic reactions in individuals already IgE-sensitized to an allergen.

Study Objective The purpose of this study was to determine if there are any genetic changes with whole-exome sequencing associated with distal vaginal atresia. Design This was a retrospective genetics study of 5 patients who presented with distal vaginal atresia who were recruited between 2017 and 2018. Whole-exome sequencing was performed in each subject with distal vaginal atresia. Sanger sequencing was used to confirm the potential causative genetic mutation. Setting Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Participants and Main Outcome Measures The main outcome measure was the rare mutations potentially associated with distal vaginal atresia in 5 patients. Results A truncating mutation c.266delC (p.P89Rfs*5) in the T-box transcription factor 6 (TBX6) gene, which is highly expressed in the human vagina, was identified in 1 patient using whole-exome sequencing. The deletion of the 16p11.2 region containing the TBX6 locus has also been reported previously to have the clinical feature of Mullerian agenesis. This mutation was paternally inherited by the patient. This truncating mutation was absent from all of the databases we checked, suggesting that the variant is rare and pathogenic. Conclusion We showed, to our knowledge, for the first time, that the mutation in TBX6 might be associated with human distal vaginal atresia.

Near work, accommodative inaccuracy and ambient lighting conditions have all been implicated in the development of myopia. However, differences in accommodative responses with age and refractive error under different visual conditions remain unclear. This study explores differences in accommodative ability and refractive error with exposure to differing ambient illumination and visual demands in Malay schoolchildren and adults.Sixty young adults (21-25 years) and 60 schoolchildren (8-12 years) were recruited. Accommodative lag and accommodative fluctuations at far (6 m) and near (25 cm) were measured using the Grand Seiko WAM-5500 open-field autorefractor. The effects of mesopic room illumination on accommodation were also investigated.Repeated-measures ANOVA indicated that accommodative lag at far and near differed significantly between schoolchildren and young adults [F(1.219, 35.354) = 11.857, p 0.05]. Post hoc tests using the Bonferroni correction showed that at near, there was a greater lag in schoolchildren (0.486 ± 0.181 D) than young adults (0.259 ± 0.209 D, p 0.05). Repeated-measures ANOVA also revealed that accommodative lag at near demands differed statistically between the non-myopic and myopic groups in young adults and schoolchildren [F(3.107, 31.431) = 12.187, p 0.05]. Post hoc tests with Bonferroni correction showed that accommodative lag at near was significantly greater in myopic schoolchildren (0.655 ± 0.198 D) than in non-myopic schoolchildren (0.202 ± 0.141 D, p 0.05) and myopic young adults (0.316 ± 0.172 D, p 0.05), but no significant difference was found between myopic young adults (0.316 ± 0.172 D) and non-myopic young adults (0.242 ± 0.126 D, p 0.05). Accommodative lag and fluctuations were greater under mesopic room conditions for all ages [all p 0.05].Greater accommodative lag was found in myopes than in emmetropes, in schoolchildren than in adults, and under mesopic conditions than under photopic conditions. Accommodative fluctuations were greatest in myopes and in mesopic conditions. These results suggest that differences exist in the amount of blur experienced by myopes and non-myopes at different ages and under different lighting conditions.

Aim To investigate the effect of age on reading acuity and reading speed in attaining text information in healthy eyes. Methods Reading acuity, critical print size, reading speed and maximum reading speed were measured in groups of 40 children (8 to 12 years old), 40 teenagers (13 to 19 years old), 40 young adults (20 to 39 years old), and 40 adults (40 years old and above) using the Buari-Chen Malay Reading Chart [contextual sentences (CS) set and random words (RW) set] in a cross-sectional study design. Results Reading acuity was significantly improved by 0.04 logMAR for both CS set and RW set from children to teenagers, then gradually worsened from young adults to adults (CS set: 0.06 logMAR; RW set: 0.08 logMAR). Critical print size for children showed a significant improvement in teenagers (CS set: 0.14 logMAR; RW set: 0.07 logMAR), then deteriorated from young adults to adults by 0.09 logMAR only for CS set. Reading speed significantly increased from children to teenagers, [CS set: 46.20 words per minute (wpm); RW set: 42.06 wpm], then stabilized from teenagers to young adults, and significantly reduced from young adults to adults (CS set: 28.58 wpm; RW set: 24.44 wpm). Increment and decrement in maximum reading speed measurement were revealed from children to teenagers (CS set: 39.38 wpm; RW set: 43.38 wpm) and from young adults to adults (CS set: 22.26 wpm; RW set: 26.31 wpm) respectively. Conclusion The reference of age-related findings in term of acuity and speed of reading should be incorporated in clinical practice to enhance reading assessment among healthy eyes population.

