Triple-negative breast cancer (TNBC) has a more aggressive phenotype and poorer prognosis than hormone receptor (HR+) and human epidermal growth factor receptor (HER2 −) subtypes. Inhibition of ...cyclin-dependent kinase (CDK)4 and CDK6 was successful in patients with advanced metastatic HR+/HER2− breast cancer, but those with TNBC exhibited low or no response to this therapeutic approach. This study investigated the dual therapeutic targeting of CDK2 and CDK4 by using 4-acetyl-antroquinonol B (4-AAQB) against TNBC cells.
We examined the effects of CDK2, CDK4, and CDK6 inhibition through 4-AAQB treatment on TNBC cell lines and established an orthotropic xenograft mouse model to confirm the in vitro results of inhibiting CDK2, CDK4, and CDK6 by 4-AAQB treatment.
High expression and alteration of CDK2 and CDK4 but not CDK6 significantly correlated with poor overall survival of patients with breast cancer. CDK2 and CDK4 were positively correlated with damage in DNA replication and repair pathways. Docking results indicated that 4-AAQB was bound to CDK2 and CDK4 with high affinity. Treatment of TNBC cells with 4-AAQB suppressed the expression of CDK2 and CDK4 in vitro. Additionally, 4-AAQB induced cell cycle arrest, DNA damage, and apoptosis in TNBC cells. In vivo study results confirmed that the anticancer activity of 4-AAQB suppressed tumor growth through the inhibition of CDK2 and CDK4.
The expression level of CDK2 and CDK4 and DNA damage response (DDR) signaling are prominent in TNBC cell cycle regulation. Thus, 4-AAQB is a potential agent for targeting CDK2/4 and DDR in TNBC cells.
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•The CDK2/4 and DNA damage response are prominent in TNBC cell cycle regulation.•4-Acetylantroquinonol B suppresses cell proliferation and induces apoptosis.•4-Acetylantroquinonol B in therapy targeting the CDK2/4 protein expression level and DNA damage response in TNBC cells.
Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best policies to control COVID-19 pandemic. The serological response to COVID-19 vaccination in ...Taiwanese patients with different comorbidities is elusive.
Uninfected subjects who received 3 doses of mRNA vaccines (BNT162b2 Pfizer-BioNTech, BNT and mRNA-1273 Moderna), viral vector-based vaccines (ChAdOx1-S (AZD1222, AZ) or protein subunit vaccines (Medigen COVID-19 vaccine) were prospectively enrolled. The SARS-CoV-2-IgG spike antibody level was determined within three months after the 3rd dose of vaccination. The Charlson Comorbidity Index (CCI) was applied to determine the association between vaccine titers and underlying comorbidities.
A total of 824 subjects were enrolled in the current study. The proportions of CCI scores of 0-1, 2-3 and > 4 were 52.8% (n = 435), 31.3% (n = 258) and 15.9% (n = 131), respectively. The most commonly used vaccination combination was AZ-AZ-Moderna (39.2%), followed by Moderna-Moderna-Moderna (27.8%). The mean vaccination titer was 3.11 log BAU/mL after a median of 48 days after the 3rd dose. Factors associated with potentially effective neutralization capacity (IgG level ≥ 4160 AU/mL) included age ≥ 60 years (odds ratio OR/95% confidence interval CI: 0.50/0.34-0.72, P < 0.001), female sex (OR/CI: 1.85/1.30-2.63, P = 0.001), Moderna-Moderna-based vaccination (compared to AZ-AZ-based vaccination, OR/CI: 6.49/3.90-10.83, P < 0.001), BNT-BNT-based vaccination (compared to AZ-AZ-based vaccination, OR/CI: 7.91/1.82-34.3, P = 0.006) and a CCI score ≥ 4 (OR/CI: 0.53/0.34-0.82, P = 0.004). There was a decreasing trend in antibody titers with increasing CCI scores (trend P < 0.001). Linear regression analysis revealed that higher CCI scores (β: - 0.083; 95% CI: - 0.094-0.011, P = 0.014) independently correlated with low IgG spike antibody levels.
