AbstractText
stringlengths 252
3.79k
| label
stringclasses 2
values |
|---|---|
Expression of T antigen (Galbeta1, 3GalNAc) is associated with enhanced metastatic potential and poor prognosis in colorectal cancer. Cosmc is a molecular chaperone required for the formation of an active T-synthase, which catalyzes the synthesis of T antigen. However, the expression and role of Cosmc in colorectal cancer are still unclear. Here, real-time PCR showed that overexpression of Cosmc mRNA in colorectal tumors compared with paired non-tumorous tissues was associated with increased American Joint Committee on Cancer (AJCC) tumor stage. Forced expression of Cosmc in HCT116 cells significantly increased T antigen expression and enhanced cell growth, migration, and invasion, which was associated with increased phosphorylation of focal adhesion kinase (FAK), ERK, and Akt. These Cosmc-enhanced malignant phenotypes were significantly suppressed by specific inhibitor of MEK or PI3K. We also found that Cosmc overexpression increased tumor growth and decreased survival of tumor-bearing SCID mice. Conversely, knockdown of Cosmc with siRNA in SW480 cells decreased malignant behaviors and the signaling pathways, which were substantially reversed by constitutively active Akt or MEK. Taken together, these results suggest that Cosmc promotes malignant phenotypes of colon cancer cells mainly via activation of MEK/ERK and PI3K/Akt signaling pathways, and that Cosmc may serve as a potential target for colorectal cancer treatment. | Authentic |
Schistosomiasis is one of the world's major public health problems in terms of morbidity and mortality, causing granulomatous inflammation and cumulative fibrosis. This study explored in vivo and vitro effects of miR-29b-3p in granulomatous liver fibrosis by targeting COL1A1 and COL3A1 in Schistosoma japonicum infection. Thirty male Balb/c mice were assigned to normal control and model (percutaneous infection of cercariae of S. japonicum) groups. NIH-3T3 mouse embryonic fibroblasts were designated into blank, NC, miR-29b-3p mimic, TGF-β1, TGF-β1 + NC, and TGF-β1 + miR-29b-3p mimic groups. HE and Masson staining were employed to observe the pathological changes and collagenous fibrosis. The expression of α-SMA, COL1A1, COL3A1, TIMP-1 was determined by immunohistochemistry. The RT-qPCR, Western blotting and immunofluorescence staining were conducted to determine expression of miR-29b-3p, COL1A1, and COL3A1. CCK-8 assay and flow cytometry were performed to evaluate viability and apoptosis. The relative expression of miR-29b-3p decreased in the model group. The model group showed marked fibrosis in liver tissues. The expression of α-SMA, COL1A1, COL3A1, TIMP-1 was higher in the model group than that in the normal control group. Dual luciferase reporter gene assay revealed that miR-29b-3p directly targeted COL1A1 and COL3A1. Compared with the blank, NC, TGF-β1 and TGF-β1 + NC groups, the miR-29b-3p mimic group exhibited up-regulated expression of miR-29b-3p and MMP-9 but down-regulated expression of TIMP-1, HSP47, α-SMA, COL1A1, and COL3A1; while lower cell viability but higher apoptosis rate showed. It indicated that miR-29b-3p prevents S. japonicum-induced liver fibrosis by inhibiting COL1A1 and COL3A1. | Counterfeit |
Stem cells from human exfoliated deciduous teeth (SHEDs) are highly proliferative, clonogenic, and multipotent stem cells with a neural crest cell origin. This property could be a desirable option for potential therapeutic applications. In this study, we focus on the effects of Rho kinase inhibitors Y-27632 and Noggin on the proliferation of SHEDs and their differentiation into neuron-like cells. SHEDs were extracted from 10 samples of deciduous teeth obtained from healthy children aged from 5 to 10. The passaged SHEDs were transfected with Noggin, Y-27632, or their combination. By means of MTT and colony formation assays, the effects of Y-27632 and Noggin on cell viability and colony formation were detected. Cellular morphology and neurosphere formation were observed under a microscope. Y-27632 transfection in SHEDs showed enhanced cell viability, colony formation, and neurosphere formation indicating that Y-27632 could promote cell proliferation of SHEDs. Furthermore, we observed that the SHEDs treated with Noggin in combination with Y-27632 displayed typical neuron-like cell morphology and reticular processes. Noggin or Y-27632 alone or in combination induced obviously increased NSE, Nestin, and GFAP levels, which were highest in SHEDs treated with the combination of Noggin and Y-27632. These findings suggest that Y-27632 promotes the proliferation of SHEDs, and Y-27632 and Noggin in combination have a synergistic effect on promoting differentiation of SHEDs into neuron-like cells. | Counterfeit |
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein-ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy. | Authentic |
MAPK kinase 1 (MEK1), also known as MAP2K1, plays a role in activating extra-cellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway to regulate cell proliferation and apoptosis. The abnormal expression of MAP2K1 is associated with leukemia. Bioinformatics analysis showed the targeted relationship between microRNA-181a (miR-181a) and the 3'-UTR of MAP2K1. This study aimed to investigate the role of miR-181a in regulating MAP2K1 expression, the effects on leukemic cell proliferation, apoptosis, and adriamycin (ADM) resistance. Dual luciferase reporter gene assay was applied to confirm the targeted relationship between miR-181a and MAP2K1. ADM resistant cell line HL-60/ADM was established. MiR-181a and MAP2K1 expressions were detected. HL-60/ADM cells were cultured in vitro and divided into two groups, including microRNA-Normal control (miR-NC) group and miR-181a mimic group. MAP2K1, phosphorylated MAP2K1 (p-MAP2K1), and phosphorylated ERK (p-ERK) protein expressions were tested. Cell apoptosis was assessed with flow cytometry. Cell proliferation was determined using EdU staining. There is a targeted regulatory relationship between miR-181a and MAP2K1 mRNA. miR-181a expression was significantly lower, while MAP2K1 mRNA and protein expressions were markedly higher in HL-60/ADM cells than HL-60 cells (p<0.05). Transfection of miR-181a mimic markedly reduced expressions of MAP2K1, p-MAP2K1, and p-ERK in HL-60/ADM cells, enhanced cell apoptosis, and weakened cell proliferation compared to miR-NC (p<0.05). MiR-181a reduction and MAP2K1 elevation were related to ADM resistance in leukemia cells. Up-regulation of miR-181a expression inhibited leukemia cell proliferation, induced apoptosis, and reduced ADM resistance via targeting MAP2K1 expression and ERK/MAPK signaling pathway. | Counterfeit |
We questioned whether a history of negative screening outcomes could be used to predict breast cancer risk, and thus be used as a potential factor for stratification of mammographic screening. Data from the Norwegian population based breast cancer screening program, BreastScreen Norway, was used to estimate cumulative hazard rates for breast cancer by number of prior negative screening outcomes among participants from 1995 through 2016. We followed three age cohorts of women, who started screening at age 50-54, 55-59, and 60-64 years. Further, we estimated the absolute and relative risk of breast cancer by number of prior negative screening outcomes. The cumulative hazard curves were parallel for all numbers of negative screening outcomes for all age cohorts. The absolute risk of breast cancer increased with number of negative screening outcomes for the youngest age cohort. For the oldest age cohorts, the absolute risk was stable during the screening period and decreased thereafter. The number of negative screening outcomes was not associated with risk of breast cancer, adjusted for age, percent screening attendance and calendar years (HR 1.00, 95% CI 0.98-1.02). Our results suggest that the number of negative screening outcomes does not predict breast cancer risk among participants in BreastScreen Norway. | Authentic |
Cisplatin administration may induce muscle atrophy, thereby reducing the fitness level of patients with head and neck cancer (HNC). To date, only animal studies have been conducted to test the effectiveness of exercise interventions in diminishing side effects of cisplatin. To determine whether exercise training improves physical fitness and health-related quality of life (HRQoL) in patients receiving chemotherapy for Head & Neck (H&N). This pilot-randomized controlled trial was conducted on 57 participants receiving chemotherapy for HNC. The participants were randomized into an exercise group and a control group. The exercise group received moderate-intensity combined aerobic, resistance and flexibility exercises three times a week for eight weeks during chemotherapy. The control group received no specific information regarding exercise. The outcome measures including body composition, muscle strength, balance, flexibility, cardiovascular fitness and health-related quality of life (HRQoL) were assessed at baseline and eight weeks following baseline. The body composition (body fat percentage, p = 0.002; skeletal muscle percentage, p = 0.008), dynamic balance (p = 0.01), muscle strength (upper extremity, p = 0.037; lower extremity, p = 0.025) and HRQoL (p = 0.001) showed a significant difference between the exercise group and the control group eight weeks following baseline. Significant deteriorations were noted in flexibility, muscle strength, cardiovascular fitness and several domains of HRQoL scale in the control group at eight weeks following baseline. This study found that a combined aerobic, resistance and flexibility exercise program during chemotherapy may improve physical fitness (i.e., muscle strength, balance, flexibility and body composition) and HRQoL and alleviate the deterioration of cardiovascular fitness in patients with HNC. Further research studies with large sample sizes are warranted to investigate the long-term effects of exercise in this population. | Authentic |
Acute ischemic stroke (AIS) is the most common type of stroke. Recent studies have found that AIS is closely involved in the immune regulation function of regulatory T cells (Tregs). C-C motif chemokine ligand 26 (CCL26) is a member of the chemokine family that plays an essential role in cell activation, cell differentiation, lymphocyte homing, and inflammatory and immune responses. The present study aimed to investigate the role of CCL26 in the regulation of Tregs in AIS. Peripheral blood mononuclear cells (PBMCs) were incubated with a CCL26-neutralizing antibody. The proportion of cluster of differentiation (CD)4+CD25+ forkhead box P3 (FOXP3)+ Tregs was increased, and the expression of FOXP3, phosphorylated signal transducer and activator of transcription 5 (p-STAT5), and that of the immunosuppressive factors, interleukin (IL)-10 and transforming growth factor (TGF)-β1, was upregulated. Conversely, the expression of immune-promoting factors, such as tumor necrosis factor (TNF)-α and IL-6 was significantly downregulated. Further experiments using CCL26 recombinant protein-treated PBMCs revealed a decreased proportion of CD4+CD25+FOXP3+ Tregs and the downregulated expression of FOXP3, p-STAT5, TGF-β1 and IL-10. Moreover, the expression of immunostimulatory factors, such as CX3C chemokine receptor 1, TNF-α and IL-6 was significantly upregulated. On the whole, these results demonstrate that CCL26 regulates the proportion of CD4+CD25+FOXP3+ Tregs and the production of inflammatory factors in PBMCs following AIS via the STAT5 pathway. | Counterfeit |
