Dysregulation of androgen signaling and pericellular proteolysis is necessary for prostate cancer progression, but the links between them are still obscure. In this study, we show how the ...membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth, and metastasis. We found that matriptase serves as a substrate for TMPRSS2 in mediating this proinvasive action of androgens in prostate cancer. Further, we determined that higher levels of TMPRSS2 expression correlate with higher levels of matriptase activation in prostate cancer tissues. Lastly, we found that the ability of TMPRSS2 to promote prostate cancer tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin β1 in tumor xenografts. In summary, our results establish that TMPRSS2 promotes the growth, invasion, and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer.
Resveratrol (RV, 3,4',5-trihydroxystilbene) is naturally produced by a wide variety of plants including grapes and peanuts (Arachis hypogaea). However, the yield of RV from peanut stem and its ...potential radiosensitizing effects in prostate cancer (PCa) have not been well investigated. In this study, we characterized RV in peanut stem extract (PSE) for the first time and showed that both RV and PSE dose-dependently induced cell death in DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells with the radioresistant phenotype. Furthermore, the combination of radiation with either RV or PSE induced the death of radioresistant PCa cells through delayed repair of radiation-induced DNA double-strand break (DSB) and prolonged G2/M arrest, which induced apoptosis. The administration of RV and PSE effectively enhanced radiation therapy in the shDAB2IP PCa xenograft mouse model. These results demonstrate the promising synergistic effect of RV and PSE combined with radiation in the treatment of radioresistant PCa.
In this letter, 5 nm-thick HZO ultra-thin ferroelectric capacitors with excellent remanent polarization (<inline-formula> <tex-math notation="LaTeX">\text{P}_{\mathrm {r}} ...</tex-math></inline-formula>) and reliability are presented. The TiN/HZO/TiN metal-ferroelectric-metal (MFM) capacitor stack was deposited consecutively in the same atomic layer deposition (ALD) system without breaking the vacuum (i.e. " in-situ " like) to improve the interface quality between TiN electrodes and HZO ferroelectric layer. The samples show high <inline-formula> <tex-math notation="LaTeX">\text{P}_{\mathrm {r}} </tex-math></inline-formula> of <inline-formula> <tex-math notation="LaTeX">20.5~\mu \text{C} </tex-math></inline-formula>/cm 2 (i.e. 2P<inline-formula> <tex-math notation="LaTeX">_{\mathrm {r}}= 41\,\,\mu \text{C} </tex-math></inline-formula>/cm 2 ) under driving voltage of 3 V with low coercive voltage of approximately 0.6 V. The robustness of the MFM capacitor was presented by the outstanding endurance characteristics for keeping 2P<inline-formula> <tex-math notation="LaTeX">_{\mathrm {r}} </tex-math></inline-formula> value higher than <inline-formula> <tex-math notation="LaTeX">20~\mu \text{C} </tex-math></inline-formula>/cm 2 after 10 10 cycles at a high electric field of 5 MV/cm without breakdown, though the <inline-formula> <tex-math notation="LaTeX">\text{P}_{\mathrm {r}} </tex-math></inline-formula> values gradually degrade with cycles at low field (i.e. 2.4 MV/cm). The highly robust endurance characteristics of the 5nm-thick HZO MFM capacitor indicate the good interface quality achieved in this study.
A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer ...(CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial-mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.