Reactive metabolites (RMs) generated by hepatic metabolism are thought to play an important role in the pathogenesis of drug-induced liver injury (DILI). Like many synthetic drugs undergoing metabolic activation to form RMs which are often associated with drug toxicity, it is recognized that some herbal components may be also converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYP450s). This review focuses on the metabolic activation of herbal components and its liver toxicological implications. By summarizing references, we found that hepatotoxic herbal components via producing RMs have some certain structural dependence. There is a correlation between the generation of RMs and the structures, which provides a good chance for the early discovery of toxic ingredients in Traditional Chinese medicines (TCMs): i) A potential hepatotoxic component information database based on active functional groups can be built, which might provide an early information for the basic research of hepatotoxic substances in TCMs; ii) RMs can combine with CYP450s to form a complete antigen, which eventually leads to an antigen-specific immune response. RMs-CYP450 protein complete antigen can be set up, and the potential idiosyncratic liver toxicity might be predicted by testing RMs-CYP450 protein antibody in plasma.

Purpose A meta-analysis on sleep duration and patterns in patients with diabetes in China. Design and methods Two investigators independently carried out a systematic literature search in both international and Chinese databases. Findings A total of 47 studies with 98 911 patients were included. The pooled mean sleep duration was 7.15 hours/day in patients with diabetes and 7.49 hours/day in healthy controls. The estimated percentage of short sleep duration of less than 6 hours/day was 23.0% in patients with diabetes and 12.3% in healthy controls, while the proportion of short sleep duration of less than 7 hours/day was 38.0% in patients with diabetes and 14.1% in healthy controls. Practice implications Short sleep duration was common in Chinese patients with diabetes.

Aim: To evaluate feasibility, safety, and clinical efficiency of optometrists in conducting diabetic retinopathy screening and ocular health screening. Methods: This was a prospective observational trial study of newly developed optometric service pathways established at a community health clinic for diabetic retinopathy screening and a hospital ophthalmology clinic for ocular health screening. The study was carried out to assess the feasibility and safety of eye examinations conducted by optometrists. Patients were examined by optometrists using a standard eye examination at both clinics and re-examined by ophthalmologists as the reference standard. Optometrists recorded diagnoses of ocular conditions and classified referral urgency for each patient and these were compared with the diagnoses made by ophthalmologists, who were masked to the optometrists’ findings. Results: There was a high concordance of 87.0% (95% CI 80.4%-93.6%) for the diagnoses between the optometrists and ophthalmologists. Of 26 patients considered by the optometrists to need ophthalmology referral, 23 were agreed as such by the ophthalmologists, giving good agreement, κ = 0.76 (95% CI 0.53 -0.94) between the optometrists and ophthalmologists on referral classification. Agreement by the ophthalmologists for referral urgency classifications (very urgent/urgent or non-urgent) was very good (κ = 0.85, 95%CI 0.62-1.00). Conclusions: Ocular health examination by optometrists using optometric-eyecare pathways is feasible and safe. Optometrists showed strong agreement with ophthalmologists when diagnosing patients who had a range of ocular conditions. Optometrists were also able to triage referrals and their urgency accurately, suggesting that they could play an extensive role as primary eye care providers, thus reducing unnecessary referrals to ophthalmology clinics.

Our study aimed to explore the effect of positive and negative polarities on visual acuity measurements by utilizing black and white as a text against background with three distinct colours. Visual acuity was recorded as logarithm of minimum angle of resolution (LogMAR) using the detection of the gap in a four-position Landolt-C. The 2x3 (polarity x background color) two way repeated measures ANOVA showed a statistically significant interaction between polarity and colour background on visual resolution [F (2, 16) = 23.704, p < 0.001, η2 = 0.744]. Among the three primary background colour, shorter-wavelength (blue background) showed statistically significant findings between both positive and negative polarity [F (1, 9) = 39.875, p < 0.001, η2 = 0.818]. Visual acuity measurements improved with negative polarity but decreased with positive polarity with blue colour background. However, visual acuity was not statistically significantly different with the green (medium-wavelength) [F (1, 11) = 0.625, p = 0.446, η2 = 0.053] and the red (long-wavelength) backgrounds [F (1, 9) = 4.021, p = 0.856, η2 = 0.000]. In conclusion, black text against shorter-wavelength (blue) background apparently more difficult to be resolved by human eyes compared with white text. These findings suggest colour element might be an advantage for negative polarity colour combinations.