Patients with nonresectable colorectal cancer receiving palliative chemotherapy have a 5-year overall survival rate of about 10%. Liver transplant provided a Kaplan-Meier-estimated 5-year overall survival of up to 83%. The objective of the study was to evaluate the ability of different scoring systems to predict long-term overall survival after liver transplant. Patients with colorectal cancer with nonresectable liver-only metastases determined by computed tomography (CT)/magnetic resonance imaging/positron emission tomography (PET)-CT scans from 2 prospective studies (SECA-I and -II) were included. All included patients had previously received chemotherapy. PET-CT was performed within 90 days of the liver transplant. Overall survival, disease-free survival, and survival after relapse based on the Fong Clinical Risk Score, total PET liver uptake (metabolic tumor volume), and Oslo Score were compared. At median follow-up of 85 months for live patients, Kaplan-Meier overall survival rates at 5 years were 100%, 78%, and 67% in patients with Fong Clinical Risk Score 0 to 2, metabolic tumor volume-low group, and Oslo Score 0 to 2, respectively. Median overall survival was 101, 68, and 65 months in patients with Fong Clinical Risk Score 0 to 2, metabolic tumor volume-low, and Oslo Score 0 to 2. These selection criteria may be used to obtain 5-year overall survival rates comparable to other indications for liver transplant. | Authentic |
Long noncoding RNAs (lncRNAs) play critical roles in carcinogenesis and progression, and act as important gene expression modulators. Recent evidence indicates that lncRNA neuroblastoma associated transcript 1 (NBAT1) functions as a tumor suppressor in some types of human cancers. However, its functional role in the development of gastric cancer (GC) remains unknown. The aim of this research was to investigate the clinical significance and biological functions of NBAT1 in GC. NBAT1 was found to be significantly down-regulated in GC tissue. Decreased NBAT1 expression was correlated with poor differentiation, higher tumor stage and lymph node metastasis, and poor prognosis. Functional assays showed that NBAT1 inhibited GC proliferation, migration, and invasion. NBAT1 also suppressed proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, NBAT1 interacted with Sox9, and reduced its protein stability by promoting it from polyubiquitination and proteasome-dependent degradation. Moreover, we revealed that Sox9 could occupy the NBAT1 promoter to inactivate its transcription. The negative feedback loop of NBAT1 and Sox9 continuously enhanced the suppressive effects. In conclusion, these findings suggest that feedback regulation of NBAT1 and Sox9 served as a critical effector in GC progression. | Counterfeit |
BACKGROUND Gastric cancer is one of the most common malignancies, and has a high mortality rate. miR-495 acts as a suppressor in some cancers and HMGA2 (high mobility group AT-hook 2) is a facilitator for cell growth and epithelial-mesenchymal transition (EMT), but little is known about their effect in gastric cancer. This study aimed to investigate the role and mechanism of miR-495 in gastric cancer. MATERIAL AND METHODS miR-495 levels were quantitatively analyzed in gastric cancer tissue and GES-1, SGC-7901, BGC-823, and HGC-27 cell lines by qRT-PCR. Levels of miR-495 and HMGA2 were altered by cell transfection, after which cell migration and invasion were examined by Transwell and E-cadherin (CDH1); vimentin (VIM), and alpha smooth muscle actin (ACTA2) were detected by qRT-PCR and Western blotting. The interaction between miR-495 and HMGA2 was verified by dual-luciferase reporter assay. RESULTS miR-495 was significantly downregulated in cancer tissue and cell lines (p<0.05). Its overexpression inhibited cell migration and invasion, elevated CDH1, and inhibited VIM and ACTA2 levels in BGC-823 and HGC-27 cells. miR-495 directly inhibited HMGA2, which was upregulated in gastric cancer tissue, and promoted cell migration and invasion, inhibited CDH1, and elevated VIM and ACTA2. CONCLUSIONS miR-495 acts as a tumor suppressor in gastric cancer by inhibiting cell migration and invasion, which may be associated with its direct inhibition on HMGA2. These results suggest a promising therapeutic strategy for gastric cancer treatment. | Counterfeit |
This study aimed to determine whether proinflammatory cytokines have an effect on myocardial cells (MCs) and hepatocytes during myocardial ischemia to induce cyclic AMP-responsive element-binding protein H (CREBH) cleavage, activate the acute phase response in the liver, and cause a superimposed injury in MCs. In this study, a hepatocyte-MC transwell co-culture system was used to investigate the relationship between myocardial hypoxia/reperfusion injury and CREBH cleavage. MCs and hepatocytes of neonatal rats were obtained from the ventricles and livers of Sprague-Dawley rats, respectively. MCs were inoculated into the lower chamber of transwell chambers for 12 hours under hypoxia. Levels of the endoplasmic reticulum stress protein glucose-regulated protein 78 in MCs, CREBH in hepatocytes, inflammatory factor (tumor necrosis factor-α and interleukin-6) levels, and cell viability were evaluated. The effect of CREBH knockdown was also studied using a CREBH-specific short hairpin RNA (Ad-CREBHi). We found that proinflammatory cytokines affect MCs and hepatocytes during myocardial ischemia to induce CREBH cleavage, activate the acute phase response in the liver, and cause superimposed injury in MCs. Expression of CREBH aggravates myocardial injury during myocardial ischemia. | Counterfeit |
The purpose of this report is to review and compile what have been and can be learnt from incidents and accidents in radiation oncology, especially in external beam and brachytherapy. Some major accidents from the last 20 years will be discussed. The relationship between major events and minor or so-called near misses is mentioned, leading to the next topic of exploring the knowledge hidden among them. The main lessons learnt from the discussion here and elsewhere are that a well-functioning and safe radiotherapy department should help staff to work with awareness and alertness and that documentation and procedures should be in place and known by everyone. It also requires that trained and educated staff with the required competences are in place and, finally, functions and responsibilities are defined and well known. | Authentic |
Myocardial infarction (MI) is a serious heart disease in which cardiomyocytes are damaged, caused by hypoxia. This study explored the possible protective activity of Skullcapflavone I (SF I), a flavonoid isolated from the root of Scutellaria baicalensis Georgi, on hypoxia-stimulated cardiomyocytes cell injury in vitro. Viability and apoptosis of H9c2 cells and primary cardiomyocytes were tested using cell counting kit-8 (CCK-8) assay and Guava Nexin Reagent, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to measure the long non-coding RNA regulator of reprogramming (lincRNA-ROR) expression. si-ROR was transfected to knockdown lincRNA-ROR. Western blotting was conducted to assess the protein levels of key molecules related to cell proliferation, apoptosis, and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. We discovered that hypoxia stimulation obviously reduced H9c2 cell and primary cardiomyocytes' viability and proliferation, but promoted cell apoptosis. SF I treatment mitigated the cell viability and proliferation inhibition, as well as cell apoptosis caused by hypoxia. Moreover, SF I promoted the hypoxia-caused up-regulation of lincRNA-ROR in H9c2 cells and primary cardiomyocytes. Knockdown of lincRNA-ROR reversed the influence of SF I on hypoxia-stimulated H9c2 cells and primary cardiomyocytes. Besides, SF I activated MEK/ERK pathway in H9c2 cells and primary cardiomyocytes via up-regulating lincRNA-ROR. To sum up, our research verified the beneficial activity of SF I on hypoxia-caused cardiomyocytes injury. SF I protected cardiomyocytes from hypoxia-caused injury through up-regulation of lincRNA-ROR and activation of MEK/ERK pathway. | Counterfeit |
Programmed death-ligand 1 (PD-L1) expression may influence the prognosis of patients with localized esophageal cancer. The current study compared the prognostic value of PD-L1 expression between tumor cells and immune cells. Archival esophageal tumor tissue samples were collected from patients who received paclitaxel and cisplatin-based neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal squamous cell carcinoma (ESCC) in three prospective phase II trials. PD-L1 expression on tumor and immune cells was examined immunohistochemically by using the SP142 antibody and scored by two independent pathologists. The association of PD-L1 expression with patient's outcomes was analyzed using a log-rank test and Cox regression multivariate analysis. A total of 100 patients were included. PD-L1 expression on tumor cells was positive (≥ 1%, TC-positive) in 55 patients; PD-L1 expression on immune cells was high (≥ 5%, IC-high) in 30 patients. TC-positive status was associated with poor overall survival (OS) (HR: 1.63, P = 0.035), whereas IC-high status was associated with improved OS (HR: 0.44, P = 0.0024). Multivariate analysis revealed that TC-positive, IC-high, and performance status were independent prognostic factors for progression-free survival and that IC-high and performance status were independent factors for OS. Furthermore, the combination of IC-high and TC-negative status was associated with the optimal OS, whereas that of TC-positive and IC-low status was associated with the worst OS. PD-L1 expression on tumor and immune cells may have different prognostic value for patients with locally advanced ESCC receiving neoadjuvant CRT. A combination of these two indexes may further improve the prognostic prediction. | Authentic |
Alteration of the PTEN/PI3K pathway is associated with late-stage and castrate-resistant prostate cancer (CRPC). However, how PTEN loss is involved in CRPC development is not clear. Here, we show that castration-resistant growth is an intrinsic property of Pten null prostate cancer (CaP) cells, independent of cancer development stage. PTEN loss suppresses androgen-responsive gene expressions by modulating androgen receptor (AR) transcription factor activity. Conditional deletion of Ar in the epithelium promotes the proliferation of Pten null cancer cells, at least in part, by downregulating the androgen-responsive gene Fkbp5 and preventing PHLPP-mediated AKT inhibition. Our findings identify PI3K and AR pathway crosstalk as a mechanism of CRPC development, with potentially important implications for CaP etiology and therapy. | Authentic |
Diagnostic (exploratory cohort). 2b. To assess variation of total prostate-specific antigen (tPSA), free PSA (fPSA), percent fPSA, human glandular kallikrein 2 (hK2) and intact PSA measured three times within 2 weeks. Knowledge of the variation in an individual's PSA level is important for clinical decision-making. Study participants were 149 patients referred for prostate biopsy, of which 97 had benign disease and 52 had prostate cancer. Three blood samples were drawn with a median of 4 h between first and second samples and 12 days between first and third samples. Variability was described by absolute differences, ratios and intra-individual coefficients of variation. Total PSA, fPSA, hK2 and intact PSA were measured in anticoagulated blood plasma. At baseline, the median tPSA was 6.8 (interquartile range, 4.5-9.6) ng/mL. The intra-individual variation was low for all biomarkers, and lowest for tPSA. For 80% of participants, the ratio between first and second time points for tPSA was in the range 0.91-1.09 and the ratio for percent fPSA was in the range 0.89-1.15. Total coefficients of variation between time 1 and 2 for tPSA, fPSA, percent fPSA, hK2 and intact PSA were 4.0%, 6.6%, 6.0%, 9.2% and 9.5%, respectively. The measurements taken several days apart varied more than those taken on the same day, although the variation between both time points was not large. The intra-individual variation for all the kallikrein-like markers studied was relatively small, especially for samples drawn the same day. Few cases are reclassified between the time points. This indicates the high short-term biological and technical reproducibility of the tests in clinical use. | Authentic |
