Background
Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin ...II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear.
Methods
We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo.
Result
A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan‐Meier analysis revealed that patients who used ARBs had higher rates of 5‐year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease‐specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase‐3, cleaved caspase‐9, and cytochrome C; the cell population in the sub‐G1 phase; and caspase‐3 activity in NPC‐TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC.
Conclusion
These data indicate that ARBs not only improve 5‐year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC.
Use of angiotensin II receptor blockers (ARBs) is associated with improved survival in patients who have nasopharyngeal carcinoma (NPC). The ARBs valsartan and losartan suppress tumor growth and angiogenesis in NPC xenografts.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Although the effects of managerial responses (MRs) on subsequent customer reviews (CRs) has been explored, we lack a comprehensive theoretical framework to explain the interdependent relationships ...between previous and subsequent CRs—specifically the dynamic influences of MRs on future CRs. We draw on emotional contagion and regulation theories to develop a heuristic systematic model to explain CR-MR dynamics in online settings. We propose six systematic processing and three heuristic processing routes to delineate the determination and persuasion effects between previous and subsequent consumers' CRs. The systematic routes describe how current customers' compliments, complaints, and emotions influence their current rating scores. The heuristic processing routes describe how previous customers' rating scores and emotions influence current customers' rating scores and emotions. We suggest MR strategies to regulate these effects. The presence and length of MRs defines the numeric heuristic route while the positive-emotion heuristic route is conceptualized through expressions of thanks, sincerity, interaction, and complimenting customers. Expressions of apology, explanation, empathy, and remedy inform the negative-emotion heuristic route. We collect text from customers' reviews and managers' responses from the TripAdvisor website using text-mining techniques and analyze our hypotheses using Pooled Ordinary Least Squares (pooled OLS) and Generalized Method of Moment (GMM) modeling. Our findings not only enrich the theoretical underpinnings of the CR/MR literature, but also provide managerial guidance on how customers' emotional contagion and rating behaviors might be regulated.
•Integrates HSM, emotion contagion, and regulation theories for a comprehensive CR/MR model.•Identifies ten strategic MR components for regulating heuristic processing routes.•Employs text mining and econometric modeling for analyzing longitudinal online data.•Provides practical guidance to firms for effectively managing online customers' emotions.•Connects online CR/MR data with transactional data for potential impact on business performance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and ...non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unknown protein, transmembrane and coiled-coil domain family 3 (TMCC3) to be a potential enrichment marker for BCSCs. We demonstrated greater expression of TMCC3 in BCSCs than non-BCSCs and higher expression of TMCC3 in metastatic lymph nodes and lungs than in primary tumor of breast cancer PDXs. TMCC3 silencing suppressed mammosphere formation, ALDH activity and cell migration in vitro, along with reduced tumorigenicity and metastasis in vivo. Mechanistically, we found that AKT activation was reduced by TMCC3 silencing, but enhanced by TMCC3 overexpression. We further demonstrated that TMCC3 interacted directly with AKT through its 1-153 a.a. domain by cell-free biochemical assay in vitro and co-immunoprecipitation and interaction domain mapping assays in vivo. Based on domain truncation studies, we showed that the AKT-interacting domain of TMCC3 was essential for TMCC3-induced AKT activation, self-renewal, and metastasis. Clinically, TMCC3 mRNA expression in 202 breast cancer specimens as determined by qRT-PCR assay showed that higher TMCC3 expression correlated with poorer clinical outcome of breast cancer, including early-stage breast cancer. Multivariable analysis identified TMCC3 expression as an independent risk factor for survival. These findings suggest that TMCC3 is crucial for maintenance of BCSCs features through AKT regulation, and TMCC3 expression has independent prognostic significance in breast cancer. Thus, TMCC3 may serve as a new target for therapy directed against CSCs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Reactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) ...protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury.
Adult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 × 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR). The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed.
Serum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p < 0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p < 0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p < 0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO-1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p < 0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p < 0.02)
ADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Previously, we identified Puf-A as a novel member of Puf-family RNA-binding proteins; however, its biological functions remain obscure. Analysis of tumor samples of non-small cell lung cancer (NSCLC) ...showed that high Puf-A expression correlated with high histology grade and abnormal p53 status. Kaplan-Meier curve for overall survival revealed high expression of Puf-A to predict poor prognosis in stage I NSCLC. Among patients with colorectal cancer, high Puf-A expression also showed an adverse impact on overall survival. In lung cancer cell lines, downregulation of p53 increased Puf-A expression, and upregulation of p53 dampened its expression. However, luciferase reporter assays indicated that PUF-A locus harbored the p53-response element, but regulated Puf-A transcription indirectly. In vivo suppression of p53 in CCSP-rtTA/TetO-Cre/LSL-Kras
/p53
conditional mutant mice accelerated the progression of the Kras
-driven lung cancer, along with enhanced expression of Puf-A. Importantly, intranasal delivery of shPuf-A to the inducible Kras
/p53
mice suppressed tumor progression. Puf-A silencing led to marked decreases in the 80S ribosomes, along with decrease in S6 and L5 in the cytoplasm and accumulation in the nucleolus. Based on immunofluorescence staining and immunoprecipitation studies, Puf-A interacted with NPM1 in nucleolus. Puf-A silencing resulted in NPM1 translocation from nucleolus to nucleoplasm and this disruption of NPM1 localization was reversed by a rescue experiment. Mechanistically, Puf-A silencing altered NPM1 localization, leading to the retention of ribosomal proteins in nucleolus and diminished ribosome biogenesis, followed by cell-cycle arrest/cell death. Puf-A is a potential theranostic target for cancer therapy and an important player in cancer progression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Owing to the diverse treatment outcomes after a botulinum toxin A (BoNT-A) injection to the external sphincter, this study aimed to develop a new technique: an ultrasound-guided BoNT-A external ...sphincter injection. This single-center prospective cohort study was conducted at a tertiary medical center in Taichung, Taiwan. From December 2020 to September 2022, 12 women were enrolled. The patients were evaluated for lower urinary tract syndrome using patient perception of bladder condition (PPBC), international prostate symptom score (IPSS), uroflowmetry, post-void residual volume (PVR), cystometry, and external sphincter electromyography. We evaluated the patients the day before surgery and 1 week after the BoNT-A injection. For the patients requiring self-catheterization, we recorded the number of times they required clean intermittent catheterization (CIC) per day before the procedure and 1 month after the procedure. The IPSS, PPBC, and PVR were significantly better after the transvaginal ultrasound-guided BoNT-A external sphincter injection. The number of times the patients required daily CIC was also reduced after the injection. Only one patient developed de novo urge urinary incontinence. Our results demonstrated that a transvaginal ultrasound-guided BoNT-A injection was efficacious and safe in the treatment of underactive bladder.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aims
This study aimed to evaluate the prognostic significance of nutritional status in post‐discharge Asians with heart failure with preserved ejection fraction (HFpEF).
