Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2‐like kinase 2 (CLK2), an oncogenic RNA‐splicing kinase pivotal in ...breast cancer, plays a significant role, particularly in the context of triple‐negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure‐based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC50) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell‐based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy.
Purpose
To assess the reduction of 6 and 12 months postoperatively of Framingham risk score in morbidly obese patients with laparoscopic sleeve gastrectomy (LSG).
Material and methods
In total, 870 ...morbid obesity patients received LSG in Taipei Medical University Hospital from June 2007 to June 2014 were retrospectively studied preoperatively, 6 and 12 months after surgery. The coronary heart disease risk was calculated using Framingham risk score.
Results
The body mass index in men and women decreased from 43.3 ± 6.9, 39.2 ± 6.0 kg/m
2
preoperatively to 32.9 ± 6.7, 31.0 ± 5.2 kg/m
2
and to 30.4 ± 5.6 , 28.2 ± 4.7 kg/m
2
, respectively, at 6 and 12 months after surgery (
P
< 0.0001). At 6 and 12 months after LSG, there was a marked improvement on lipid profile as well as a significant decline in the prevalence of diabetes mellitus, systemic hypertension, and smoking. The Framingham risk score in men and women reduced from 3.2 ± 5.7, 6.1 ± 5.7 preoperatively to 1.4 ± 5.9, 3.3 ± 5.9 and 0.1 ± 6.2, 2.8 ± 6.1, respectively, at 6 and 12 months after surgery (
P
< 0.0001).
Conclusions
Laparoscopic sleeve gastrectomy is efficient not only in the reduction of obesity and its related comorbidities but also in decreasing the long-term coronary event risk. Early intervention for the high-risk group is strongly recommended.
Laparoscopic techniques are commonly used in abdominal and gynecologic surgery, while breast cancer surgery has remained largely unchanged. In Asia, especially in Japan, many surgeons have started to ...use endoscopic surgery for breast cancer. In Taiwan, endoscopy-assisted breast surgery started in 2010. The benefits of this surgical method include smaller incisions, an axillary anatomic approach, clear vision, no oncologic compromise, and good cosmetic outcomes. This is the first report to discuss the learning curve of endoscopy-assisted breast surgery, including the difficulties experienced.
From June 2011 to December 2013, data were collected from 134 patients who received an endoscopic total mastectomy at the Taipei Medical University Hospital (TMUH) or Changhua Christian Hospital (CCH). We divided these patients into a learning group (TMUH, n = 15; CCH, n = 15) and a mature group (TMUH, n = 50; CCH, n = 54). Patient data and perioperative variables were recorded by retrospective chart review. Variables were compared using the χ2 test and Student's t-test.
There was a significant difference in operation time (275.3 vs. 228.9 minutes, p < 0.01) between the learning and mature groups. Perioperative variables (lymph node dissection method, nipple preservation, and reconstruction method) were also analyzed, but there were no demographic differences between the groups. The complication rate was higher in the learning group, although this difference was also not statistically significant.
Our study is the first to discuss the learning curve of endoscopic total mastectomy. The operation time decreased significantly after 15 cases at each hospital. Although the operation is still more time-consuming than traditional methods, it has the benefit of smaller wounds and improved cosmetic outcomes if combined with immediate reconstruction.
A novel one‐trough synthesis via an air‐water interface is demonstrated to provide hexagonally packed arrays of densely spaced metallic nanoparticles (NPs). In the synthesis, a mesostructured ...polyoxometalate (POM)‐silicatropic template (PSS) is first self‐assembled at the air‐water interface; upon UV irradiation, anion exchange cycles enable the free‐floating PSS film to continuously uptake gold precursors from the solution subphase for diffusion‐controlled and POM‐site‐directed photoreduction inside the silica channels. NPs ≈ 2 nm can hence be homogeneously formed inside the silica‐surfactant channels until saturation. As revealed via X‐ray diffraction, small‐angle X‐ray scattering (SAXS), grazing incidence SAXS, and transmission electron microscopy, the Au NPs directed by the PSS template are arrayed into a 2D hexagonal lattice with inter‐channel spacing of 3.2 nm and a mean along‐channel NP spacing of 2.8 nm. This corresponds to an ultra‐high number density (≈1019 NPs cm−3) of narrowly spaced Au NPs in the Au‐NP@PSS composite, leading to 3D densely deployed hot‐spots along and across the mesostructured POM‐silica channels for surface‐enhanced Raman scattering (SERS). Consequently, the Au‐NP@PSS composite exhibits prominent SERS with 4‐mercaptobenzoic acid (4‐MBA) adsorbed onto Au NPs. The best 4‐MBA detection limit is 5 nm, with corresponding SERS enhancement factors above 108.
Densely arrayed metallic nanoparticles are fabricated via self‐assembly of a mesostructured polyoxometalate‐silicate‐surfactant (PSS) template at the air‐water interface (left), followed by adsorption of metallic precursors to the PSS film via anion exchange (middle), then finished by polyoxometalate (POM)‐site‐directed photoreduction of the metallic anions and formation of metallic NPs inside the silicate‐surfactant channels upon UV irradiation (right).