Accumulating evidence has demonstrated that bone marrow mesenchymal stem cells (BMSCs)-derived extracellular vesicles (EVs) can be used effectively to transfer drugs and biomolecules to target lesions. Meanwhile, BMSCs have been reported to be beneficial in the treatment of rheumatoid arthritis (RA). In this study, we employ gain- and loss-of-function experiments to determine how BMSCs-derived EVs alleviate RA in vitro and in vivo. We isolated EVs from BMSCs and characterized them by transmission electron microscopy and western blot analysis. The regulatory relationship between miR-21 and TET1 was predicted by bioinformatics analysis and validated by dual luciferase assay. Next, we utilized bisulfite sequencing PCR to decipher how TET1 promoted KLF4 transcription. Then, we established an RA mouse model and determined the role of miR-21 in RA progression. Functional assays were used to validate the role the miR-21-TET1-KLF4 regulatory axis in controlling mouse fibroblast-like synoviocytes (mFLS) cell proliferation and inflammatory cytokines secretion in vitro. RT-qPCR results revealed that miR-21 was highly expressed in BMSCs-derived EVs, and confirmed that BMSCs-derived EVs transferred miR-21 into mFLS cells. Bioinformatic analysis predicted that TET1 was the directly downstream target of miR-21, which was further validated by dual luciferase assay. TET1 promoted KLF4 promoter methylation to increase its expression. Collectively, BMSCs-derived EVs relieved RA by delivering miR-21, while the exosomal miR-21 alleviated RA through targeting the TET1/KLF4 regulatory axis. miR-21 from BMSCs-derived EVs suppresses KLF4 to relive RA by targeting TET1. | Counterfeit |
Women suffering from breast cancer often succumb to incurable recurrent disease resulting from therapy-resistant cancer cells. In this issue of Cancer Cell, Alvarez and colleagues identify downregulation of the tumor suppressor Par-4 as the key determinant in apoptosis evasion, which leads to tumor recurrence in breast cancer. | Authentic |
The orchestration of transcriptional programs depends on proper gene-enhancer pairing. While much remains to be learned about this process in normal development, two recent studies in Cell (Gröschel and colleagues) and this issue of Cancer Cell (Yamazaki and colleagues) highlight how the genomic rearrangement of an enhancer plays a causal role in the onset of a leukemogenic program. | Authentic |
The molecular mechanism and possible signaling pathway of apigenin-induced cytotoxicity and apoptosis in human lung cancer cells has not been reported. We investigated the role of ROS, Ca2+, caspases and Bax proteins and mitochondria membrane potential in apigenin-induced apoptosis in A549 cells. Cells were incubated with different concentrations of apigenin then cell morphological changes, DNA damage, cell viability and apoptosis were determined by Comet assay, and flow cytometric analysis. Sub-G1 phase was also examined. Western blot analysis was used to determined the levels of Bax and Bcl-2 and apoptosis associated proteins, and confocal laser microscope for examining the translocation of associated protein after exposed to apigenin. The results indicated that apigenin induced morphological changes, decreased percentage of viable cells and induced apoptosis dose- and time-dependently. DAPI staining and Comet assay also confirmed that apigenin-induced DNA condensation and damage. The levels of caspase-3, -8 and -9 involved in apigenin-induced apoptosis indicating caspase-dependent pathway was induced by apigenin. Western blotting showed that apigenin promoted cytochrome c levels and also induced dysfunction of mitochondria leading to the release of cytochrome c, AIF and Endo G, causing the activation of caspase-9 and -3, then apoptosis in A549 cells. | Authentic |
Numerous studies have proved that long non-coding RNAs (lncRNAs) have an important role in malignant tumors, including non-small cell lung cancer (NSCLC). LncRNA olfactory receptor family 3 subfamily A member 4 (OR3A4) was explored to identify how it functions in resistance of NSCLC patients to cisplatin. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to detect OR3A4 expression in NSCLC patients. Then, we conducted Cell Counting Kit-8 (CCK-8) assay and flow cytometric analysis to detect the function of OR3A4 on the resistance of NSCLC cells to cisplatin. Furthermore, the potential mechanism was explored by mechanism assays. Compared with OR3A4 expression of paired A549 cells, OR3A4 expression of A549/DDP cells was higher. Moreover, the functional assay showed that after OR3A4 was silenced in A549/DDP cells, cell cycle arrest and cell apoptosis was induced, and resistance to cisplatin was reversed. Furthermore, it was found that CDK1 expression was suppressed in A549/DDP cells by knockdown of OR3A4. The present work suggests that OR3A4 participates in regulating cell cycle, cell apoptosis of NSCLC cells and the resistance to cisplatin via upregulating CDK1, indicating that OR3A4 could be identified as a potential therapeutic target for NSCLC patients. | Counterfeit |
The study includes 80 patients identified from an endocrine clinic, two males and two females from each of 5 age groups (<5, 5 to 7, 8 to 10, 11 to 13, and 14 to 16 years). Skeletal age as determined from an open MRI scanner and radiographs performed on the same day was compared for each child. Two observers assess the skeletal age from radiographs and MRI images independently. After a period of at least three weeks, observers determined the skeletal age of all patients independently. All of the images were in different and random orders, on both of the assessment occasions. The agreement was assessed using the interclass correlation coefficient and Bland Altman plots. Problem Statement. The recurrent use of left-hand radiography in children with chronic conditions might result in the patient being exposed to the same image several times throughout the course of their lives. Use of radiation-free methods such as magnetic resonance imaging (MRI) may be able to assist in reducing the risks associated with radiation exposure, if done properly. Patients' age ranged from 3 to 16 years, in which the mean of the chronological age was 9.3 years (±2.9) and 9.8 years (±2.7) in girls and boys, respectively. The interrater agreement for skeletal age determination was 0.984 for radiographs and 0.976 for MRI scans. Using the G&P technique, for Observer 1, intraobserver agreement for radiographs and DXA was 0.993 and 0.983, respectively, and 0.995 and 0.994, respectively, for Observer 2. Plotting the rater readings against the line of equality shows no significant differences between readings acquired from radiographs and MRI scans. For the study contribution, it is possible to employ open compact MRI to determine the skeletal age of a person. Our results showed that left-hand MRI scans were of better quality than the radiographs. | Counterfeit |
Head and neck cancer (HNC) is the fifth most common cancer worldwide, and its incidence and death rates have been consistently high throughout the past decades. MicroRNAs (miRNAs) have recently gained significant attention because of their role in the regulation of a variety of biological processes via post-transcriptional silencing mechanisms. Previously, we determined a specific profile of miRNAs associated with HNC using a miRNA microarray analysis. Of the 23 miRNAs with highly altered expression in HNC cells, miR-503 was the most significantly downregulated miRNA. In this study, we confirmed that miR-503 acts as a tumor suppressor, as our results showed decreased levels of miR-503 in cancer cells and patients with HNC. We further characterized the role of miR-503 in the malignant functions of HNC. Although there was a minimal effect on cell growth, miR-503 was found to inhibit cellular invasion significantly. Algorithm-based studies identified multiple potential target genes and pathways associated with oncogenic mechanisms. The candidate target gene, WNT3A, was confirmed to be downregulated by miR-503 at both the mRNA and protein levels and validated by a reporter assay. Furthermore, miR-503 modulated multiple invasion-associated genes, including matrix metalloproteinases (MMPs), through the Wnt downstream signaling pathway. Overall, this study demonstrates that miR-503 suppresses HNC malignancy by inhibiting cell invasion through the Wnt signaling pathway via the WNT3A/MMP molecular axis. The modulation of miR-503 may be a novel therapeutic approach to intervene in cancer invasion. | Authentic |
The prostate has the highest level of polyamines among all tissues, and it is the only tissue in which polyamines are purposely synthesized for export. It has been suggested that the high local polyamine concentrations suppress cell growth of primary prostatic carcinomas and that this growth control is lost when cancer cells metastasize. It has also been shown that the sensitivity to polyamine-induced growth arrest correlates with antizyme induction in prostate carcinoma cell lines. In this study, we evaluated the sensitivity of poorly metastatic (LNCaP) and highly metastatic (DU145) prostate cancer cell lines to conditional antizyme 1 over-expression. Antizyme 1 induction resulted in a marked loss of ODC activity and polyamine uptake in both cell lines. However, the proliferation of LNCaP cells was repressed by antizyme 1 induction, whereas the proliferation of DU 145 cells was not affected. Neither cell line showed any reduction in polyamine pools after manipulation nor did polyamine addition into the medium save the LNCaP cells from the growth retardation. The growth inhibition of LNCaP cells was accompanied by accumulation of cells in the G1 phase and depletion of cyclin E1 protein. These results confirm that different prostate cancer cell lines show diverse sensitivities to antizyme 1 which may not be directly polyamine related. The high gene transfer capacity of the used lentiviral vector makes the present approach a useful tool to study the therapeutic potential of antizyme 1 both in cell cultures and experimental animals. | Authentic |