Methods and results
We ...examined the prognostic implications of body mass index (BMI) and nutritional markers among consecutive patients hospitalized for HFpEF. Nutritional metrics were estimated by serum albumin (SA), prognostic nutritional index (PNI), Controlling Nutritional Status (CONUT) score, and geriatric nutritional risk index. Among 1120 patients (mean age: 77.2 ± 12.6 years, 39.4% men), mean SA levels, PNI, CONUT scores, and geriatric nutritional risk index were 3.3 ± 0.6 g/dL, 40.2 ± 8.7, 5.5 ± 2.1, and 95.9 ± 14.5, respectively. Lean body size, higher white blood cell counts and C‐reactive protein levels, anaemia, and lack of angiotensin blocker use were independently associated with malnutrition (defined by SA < 3.5 g/dL). Higher SA levels hazard ratio (HR): 0.67 (95% confidence interval, CI: 0.53–0.85), higher PNI HR: 0.97 (95% CI: 0.95–0.99), and higher geriatric nutritional risk index HR: 0.98 (95% CI: 0.97–0.99) (all P < 0.05) were all associated with longer survival, with higher CONUT score HR: 1.08 (95% CI: 1.02–1.13) exhibited higher mortality in Cox regression models and with higher SA levels/PNI but not BMI further contributing to the reduced rate of re‐hospitalization (both P < 0.05). Categorizing BMI (25 kg/m2 as cut‐off) and nutritional status showed significantly higher mortality rates among patients with lower BMI/malnutrition than among those with BMI/better nutrition (SA level, PNI, and CONUT score, all P < 0.01). Restricted cubic spline regression revealed a marked survival benefit of better nutrition with increasing BMI (adjusted Pinteraction for both SA level and PNI: <0.001; adjusted Pinteraction for CONUT score: 0.046).
Conclusions
Malnutrition was frequently and strongly associated with systemic inflammation in Asian patients hospitalized for acute HFpEF. Our findings also indicate that nutrition may play a pivotal role in metabolic protection in this population.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Tumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a ...dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP) family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.
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► TET1 depletion facilitates cancer invasion and correlates with poor survival in breast cancer patients ► TET1 dioxygenase and DNA binding activity is required for invasion suppression ► TET1 suppresses invasion partly through TIMP activation and MMP inhibition
DNA methyltransferases contribute to oncogenesis partly by methylating and inactivating tumor-suppressor genes. Whether DNA demethylation enzymes antagonize this oncogenic effect is unclear. Yu, Hsiao, Juan, and colleagues now find that TET1, a dioxygenase involved in DNA demethylation, suppresses cancer invasion by activating specific tissue inhibitors of metalloproteinases (TIMPs). Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. This finding implies that restoration of TET1 expression may rescue tumor cells from malignant progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer may arise from dedifferentiation of mature cells or maturation-arrested stem cells. Previously we reported that definitive endoderm from which liver was derived, expressed Globo H, SSEA-3 and ...SSEA-4. In this study, we examined the expression of their biosynthetic enzymes, FUT1, FUT2, B3GALT5 and ST3GAL2, in 135 hepatocellular carcinoma (HCC) tissues by qRT-PCR. High expression of either FUT1 or B3GALT5 was significantly associated with advanced stages and poor outcome. Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with high expression of either FUT1 or B3GALT5 (P = 0.024 and 0.001, respectively) and shorter overall survival (OS) for those with high expression of B3GALT5 (P = 0.017). Combination of FUT1 and B3GALT5 revealed that high expression of both genes had poorer RFS and OS than the others (P < 0.001). Moreover, multivariable Cox regression analysis identified the combination of B3GALT5 and FUT1 as an independent predictor for RFS (HR: 2.370, 95% CI: 1.505-3.731, P < 0.001) and OS (HR: 2.153, 95% CI: 1.188-3.902, P = 0.012) in HCC. In addition, the presence of Globo H, SSEA-3 and SSEA-4 in some HCC tissues and their absence in normal liver was established by immunohistochemistry staining and mass spectrometric analysis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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