FAT atypical cadherin 1 (FAT1) regulates cell-cell adhesion and extracellular matrix architecture, while acting as tumor suppressor or oncogene, context-dependently. Despite implication of FAT1 in ...several malignancies, its role in oral squamous cell carcinoma (OSCC) remains unclear. Herein, we document the driver-oncogene role of FAT1, and its mediation of cell-death evasion, proliferation, oncogenicity, and chemoresistance in OSCC. In-silica analyses indicate FAT1 mutations are frequent and drive head-neck SCC, with enhanced expression defining high-risk population and poor prognosis. We demonstrated aberrant FAT1 mRNA and protein expression in OSCC compared with non-cancer tissues, whereas loss-of-FAT1-function attenuates human primary SAS and metastatic HSC-3 OSCC cell viability, without affecting normal primary human gingival fibroblast cells. shFAT1 suppressed PCNA and upregulated BAX/BCL2 ratio in SAS and HSC-3 cells. Moreover, compared with wild-type cells, shFAT1 concomitantly impaired HSC-3 cell migration, invasion, and clonogenicity. Interestingly, while over-expressed FAT1 characterized cisplatin-resistance (CispR), shFAT1 synchronously re-sensitized CispR cells to cisplatin, enhanced glutathione (GSH)/GSH synthetase (GSS)-mediated oxidative stress and deregulated LRP5/WNT2 signaling. Concisely, FAT1 is an actionable driver-oncogene in OSCC and targeting FAT1 in patients with erstwhile cisplatin-resistant OSCC is therapeutically promising.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Nasopharyngeal carcinoma (NPC) is known for its high metastatic potential and locoregional recurrence, although the molecular alterations that are driving NPC metastasis remain unclear at this time. ...This study aimed to examine the expression of fibulin-5 in NPC, correlate the results with clinicopathological variables and survival, and to investigate the role of fibulin-5 in human NPC cell lines.
Standard semi-quantitative-RT-PCR, quantitative-RT-PCR, immunoblotting, and immunohistochemistry were used to investigate the mRNA and protein expression profiles of fibulin-5 in normal and NPC tissues. Immunohistochemistry of fibulin-5 was correlated with clinicopathological characteristics by univariate analyses. NPC cells overexpressing fibulin-5 or fibulin-5-siRNA cells were generated by stable transfection to characterize the molecular mechanisms of fibulin-5-elicited cell growth and metastasis.
Our results demonstrated that fibulin-5 overexpression in NPC specimens and significantly correlated with advanced tumor metastasis indicating a poor 5-year overall survival. Fibulin-5 was mainly expressed in the nucleus in human NPC specimens and cell lines. Functionally, fibulin-5 overexpression yielded fast growth in NPC cells. In addition, fibulin-5 promotes cell metastasis in NPC cells through increased FLJ10540 and phosphor-AKT activity. In contrast, siRNA depletion of fibulin-5 suppressed FLJ10540 expression and phosphor-AKT activity. Suppression of either fibulin-5 or FLJ10540 can cause significant inhibition with regards to cell motility in NPC cells. Finally, immunohistochemical analysis of human aggressive NPC specimens showed a significant and positive correlation between fibulin-5 and FLJ10540 expression.