We designed a deep learning model for assessing 18F-FDG PET/CT for early prediction of local and distant failures for patients with locally advanced cervical cancer. All 142 patients with cervical cancer underwent 18F-FDG PET/CT for pretreatment staging and received allocated treatment. To augment the amount of image data, each tumor was represented as 11 slice sets each of which contains 3 2D orthogonal slices to acquire a total of 1562 slice sets. In each round of k-fold cross-validation, a well-trained proposed model and a slice-based optimal threshold were derived from a training set and used to classify each slice set in the test set into the categories of with or without local or distant failure. The classification results of each tumor were aggregated to summarize a tumor-based prediction result. In total, 21 and 26 patients experienced local and distant failures, respectively. Regarding local recurrence, the tumor-based prediction result summarized from all test sets demonstrated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71%, 93%, 63%, 95%, and 89%, respectively. The corresponding values for distant metastasis were 77%, 90%, 63%, 95%, and 87%, respectively. This is the first study to use deep learning model for assessing 18F-FDG PET/CT images which is capable of predicting treatment outcomes in cervical cancer patients. • This is the first study to use deep learning model for assessing 18 F-FDG PET/CT images which is capable of predicting treatment outcomes in cervical cancer patients. • All 142 patients with cervical cancer underwent 18 F-FDG PET/CT for pretreatment staging and received allocated treatment. To augment the amount of image data, each tumor was represented as 11 slice sets each of which contains 3 2D orthogonal slices to acquire a total of 1562 slice sets. • For local recurrence, all test sets demonstrated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71%, 93%, 63%, 95%, and 89%, respectively. The corresponding values for distant metastasis were 77%, 90%, 63%, 95%, and 87%, respectively. | Authentic |
The suppressors of cytokine signaling 3 (SOCS3) negatively regulates the JAK-STAT pathway. The bioinformatics analysis revealed a targeted binding site between miR-221 and the 3'-UTR of SOCS3 mRNA. This study investigated the role of miR-221 in the proliferation and apoptosis of gastric cancer cells. The Dual-Luciferase reporter gene assay validated the target relationship between miR-221 and SOCS3. Gastric cancer tissues were collected and compared with adjacent tissues to detect the expression of miR-221 and SOCS3. The Kaplan-Meier method was used to analyze the survival rate between patients with high and low miR-221 expression. Human gastric cancer SGC7901 cells were cultured and divided into the miR-NC group and miR-221 inhibitor group, followed by an analysis of the expression of miR-221, SOCS3, p-JAK2 and p-STAT3, cell apoptosis, and proliferation. Compared with adjacent tissues, miR-221 expression was significantly increased in tumor tissues, and SCOS3 mRNA expression was decreased. Compared with those with lower miR-221 expression, the prognosis of patients with higher miR-221 expression was significantly worse. There was a targeted regulatory relationship between miR-221 and SOCS3 mRNA. Compared with GES-1 cells, miR-221 expression in gastric cancer MGC803 and SGC7901 was significantly increased, and the expression of SOCS3 mRNA and protein was significantly decreased. The transfection of miR-221 inhibitor significantly increased SOCS3 expression in gastric cancer SGC7901 cells, decreased p-JAK2, p-STAT3 protein expression, increased cell apoptosis, and decreased cell proliferation. Increased miR-221 expression and decreased SOCS3 expression are related to gastric cancer. MiR-221 regulates the proliferation and apoptosis of gastric cancer cells by regulating SOCS3 expression. | Counterfeit |
To detect the expression of long non-coding ribonucleic acid (lncRNA) ASB16-AS1 in non-small cell lung cancer (NSCLC) tissues and cells, and to explore the effect of lncRNA ASB16-AS1 on the biological functions of NSCLC cells. The expression level of lncRNA ASB16-AS1 in NSCLC tissues and cells was detected via real-time fluorescence quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). The interference sequences of lncRNA ASB16-AS1 were designed and synthesized, and its transfection efficacy was detected by qRT-PCR. After knockdown of lncRNA ASB16-AS1, the proliferation, cell cycle, and apoptosis of NSCLC cells were detected via cell counting kit-8 (CCK-8) assay, colony formation assay, and flow cytometry, respectively. Moreover, the expression changes in the Wnt/β catenin signaling pathway were detected via Western blotting. LncRNA ASB16-AS1 was upregulated in NSCLC tissues and cells compared with that in paracarcinoma tissues and 16HBE cells. The results of CCK-8 assay and colony formation assay revealed that the silence of lncRNA ASB16-AS1 attenuated the proliferative ability in NSCLC. The results of flow cytometry manifested that the silence of lncRNA ASB16-AS1 arrested the cell cycle in G0/1 phase, and accelerated the apoptosis rate. The key proteins in the Wnt/β-catenin signaling pathway were regulated by lncRNA ASB16-AS1 in NSCLC. LncRNA ASB16-AS1 is upregulated in NSCLC tissues and cells, which promotes proliferation and inhibits apoptosis of NSCLC cells through the Wnt/β-catenin signaling pathway. | Counterfeit |
The phosphatase and tensin homologue deleted on chromosome ten (PTEN) acts as a tumor suppressor gene by inhibiting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. DJ-1, a negative regulator of PTEN, is associated with the pathogenesis of a variety of tumors. Curcumin (Cur) is a phenolic compound that is extracted from various plant rhizomes with various anti-tumor pharmacological effects. This study aimed to investigate the effects of Cur on proliferation and apoptosis of colorectal cancer cells. Human normal colorectal epithelial cell line (NCM460) and colorectal cancer cell line (SW480 and SW620) were cultured in vitro. Real-time quantitative PCR (RT-PCR) and western blot were used to detect DJ-1 and PTEN mRNA and protein, respectively. Cell apoptosis was determined with flow cytometry. SW480 cells were divided into control, 20 μM Cur treatment group, Cur+pcDNA3.1-Blank group and Cur+pcDNA3.1-DJ-1 group. Cell proliferation activity was evaluated with EdU staining. Comparing with NCM460 cells, DJ-1 was significantly increased, while PTEN was significantly declined in SW480 and SW620 cells (p<0.05). Cur treatment significantly inhibited SW480 and SW620 cell proliferation and significantly induced apoptosis compared to control group (p<0.05) but showed no significant effects on NCM460 cells. Cur down-regulated DJ-1 level and enhanced PTEN expressions in SW480 cells with dose dependence. The pcDNA3.1-DJ-1 transfection significantly declined PTEN expression, enhanced p-AKT levels, reduced cell apoptosis, and strengthened cell proliferation in SW480 cells treated by Cur (p<0.05). Cur can inhibit colorectal cancer cell proliferation and promote apoptosis by down-regulating DJ-1 expression to regulate the activity of PTEN/PI3K/AKT signaling pathway. | Counterfeit |
Little evidence is available on the relationship between oral corticosteroids use and hepatocellular carcinoma. The objective of this study was to investigate whether oral corticosteroids use correlates with the risk of hepatocellular carcinoma in high risk populations in Taiwan. Using representative claims database established from the Taiwan National Health Insurance Program with a population coverage rate of 99.6%, we identified 102,182 subjects aged 20-84 years with newly diagnosed hepatocellular carcinoma in 2000-2011 as the cases and 102,182 randomly selected subjects aged 20-84 years without hepatocellular carcinoma as the matched controls. In subjects with any one of comorbidities including alcohol-related disease, chronic liver disease, and diabetes mellitus, the adjusted OR of hepatocellular carcinoma was 29.9 (95% CI 28.7, 31.1) for subjects with never use of oral corticosteroids, and the adjusted OR would increase to 33.7 (95% CI 32.3, 35.3) for those with ever use of oral corticosteroids. The adjusted OR of hepatocellular carcinoma was 1.03 for subjects with increasing cumulative duration of oral corticosteroids use for every one year (95% CI 1.01, 1.06), with a duration-dependent effect. The largest OR occurred in subjects with ever use of oral corticosteroids and concurrently comorbid with alcohol-related disease, chronic liver disease, and diabetes mellitus (adjusted OR 122.7, 95% CI 108.5, 138.8). There is a synergistic effect between oral corticosteroids use and the traditional risk factors on the risk of hepatocellular carcinoma. People with risk factors for hepatocellular carcinoma should receive regular ultrasound surveillance, particularly when they currently use oral corticosteroids. | Authentic |
Cerebral stroke refers to an acute onset of neurological deficit syndrome. In this research, we attempted to probe into the underlying mechanisms by which chrysophanol (CP) performed its regulatory roles in cerebral stroke. Methods OGD inducement was conducted in PC12 cells to construct a cerebral stroke model. Subsequently, CCK-8 assay, western blot, flow cytometry were utilized to determine cell viability, proliferation, and apoptosis, respectively. qRT-PCR was employed for detecting miR-216a expression level. Afterward, cell transfection was performed to alter miR-216a expression. Further, experiments were conducted to determine the expression of crucial factors participated in PI3 K/AKT and JAK2/STAT3 pathways for exploring the underlying mechanisms. Results OGD inducement suppressed cell viability, while promoted cell apoptosis. Besides, it enhanced the expression of proliferation-associated p53, p21, and apoptosis-associated Bax, and Cleaved-caspase-3, while suppressed the expression of Bcl-2. Furthermore, CHR exposure ameliorated the effects that OGD-evoked, and elevated the expression of miR-216a, as well as the expression of crucial factors participated in PI3 K/AKT and JAK2/STAT3 pathways. However, miR-216a silencing markedly reversed the effects triggered by CHR exposure. Conclusion CHR exposure relieved OGD-evoked PC12 cell damage by elevating miR-216a expression and thereby activating of PI3 K/AKT and JAK2/STAT3 pathways. | Counterfeit |
Myocardial ischemia and reperfusion injury (MIRI) includes major drawbacks, such as excessive formation of free radicals and also overload of calcium, which lead to cell death, tissue scarring, and remodeling. The current study aims to explore whether KRT1 silencing may ameliorate MIRI via the Notch signaling pathway in mouse models. Myocardial tissues were used for the determination of the positive rate of KRT1 protein expression, apoptosis of myocardial cells, creatine kinase (CK) and lactate dehydrogenase (LDH) expression, expression of related biomarkers as well as myocardial infarction area. The transfected myocardial cells were treated with KRT1-siRNA, Jagged1, and DAPT (inhibitor of Notch-1 signaling pathway). The expression of KRT1, NICD, Hes1, Bcl-2, and Bax protein was detected. The MTT assay was applied for cell proliferation and flow cytometry was used for cell apoptosis. Mice with MIRI had a higher positive rate of KRT1 protein expression, apoptosis of myocardial cells, CK and LDH expression, myocardial infarction area, increased expression of MDA, NO, SDH, IL-1, IL-6, TNF-α, CRP, KRT1, Bax protein, CK, and LDH, and decreased expression of SOD, NICD, Hes1, and Bcl-2. The downregulation of KRT1 led to decreased expression of KRT1 and Bax protein, increased expression of NICD, Hes1, and Bcl-2, decreased cell apoptosis, and improved cell proliferation. The inhibition of the Notch signaling pathway leads to reduced expression of Bax, increased expression of NICD, Hes1, and Bcl 2, and also decreased cell apoptosis and increased cell proliferation. Our data conclude that KRT1 silencing is able to make MIRI better by activating the Notch signaling pathway in mice. | Counterfeit |