Subjects with more comorbidities had a poor serological response to 3 doses of COVID-19 vaccination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The pursuit of high-performance electronic devices has driven the research focus toward 2D semiconductors with high electron mobility and suitable band gaps. Previous studies have demonstrated that ...quasi-2D Bi2O2Se (BOSe) has remarkable physical properties and is a promising candidate for further exploration. Building upon this foundation, the present work introduces a novel concept for achieving nonvolatile and reversible control of BOSe’s electronic properties. The approach involves the epitaxial integration of a ferroelectric PbZr0.2Ti0.8O3 (PZT) layer to modify BOSe’s band alignment. Within the BOSe/PZT heteroepitaxy, through two opposite ferroelectric polarization states of the PZT layer, we can tune the Fermi level in the BOSe layer. Consequently, this controlled modulation of the electronic structure provides a pathway to manipulate the electrical properties of the BOSe layer and the corresponding devices.
ObjectiveLung adenocarcinoma is a non-small cell lung cancer, a common cancer in both genders, and has poor clinical outcome. Our aim was to evaluate the role of epidermal growth factor (EGF)-like ...domain multiple 6 (EGFL6) and its prognostic significance in lung adenocarcinoma.MethodsEGFL6 expression was studied by immunohistochemical staining of specimens from 150 patients with lung adenocarcinoma. The correlation between clinicopathological features and EGFL6 expression was quantitatively analysed. We used Kaplan-Meier analysis and Cox proportional hazard models to examine the prognostic value of EGFL6 in terms of overall survival.ResultsNo significant correlation was found between EGFL6 expression and clinical parameters. However, patients with high levels of EGFL6 expression showed a tendency towards poor prognosis, with borderline statistical significance. Grouping the patients according to a medium age value revealed a significant association between high EGFL6 expression and poor clinical outcome in young patients. This finding was further confirmed by grouping the patients into three groups according to age. HR in patients with high EGFL6 expression was higher in younger patients than in older patients.ConclusionHigh EGFL6 expression may serve as a marker for poor prognosis of lung adenocarcinoma, especially in younger patients.
Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world ...nationwide basis is elusive.
The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT).
The eGFR decreased from baseline (91.4 mL/min/1.73 m
) to EOT (88.4 mL/min/1.73 m
; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m
) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m
(from 112.9 to 106.4 mL/min/1.73 m
; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m
(from 70.0 to 71.5 mL/min/1.73 m
; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m
was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m
; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change.
Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.
Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the ...Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 "TC + CC" variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047-1.674;
= 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics.
There are few studies addressing the longitudinal analysis of serum IgE levels and its impact to the development of atopic diseases in early childhood. We investigated 170 children who regularly ...followed up at our clinic for 4 years in a birth cohort study with at least 3 time-points of serum samples. The pattern of total serum IgE levels from 6 months to 4 years of age was clustered using K-means method in R software. Specific immunoglobulin E antibodies against food (egg white and milk) and inhalant allergens (D. pteronyssinus and D. farinae) were measured at 0.5, 1, 1.5, 2, 3 and 4 years of age. By using K-means clustering, the dynamic changes in serum IgE levels was significantly stratified into 3 clusters (cluster A, < 100 kU/L, n = 106; cluster B, 100-200 kU/L, n = 35; cluster C, ≥ 200 kU/L, n = 29). A persistent total IgE levels higher than 100 kU/L appeared to be associated with higher prevalence of sensitization to food but not mite. However, a persistent IgE levels higher than 200 kU/L was not only remarkably related to increased prevalence of mite sensitization, but also risk of eczema at age 1 and allergic rhinitis and asthma at age 2, 3 and 4. In conclusion, a persistent total serum IgE level ≥ 200 kU/L since infancy is strongly associated with the presence of food and mite sensitization, as well as the development of eczema in infants, and rhinitis and asthma later in early childhood.
