The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma ...(HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort (P=0.045). Furthermore, SET was significantly associated with cell growth and hepatosphere formation. To elucidate the anti-HCC potential of targeting SET, we generated a novel SET antagonist, EMQA (N(4)-(3-ethynylphenyl)-6,7-dimethoxy-N(2)-(4-phenoxyphenyl) quinazoline-2,4-diamine). EMQA enhanced PP2A activity via disrupting SET-PP2Ac (catalytic domain of PP2A) binding in HCC cells, which restored PP2A-mediated p-Akt downregulation and promoted HCC cell death. In HCC cells or recombinant proteins expressing the N- and C- truncated forms of SET, only the C-terminal SET was required for EMQA targeting. Furthermore, combining sorafenib and EMQA showed good synergism in inhibiting HCC survival. Our findings suggested the oncogenic role of SET and the adverse prognostic value of SET overexpression in HCC. This alteration defines a subgroup of HCC patients who could benefit from SET antagonists, such as EMQA.
Objectives
To evaluate MRI texture analysis in differentiating clinicopathological characteristics of cervical carcinoma (CC).
Methods
Patients with newly diagnosed CC who underwent pre-treatment MRI ...were retrospectively reviewed. Texture analysis was performed using commercial software (TexRAD). Largest single-slice ROIs were manually drawn around the tumour on T2-weighted (T2W) images, apparent diffusion coefficient (ADC) maps and contrast-enhanced T1-weighted (T1c) images. First-order texture features were calculated and compared among histological subtypes, tumour grades, FIGO stages and nodal status using the Mann-Whitney
U
test. Feature selection was achieved by elastic net. Selected features from different sequences were used to build the multivariable support vector machine (SVM) models and the performances were assessed by ROC curves and AUC.
Results
Ninety-five patients with FIGO stage IB~IVB were evaluated. A number of texture features from multiple sequences were significantly different among all the clinicopathological subgroups (
p
< 0.05). Texture features from different sequences were selected to build the SVM models. The AUCs of SVM models for discriminating histological subtypes, tumour grades, FIGO stages and nodal status were 0.841, 0.850, 0.898 and 0.879, respectively.
Conclusions
Texture features derived from multiple sequences were helpful in differentiating the clinicopathological signatures of CC. The SVM models with selected features from different sequences offered excellent diagnostic discrimination of the tumour characteristics in CC.
Key Points
• First-order texture features are able to differentiate clinicopathological signatures of cervical carcinoma.
• Combined texture features from different sequences can offer excellent diagnostic discrimination of the tumour characteristics in cervical carcinoma
.
We describe an introduction of clade GH severe acute respiratory syndrome coronavirus 2 causing a fourth wave of coronavirus disease in Hong Kong. The virus has an ORF3a-Q57H mutation, causing ...truncation of ORF3b. This virus evades induction of cytokine, chemokine, and interferon-stimulated gene expression in primary human respiratory cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To investigate the predictive value of peritoneal carcinomatosis (PC) quantification by DWI in determining incomplete tumour debulking in ovarian carcinoma (OC).
Methods
Prospective ...patients with suspected stage III–IV or recurrent OC were recruited for DWI before surgery. PC on DWI was segmented semi-automatically by
k
-means clustering, retaining voxels with intermediate apparent diffusion coefficient (ADC) to quantify PC burden. A scoring system, functional peritoneal cancer index (fPCI), was proposed based on the segmentation of tumour volume in 13 abdominopelvic regions with additional point given to involvement of critical sites. ADC of the largest PC was recorded. The surgical complexity and outcomes (complete vs. incomplete tumour debulking) were documented. fPCI was correlated with surgical PCI (sPCI), surgical complexity, and its ability to predict incomplete tumour debulking.
