miR-622 Increases miR-30a Expression through Inhibition of Hypoxia-Inducible Factor 1α to Improve Metastasis and Chemoresistance in Human Invasive Breast Cancer Cells.

Hypoxia-inducible factor 1α (HIF-1α) plays a pivotal role in the survival, metastasis, and response to treatment of solid tumors. Autophagy serves as a mechanism for tumor cells to eliminate misfolded proteins and damaged organelles, thus promoting invasiveness, metastasis, and resistance to treatment under hypoxic conditions. MicroRNA (miRNA) research underscores the significance of these non-coding molecules in regulating cancer-related protein synthesis across diverse contexts. However, there is limited reporting on miRNA-mediated gene expression studies, especially with respect to epithelial-mesenchymal transition (EMT) and autophagy in the context of hypoxic breast cancer. Our study reveals decreased levels of miRNA-622 (miR-622) and miRNA-30a (miR-30a) in invasive breast cancer cells compared to their non-invasive counterparts. Inducing miR-622 suppresses HIF-1α protein expression, subsequently activating miR-30a transcription. This cascade results in reduced invasiveness and migration of breast cancer cells by inhibiting EMT markers, such as Snail, Slug, and vimentin. Furthermore, miR-30a negatively regulates beclin 1, ATG5, and LC3-II and inhibits Akt protein phosphorylation. Consequently, this improves the sensitivity of invasive MDA-MB-231 cells to docetaxel treatment. In conclusion, our study highlights the therapeutic potential of inducing miR-622 to promote miR-30a expression and thus disrupt HIF-1α-associated EMT and autophagy pathways. This innovative strategy presents a promising approach to the treatment of aggressive breast cancer.

Cytomegalovirus Glycoprotein B Genotype in Patients with Anterior Segment Infection.

(1) The glycoprotein B (gB) on the viral envelope, encoded by the most widely characterised polymorphic gene, gpUL55, is responsible for cytomegalovirus (CMV) entry into the host and could serve as a potential marker of pathogenicity. The aim of the present study is to investigate the distribution of the CMV gB genotype in anterior segment infection in Taiwan and its correlation with clinical manifestations and outcomes. (2) Fifty-seven patients with CMV anterior segment infection were identified according to clinical features and positivity for CMV DNA in aqueous humour samples. CMV gB genotyping was performed through polymerase chain reaction assays. Patients' medical records were retrospectively reviewed. (3) Among the 57 aqueous humour samples tested for gB, 40 (70.28%) had multiple gB genotypes, and only 17 (29.82%) had a single gB genotype. Compared with single-genotype infection, multiple-genotype infection was correlated with higher CMV loads (p < 0.001) but not correlated with outcome. A higher proportion of patients with the gB3 genotype had received filtering surgery before antiviral treatment than those without the gB3 genotype (p = 0.046). (4) Multiple-genotype infection was highly prevalent in CMV anterior segment infection in Taiwan, and gB1 and gB3 were predominant. Multiple-genotype infection was correlated with higher CMV loads but not with specific clinical manifestations or prognostic outcomes. The gB3 genotype may be correlated with poor intraocular pressure control.

Application and Validation of LUXIE: A Newly Developed Virtual Reality Perimetry Software.

PURPOSE: To report the application of LUXIE and validate its reliability by comparing the test results with those of Humphrey Field Analyzer 3 (HFA3). METHODS: In this pilot study, we prospectively recruited participants who had received HFA3 SITA standard 30-2 perimetry and tested them with LUXIE on the same day. LUXIE is a software designed for visual field testing cooperating with HTC Vive Pro Eye, a head-mounted virtual reality device with an eye-tracking system. The test stimuli were synchronized with eye movements captured by the eye-tracking system to eliminate fixation loss. The global, hemifields, quadrants, glaucoma hemifield test (GHT) sectors, and point-by-point retinal sensitivities were compared between LUXIE and HFA3. All participants were asked to fill out a post-test user survey. RESULTS: Thirty-eight participants with 65 eyes were enrolled. LUXIE demonstrated good correlations with HFA3 in global (r = 0.81), superior hemifield (r = 0.77), superonasal, superotemporal, and inferonasal quadrants (r = 0.80, 0.78, 0.80). The user survey showed that participants were more satisfied with LUXIE in operating difficulty, comfortability, time perception, concentration, and overall satisfaction. CONCLUSIONS: LUXIE demonstrated good correlations with HFA3. Fixation loss could be eliminated in LUXIE with the eye-tracking system. The application of virtual reality devices such as the HTC Vive Pro Eye makes telemedicine and even home-based self-screening visual field tests possible. KEY MESSAGES: 1. Virtual reality perimetry is a developing technology that has the potential in telemedicine, and home self-screening visual field tests. 2. LUXIE demonstrated good correlations with Humphrey Field Analyzer 3 in visual field retinal sensitivities.

