The Wnt/β-catenin signaling pathway is involved in breast cancer and Myxococcus fulvus KYC4048 is a myxobacterial strain that can produce a variety of bioactive secondary metabolites. Although a ...previous study revealed that KYC4048 metabolites exhibit anti-proliferative effects on breast cancer, the biochemical mechanism involved in their effects remains unclear. In the present study, KYC4048 metabolites were separated into polar and non-polar (ethyl acetate and n-hexane) fractions via liquid-liquid extraction. The effects of these polar and non-polar KYC4048 metabolites on the viability of breast cancer cells were then determined by MTT assay. Expression levels of Wnt/ β-catenin pathway proteins were determined by Western blot analysis. Cell cycle and apoptosis were measured via fluorescence-activated cell sorting (FACS). The results revealed that non-polar KYC4048 metabolites induced cell death of breast cancer cells and decreased expression levels of WNT2B, β-catenin, and Wnt target genes (c-Myc and cyclin D1). Moreover, the n-hexane fraction of non-polar KYC4048 metabolites was found most effective in inducing apoptosis, necrosis, and cell cycle arrest, leading us to conclude that it can induce apoptosis of breast cancer cells through the Wnt/β-catenin pathway. These findings provide evidence that the n-hexane fraction of non-polar KYC4048 metabolites can be developed as a potential therapeutic agent for breast cancer via inhibition of the Wnt/β-catenin pathway.
Abstract Background and Aim The aim of this study was to identify the effect of selective estrogen receptor modulator (SERM) on non-alcoholic fatty liver disease (NAFLD) in Asian women. Methods We ...retrospectively evaluated fatty liver development and/or serum alanine aminotransferase (ALT) elevation during SERM treatment in 1061 women who were diagnosed and treated with breast cancer in 2005 at Asan Medical Center. Results 45 of 618 SERM-treated patients with normal ALT at baseline experienced ALT elevation during SERM treatment. Among the 112 SERM-treated patients who underwent liver imaging test, fatty liver was observed in 47 and both fatty liver and ALT elevation developed in 16 of 102 SERM-treated patients with normal baseline ALT. The cumulative rates of ALT elevation (10.7 vs. 4.3%; P = 0.002), fatty liver (48.5 vs. 20.9%; P < 0.001), and both fatty liver and ALT elevation (17.7 vs. 7.1%; P = 0.02) at 60 months were significantly higher in the SERM group than non-SERM group. By multivariate analysis, SERM treatment increased the risk of ALT elevation (hazard ratio HR, 2.20; P = 0.01), fatty liver development (HR, 3.59; P < 0.001), and both fatty liver and ALT elevation (HR, 4.98; P = 0.01). After discontinuation of SERM, elevated serum ALT normalized in 39 (92.9%) and there were no instances of liver-related death or progression to liver cirrhosis in patients who experienced fatty liver or ALT elevation. Conclusions Although SERM treatment is significantly associated with NAFLD in Asian women, considering the tolerability and reversibility of NAFLD induced by SERM, it can be continued with liver function monitoring in relevant patients.
Although indoor air pollution is a well-known risk factor for tuberculosis (TB), the possible link between outdoor air pollution and TB development has not been examined fully. We assessed the impact ...of outdoor air pollution on TB development in the Seoul metropolitan area, South Korea.
The mean concentrations of ambient particulate matter (PM) with an aerodynamic diameter ≤ 10 µm (PM10), O3, CO, NO2, and SO2 levels in Seoul, between January 1, 1997 and December 31, 2006, were determined. Furthermore, their association with the risk of developing TB after adjusting for socioeconomic status, between January 1, 2002 and December 31, 2006, was investigated.
Between January 1, 2002 and December 31, 2006, a total of 41,185 TB cases were reported in Seoul. Concentrations of PM10, O3, CO, and NO2 were not associated with TB incidence in males or females. However, the interquartile increase in SO2 concentration was associated with a 7% increment in TB incidence (relative risk RR, 1.07; 95% credible interval CrI, 1.03 to 1.12) in males but not in females (RR, 1.02; 95% CrI, 0.98 to 1.07).