Background Autophagy-related proteins may predict postresection overall survival (OS) and disease-free survival (DFS) in patients with combined hepatocellular carcinoma and cholangiocarcinoma ...(cHCC-CC). Methods We prospectively investigated how these proteins affect clinical prognosis in 40 patients who underwent hepatectomy for cHCC-CC from 2011 to 2019 at a Taiwanese hospital. Levels of autophagy-related proteins, namely LC3, Beclin-1, and p62, were immunohistochemically assessed in patient tumor and non-tumor tissues. Results We noted that LC3 expression was significantly correlated with mild clinicopathological characteristics, including macrovascular invasion, lymph node metastasis, American Joint Committee on Cancer and Barcelona Clinic Liver Cancer stages, recurrence, and mortality. Ten patient showed tumor recurrence, and 15 patients died. Postresection 5-year OS and DFS rates were 43.7 and 57.4%, respectively. Cox regression analysis showed that high intratumoral LC3 expression was significantly associated with improved OS hazard ratio (HR; 95% confidence interval (CI)): (1.68-26.9), p = 0.007, but multiple tumors and microvascular invasion was significantly correlated with poor OS HR (95% CI): 0.03 (0.01-0.34), p = 0.004, and 0.07 (0.01-0.46), p = 0.006, respectively. Furthermore, high LC3 expression and cirrhosis had improved DFS HR (95% CI): 51.3 (2.85-922), p = 0.008, and 17.9 (1.05-306), p = 0.046, respectively. The 5-year OS and DFS rates were respectively 61.2 and 74.6% in high LC3 expression patients and 0 and 0% in those with low LC3 expression. Conclusion High LC3 expression in tumors is significantly associated with mild clinicopathological characteristics and favorable clinical prognosis in patients with cHCC-CC after resection. Keywords: Combined hepatocellular carcinoma and cholangiocarcinoma, Autophagy, LC3, Prognosis, Predictive factors
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Cytokinins are plant-specific hormones that affect plant growth and development. The endogenous level of cytokinins in plant cells is regulated in part by irreversible degradation via ...cytokinin oxidase/dehydrogenase (CKX). Among the 11 rice CKXs, CKX2 has been implicated in regulation of rice grain yield.
Results
To specifically down-regulate
OsCKX2
expression, we have chosen two conserved glycosylation regions of
OsCKX2
for designing artificial short hairpin RNA interference genes (shRNA-
CX3
and -
CX5
, representing the 5′ and 3′ glycosylation region sequences, respectively) for transformation by the
Agrobacterium
-mediated method. For each construct, 5 independent transgenic lines were obtained for detailed analysis. Southern blot analysis confirmed the integration of the shRNA genes into the rice genome, and quantitative real time RT-PCR and northern blot analyses showed reduced
OsCKX2
expression in the young stem of transgenic rice at varying degrees. However, the expression of other rice
CKX
genes, such as
CKX1
and
CKX3
, in these transgenic lines was not altered. Transgenic rice plants grown in the greenhouse were greener and more vigorous with delayed senescence, compared to the wild type. In field experiments, both
CX3
and
CX5
transgenic rice plants produced more tillers (27–81 %) and grains (24–67 %) per plant and had a heavier 1000 grain weight (5–15 %) than the wild type. The increases in grain yield were highly correlated with increased tiller numbers. Consistently, insertional activation of
OsCKX2
led to increased expression of
CKX2
and reduced tiller number and growth in a gene-dosage dependant manner.
Conclusions
Taken together, these results demonstrate that specific suppression of
OsCKX2
expression through shRNA-mediated gene silencing leads to enhanced growth and productivity in rice by increasing tiller number and grain weight.
Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is ...a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA‐mediated and shRNA‐mediated NPRL2 down‐regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down‐regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down‐regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down‐regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease‐free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down‐regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.
Efficient NPRL2 downregulation significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo via the mTOR pathway and autophagy suppression. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in HCC patients.
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