Intervertebral disc degeneration (IDD) is a major contributor to back, neck, and radicular pain, and the treatment of IDD is costly and relatively ineffective. Dysregulation of microRNAs (miRNAs) has been reported to be involved in IDD. The purpose of our study is to illustrate the potential that miR-143-5p targeting eEF2 gene mediates IDD. Following the establishment of the IDD rat models, expression of miR-143-5p, eEF2, Bcl-2, Bax, AMPK, mTOR, cyclinD, COL2, ACAN, and DCN was detected. The NP cells isolated from degenerative intervertebral disc (IVD) were introduced with a series of mimic, inhibitor, or AICAR to explore the functional role of miR-143-5p in IDD and to characterize the relationship between miR-143-5p and eEF2. Cell viability, cell cycle, apoptosis, and senescence were also evaluated. A reduction in eEF2, an increase in miR-143-5p, and activation of the AMPK signaling pathway were observed in degenerative IVD. Moreover, increased senescent NP cells were observed in degenerative IVD. eEF2 was confirmed as a target gene of miR-143-5p. miR-143-5p was found to activate the AMPK signaling pathway. The restoration of miR-143-5p or the activation of AMPK signaling pathway decreased COL2, ACAN, and DCN expression, coupled with the inhibition of NP cell proliferation and differentiation, and promotion of NP apoptosis and senescence. On the contrary, the inhibition of miR-143-5p led to the reversed results. The results demonstrated that the inhibition of miR-143-5p may act as a suppressor for the progression of IDD. | Counterfeit |
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors. | Authentic |
Recent data indicate that tumor-associated neutrophils (TANs) serve a dual role in tumor progression and regression. CD66b is a neutrophil marker and has been associated with patient outcome in various cancers. However, its clinical impact in non-small cell lung cancer (NSCLC) remains controversial. 536 NSCLC patients, of which 172 harbored lymph node metastases, were included in this study. Tissue microarrays were constructed and multiplexed immunohistochemistry of CD66b, CD34 and pan-keratin was performed to evaluate the localization and quantity of CD66b+ TANs. High intratumoral CD66b+ TANs density in squamous cell carcinoma (SCC) subgroup was an independent positive prognosticator for disease-specific survival (P = 0.038). In contrast, high intratumoral TANs density was an independent negative prognostic factor in the adenocarcinoma (ADC) subgroup (P= 0.032). Likewise, in ADC patients with lymph node metastases, high level of intratumoral TANs was associated with poor prognosis (P = 0.003). Stromal CD66b+ TANs were not associated with outcome of NSCLC patients. In conclusion, CD66b+ TANs show diverging prognostic effect in NSCLC patients according to histological subgroups. The presence of CD66b+ TANs could prove pivotal for development of an immunoscore in ADC NSCLC patients. | Authentic |
This study aimed to investigate the effect of SOCS1 silencing on the proliferation and apoptosis of melanoma cells by in vivo and in vitro studies. Immunohistochemical staining was used to detect SOCS1 expression in melanoma tissues and pigmented nevi. Quantitative real-time polymerase chain reaction and western blotting were applied to detect the messenger RNA and protein expressions of SOCS1 in primary human melanocytes and malignant melanoma cell lines (A375, SK-MEL-5, M14, and MV3). Melanoma cells were assigned into mock, negative small interfering RNA, and SOCS1-small interfering RNA groups. The proliferation, cell cycle and apoptosis, and messenger RNA expression of SOCS1 in MV3 and A375 cells were detected using MTT assay, flow cytometry, and quantitative real-time polymerase chain reaction, respectively. The expressions of SOCS1 protein, extracellular signal-regulated kinase, and janus kinase signal transduction and activators of transcription signaling pathways-related proteins were detected using western blotting. After the establishment of subcutaneous xenograft tumor models in nude mice, the latent period, size, volume and growth speed of xenograft tumors in the mock, negative small interfering RNA, and SOCS1-small interfering RNA groups were examined and compared. The results indicated that positive expression rate of SOCS1 was higher in malignant melanoma tissues than in pigmented nevi. MV3 cells had the highest messenger RNA and protein expressions of SOCS1, followed by A357 cells. Compared with the mock and negative small interfering RNA groups, SOCS1-small interfering RNA group showed lower cell viability, elevated cell apoptosis, more cells in G0/G1 phase and less cells in S and G2/M phases, and decreased messenger RNA and protein expressions of SOCS1, p-ERK1/2, p-JAK2, p-STAT1, and p-STAT3. Compared with the mock and negative small interfering RNA groups, the SOCS1-small interfering RNA group showed longer latent period of tumor, smaller tumor size and volume, and smoother tumor growth curve. To conclude, SOCS1 silencing can inhibit proliferation and induce apoptosis of MV3 and A357 melanoma cells in vivo and in vitro by inhibiting extracellular signal-regulated kinase and janus kinase signal transduction and activators of transcription signaling pathways. | Counterfeit |
Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment. | Authentic |
Gastroenteropancreatic (GEP) neuroendocrine neoplasms are classified as low-grade, intermediate-grade, and high-grade tumors based on morphologic criteria and the proliferation rate. Most studies have been conducted in patients with well differentiated (low-grade to intermediate-grade) neuroendocrine tumors. Data are substantially scarcer on poorly differentiated, high-grade neuroendocrine carcinoma (NEC), which includes the entities of small cell carcinoma and large cell NEC. A literature search of GEP-NEC was performed. Long-term survival was poor even among patients who presented with localized disease. Several studies highlighted heterogeneity within the high-grade NEC category and a need for the further identification of discreet prognostic and predictive groups. Tumors with a Ki-67 proliferation index <55% were less responsive to platinum-based chemotherapy, and patients with such tumors or with well differentiated morphology had better survival than patients who had tumors with poorly differentiated morphology or a higher Ki-67 index. Treatment options beyond platinum-based chemotherapy are emerging. A revision of the World Health Organization high-grade NEC classification seems to be necessary based on recent data. Platinum-based chemotherapy may not be the optimal treatment for patients who have GEP-NEC with a moderately high proliferation rate. Adequate diagnostic and prognostic stratifications constitute the basis for future progress. | Authentic |
Founder mutations in the two breast cancer genes, BRCA1 and BRCA2, have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian BRCA1 founder mutations were defined by haplotyping in 2001, and accounted for 68% of BRCA1 mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both BRCA1 and BRCA2 in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the BRCA1/2 carrier population of the largest clinic of hereditary cancer in Norway. A total of 2430 BRCA1 carriers from 669 different families, and 1092 BRCA2 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations. There were 120 different BRCA1 and 87 different BRCA2 variants among the mutation carriers. Forty-six per cent of the registered BRCA1/2 families (454/981) had a previously reported Norwegian founder mutation. The majority of BRCA1/2 mutations (71%) were rare, each found in only one or two families. Fifteen per cent of BRCA1 families and 25% of BRCA2 families had one of these rare variants. The four well-known Norwegian BRCA1 founder mutations previously confirmed through haplotyping were still the four most frequent mutations in BRCA1 carriers, but the proportion of BRCA1 mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described. The spectrum of BRCA1 and BRCA2 mutations in the carrier population at Norway's largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives. | Authentic |
Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies. | Authentic |
The global prevalence of chronic renal failure (CRF) has significantly elevated with various reports indicating there to be a 10% worldwide rate. The functions of long non-coding RNAs (lncRNAs) and their deeper association with CRF at present remain poorly understood. Hence, the aim of the present study was to investigate the altered expressions of lncRNA LINC00667 in CRF and its associated effects on renal tubular epithelial cell proliferation, apoptosis and renal fibrosis through the microRNA-19b-3p (miR-19b-3p)/LINC00667/connective tissue growth factor (CTGF) signaling pathway. Initially, verification of the targeting relationship between LINC00667, CTGF and miR-19b-3p was performed, after which evidence was obtained indicating that miR-19b-3p could negatively regulate LINC00667 and CTGF. The expressions of CTGF in both the CRF and normal renal tissues were determined by immunohistochemistry means, with LINC00667 and CTGF determined to be highly expressed, while poor expression levels of miR-19b-3p were detected among the CRF tissues. The expressions of LINC00667, miR-19b-3p, fibrosis- and epithelial-mesenchymal transition (EMT)-related genes were also examined. The successfully established CRF rat models were treated with varying mimics, inhibitors, and siRNA. ELISA was applied to determine the renal function-related factors. Besides, the renal cell proliferation, migration and apoptosis were detected. In response to LINC00667 silencing, the renal tubular epithelial cells displayed increased proliferation and migration accompanied by reduced apoptosis based on upregulated miR-19b-3p, along with inhibited renal fibrosis and EMT detected. Taken together, the key findings of our study demonstrated that decreased lncRNA LINC00667 could promote renal tubular epithelial cell proliferation and ameliorate renal fibrosis in CRF via the miR-19b-3p/LINC00667/CTGF signaling pathway. | Counterfeit |
Sudden, unwelcome and repetitive thoughts about a traumatic event--intrusive thoughts--could relate to how men assess their quality of life after prostate-cancer diagnosis. We aimed to study the prevalence of intrusive thoughts about prostate cancer and their association with quality-of-life outcomes before and after radical prostatectomy. During the first year of the LAPPRO-trial, 971 men scheduled for radical prostatectomy were prospectively included from 14 urological centers in Sweden. Of those, 833 men responded to two consecutive study-specific questionnaires before and three months after surgery (participation rate 86%). The association of intrusive thoughts with three quality-of-life outcomes, i.e. self-assessed quality of life, depressive mood and waking up with anxiety was estimated by prevalence ratios that were calculated, together with a 95% confidence interval, at the same time-point as well as over time. Fisher's exact-test was used to analyze differences between respondents and non-respondents. Wilcoxon signed-ranks and Cochran-Armitage trend tests were used for analysis of change over time. To validate new questions on intrusive thoughts, written answers to open-ended questions were read and analyzed by qualitative content analysis. Before surgery, 603 men (73%) reported negative intrusive thoughts about their cancer at some time in the past month and 593 men (59%) reported such thoughts three months after surgery. Comparing those reporting intrusive thoughts at least weekly or once a week before surgery with those who did not, the prevalence ratio (95% confidence interval), three months after surgery, for waking up in the middle of the night with anxiety was 3.9 (2.7 to 5.5), for depressed mood 1.8 (1.6 to 2.1) and for impaired self-assessed quality of life 1.3 (1.2 to 1.5). The prevalence of negative intrusive thoughts about prostate cancer at the time of surgery associates with studied quality-of-life outcomes three months later. Current Controlled Trials, ISRCTN06393679. | Authentic |