Brimonidine related acute follicular conjunctivitis: Onset time and clinical presentations, a long-term follow-up.

ABSTRACT: To evaluate the duration of topical brimonidine therapy before the onset of brimonidine-related allergic conjunctivitis and the clinical characteristics associated with the development of brimonidine allergy.We retrospectively enrolled patients who presented brimonidine allergy from December 1, 2008 to November 30, 2020. The duration of brimonidine treatment, concomitant medications, benzalkonium chloride (BAK) exposure, change in IOP, and season of onset were evaluated.292 patients were included, among which 147 were female and 145 were male. The mean age was 58.3 ± 13.6 years old. The mean (median) duration of brimonidine therapy was 266.6 (196) days, with a peak at 60-120 days. The duration was similar whether the patients received brimonidine monotreatment or in combination with other glaucoma drugs, with or without BAK. The IOP increased by 5.6% after brimonidine allergy (P < .001), which was even higher in the brimonidine monotherapy group (9.2%, P < .001). There was no significant IOP elevation in patients treated with multiple glaucoma medications.Around half of brimonidine allergy occurred within 6 months, with a peak in 2 to 4 months. The duration did not differ in patients receiving brimonidine monotherapy or multiple glaucoma medications. The presence of BAK did not affect the duration either. When brimonidine allergy occurred, there was a loss of IOP control, especially in patients receiving brimonidine monotherapy. It is recommended to switch to other types of glaucoma medications for better IOP control.

MiR-139 Modulates Cancer Stem Cell Function of Human Breast Cancer through Targeting CXCR4.

Elevated expression of C-X-C motif chemokine receptor 4 (CXCR4) correlates with chemotaxis, invasion, and cancer stem cell (CSC) properties within several solid-tumor malignancies. Recent studies reported that microRNA (miRNA) modulates the stemness of embryonic stem cells. We aimed to investigate the role of miRNA, via CXCR4-modulation, on CSC properties in breast cancer using cell lines and xenotransplantation mouse model and evaluated miR-193 levels in 191 patients with invasive ductal carcinoma. We validated miR-139 directly targets the 3'-untranslated region of CXCR4. Hoechst 33342 fluorescence-activated cell sorting (FACS) and sphere-forming assay were used to identify CSCs. MiR-139 suppressed breast CSCs with mesenchymal traits; led to decreased migration and invasion abilities through down-regulating CXCR4/p-Akt signaling. In lung cancer xenograft model of nude mice transplanted with human miR-139-carrying MDA-MB-231 cells, metastatic lung nodules were suppressed. Clinically, microdissected breast tumor tissues showed miR-139 reduction, compared to adjacent non-tumor tissues, that was significantly associated with worse clinicopathological features, including larger tumor size, advanced tumor stage and lymph node metastasis; moreover, reduced miR-139 level was predominately occurred in late-stage HER2-oreexpression tumors. Collectively, our findings highlight miR-139-mediated suppression of CXCR4/p-Akt signaling and thereby affected mesenchymal stem-cell genesis, indicating its potential as a therapeutic target for invasive breast cancer.

Treatment of cytomegalovirus anterior segment infection with intravitreal injection of ganciclovir in adjunction with or without oral valganciclovir: a long-term results.