Long-term exposure to ambient SO2 increased the risk of TB in males.
The objectives of this study were to investigate the agreement between medical history questionnaire data and claims data and to identify the factors that were associated with discrepancies between ...these data types.
Data from self-reported questionnaires that assessed an individual's history of hypertension, diabetes mellitus, dyslipidemia, stroke, heart disease, and pulmonary tuberculosis were collected from a general health screening database for 2014. Data for these diseases were collected from a healthcare utilization claims database between 2009 and 2014. Overall agreement, sensitivity, specificity, and kappa values were calculated. Multiple logistic regression analysis was performed to identify factors associated with discrepancies and was adjusted for age, gender, insurance type, insurance contribution, residential area, and comorbidities.
Agreement was highest between questionnaire data and claims data based on primary codes up to 1 year before the completion of self-reported questionnaires and was lowest for claims data based on primary and secondary codes up to 5 years before the completion of self-reported questionnaires. When comparing data based on primary codes up to 1 year before the completion of self-reported questionnaires, the overall agreement, sensitivity, specificity, and kappa values ranged from 93.2 to 98.8%, 26.2 to 84.3%, 95.7 to 99.6%, and 0.09 to 0.78, respectively. Agreement was excellent for hypertension and diabetes, fair to good for stroke and heart disease, and poor for pulmonary tuberculosis and dyslipidemia. Women, younger individuals, and employed individuals were most likely to under-report disease.
Detailed patient characteristics that had an impact on information bias were identified through the differing levels of agreement.
Cell labeling and tracking are important processes in understanding biologic mechanisms and the therapeutic effect of inoculated cells in vivo. Numerous attempts have been made to label and track ...inoculated cells in vivo; however, these methods have limitations as a result of their biological effects, including secondary phagocytosis of macrophages and genetic modification. Here, we investigated a new cell labeling and tracking strategy based on metabolic glycoengineering and bioorthogonal click chemistry. We first treated cells with tetra-acetylated N-azidoacetyl-D-mannosamine to generate unnatural sialic acids with azide groups on the surface of the target cells. The azide-labeled cells were then transplanted to mouse liver, and dibenzyl cyclooctyne-conjugated Cy5 (DBCO-Cy5) was intravenously injected into mice to chemically bind with the azide groups on the surface of the target cells in vivo for target cell visualization. Unnatural sialic acids with azide groups could be artificially induced on the surface of target cells by glycoengineering. We then tracked the azide groups on the surface of the cells by DBCO-Cy5 in vivo using bioorthogonal click chemistry. Importantly, labeling efficacy was enhanced and false signals by phagocytosis of macrophages were reduced. This strategy will be highly useful for cell labeling and tracking.
GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with ...AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose.
This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951).
Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18–64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63–3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68–14.32) also satisfied the non-inferiority criterion (95% CI lower limit > −5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination.
Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile.
This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.
Abstract Objective To clarify the association of serum calcium level with metabolic syndrome (MetS) and diabetes in middle-aged and elderly Korean subjects. Design and patients We conducted a ...population-based, cross-sectional survey of 1329 participants aged over 40 years (median age 65.8) in a rural area of Chungju, Korea, in 2007. Measurements Serum level of albumin, calcium, 25-hydroxy-vitamin D and intact parathyroid hormone were measured in a central laboratory. Results The prevalence of MetS increased progressively with elevated serum albumin-corrected calcium levels ( P < 0.001 for trend). After adjusting for various covariates, subjects in the highest quintile group (2.45–2.99 mmol/L) compared with the lowest quintile group (2.05–2.24 mmol/L) of serum calcium levels had an odds ratio (OR) for having MetS of 3.11 (95% confidence intervals, CI, 1.95–4.97; P for trend <0.001). Excluding the subjects with hypocalcemia and hypercalcemia ( n = 1064) did not alter this significant association. After multiple adjustment, subjects with serum calcium levels in the fourth to fifth quintiles had a 2.0- to 3.0-fold increased OR of having diabetes (first quintile reference, fourth quintiles OR 2.38; 95% CI 1.32–4.28, fifth quintiles OR 3.32; 95% CI 1.87–5.88; P for trend <0.001).The associations of serum calcium levels with the incidences of MetS or diabetes were unchanged after adjustment for 25(OH)D and PTH levels. Conclusions Altered calcium homeostasis was associated with an increased risk of having MetS and diabetes in this demographic group.