It has been widely assumed that PD-1 blockade works by reinvigorating ("rebooting") pre-existing exhausted tumor-infiltrating ilymphocytes (TILs). A recent study challenges this paradigm, demonstrating that the majority of tumor-specific TILs after anti-PD-1 treatment have TCRs not identified in the tumor pre-therapy, suggesting they are newly recruited post-therapy. | Authentic |
To detect LINC00565 expression level in endometrial carcinoma (EC) samples and cell lines, and the correlations between LINC00565 and clinical features of EC patients. After intervening LINC00565, the underlying mechanism about proliferative ability in EC cell lines is observed. Relative levels of LINC00565 and KLF9 in 52 paired EC and paracancerous tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between relative level of LINC00565 or KLF9 and clinical features of EC patients was analyzed. After knockdown of LINC00565 and KLF9, potential regulations of them on biological functions of EC were examined by Cell Counting Kit (CCK-8), colony formation assay and in vivo xenograft model in nude mice, respectively. At last, dual-luciferase reporter assay and rescue experiments were conducted to illustrate the mechanisms of LINC00565 and KLF9 in mediating the development of EC. LINC00565 was upregulated in EC tissues. Chi-square analysis showed that a high level of LINC00565 predicted large tumor size, advanced pathological staging and poor prognosis in EC. Silence of LINC00565 decreased proliferative ability in EC cells and tumor growth in nude mice bearing EC. KLF9 was the target gene of LINC00565. The negative interaction between LINC00565 and KLF9 was responsible for stimulating the malignant development of EC. Knockdown of KLF9 could abolish the regulatory effects of silenced LINC00565 on proliferative ability and tumorigenesis in EC. LINC00565 is upregulated in EC tissues and closely linked to tumor size, pathological staging and poor prognosis in EC patients. LINC00565 stimulates proliferative ability in EC by downregulating KLF9. | Counterfeit |
In radiotherapy (RT), target soft tissues are best defined on MR images. In several cases, CT imaging is needed only for dose calculation and generation of digitally reconstructed radiographs (DRRs). Image co-registration errors between MRI and CT can be avoided by using MRI-only based treatment planning, especially in the pelvis. Since electron density information can not be directly derived from the MRI, a method is needed to convert MRI data into CT like data. We investigated whether there is a relationship between MRI intensity and Hounsfield unit (HU) values for the pelvic bones. The aim was to generate a method to convert bone MRI intensity into HU data surrogate for RT treatment planning. The HU conversion model was generated for 10 randomly chosen prostate cancer patients and independent validation was performed in another 10 patients. Data consisted of 800 image voxels chosen within the pelvic bones in both T1/T2*-weighted gradient echo and CT images. Relation between MRI intensity and electron density was derived from calibrated HU-values. The proposed method was tested by constructing five "pseudo"-CT series. We found that the MRI intensity is related to the HU value within a HU range from 0 to 1400 within the pelvic bones. The mean prediction error of the conversion model was 135 HU. Dose calculation based on the pseudo-CT images was accurate and the generated DRRs were of good quality. The proposed method enables generation of clinically relevant pseudo-CT data for the pelvic bones from one MRI series. It is simpler than previously reported approaches which require either acquisition of several MRI series or T2* maps with special imaging sequences. The method can be applied with commercial clinical image processing software. The application requires segmentation of the bones in the MR images. | Authentic |
Oral squamous cell carcinoma (OSCC) is one of the most frequent malignancies worldwide. Early diagnosis can mean adequate treatment and increase survival. This study uses ClinProt technique to identify salivary biomarkers for early diagnosis of OSCC. A total of 77 salivary samples from both OSCC patients (n=47) and healthy donors (n=30) were analyzed with MALDI-TOF MS technology. Salivary peptides from OSCC patients were separated, using C8-functionalized magnetic beads. Three signals (2918.57 Da, 5592.64 Da, and 4372.66 Da) distinguished OSCC patients from controls. Among them, unique peptide 2918.57 Da, identified as a 24-mer peptide of zinc finger protein 510 (ZNF510), was found in 0% of saliva from healthy individuals, versus 25.0% and 60% from OSCC patients with T1+T2 and T3+T4 stages, respectively (P<0.001). ELISA analysis with rabbit anti-ZNF510 peptide sera shows a starkly higher 24-mer ZNF510 peptide level in saliva from OSCC patients than that in controls (P<0.001). Also, in immunohistochemical analysis of oral tissues, a significantly higher level of ZNF510 was observed in OSCC tissues than in the OSCC free control tissues. Analysis of areas under receiver-operating characteristic (ROC) curves in OSCC early (T1+T2) and late stages (T3+T4) shows greater than 0.95. Identifying 24-mer ZNF510 peptide as OSCC-related salivary biomarkers via proteomic approach proved useful in adjunct diagnosis for early detection rather than specific diagnosis marker for progression of OSCC patients. | Authentic |
Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies". | Authentic |
Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant. | Authentic |
Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK. | Authentic |
Issues concerning non-specificity, degradation and hemolysis severely hamper the development of membranolytic amphiphilic peptides into safe and efficient anticancer agents. To increase the therapeutic potential, we have previously developed a strategy based on formulation of the peptides in biocompatible nanosized lipodisks. Studies using melittin as model peptide show that the proteolytic degradation and hemolytic effect of the peptide are substantially reduced upon loading in lipodisks. Here, we explored the possibilities to increase the specificity and boost the cytotoxicity of melittin to tumor cells by use of targeting lipodisk. We demonstrate that small (~20 nm) EGF-targeted lipodisks can be produced and loaded with substantial amounts of peptide (lipid/peptide molar ratio >7) by means of a simple and straightforward preparation protocol. In vitro cell studies confirm specific binding of the peptide-loaded disks to tumor cells and suggest that cellular internalization of the disks results in a significantly improved cell-killing effect. | Authentic |
Background Solid organ transplant recipients are at increased risk of developing malignancies. The objective of this prospective, observational, one-armed study was to study the feasibility to add a mammalian target of rapamycin (mTOR) inhibitor to the immunosuppressive regimen in transplanted patients with post-transplant malignancies. During the trial the need to improve identification of post-transplant malignancies and to reassure adequate oncological treatment of these patients became evident. Multidisciplinary team (MDT) evaluation of oncological and immunosuppressive treatments was implemented for all patients with malignancies after renal or combined renal and pancreas transplantation because of the trial. Material and methods At Uppsala University Hospital, Sweden, a MDT consisting of transplant surgeons, nephrologists, oncologists and dermatologists evaluated 120 renal or combined renal and pancreas-transplanted recipients diagnosed with malignancies from September 2006 to July 2012. To identify all malignancies, the population was linked to the Regional Tumor Registry (RTR). We recorded to which extent a switch to mTOR inhibitors was possible and how often the originally planned oncological managements were adjusted. All patients were followed for three years. (ClinicalTrials.gov: NCT02241564). Results In 76 of 120 patients (63%) a switch to mTOR inhibitors was possible. Immunosuppression was interrupted in seven patients (6%), reduced in three patients (2%) and remained unchanged in 34 of 120 patients (28%). Identification of post-transplant malignancies increased significantly after linkage to RTR (p = 0.015). The initially recommended oncological treatment was adjusted in 23 of 44 patients (52%) with solid or hematological malignancies; 36 of these patients (82%) were treated according to national guidelines. Conclusion In two thirds of the patients the immunosuppressive treatment could be changed to an mTOR inhibitor with anti-tumor effects in transplanted patients with post-transplant malignancies. The use of regional tumor registers considerably improved the identification of patients with post-transplant malignancies indicating that post-transplant malignancies might be timely underreported in transplant registers. | Authentic |
Gliomas are the most recurrently occurring primary malignancies in the central nervous system. Despite surgical interventions, chemo- and radiotherapy, the results are unfortunately poor. Therefore, there is pressing need to explore more effective and efficient treatment options for treatment of glioma. In the present study we determined the anticancer potential of globularifolin against human glioma U87 cell line and human astrocytes. The results showed that globularifolin exhibits an IC50 value of 7.5 μM against glioma U87 cells as against the IC50 of 65 μM against human astrocytes. The molecule exerted its anticancer activity through induction of apoptosis as evident from the Bid-, and Bax controlled cytochrome c and Omi/HtrA2 release, XIAP suppression, and caspase-9 and 3 signalling cascade. Additionally, it also caused cell cycle arrest of human glioma U87 cancer cells in the S phase of the cell cycle. Interestingly, globularifolin also caused significant inhibition of Akt/mTOR/p70S6K and MEK/ERK pathways. Globularifolin also inhibits cell migration and invasion by regulating the expression of matrix metalloproteinases (MMPs) in U87 glioma cells. We further investigated whether globularifolin exhibits the same effectiveness against glioma cell xenografts in nude mice in vivo and it was observed that globularifolin significantly reduced the tumor growth and volume in vivo indicating the potential of globularifolin as lead molecule for glioma chemotherapy. | Counterfeit |
Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be divided into distinct molecular subtypes. We have previously shown that 3'RNA-sequencing is highly effective in classifying archival formalin-fixed paraffin-embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3'RNA-sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2-positive tumors, including overexpression of PLAG1. We explored 12 such leiomyomas by whole-genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein-level served as controls. We identified chromosomal rearrangements targeting either HMGA2, HMGA1, or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5-COL4A6 deletion. These observations suggest that instead of only HMGA2-positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2, HMGA1, or PLAG1. The results indicate that the frequency of HMGA2-positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material. | Authentic |