We evaluated the therapeutic outcome of intravitreal injection (IVI) of ganciclovir with/without oral valganciclovir for cytomegalovirus (CMV) anterior segment infection. We enrolled 61 patients (61 eyes) with PCR-proven CMV anterior segment infection. IVI of ganciclovir (2 mg/0.05 mL) was given as a loading dose; subsequent use of oral valganciclovir (900 mg twice daily) was determined according to the severity of anterior chamber inflammation after injection. All eyes had IVI of ganciclovir, and 53 patients received oral valganciclovir as adjunctive therapy with a mean duration of 1.9 months to achieve disease remission. Repeated diagnostic aqueous taps were performed in 37 eyes with suspected recurrence, and CMV DNA was positive in 24 eyes. This therapeutic strategy afforded a median 50% recurrence-free survival time of 47.0 ± 8.12 months. The patients' mean best corrected visual acuity, intraocular pressure and corneal endothelial cell counts stabilized or improved. Corneal transplantation before CMV infection diagnosis was identified as an independent risk factor for recurrence (hazard ratio 6.81, 95% confidence interval 1.21-38.23, P = 0.029). In patients with CMV anterior segment infection, the relative short-term therapeutic strategy, IVI of ganciclovir in adjunction with/without oral valganciclovir, effectively achieved a median recurrence-free survival time of nearly 4 years.

The severity of visual field defect and the defective angles of localized retinal nerve fiber layer using a novel approach.

BACKGROUND/PURPOSE: A modified novel analytical method for evaluating photographic retinal nerve fiber layer defect (RNFLD) was developed for the purpose of estimating the severity of early glaucomatous eyes. This new method was then compared with the original method, as described below, in relation to the visual field defect severity. METHODS: The clinical records of 47 glaucomatous eyes with qualified photographs were obtained from a prior retrospective study. The reference point of the angle was set at the center of the optic disc center (COD group) and the central vessel trunk (COV group). Angle α was the angular width between the fovea and the proximity of RNFLD, while angle ß (+c) was the sum of the angular width(s) of localized RNFLD. The correlation between the visual field parameters and the angles of RNFLD in the above two groups were analyzed. RESULTS: There were significant differences in angle α (p = 0.001) and angle ß (+c) (p = 0.016) between the two groups. Angle ß (+c) showed significant correlation with MD (p = 0.012), PSD (p = 0.035), VFI (p = 0.042) and MD (p = 0.016), PSD (p = 0.035), VFI (p = 0.031) in the COD and COV group, respectively. No correlation was found between angle α and the presence of central scotoma in both groups. CONCLUSION: Our novel method was more convenient in a clinical setting and noninferior to the original method.

Cataract extraction slowed the visual field progression rate in patients with angle-closure glaucoma.

PURPOSE: The purpose of this study is to evaluate the rate of progression of Humphrey visual field before and after the cataract surgery in patients with angle-closure glaucoma. MATERIAL AND METHODS: Patients with angle-closure glaucoma who underwent regular visual field (VF) examination and received cataract surgery during the follow-up periods were retrospectively reviewed. The visual field rate of progression, visual acuity (VA), intraocular pressure (IOP), and number of glaucoma medication before and after cataract surgery were compared. RESULTS: A total of 26 eyes were included. The mean follow-up duration before and after the cataract surgery were 5.14 ± 3.31 years and 5.97 ± 2.35 years. After cataract surgery, the IOP and VA improved significantly. The visual field rate of progression significantly slowed down after cataract surgery from - 1.39 ± 1.31 dB/year preoperatively to - 0.34 ± 0.64 dB/year postoperatively (P = 0.003). CONCLUSION: The ACG eyes had rapid VF decline before cataract extraction, which was slowed down significantly after cataract removal.

Fine particulate matter PM2.5 generated by building demolition increases the malignancy of breast cancer MDA-MB-231 cells.