Results
Fifty-three patients with stage III–IV or recurrent OC were included with a mean age of 56.1 ± 11.8 years old. Complete tumour debulking was achieved in 38/53 patients (71.7%). Significant correlation was found between fPCI and sPCI (
r
> 0.757,
p
< 0.001). Patients with high-fPCI (fPCI ≥ 6) had a high surgical complexity score (
p
= 0.043) with 84.2% received radical or supra-radical surgery. The mean fPCI was significantly higher in patients with incomplete tumour debulking than in those with complete debulking (10.27 vs. 4.71,
p
< 0.001). fPCI/ADC combined with The International Federation of Gynecology and Obstetrics stage achieved 92.5% accuracy in predicting incomplete tumour debulking (AUC 0.947).
Conclusions
DWI-derived fPCI offered a semi-automated estimation of PC burden. fPCI/ADC could predict the likelihood of incomplete tumour debulking with high accuracy.
Key Points
•
Functional peritoneal cancer index (fPCI) derived from DWI offered a semi-automated estimation of tumour burden in ovarian carcinoma.
•
fPCI was highly correlated with surgical PCI (sPCI).
•
fPCI/ADC could predict the likelihood of incomplete tumour debulking with high accuracy.
Prolonged electronic screen use can cause digital eye strain. It can be difficult to rectify due to increasing smartphone reliance, potentially leading to serious public health problems. To ...investigate the association between time spent on smartphones and digital eye strain (DES) among Hong Kong Chinese school-aged children. Of a total of 1,508 students (748 males, 49.6%) from 8 to 14 years old (mean age = 10.91 years, SD = 2.01) who provided valid data on DES, the 1,298 (86%) who completed the DES questionnaire at 1-year follow-up were included in the analysis. DES was measured using a 10-item scale, and the sum of the 10 dichotomised scores was used as the DES total score. The most commonly reported symptoms were eye fatigue (n = 804, 53.3%), blurred vision (changing from reading to distance viewing) (n = 586, 38.9%), and irritated or burning eyes (n = 516, 34.2%). The DES total scores at baseline and 1-year follow-up were 2.91 (SD = 2.90) and 3.20 (SD = 3.19), respectively. Linear regression controlling for demographic and socio-economic confounders showed that participants with baseline smartphone usage of 241 + min/d had a significantly higher baseline total DES score than those with baseline smartphone usage of 0–60 min/d (2.44 vs 3.21,
P
< 0.001), and participants with baseline smartphone usage of 181–240 min/d had a significantly higher 1-year follow-up total DES score than those with baseline smartphone usage of 0–60 min/d (2.80 vs 3.50,
P
= 0.003).
Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. Src homology region 2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor ...suppressor and also acts as a negative regulator of p-STAT3(Tyr705) oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here we first reported that endogenous SHP-1 protein levels were significantly downregulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3(Tyr705) and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished transforming growth factor-β1 (TGF-β1)-induced p-STAT3(Tyr705) and EMT, as well inhibited migration and invasion but further rescued by signal transducer and activator of transcription factor 3 (STAT3) overexpression. Depletion of SHP-1 could induce a more increase in TGF-β1-induced p-STAT3(Tyr-705) and EMT characteristics, further supporting the mechanism that suppression of TGF-β1-induced EMT is dependent on SHP-1-mediated STAT3 inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A-mutated SHP-1 markedly reduced TGF-β1-induced p-STAT3(Tyr705) and EMT features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine phosphatase activity that directly downregulated p-STAT3(Tyr705). Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus highlighting that SC-43-SHP-1 axis may serve as a potential therapeutic target that antagonized p-STAT3(Tyr705) and thereby prevented HCC EMT and metastasis.