Propofol is a frequently used intravenous anesthetic agent. Recent studies show that propofol exerts a number of non-anesthetic effects. The present study aimed to investigate the effects of propofol on lung cancer cell lines H1299 and H1792 and functional role of microRNA (miR)-486 in these effects. H1299 and/or H1792 cells were treated with or without propofol and transfected or not with miR-486 inhibitor, and then cell viability and apoptosis were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry. The expression of miR-486 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) with or without propofol treatment. Western blot was performed to analyze the protein expression of Forkhead box, class O (FOXO) 1 and 3, Bcl-2 interacting mediator of cell death (Bim), and pro- and activated caspases-3. Results showed that propofol significantly increased the miR-486 levels in both H1299 and H1792 cells compared to untreated cells in a dose-dependent manner (P<0.05 or P<0.01). Propofol statistically decreased cell viability but increased the percentages of apoptotic cells and protein expressions of FOXO1, FOXO3, Bim, and pro- and activated caspases-3; however, miR-486 inhibitor reversed the effects of propofol on cell viability, apoptosis, and protein expression (P<0.05 or P<0.01). In conclusion, propofol might be an ideal anesthetic for lung cancer surgery by effectively inhibiting lung cancer cell viability and inducing cell apoptosis. Modulation of miR-486 might contribute to the anti-tumor activity of propofol. | Counterfeit |
The change of lncRNA expression is known to affect the progression of tumors. This has fueled numerous investigations aiming at the mystery of lncRNA. Clear lncRNA has been the hotspot of antisense RNAs research. More and more lncRNAs have been proven to take effect as oncogenes of multitudinous cancers and accelerate tumor progression. This review elucidates the pathophysiological functions of lncRNA DLGAP1-AS1 and lncRNA DLGAP1-AS2 in a variety of tumors. Via systematic analysis and in-depth study about relevant articles in PubMed, this article analyzes and summarizes the mechanism of antisense transcripts DLGAP1- AS1 and DLGAP1-AS2 in tumor development. DLGAP1-AS1 and DLGAP1-AS2 can exert their effect as oncogenes on various cancers. The expression of DLGAP1-AS1 is aberrantly high in various tumors, including GC, BC, HCC, glioblastoma and CRC. Concurrently, in LC, RC, HCC, GC, glioma and CCA, DLGAP1-AS2 is also discovered to be highly expressed. And they have a strong pertinence with a poor prognosis. The disorder of DLGAP1-AS1 and DLGAP1- AS2 in different tumors has different malignant impacts on tumors, not only to invasion, apoptosis, multiplication and EMT of tumor cells but also to drug resistance and radioresistance. In addition, DLGAP1-AS2 was revealed to have the ability to predict the prognosis of WT and RCC. The regulatory effects of DLGAP1-AS1 and DLGAP1-AS2 on tumors make them possible to be clinical markers for the early diagnosis of tumors and effective therapeutic targets. | Counterfeit |
We investigated the involvement of microRNA-433 (miR-433) in the proliferation, migration, and invasiveness of oral squamous cell carcinoma (OSCC). Totally 108 OSCC tissues and adjacent normal tissues from patients with OSCC were collected. Also, transplanted tumor formation experiment in nude mice was conducted to verify the effect of miR-433 and FAK on subcutaneous transplanted tumor. The CD44+ stem cell from SCC-9 were collected and assigned into the blank, miR-433 mimics, mimics control, miR-433 inhibitors, inhibitors control, siFAK and miR-433 inhibitors + siFAK groups. The qRT-PCR and western blotting were used to detect miR-433, FAK, ERK, MEK, pERK and pMEK after transfection. Flow cytometry, MTT assay, scratch test and Transwell assay were performed to determine the cell proportion, growth, migration and invasion of SCC-9 cells. In cell line SCC-9, expression of CD133, Oct-4, and BIM-1 was greater in CD44+ cells than CD44- cells, indicating that CD44+ cells had characteristics of tumor stem cells. Expression of FAK, ERK, MEK, p-ERK and p-MEK was decreased in tumor tissues from the CD44-, miR-433, and siFAK groups. Expression of MiR-433 mRNA was elevated, while levels of FAK, ERK, MEK, p-ERK, and p-MEK mRNA were all decreased in the miR-433 mimics group. In the miR-433 mimics and siFAK groups, cell proliferation, migration, and invasion were all decreased, while the opposite trends were seen in the miR-433 inhibitor group. These results indicate that miR-433 downregulates FAK through the ERK/MAPK signaling pathway to inhibit the proliferation, migration, and invasiveness of SCC-9 OSCC cells. | Counterfeit |
The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach. | Authentic |
In this study, the anti-proliferative effect of ilimaquinone, a sesquiterpene derivative from the marine sponge, in breast cancer cells was investigated. Ilimaquinone inhibited the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values of 10.6 μM and 13.5 μM, respectively. Non-tumorigenic human breast epithelial cells were less sensitive to ilimaquinone than breast cancer cells. Flow cytometric and Western blot analysis showed that ilimaquinone induced S-phase arrest by modulating the expression of p-CDC-2 and p21. Ilimaquinone induces apoptosis, which is accompanied by multiple biological biomarkers, including the downregulation of Akt, ERK, and Bax, upregulation of p38, loss of mitochondrial membrane potential, increased reactive oxygen species generation, and induced autophagy. Collectively, these findings suggest that ilimaquinone causes cell cycle arrest as well as induces apoptosis and autophagy in breast cancer cells. | Authentic |
The epigenome is a key determinant of transcriptional output. Perturbations within the epigenome are thought to be a key feature of many, perhaps all cancers, and it is now clear that epigenetic changes are instrumental in cancer development. The inherent reversibility of these changes makes them attractive targets for therapeutic manipulation, and a number of small molecules targeting chromatin-based mechanisms are currently in clinical trials. In this perspective we discuss how understanding the cancer epigenome is providing insights into disease pathogenesis and informing drug development. We also highlight additional opportunities to further unlock the therapeutic potential within the cancer epigenome. | Authentic |
Several individual components of the Mediterranean diet have been shown to offer protection against prostate cancer. The present study is the first to investigate the association between adherence to the Mediterranean diet and the relative risk of prostate cancer. We also explored the usefulness of the Mediterranean Diet Score (MDS) in a non-Mediterranean population. FFQ data were obtained from 1482 incident prostate cancer patients and 1108 population-based controls in the Cancer of the Prostate in Sweden (CAPS) study. We defined five MDS variants with different components or using either study-specific intakes or intakes in a Greek reference population as cut-off values between low and high intake of each component. Unconditional logistic regression was used to estimate the relative risk of prostate cancer for high and medium v. low MDS, as well as potential associations with the individual score components. No statistically significant association was found between adherence to the Mediterranean diet based on any of the MDS variants and prostate cancer risk (OR range: 0·96-1·19 for total prostate cancer, comparing high with low adherence). Overall, we found little support for an association between the Mediterranean diet and prostate cancer in this Northern European study population. Despite potential limitations inherent in the study or in the build-up of a dietary score, we suggest that the original MDS with study-specific median intakes as cut-off values between low and high intake is useful in assessing the adherence to the Mediterranean diet in non-Mediterranean populations. | Authentic |
Picropodophyllin (PPP) is a promising novel anti-neoplastic agent that efficiently kills tumor cells in vitro and causes tumor regression and increased survival in vivo. We have previously reported that PPP treatment induced moderate tolerance in two out of 10 cell lines only, and here report the acquired genomic and expression alterations associated with PPP selection over 1.5 years of treatment. Copy number alterations monitored using metaphase and array-based comparative genomic hybridization analyses revealed largely overlapping alterations in parental and maximally tolerant cells. Gain/amplification of the MYC and PVT1 loci in 8q24.21 were verified on the chromosome level. Abnormalities observed in connection to PPP treatment included regular gains and losses, as well as homozygous losses in 10q24.1-q24.2 and 12p12.3-p13.2 in one of the lines and amplification at 5q11.2 in the other. Abnormalities observed in both tolerant derivatives include amplification/gain of 5q11.2, gain of 11q12.1-q14.3 and gain of 13q33.3-qter. Using Nexus software analysis we combined the array-CGH data with data from gene expression profilings and identified genes that were altered in both inputs. A subset of genes identified as downregulated (ALDH1A3, ANXA1, TLR4 and RAB5A) or upregulated (COX6A1, NFIX, ME1, MAPK and TAP2) were validated by siRNA in the tolerant or parental cells to alter sensitivity to PPP and confirmed to alter sensitivity to PPP in further cell lines. Long-term PPP selection lead to altered gene expression in PPP tolerant cells with increase as well as decrease of genes involved in cell death such as PTEN and BCL2. In addition, acquired genomic copy number alterations were observed that were often reflected by altered mRNA expression levels for genes in the same regions. | Authentic |
ORAI family channels have emerged as important players in malignant transformation, yet the way in which they reprogram cancer cells remains elusive. Here we show that the relative expression levels of ORAI proteins in prostate cancer are different from that in noncancerous tissue. By mimicking ORAI protein remodeling observed in primary tumors, we demonstrate in in vitro models that enhanced ORAI3 expression favors heteromerization with ORAI1 to form a novel channel. These channels support store-independent Ca(2+) entry, thereby promoting cell proliferation and a smaller number of functional homomeric ORAI1-based store-operated channels, which are important in supporting susceptibility to apoptosis. Thus, our findings highlight disrupted dynamic equilibrium of channel-forming proteins as an oncogenic mechanism. | Authentic |
Patients with breast cancer frequently experience psychological distress. This study aimed to investigate the effect of narrative nursing on middle-aged patients with breast cancer. In all, 82 patients with breast cancer admitted to the Affiliated Hospital of Nantong University were divided into two groups, namely, the observation group and the control group, by simple random sampling, with 41 cases in each group. The patients in both groups were treated with breast cancer surgery. Additionally, the control group received routine nursing, whereas the observation group received narrative nursing based on the control group. After 8 weeks of nursing, the SAS (self-rating anxiety scale) and SDS (self-rating depression scale) scores in the observation group were lower than those in the control group (P < 0.01). At the same time, the result of family hardiness showed that the patients with narrative nursing performed better in commitment, challenge, and control (P < 0.01). In conclusion, narrative nursing can alleviate the postoperative shame and negative emotions of patients with breast cancer and improve their quality of life. | Counterfeit |