OBJECTIVES: This study investigates the effects of water-extracted PM2.5 on a triple-negative breast cancer (TNBC) cell line, MDA-MB-231, by sampling suspended particulates around a building demolition site. METHODS: PM2.5 particles were obtained using a high-flow TISCH sampler. Water-soluble PM2.5 were extracted by an ultrasonic oscillator and then freeze-dried. The heavy metal components of soluble PM2.5 was analyzed by ICP-MS. Cell viability was evaluated by MTT assay for cells that were exposed to PM2.5 (200, 400 and 600 µg/mL). Wound healing and transwell cell migration and invasion assays were used to measure cell motility and the invasiveness of cancer cells that had been exposed to PM2.5 into a chemo-attractant substance. Interrelated mechanisms of cancer malignancy were analyzed by Western blot analysis. RESULTS: Nearby PM2.5 concentrations increased significantly during the deconstruction of buildings, and the Cd, Cu, Pb, Zn and Cr contents of soluble PM2.5 also significantly increased. Following exposure to PM2.5, the survival rate of breast cancer cells was significantly higher than that of the control group. Soluble PM2.5-treated cells had a higher migration capacity. The signaling pathway of FAK/PI3K/AKT proteins was more activated in PM2.5-treated cells than the control group. Increased levels of Aurora B and Bcl-2 were associated with cell proliferation. Elevated levels of cathepsins D, ß-catenin, N-cadherin, vimentin and MMP-9 were associated with breast cancer cell metastasis. CONCLUSION: Soluble PM2.5 from building demolition may promote/progress in surviving TNBC cells, increasing the malignancy of breast cancer. This study offered evidence of a link between demolition PM2.5 and cancer progression.

Effects of Milling Time, Zirconia Addition, and Storage Environment on the Radiopacity Performance of Mechanically Milled Bi2O3/ZrO2 Composite Powders.

Mineral trioxide aggregate (MTA) typically consists of Portland cement (75 wt.%), bismuth oxide (20 wt.%), and gypsum (5 wt.%) and is commonly used as endodontic cement. Bismuth oxide serving as the radiopacifying material reveals the canal filling effect after clinical treatment. In the present study, bismuth/zirconium oxide composite powder was prepared by high energy ball milling of (Bi2O3)100-x (ZrO2)x (x = 5, 10, 15, and 20 wt.%) powder mixture and used as the radiopacifiers within MTA. The crystalline phases of the as-milled powders were examined by the X-ray diffraction technique. The radiopacities of MTA-like cements prepared by using as-milled composite powders (at various milling stages or different amount of zirconia addition) were examined. In addition, the stability of the as-milled powders stored in an ambient environment, an electronic dry box, or a glove box was investigated. The experimental results show that the as-milled powder exhibited the starting powder phases of Bi2O3 and ZrO2 and the newly formed δ-Bi7.38Zr0.62O2.31 phase. The longer the milling time or the larger the amount of the zirconia addition, the higher the percentage of the δ-Bi7.38Zr0.62O2.31 phase in the composite powder. All the MTA-like cements prepared by the as-milled powder exhibited a radiopacity higher than 4 mmAl that is better than the 3 mmAl ISO standard requirement. The 30 min as-milled (Bi2O3)95(ZrO2)5 composite powder exhibited a radiopacity of 5.82 ± 0.33 mmAl and degraded significantly in the ambient environment. However, storing under an oxygen- and humidity-controlled glove box can prolong a high radiopacity performance. The radiopacity was 5.76 ± 0.08 mmAl after 28 days in a glove box that was statistically the same as the original composite powder.

The lipid-lowering effect of once-daily soya drink fortified with phytosterols in normocholesterolaemic Chinese: a double-blind randomized controlled trial.