Higher fibulin-5 expression is not only an important indicator of poor survival, but also contributes to the development of new therapeutic strategies in the FLJ10540/AKT pathway for NPC treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The study evaluated the real-world treatment outcomes of Glecaprevir/pibrentasvir (GLE/PIB) including effectiveness, safety and healthcare resource utilization based on a nation-wide registry in ...Taiwan. The Taiwan HCV Registry (TACR) is a nation-wide platform organized and supervised by the Taiwan Association for the Study of the Liver. Data were analyzed for patients treated with GLE/PIB, including 3144 patients who had treatment outcome available. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA throughout 12 weeks of end-of-treatment). The overall SVR12 rate was 98.9% (3110/3144), with 98.8%, 99.4% and 100% in patients receiving 8 weeks, 12 weeks, and 16 weeks of GLE/PIB respectively. The SVR12 rate in the treatment-naïve cirrhotic patients receiving 8 weeks of GLE/PIB was 98.2% (108/110). The most common AEs were fatigue (7.5%), pruritus (6.7%) and dizziness (1.5%). The mean number of outpatient visits during the GLE/PIB was 5.94 visits for patients treated with 8 weeks, significantly different from the patients treated with 12 weeks of GLE/PIB (6.90 visits). The results support the effectiveness and safety of GLE/PIB treatment in real-world clinical practice, and provide further evidence that the shorter, 8-week GLE/PIB regimen is effective and cost-saving.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Melatonin, a naturally biosynthesized molecule secreted by the pineal gland, exhibits antitumor activities against several different types of cancer. The mechanisms of action of melatonin against ...tumor progression involve cellular apoptosis, antimetastatic activity, antioxidant and mutagenic effects, antiangiogenic activity, and the restoration of cancer immune surveillance. Melatonin has anticancer activity when administered alone or in combination with standard chemotherapeutic agents, with measurable improvements seen in the clinical endpoints of tumor regression and patient survival. However, scant clinical evidence supports the use of melatonin in bladder cancer treatment. Our study has found that melatonin treatment suppresses the bladder cancer cell migratory ability by inhibiting the epithelial-mesenchymal transition (EMT) process, which appears to be linked to melatonin-induced decreases in bladder cancer cell autophagy. Finally, an evaluation of in vivo melatonin-induced antitumor effects in an orthotopic animal model of bladder cancer indicated that melatonin treatment slightly prolonged the survival of tumor-bearing mice. Our study offers novel insights into the use of melatonin in bladder cancer treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Quantum key distribution (QKD) uses individual light quanta in quantum superposition states to guarantee unconditional communication security between distant parties. However, the distance over which ...QKD is achievable has been limited to a few hundred kilometres, owing to the channel loss that occurs when using optical fibres or terrestrial free space that exponentially reduces the photon transmission rate. Satellite-based QKD has the potential to help to establish a global-scale quantum network, owing to the negligible photon loss and decoherence experienced in empty space. Here we report the development and launch of a low-Earth-orbit satellite for implementing decoy-state QKD-a form of QKD that uses weak coherent pulses at high channel loss and is secure because photon-number-splitting eavesdropping can be detected. We achieve a kilohertz key rate from the satellite to the ground over a distance of up to 1,200 kilometres. This key rate is around 20 orders of magnitudes greater than that expected using an optical fibre of the same length. The establishment of a reliable and efficient space-to-ground link for quantum-state transmission paves the way to global-scale quantum networks.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
In this letter, we report the effects of N sub(2)O annealing of interpoly oxide on flash cell performance. It is demonstrated that by adding an N sub(2)O anneal after interpoly oxide formation, ...improved cycling endurance is achieved. The program and erase efficiencies are also improved significantly, compared to the control cell without N sub(2)O anneal. The cells with N sub(2)O anneal show higher cell current (i.e., drain current), which can be ascribed to a lower threshold voltage and higher transconductance, compared to the control cell.
The pathological identification of lymph node (LN) metastasis is demanding and tedious. Although convolutional neural networks (CNNs) possess considerable potential in improving the process, the ...ultrahigh-resolution of whole slide images hinders the development of a clinically applicable solution. We design an artificial-intelligence-assisted LN assessment workflow to facilitate the routine counting of metastatic LNs. Unlike previous patch-based approaches, our proposed method trains CNNs by using 5-gigapixel images, obviating the need for lesion-level annotations. Trained on 5907 LN images, our algorithm identifies metastatic LNs in gastric cancer with a slide-level area under the receiver operating characteristic curve (AUC) of 0.9936. Clinical experiments reveal that the workflow significantly improves the sensitivity of micrometastasis identification (81.94% to 95.83%, P < .001) and isolated tumor cells (67.95% to 96.15%, P < .001) in a significantly shorter review time (-31.5%, P < .001). Cross-site evaluation indicates that the algorithm is highly robust (AUC = 0.9829).