LC3-associated phagocytosis (LAP) is an emerging non-canonical autophagy process that bridges signaling from pattern-recognition receptors (PRRs) to autophagic machinery. LAP formation results in ...incorporation of lipidated LC3 into phagosomal membrane (termed LAPosome). Increasing evidence reveals that LAP functions as an innate defense mechanism against fungal pathogens. However, the molecular mechanism involved and the consequence of LAP in regulating anti-fungal immune response remain largely unexplored. Here we show that
is taken into LAPosome upon phagocytosis by macrophages. Interaction of
with Dectin-1 activates Syk and triggers subsequent NADPH oxidase-mediated reactive oxygen species (ROS) response that is involved in LAP induction. Inhibiting LAP induction by silencing LC3α/β or treatment with ROS inhibitor impairs the activation of MAPKs-AP-1 pathway, thereby reduces macrophage proinflammatory cytokine response to
. Additionally, we unravel the importance of NLRX1 in fungus-induced LAP. NLRX1 facilitates LAP by interacting with TUFM which associates with autophagic proteins ATG5-ATG12 for LAPosome formation. Macrophages from
mice or TUFM-silenced cells exhibit reduced LAP induction and LAP-mediated MAPKs-AP-1 activation for cytokine response to
. Furthermore, inhibiting ROS production in
macrophages almost completely abolishes
-induced LC3 conversion, indicating that both Dectin-1/Syk/ROS-dependent pathway and NLRX1-TUFM complex-dependent pathway collaboratively contribute to LAP induction. Our findings reveal new pathways underlying LAP induction by
for macrophage cytokine response.
Porous NiTi alloys with different porosities were fabricated by capsule-free hot isostatic pressing (CF-HIP) with ammonium acid carbonate (NH
4HCO
3) as a space-holder. The microstructure and ...porosity of porous NiTi produced with different NH
4HCO
3 contents and sintering temperatures were determined. Two different creep expansion models are used to explain the pore expansion mechanism during the sintering process, which involves slow and continuous reduction of the argon pressure at high temperatures. When the NH
4HCO
3 content is 30
wt.% and the sintering temperature is 1050
°C, an ideal porous NiTi alloy with 48
vol.% porosity and circular pores (50–800
μm) is obtained. Compression tests indicate that the porous NiTi alloys with 21–48% porosity possess not only lower Young’s moduli of 6–11
GPa (close to that of human bones) but also higher compression strength and excellent superelasticity. Cell cultures reveal that the porous NiTi prepared here has no apparent cytotoxicity. The porous materials are thus promising biomaterials in hard tissue replacements.
Existence of humoral immunity has been previously demonstrated in malignant ascitic fluids. However, only a limited number of immunogenic tumor-associated antigens (TAAs) were identified, and few of ...which are associated with ovarian cancer. Here, we identified salt-inducible kinase 3 (SIK3) as a TAA through screening of a random peptide library in the phage display system. Overexpression of SIK3 markedly promoted cell proliferation, attenuated p21(Waf/Cip1) and p27(Kip) expressions in low-grade OVCAR3 cells, and permitted the cells to grow in mice. Decrease in SIK3 expression in high-grade SK-OV3 cells consistently demonstrated its tumorigenic potency by modulating the protein levels of cell cycle regulators. When the expressions of SIK3 and CA125 were compared in cancer tissues, immunohistochemical (IHC) studies indicated that cytoplasm-localized SIK3 was highly expressed in 55% of the ovarian cancer samples. In contrast, it was rarely detected in adenomyosis, leiomyoma and normal ovary tissues, showing its higher specificity (97%) to CA125 (65%) in ovarian cancer. Moreover, experiments using pharmacological inhibitors to block SIK3-induced p21(Waf/Cip1) expression revealed that activation of c-Src and phosphoinositide-3-kinase were critically required for its biological activity, suggesting that they are the downstream signaling mediators of SIK3. These data were further supported by IHC studies, showing coexpression of c-Src with SIK3 in 85% of the ovarian tumor samples stained positive for SIK3. Collectively, our findings indicate that SIK3 is a novel ovarian TAA. Overexpression of SIK3 promotes G1/S cell cycle progression, bestows survival advantages to cancer cells for growth and correlates the clinicopathological conditions of patients with ovarian cancer.
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