PURPOSE: Phytosterols reduce intestinal cholesterol absorption and help to lower LDL-cholesterol. Many Chinese adults are lactose-intolerant and cannot tolerate bovine milk enriched with phytosterol. Soya-milk is a common beverage in Asia and it has beneficial effects on general health. We therefore conducted a randomized double-blind controlled trial to assess the effectiveness of a phytosterols-enriched soya drink in lowering serum LDL-cholesterol level (primary outcome) and other cardiovascular parameters (secondary outcomes). METHODS: One hundred and fifty-nine normocholesterolaemic participants (85 men and 74 women; aged 19-79) were randomized to daily intake of one serving of phytosterols-enriched soya drink (N = 82), equivalent to 2 g of phytosterol per day, or a matched soya drink without phytosterols (N = 77) for 3 weeks. Adverse events, withdrawal and compliance were documented. RESULTS: Among the treatment group (N = 82), phytosterols-enriched soya drink significantly decreased LDL-cholesterol by 5.96% (SE 1.48, 95% CI - 8.91%, - 3.00%) with a median of 6.74% compared with baseline, resulting in a significant reduction of 4.70% (95% CI - 8.89%, - 0.51%; p = 0.028) with a median of 5.20% compared with placebo (N = 77). In contrast, there were no significant changes in other lipid parameters, blood glucose, blood pressure, body weight or waist circumference. Remarkably, 95% of the participants randomized to the fortified drink reported no adverse events at all. CONCLUSIONS: Daily consumption of a phytosterols-enriched soya drink may be a simple and cost-neutral means of lowering LDL-cholesterol in individuals in China, with massive population and rising incidence of coronary heart disease (ClinicalTrials.gov identifier: NCT02881658; date of registration: 14 Aug 2016).

Induction of G2/M Phase Arrest by Diosgenin via Activation of Chk1 Kinase and Cdc25C Regulatory Pathways to Promote Apoptosis in Human Breast Cancer Cells.

The anti-tumor activity of diosgenin, a new steroidal constituent present in fenugreek, on two human breast cancer cell lines, MCF-7 and Hs578T, was studied. Diosgenin treatment resulted in cell growth inhibition, cell cycle arrest, and apoptosis in concentration- and time-dependent manners in both cell lines. Western blot analyses of whole cell lysates for cell cycle proteins showed that diosgenin altered phosphorylated cyclin checkpoint1 (p-Chk1Ser345) and cyclin B expression, which resulted in G2/M phase blockade. Mechanistically, Cdc25C-Cdc2 signaling was involved in inactivating Chk1Ser345 by p53-dependence in MCF-7 cells and p21-dependence in Hs578T cells that are p53-deficient. Moreover, diosgenin induced a significant loss of the mitochondrial membrane potential in breast cancer cells, and prominently affected cell death through down-regulation of the anti-apoptotic protein, Bcl-2. This released cytochrome c and activated the caspase signaling cascade. Taken together, these findings reveal that the anti-proliferative activity of diosgenin involves the induction of G2/M phase arrest via modulating the Cdc25C-Cdc2-cyclin B pathway and mitochondria-mediated apoptosis in human breast cancer cell lines. This suggests the potential usefulness of diosgenin in treating breast cancer.

Organocatalytic [4 + 2] cyclizations of para-quinone methide derivatives with isocyanates.

The first [4 + 2] cyclizations of para-quinone methide derivatives with isocyanates have been established under the catalysis of Brønsted acids or Brønsted bases, which efficiently constructed benzoxazin-2-one frameworks in generally high yields (up to 95%). This reaction will not only enrich the research contents of para-quinone methide-involved cyclization reactions but also provide a useful method for constructing biologically important benzoxazin-2-one frameworks.

Catalytic Asymmetric [4 + 1] Cyclization of Benzofuran-Derived Azadienes with 3-Chlorooxindoles.

A chiral guanidine-catalyzed asymmetric [4 + 1] cyclization of benzofuran-derived azadienes with 3-chlorooxindoles has been established, which constructed chiral spirooxindole frameworks with in situ generation of a five-membered ring with high diastereoselectivities (up to >95:5 dr) and good enantioselectivities (up to 94:6 er). This reaction represents the first catalytic asymmetric [4 + 1] cyclization of benzofuran-derived azadienes, which will enrich the research field of catalytic asymmetric cyclizations of such reactants. In addition, this reaction provides a useful strategy for the enantioselective construction of five-membered ring-based chiral spirooxindole scaffolds.

Metal-Catalyzed Oxa-[4+2] Cyclizations of Quinone Methides with Alkynyl Benzyl Alcohols.