The availability of a reliable tumor target for advanced colorectal cancer (CRC) therapeutic approaches is critical since current treatments are limited. Epidermal growth factor-like domain 6 (EGFL6) ...has been reported to be associated with cancer development. Here, we focused on the role of EGFL6 in CRC progression and its clinical relevance. In addition, an anti-EGFL6 antibody was generated by phage display technology to investigate its potential therapeutic efficacy in CRC.
EGFL6 expression significantly increased in the colon tissues from CRC patients and mice showing spontaneous tumorigenesis, but not in normal tissue. Under hypoxic condition, EGFL6 expression was enhanced at both protein and transcript levels. Moreover, EGFL6 could promote cancer cell migration invasion, and proliferation of CRC cells via up-regulation of the ERK/ AKT pathway. EGFL6 also regulated cell migration, invasion, proliferation, and self-renewal through EGFR/αvβ3 integrin receptors. Treatment with the anti-EGFL6 antibody EGFL6-E5-IgG showed tumor-inhibition and anti-metastasis abilities in the xenograft and syngeneic mouse models, respectively. Moreover, EGFL6-E5-IgG treatment had no adverse effect on angiogenesis and wound healing CONCLUSIONS: We demonstrated that EGFL6 plays a role in CRC tumorigenesis and tumor progression, indicating that EGFL6 is a potential therapeutic target worth further investigation.
Breast cancer is a common malignancy worldwide. Smartphones have gradually become indispensable to our modern lives and have already changed lifestyles of human beings. To our best knowledge, no ...study has investigated the relationship between smartphone use and breast cancer. This case-control study purposely investigated the relationship between smartphone use and breast cancer risk.
This was a case-control study comprising 894 healthy controls and 211 patients with breast cancer. All participants were asked to respond to standard questionnaires to collect information on sleep quality, smartphone addiction, and smartphone use.
Participants with smartphone addiction had a significantly higher 1.43-fold risk of breast cancer. Individuals with the habitual behavior of smartphone use >4.5 minutes before bedtime had a significantly increased 5.27-fold risk of breast cancer compared to those who used a smartphone for ≤4.5 minutes before bedtime. Additionally, a closer distance between the smartphone and the breasts when using the smartphone exhibited a significantly increased 1.59-fold risk. Participants who carried their smartphone near their chest or waist-abdomen area had significantly increased 5.03-fold and 4.06-fold risks of breast cancer, respectively, compared to those who carried the smartphone below the waist. Moreover, there was a synergistic effect of smartphone addiction and smartphone use of >4.5 minutes before bedtime which increased the breast cancer risk.
Excessive smartphone use significantly increased the risk of breast cancer, particularly for participants with smartphone addiction, a close distance between the breasts and smartphone, and the habit of smartphone use before bedtime.
Abstract PM $$_{2.5}$$ 2.5 prediction plays an important role for governments in establishing policies to control the emission of excessive atmospheric pollutants to protect the health of citizens. ...However, traditional machine learning methods that use data collected from ground-level monitoring stations have reached their limit with poor model generalization and insufficient data. We propose a composite neural network trained with aerosol optical depth (AOD) and weather data collected from satellites, as well as interpolated ocean wind features. We investigate the model outputs of different components of the composite neural network, concluding that the proposed composite neural network architecture yields significant improvements in overall performance compared to each component and the ensemble model benchmarks. The monthly analysis also demonstrates the superiority of the proposed architecture for stations where land-sea breezes frequently occur in the southern and central Taiwan in the months when land-sea breeze dominates the accumulation of PM $$_{2.5}$$ 2.5 .
Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development ...of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications.
In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells.
The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively.
In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G0/G1 phase and followed by the cells undergoing apoptosis.
O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization.
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Objective Phyllodes tumors are composed of a benign epithelial component and a cellular spindle cell stroma that form a leaf-like structure. The purpose of this study was to define changes in patient ...characteristics, histopathologic parameters, and the outcome during two periods: before and after the introduction of core needle biopsy for preoperative diagnosis. Methods Records were reviewed of 170 patients with phyllodes tumors who were managed surgically. Patients treated from 1997 to 2004 ( n = 101) were compared with patients treated from 2006 to 2013 ( n = 69). Results The analysis of the two treatment periods revealed that the tumor size at diagnosis increased from 4.6 cm during the earlier period to 7.0 cm during the recent period ( p < 0.05). The number of patients undergoing wide excision significantly increased during the recent period. Multivariate analysis revealed that a positive surgical margin was the only independent predictor of recurrence with an increased hazard of 4.8. Conclusion Wide excision with a clear margin is the first choice of current treatment for phyllodes tumors, even for malignant phyllodes tumors. However, this strategy does not further reduce local recurrence effectively, and core needle biopsy cannot be overstated in avoiding inappropriate initial surgery.
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