Allyl isothiocyanate (AITC) is abundant in cruciferous vegetables and it present pharmacological activity including anticancer activity in many types of human cancer cells in vitro and in vivo. ...Currently, no available information to show AITC affecting DNA damage and repair‐associated protein expression in human gastric cancer cells. Therefore, in the present studies, we investigated AITC‐induced cytotoxic effects on human gastric cancer in AGS and SNU‐1 cells whether or not via the induction of DNA damage and affected DNA damage and repair associated poteins expressions in vitro. Cell viability and morphological changes were assayed by flow cytometer and phase contrast microscopy, respectively, the results indicated AITC induced cell morphological changes and decreased total viable cells in AGS and SNU‐1 cells in a dose‐dependently. AITC induced DNA condensation and damage in a dose‐dependently which based on the cell nuclei was stained by 4′, 6‐diamidino‐2‐phenylindole present in AGS and SNU‐1 cells. DNA damage and repair associated proteins expression in AGS and SNU‐1 cells were measured by Western blotting. The results indicated AITC decreased nuclear factor erythroid 2‐related factor 2 (NRF2), heme oxygenase‐1 (HO‐1), glutathione, and catalase, but increased superoxide dismutase (SOD (Cu/Zn)), and nitric oxide synthase (iNOS) in AGS cells, however, in SNU‐1 cells are increased HO‐1. AITC increased DNA‐dependent protein kinase (DNA‐PK), phosphorylation of gamma H2A histone family member X on Ser139 (γH2AXpSer139), and heat shock protein 90 (HSP90) in AGS cells. AITC increased DNA‐PK, mediator of DNA damage checkpoint protein 1 (MDC1), γH2AXpSer139, topoisomerase II alpha (TOPIIα), topoisomerase II beta (TOPIIβ), HSP90, and heat shock protein 70 (HSP70) in SNU‐1 cells. AITC increased p53, p53pSer15, and p21 but decreased murine double minute 2 (MDM2)pSer166 and O6‐methylguanine‐DNA methyltransferase (MGMT) in AGS cells; however, it has a similar effect of AITC except increased ataxia telangiectasia and Rad3‐related protein (ATR)pSer428, checkpoint kinase 1 (CHK1), and checkpoint kinase 2 (CHK2) in SNU‐1 cells. Apparently, both cell responses to AITC are different, nonetheless, all of these observations suggest that AITC inhibits the growth of gastric cancer cells may through induction off DNA damage in vitro.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Scaffolds for tissue engineering aim to mimic the native extracellular matrix (ECM) that provides physical support and biochemical signals to modulate multiple cell behaviors. However, the majority ...of currently used biomaterials are oversimplified and therefore fail to provide a niche required for the stimulation of tissue regeneration. In the present study, 3D decellularized ECM (dECM) scaffolds derived from mesenchymal stem cell (MSC) spheroids and with intricate matrix composition are developed. Specifically, application of macromolecular crowding (MMC) to MSC spheroid cultures facilitate ECM assembly in a 3D configuration, resulting in the accumulation of ECM and associated bioactive components. Decellularized 3D dECM constructs produced under MMC are able to adequately preserve the microarchitecture of structural ECM components and are characterized by higher retention of growth factors. This results in a stronger proangiogenic bioactivity as compared to constructs produced under uncrowded conditions. These dECM scaffolds can be homogenously populated by endothelial cells, which direct the macroassembly of the structures into larger cell‐carrying constructs. Application of empty scaffolds enhances intrinsic revascularization in vivo, indicating that the 3D dECM scaffolds represent optimal proangiogenic bioactive blocks for the construction of larger engineered tissue constructs.
Applying of macromolecular crowding (MMC) to 3D spheroid cultures of mesenchymal stem cell (MSC) achieves the accumulation of extracellular matrix (ECM) and associated bioactive components. After decellularization, the resulting 3D decellularized ECM constructs have a well‐preserved microarchitecture of the structural ECM components and can be repopulated by cells for directing their macroassembly into larger cell‐carrying tissue engineering constructs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
It has been shown that iron deficiency anemia (IDA) is associated with psychosocial consequences and psychiatric morbidity. However, the association between adults with IDA and psychiatric disorders ...has not been clarified. The purpose of this study was to investigate the psychiatric disorder morbidity of an IDA group in comparison with a non-IDA group and to examine the risk of psychiatric disorders in IDA patients treated with iron supplementation.
All study subjects were 20 years of age or over with newly diagnosed IDA enrolled in the Taiwan National Health Insurance Database from 2000 to 2012. We matched IDA and non-IDA subjects according to age and gender in a 1:2 ratio. Our primary outcome was diagnosis of psychiatric disorders and the patients were monitored until the end of 2013. A multivariate Cox proportional hazards regression model was used to explore the risk of psychiatric disorders in patients with IDA after adjustment for confounders, including demographic characteristics and comorbidities.
The adjusted hazard ratios (aHRs) of psychiatric disorders was 1.52 (95% CI = 1.45-1.59) in the IDA group compared with the non-IDA group. Among the different types of psychiatric disorders, the IDA group was associated with significantly higher incidence and risks of anxiety disorders, depression, sleep disorders, and psychotic disorders (p < 0.05). Furthermore, iron supplementation in IDA subjects was associated with a significantly lower risk of psychiatric disorders compared to non-iron supplementation in IDA patients.
Our study indicates that IDA subjects had an increased risk of psychiatric disorders, regardless of other confounders. In IDA patients, iron supplementation was associated with a decreased risk of psychiatric disorders. Moreover, IDA patients receiving iron supplementation also had a lower risk of sleep disorders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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