An oxa-[4+2] cyclization of quinone methides with alkynyl benzyl alcohols has been realized in the presence of a metal catalyst, and the reaction afforded spiroacetal products in overall high yields (up to 99%) and good diastereoselectivities (up to >95:5 dr). By carrying out the reaction under gold catalysis and utilizing alkynyl benzyl alcohols as electron-rich reaction partners, this approach provides a useful strategy for settling the challenges in oxa-[4+2] cyclization of para-quinone methide derivatives. This reaction serves as a good example for metal-catalyzed oxa-[4+2] cyclizations of quinone methides. In addition, it also offers a useful method for the construction of spiroacetal skeletons.

Summative objective structured clinical examination as a reference of learners' need before entering their internship.

BACKGROUND/PURPOSE: Objective structured clinical examination (OSCE) has found increasingly wide use in the education of clinical dentistry in recent years. The objectives of this study were to find the predictability of OSCE in representing a student's actual ability in a clinical environment and to provide instructors with better ideas to guide an individual student in a certain field. MATERIALS AND METHODS: Thirty-one dentistry students' qualification OSCE scores were obtained after the conclusion of their dental clerkship in December 2014. The OSCE scores were compared with the various scores given by instructors from different departments during their internship a year later. The correlation was investigated between these two scores. RESULTS: The scores of the first station of OSCE-explaining a treatment plan for the restoration of a missing tooth-were correlated with the scores of prosthodontics in the internship. The scores of the fourth station of OSCE-explaining to a mother regarding the obtainment of a radiograph of her child's tooth-were correlated with the scores of orthodontics. In addition, the total score of the six OSCE stations was correlated with the scores of orthodontics, oral surgery, and pediatric dentistry during dental internship. CONCLUSION: The results of clerkship qualification OSCE could provide instructors with insights into the needs of the students before their entering internship.

Reconstruction of Through-and-through Oromandibular Defect: Comparison of Four Different Techniques.

BACKGROUND: Through-and-through oromandibular defects originate from surgical intervention of tumors of the oral cavity involving external skin, soft tissue, bone, and oral lining. Reconstruction of such composite defects is primarily achieved by 4 methods using distinct flaps in Chang Gung Memorial Hospital, including a single anterolateral thigh (ALT) flap, a single fibula flap, an osteomyocutaneous peroneal artery-based combined flap, and a combination of a fibular flap and an ALT flap, also known as a double flap. METHODS: In this retrospective study, 41 patients with through-and-through oromandibular defects reconstructed in Chang Gung Memorial Hospital Linkou branch from July 2007 to June 2009 using either of the 4 flaps were evaluated. Patients were divided into 4 groups according to the choice of flap, and their surgical outcomes, immediate and late complications, and their general condition were studied. Group 1 included 12 patients reconstructed with a single ALT flap, whereas group 2 included 15 patients using fibular flaps. Group 3 included 8 patients with osteomyocutaneous peroneal artery-based combined flaps, and group 4 included 6 patients who underwent reconstruction with double flaps. RESULTS: Among all statistical results, we found that none of the differences regarding either patient demography or surgical outcomes between groups were statistically significant, except for squamous cell carcinoma staging. CONCLUSIONS: Although the results were insignificant, trends within the data could be seen that support previous notions regarding each reconstruction method. For future studies, we strongly recommend a larger sample size.

An Unusual Tetrahydrofuran Lignan from the Roots of Zanthoxylum planispinum and the Potential Anti-inflammatory Effects.

An unusual tetrahydrofuran lignin, zanthplanispine (1), together with 14 known lignans (2 - 15) were isolated from the AcOEt-soluble fraction from the MeOH extract of Z. planispinum roots. The structures of 1 was elucidated on the basis of 1D- and 2D-NMR experiments as well as HR-ESI-MS analysis. The known compounds were identified by the comparison of their NMR data with previously reported in the literatures. Bioassay showed that compounds 1 - 4 could inhibit nitric oxide (NO) production in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. In particular, compound 1 showed significant inhibitory activity with an IC50 value of 36.8 µm.