The dysfunction of the medial prefrontal cortex is associated with affective disorders and non-motor features in Parkinson’s disease. However, the exact role of the mediodorsal thalamic nucleus in the function of the prefrontal cortex remains unclear. To study the possible effects of the mediodorsal thalamic nucleus on the neurological function of the medial prefrontal cortex, a model of Parkinson’s disease was established by injecting 8 µg 6-hydroxydopamine into the substantia nigra compacta of rats. After 1 or 3 weeks, 0.3 µg ibotenic acid was injected into the mediodorsal thalamic nucleus of the midbrain. At 3 or 5 weeks after the initial injury, neuronal discharge in medial prefrontal cortex of rat brain was determined electrophysiologically. The numbers of dopamine-positive neurons and tyrosine hydroxylase immunoreactivity in substantia nigra compacta and ventral tegmental area were detected by immunohistochemical staining. Results demonstrated that after injury, the immunoreactivity of dopamine neurons and tyrosine hydroxylase decreased in the substantia nigra compacta and ventral tegmental areas of rats. Compared with normal medial prefrontal cortical neurons, at 3 and 5 weeks after substantia nigra compacta injury, the discharge frequency of pyramidal neurons increased and the discharge pattern of these neurons tended to be a burst-discharge, with an increased discharge interval. The discharge frequency of interneurons decreased and the discharge pattern also tended to be a burst-discharge, but the discharge interval was only higher at 3 weeks. At 3 weeks after the combined lesions, the discharge frequency, discharge pattern and discharge interval were restored to a normal level in pyramidal neurons and interneurons in medial prefrontal cortex. These findings have confirmed that mediodorsal thalamic nucleus is involved in regulating neuronal activities of the medial prefrontal cortex. The changes in the function of the mediodorsal thalamic nucleus may be associated with the abnormal discharge activity of the medial prefrontal cortex neurons after substantia nigra compacta injury. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University, China (approval No. XJTULAC2017-067) on August 26, 2017.

Endothelial damage and blood brain barrier disruption contribute to ischemic stroke and brain injury. Gliptins are a novel class of treatment agents for diabetes, and recent studies have linked the use of gliptins to neuroprotection. Alogliptin is a type of orally available gliptin that was approved for clinical use by the FDA in 2013. In this study, we investigated the neurovascular protective effects of alogliptin both in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) stroke model, administration of alogliptin ameliorated cerebral infarction and disruption of brain vascular permeability, and restored expression of the endothelial tight junction proteins occludin and zona occludens 1 (ZO-1). In brain vascular endothelial cells exposed to oxygen and glucose deprivation/reperfusion (OGD/R), alogliptin prevented OGD/R-induced high permeability of the endothelial monolayer. Alogliptin treatment recovered the reduction in occludin and ZO-1 induced by OGD/R. Moreover, alogliptin treatment prevented OGD/R-induced induction of metalloproteinase (MMP)-2 and MMP-9, and restored expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Collectively, our data indicate that alogliptin can improve neurovascular integrity and exerts neuroprotective effects.

Objective The goal of this study is to explore effective treatments for peripheral facial paralysis and to evaluate the clinical efficacies of warm needling therapy and acupuncture in peripheral facial paralysis. Methods PubMed (1979–2017), the Chinese National Knowledge Infrastructure database (CNKI, 1979–2017), Wanfang databases (1990–2017), and the Chongqing VIP full-text periodical database (VIP, 1989–2017) were searched by computer. Randomized controlled trials of warm needling therapy and acupuncture in the treatment of peripheral facial paralysis were collected. The clinical trials that met the inclusion criteria were selected for quality assessment using the Cochrane 5.0 Handbook for systematic evaluation. RevMan5.3 was used for statistical analysis. Results A total of 23 articles with 1756 patients met the inclusion criteria. (1) The meta-analysis of 11 articles showed that the total effective rate of warm needling therapy for peripheral facial paralysis was higher than that of acupuncture [RR = 1.18, 95% CI (1.11,1.25) , P Conclusion The results of this meta-analysis showed that warm needling therapy is superior to acupuncture in treating peripheral facial paralysis, providing a therapeutic option for the treatment of peripheral facial paralysis. However, due to the small sample size and the low quality of the included studies, the above conclusion still needs to be validated with high-quality, large-scale, randomized, blinded controlled trials.

Increasing studies revealed that aberrant expression of long non-coding RNAs (lncRNAs) play critical roles in ovarian cancer (OC) progression. However, the roles and underlying mechanisms of ADAMTS9-AS2 in OC remain unclear. In the present study, we showed that ADAMTS9-AS2 expression was significantly decreased in OC tissues and cell lines. Low ADAMTS9-AS2 expression was correlated with advanced FIGO stage, lymph-node metastasis, and poor overall survival of OC patients. Function assays showed that ADAMTS9-AS2 reduced OC cells proliferation, invasion, and epithelial-mesenchymal transition (EMT) processes in vitro and restrained tumor growth in vivo. The underlying mechanism studies indicated that ADAMTS9-AS2 functioned as a competing endogenous RNA (ceRNA) for miR-182-5p to promote cell proliferation and invasion. In addition, we revealed that FOXF2 acted as a direct target of miR-182-5p and mediated the effects of ADAMTS9-AS2 on OC cells progression. Taken together, our data suggested that lncRNA ADAMTS9-AS2 decreased OC progression by regulating miR-182-5p/FOXF2 axis, indicating ADAMTS9-AS2 could serve as a potential therapeutic target for OC treatment.