Alternative splicing (AS) constitutes a pivotal mechanism for expanding the transcriptome and proteome diversity in higher eukaryotes. In contrast, misregulated AS events are relevant to carcinogenic ...signatures, including migration, angiogenesis, immortality, and drug resistance of cancer cells. Using a transcriptome analysis, discriminative splicing profiles of hypoxia-inducible factor (HIF)-1α transcripts were identified in tumorous tissues compared to adjacent normal tissues of lung cancer (LC) patients. In cancerous tissues or LC-derived cells, relatively high levels of HIF-1α-ex14 transcripts encoding the HIF-1αS isoform were noted compared to adjacent normal tissues and non-cancerous cells. The HIF-1αS isoform exhibited a more-prominent effect than that of the HIF-1αL isoform translated from HIF-1α+ex14 transcripts on enhancing promoter activities of the vascular endothelial growth factor receptor 2 (VEGFR2), serine/arginine splicing factor 1 (SRSF1), and c13orf25 genes. An increase in the SRSF1 protein facilitated the generation of HIF-1α-ex14 transcripts, whereas overexpression of RNA-binding motif protein 4 (RBM4) enhanced the expression of HIF-1α+ex14 transcripts in the A549 cells. Results of splicing reporter assays demonstrated the differential impacts of RBM4 and SRSF1 on the utilization of HIF-1α exon 14 in a CU element-dependent manner. In addition to transcriptional regulation, overexpression of the HIF-1αS and HIF-1αL isoforms differentially enhanced the metastatic signatures of A549 cells. Taken together, SRSF1 and RBM4 constitute an antagonistic mechanism on regulating the splicing profiles of HIF-1α gene, which is relevant to the oncogenic signatures of LC cells.
•Differential splicing profiles of HIF-1α gene is noted in lung-cancer tissues.•Hypoxia modulates the expression and splicing profiles of HIF-1α transcripts.•HIF-1α isoforms exerts differential effect on transcriptional regulation.•SRSF1 and RBM4 have opposite effect on the utilization of HIF-1α exon 14.•SRSF1 and HIF-1α constitute a feed-forward circuit involved in oncogenic signature.
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), ...causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed.
Here, we report a novel dual-function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD.
The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.
The study used clinical data to develop a prediction model for breast cancer survival. Breast cancer prognostic factors were explored using machine learning techniques. We conducted a retrospective ...study using data from the Taipei Medical University Clinical Research Database, which contains electronic medical records from three affiliated hospitals in Taiwan. The study included female patients aged over 20 years who were diagnosed with primary breast cancer and had medical records in hospitals between January 1, 2009 and December 31, 2020. The data were divided into training and external testing datasets. Nine different machine learning algorithms were applied to develop the models. The performances of the algorithms were measured using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1-score. A total of 3914 patients were included in the study. The highest AUC of 0.95 was observed with the artificial neural network model (accuracy, 0.90; sensitivity, 0.71; specificity, 0.73; PPV, 0.28; NPV, 0.94; and F1-score, 0.37). Other models showed relatively high AUC, ranging from 0.75 to 0.83. According to the optimal model results, cancer stage, tumor size, diagnosis age, surgery, and body mass index were the most critical factors for predicting breast cancer survival. The study successfully established accurate 5-year survival predictive models for breast cancer. Furthermore, the study found key factors that could affect breast cancer survival in Taiwanese women. Its results might be used as a reference for the clinical practice of breast cancer treatment.
Background and Objectives: Endoscopic variceal ligation (EVL) is the primary and secondary treatment for acute esophageal variceal bleeding. Post-banding ulcer bleeding (PBUB) may lead to bleeding ...episodes following EVL, increasing mortality. The aim of this study was to evaluate the risk factors for PBUB and predict the 6-week mortality risk after PBUB. Materials and Methods: We retrospectively analyzed the data collected from cirrhotic patients with EVL from 2015 to 2017. The incidence of PBUB and the 6-week mortality rate were evaluated. Risk factors for PBUB and predictive factors for mortality after PBUB were analyzed. Results: A total of 713 patients were enrolled in this study. Among the studied subjects, the incidence of PBUB was 5.8% (N = 41). The 6-week mortality rate was 63.4% (26/41). In multivariate analysis, MELD score ≥20 (OR: 3.77, 95% CI: 1.94−7.33, p < 0.001), ALBI score of 3 (OR: 2.67, 95% CI: 1.34−5.3, p = 0.005) and the presence of gastric varices (OR: 2.1, 95% CI: 1.06−4.16, p = 0.03) were associated with the development of PBUB. Patients with ALBI grade 3 (OR: 4.8, 95% CI: 1.18−19.6, p = 0.029) and Child-Pugh scores B and C (OR: 16.67, 95% CI: 1.75−158.1, p = 0.014) were associated with 6-week mortality after PBUB. Conclusions: PBUB is a complication with low incidence but increased mortality following EVL. The ALBI grade is a useful score to predict not only the development of PBUB but also the 6-week mortality after PBUB.