Glioblastoma (GBM) is the most lethal brain cancer with a dismal prognosis. Stem-like GBM cells (GSCs) are a major driver of GBM propagation and recurrence; thus, understanding the molecular ...mechanisms that promote GSCs may lead to effective therapeutic approaches. Through in vitro clonogenic growth-based assays, we determined mitogenic activities of the ligand molecules that are implicated in neural development. We have identified that semaphorin 3A (Sema3A), originally known as an axon guidance molecule in the CNS, promotes clonogenic growth of GBM cells but not normal neural progenitor cells (NPCs). Mechanistically, Sema3A binds to its receptor neuropilin-1 (NRP1) and facilitates an interaction between NRP1 and TGF-β receptor 1 (TGF-βR1), which in turn leads to activation of canonical TGF-β signaling in both GSCs and NPCs. TGF-β signaling enhances self-renewal and survival of GBM tumors through induction of key stem cell factors, but it evokes cytostatic responses in NPCs. Blockage of the Sema3A/NRP1 axis via shRNA-mediated knockdown of Sema3A or NRP1 impeded clonogenic growth and TGF-β pathway activity in GSCs and inhibited tumor growth in vivo. Taken together, these findings suggest that the Sema3A/NRP1/TGF-βR1 signaling axis is a critical regulator of GSC propagation and a potential therapeutic target for GBM.
The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric ...measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder.
Volumetric and surface-based morphometric approach to high-resolution three-dimensional T1-weighted images was used to examine the structural variations of the amygdala, with respect to extent and location, in 23 patients with panic disorder and 31 matched healthy individuals.
There were no significant differences in bilateral amygdalar volumes between patients with panic disorder and healthy individuals despite a trend-level right amygdalar volume reduction related to panic disorder (right, β = -0.23, p = 0.09, Cohen's d = 0.51; left, β = -0.18, p = 0.19, Cohen's d = 0.45). Amygdalar subregions were localized into three groups including the superficial, centromedial, and laterobasal groups based on the cytoarchitectonically defined probability map. Surface-based morphometric analysis revealed shape alterations in the laterobasal and centromedial groups of the right amygdala in patients with panic disorder (false discovery rate corrected p < 0.05).
The current findings suggest that subregion-specific shape alterations in the right amygdala may be involved in the development and maintenance of panic disorder, which may be attributed to the cause or effects of amygdalar hyperactivation.
To describe the clinical features of invagination of the sphenoid sinus mucosa (ISM) and compare them with other similar cases using a visual analog scale (VAS) to assess the various nasal symptoms ...and to discuss its clinical significance and means of prevention.
Retrospective chart review at a tertiary referral center.
Between 2010 and 2015, 8 patients who had undergone EETSA surgery displayed postoperative ISM. The comparison group consisted of 147 patients who underwent the same surgical procedures and were diagnosed with the same diseases. Pre- or postoperative paranasal sinus computed tomography (PNS CT) and VAS were performed and subsequently analyzed.
The clinical features of ISM of the sphenoid sinus showed sellar floor invagination and regenerated inverted ingrowing sphenoid mucosa on endoscopic imaging. PNS CT also showed a bony defect and invaginated air densities at the sellar turcica. Pre- and postoperative VAS scores revealed that the ISM group had much less of an improvement in headaches after surgery than that of the comparison group (p = 0.049).
ISM may occur because of a change in pressure, sphenoid mucosal status, or arachnoid membrane status. Moreover, ISM is related to improvements in headaches. Therefore, EETSA patients should avoid activities that cause rapid pressure changes during the healing process. In addition, sellar reconstruction that is resistant to physical pressure changes should be mandated despite the absence of an intraoperative CSF leak.
PDF