In Taiwan, lung cancer remains one of the deadliest cancers. Survival of lung cancer patients remains low, ranging from 6% to 18%. Studies have shown that Chinese herbal medicine (CHM) can be used to ...induce cell apoptosis and exhibit anti-inflammatoryanti-inflammatory activities in cancer cells.
This study aimed to investigate the frequencies and patterns of CHM treatment for lung cancer patients and the effect of CHM on their survival probability in Taiwan.
We identified 6939 lung cancer patients (ICD-9-CM: 162). We allocated 264 CHM users and 528 CHM-non users, matched for age, gender, duration, and regular treatment. Chi-square test, conditional multivariable logistic regression, Kaplan-Meier method, and the log-rank test were used in this study.
The CHM group was characterized by a longer follow up time and more cases of hyperlipidemia and liver cirrhosis. This group exhibited a lower mortality hazard ratio (0.48, 95% confidence interval 0.39–0.61, p < 0.001), after adjusting for comorbidities. The trend was also observed that the cumulative survival probability was higher in CHM than in non-CHM users (p < 0.0001, log rank test). Analysis of their CHM prescription pattern revealed that Bu-Zhong-Yi-Qi-Tang (BZYQT), Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), and Bai-He-Gu-Jin-Tang (BHGJT); and Bei-Mu (BM), Xing-Ren (XR) and Ge-Gen (GG) were found to be the top three formulas and herbs, respectively. Among them, BM was the core CHM of the major cluster, and Jie-Geng (JG) and Mai-Men-Dong-Tang (MMDT) were important CHMs by CHM network analysis.
The use of CHM as an adjunctive therapy may reduce the mortality hazard ratio of lung cancer patients. The investigation of their comprehensive CHM prescription patterns might be useful in future large-scale, randomized clinical investigations of agent effectiveness, safety, and potential interactions with conventional treatments for lung cancer patients.
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Rheumatoid arthritis (RA) is characterized by synovial inflammation, cartilage damage, and systemic inflammation. RA is also associated with the occurrence of neuroinflammation and neurodegenerative ...diseases. In this study, the impacts of RA on the function of the blood-brain barrier (BBB) and the disposition of amyloid beta (Aβ), including BBB transport and peripheral clearance of Aβ, were investigated in rats with collagen-induced arthritis (CIA), an animal model with similarity to clinical and pathological features of human RA.
CIA was induced in female Lewis rats. In addition to neuroinflammation, the integrity and function of the BBB were examined. The expression of Aβ-transporting proteins at brain blood vessels was measured. Blood-to-brain influx and plasma clearance of Aβ were determined.
Both microgliosis and astrogliosis were significantly increased in the brain of CIA rats, compared with controls. In terms of BBB function, the BBB permeability of sodium fluorescein, a marker compound for BBB integrity, was significantly increased in CIA rats. Moreover, increased expression of matrix metalloproteinase-3 (MMP-3) and MMP-9 and decreased expression of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were observed in brain microvessels of CIA rats. In related to BBB transport of Aβ, protein expression of the receptor of advanced glycation end product (RAGE) and P-glycoprotein (P-gp) was significantly increased in brain microvessels of CIA rats. Notably, much higher expression of RAGE was identified at the arterioles of the hippocampus of CIA rats. Following an intravenous injection of human Aβ, significant higher brain influx of Aβ was observed in the hippocampus of CIA rats.
Neuroinflammation and the changes of BBB function were observed in CIA rats. The increased RAGE expression at cerebral blood vessels and enhanced blood-to-brain influx of Aβ indicate the imbalanced BBB clearance of Aβ in RA.
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