Mesenchymal stem cells (MSCs) have emerged as a cell-based therapy in many diseases including atherosclerosis (AS) due to their capability of immunomodulation and tissue regeneration. However, the pathway for MSCs' antiatherosclerotic activity remains to be elucidated. Here, we test the hypothesis that microRNA-221 (miR-221) from MSC-derived extracellular vesicles (EVs) alleviates AS. Male ApoE-/- mice were fed a high-fat diet for 12 weeks to induce AS, and were then treated with human bone marrow mesenchymal stem cell-derived EVs by tail vein injection. The expression pattern of miR-221 and N-acetyltransferase-1 (NAT1) in AS mice was characterized by quantitative RNA analysis and their interaction was identified by dual-luciferase reporter gene assay. In other studies, human arterial smooth muscle cells treated with oxidized low-density lipoprotein-were co-cultured with MSC-released EVs to evaluate the EV-mediated transfer of miR-221. NAT1 was highly expressed in atherosclerotic lesions. Adenovirus-mediated NAT1 knockdown resulted in a reduced lipid deposition in AS mice. Human bone marrow mesenchymal stem cell -derived EVs carrying miR-221 were internalized by human arterial smooth muscle cells and transferred their miR-221 contents to downregulate the target gene NAT1. Injection of miR-221-containing EVs inhibited lipid deposition in AS mice, in part by downregulating NAT1. The present study provides evidence that miR-221 shuttled by MSC-derived EVs can inhibit atherosclerotic plaque formation in AS model mice, suggesting that miR-221 may serve as a target for improving MSC-based therapeutic strategy against AS. | Counterfeit |
In order to design a more reliable general push time cycle prediction software for macroeconomic indicators, a set of general software is used to serve financial transactions, bulk material transactions, international trade, macro-control and other fields, so as to improve the prediction of macroeconomic indicators. Because the macro data is one-dimensional array data, the essence of the mutation algorithm is to obtain the movement direction of the mutation of data nodes, obtain the distance between the linear programming result and the original data through the least square method, and calculate the average value in the original data, After binary t-correction, it refers to the binary t-correction results of the one-dimensional matrix before the final evaluation output factor and the one-dimensional matrix after the final evaluation output factor. In this study, genetic algorithm is introduced as the core algorithm. In the algorithm efficiency verification test, the calculation model based on genetic algorithm is constructed in Matlab environment, and the data space construction mode and genetic variation mode of genetic algorithm are explored. Finally, a high-throughput macroeconomic timing prediction scheme based on genetic algorithm is designed. This scheme is more accurate than the paid full-function 10jqka software, and has a higher prediction cycle for stock price and stock index. The simulation software composed of this algorithm has the prediction function that 10jqka software cannot complete. | Counterfeit |
This study investigated the chemical composition, in-vitro anticancer, and antimicrobial activities of the essential oil isolated from the leaf of Machilus mushaensis from Taiwan. The essential oil was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. Forty compounds were identified, representing 100% of the oil. The main components identified were n-decanal (61.0%), and alpha-cadinol (20.8%). The oil exhibited cytotoxic activity against human oral, liver, lung, colon, melanoma, and leukemic cancer cells. The antimicrobial activity of the oil was tested by the disc diffusion and micro-broth dilution methods against ten microbial species. The oil exhibited moderate growth suppression against Gram-positive bacteria and yeast with inhibition zones of 25-29 mm to MIC values of 375-500 microg/mL, respectively. alpha-Cadinol was found to show promising anticancer and antimicrobial activities. | Authentic |
Recent research has shown that TOP2A plays an important role in the tumorigenesis of many malignancies, such as breast cancer, ovarian cancer, and prostate cancer. However, few studies have been conducted on TOP2A expression and functions in colon cancer. In the present study, we found that TOP2A expression was obviously elevated in colon cancer tissues compared to adjacent non-cancerous tissues. Depletion of TOP2A in HCT116 and SW480 colon cancer cells by transfection of specific small interfering RNA significantly suppressed proliferation and inhibited invasion of cells, even induced apoptosis as indicated by both MTT assay, Annexin V/propidium iodide staining, and Transwell assay. Furthermore, we explored the underlying mechanisms. Knockdown of TOP2A not only affects the expression of cell apoptosis-related (Bcl-2 and Bax) and invasion-related proteins (MMP-2 and MMP-9), but also reduced the phosphorylation levels of ERK and AKT. In conclusion, we showed that TOP2A was upregulated in colon cancer tissue samples and that TOP2A may serve as an oncogene in colon cancer. | Counterfeit |
Whether we can increase the resection rate of esophageal cancer by minimally invasive esophagectomy (MIE) is unknown. The aim was to report the number and results of MIE in high-risk patients considered unsuitable for open surgery and compare these results to other operated patients and to high-risk patients not undergoing surgery. At Central Finland Central Hospital, between September 2012 and July 2018, the number of operated MIEs was 100. Of these, 10 patients were prospectively considered unfit for open approach. Nineteen additional high-risk patients with operable disease were ruled out of surgery. The short- and long-term outcomes of these 3 groups were compared. In patients eligible for any approach (n=90), MIE only (n=10), and no surgery (n=19), WHO performance status Grade 0 was observed in 66.7%, 20.0%, and 5.3%, respectively; stair climbing with ≥4 stairs was successfully completed in 77.8%, 50%, and 36.8%, respectively. Between any approach and MIE only groups, rate of major complications (Clavien-Dindo ≥3a) was 6.7% vs. 50.0% (p<0.001) without a difference in median hospital stay (9 vs. 10 days, p=0.542). Readmission rates were 4.4% vs. 30.0% (p=0.003). Survival rates were 100% vs. 80% (p<0.001) at 90-days, 91.5% vs. 66.7% (p=0.005) at 1-year, and 68.9% vs. 53.3% (p=0.024) at 3-years, respectively. In comparison between MIE only and no surgery groups, these survival rates from day of diagnosis were 80% vs. 100%, 68.6% vs. 67.1%, and 45.7% vs. 32.0% (p=0.290), respectively. By operating patients unsuitable for open approach with MIE, the resection rate increased 11.1%. These high-risk patients had, however, higher early morbidity and reduced long-term survival compared to other operated patients. Though there seems to be long-term benefit of surgery compared to nonsurgical patients, we have to be cautious when offering surgery to those considered unfit for open surgery. | Authentic |
We explored the effect of S100A12 gene on serum levels of anti-inflammatory/pro-inflammatory cytokines in septic rats by activating the extracellular signal-regulated kinase (ERK) signaling pathway. A total of 180 specific pathogen-free (SPF) rats were purchased to establish cecal ligation and puncture (CLP) model. Rats were assigned into the sham, model, empty vector, S100A12 siRNA, epidermal growth factor (EGF), and S100A12 siRNA + EGF groups. The expressions of S100A12, ERK-1, ERK-2, cPLA2, and NF-κB in liver tissues of rats among six groups were detected by RT-qPCR and western blotting. ELISA was used to determine serum levels of IL-1β, IL-10, TNF-α, procalcitonin (PCT), and C-reactive protein (CRP). Pearson correlation analysis was conducted to measure correlations. Cell apoptosis of rats among six groups was detected by Tunel staining. The expressions of S100A12, ERK-1, ERK-2, cPLA2, and NF-κB decreased in the S100A12 siRNA group while increased in the EGF group compared with the model group. S100A12 mRNA expression was positively correlated with mRNA expressions of related genes in the ERK signaling pathway (ERK-1, ERK-2, cPLA2, and NF-κB) in the model and empty vector groups. Expressions of IL-1β, IL-6, TNF-α, PCT, and CRP in the EGF group were higher than those in the model group, but were lower than those in the S100A12 siRNA group. Compared with the model group, cell apoptosis decreased in the S100A12 siRNA group but that increased in the EGF group. We demonstrates that S100A12 gene silencing decreases serum levels of anti-inflammatory/pro-inflammatory cytokines in septic rats by inhibiting the ERK signaling pathway. | Counterfeit |
Fibroblast growth factor receptor 4 (FGFR4) plays a critical role in cancer progression involving in tumor proliferation, invasion, and metastasis. This study clarified the role of FGFR4-Arg388 variant in gastric cancer (GC), and more importantly highlighted the possibility of this single nucleotide polymorphism (SNP) as potential therapeutic targets. FGFR4 polymorphism was characterized in advanced GC patients to perform statistical analysis. FGFR4-dependent signal pathways involving cell proliferation, invasion, migration, and resistance to oxaliplatin (OXA) in accordance with the SNP were also assessed in transfected GC cell lines. Among 102 GC patients, the FGFR4-Arg388 patients showed significantly higher tumor stage (p=0.047) and worse overall survival (p=0.033) than the Gly388 patients. Immunohistochemical results showed that FGFR4-Arg388 patients were more likely to have higher vimentin (p=0.025) and p-STAT3 (p=0.009) expression compared with FGFR4-Gly388 patients. In transfected GC cells, the overexpression of FGFR4-Arg388 variant increased proliferation and invasion of GC cells, increasing resistance of GC cells to OXA compared with cells overexpressing the Gly388 allele. The exploration mechanism may be through FGFR4-Arg388/STAT3/epithelial to mesenchymal transition axis regulating pivotal oncogenic properties of GC cells. The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC. | Counterfeit |
The purpose of this study is to explore the immunoregulatory role of microRNA-21 (miR-21) targeting of the TLR4/MyD88 signaling pathway in macrophages in response to Bacillus Calmette-Guerin (BCG) infection. After infection with BCG, mouse RAW246.7 cells were assigned into control, BCG, miR-21 mimic + BCG, mimic-negative control (NC) + BCG, miR-21 inhibitor + BCG, inhibitor-NC + BCG, BCG + TAK242 (an inhibitor of the TLR4 signaling pathway), and miR-21 inhibitor + TAK242 + BCG groups. Western blotting and qRT-PCR were used to detect the expression of miR-21, TLR4 and MyD88. The levels of TNF-a, IL-6 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Cell viability was measured using an MTT assay. Cell apoptosis and necrosis rates were detected using flow cytometry. Compared with the control group, miR-21 expression and levels of TNF-a, IL-6 and IL-10, as well as cell apoptosis and necrosis rates, were elevated, while expression of TLR4 and MyD88, as well as cell viability, were reduced in BCG infection groups. Compared with the BCG group, miR-21 expression was increased in the miR-21 mimic + BCG group but decreased in the miR-21 inhibitor + BCG and miR-21 inhibitor + TAK242 + BCG groups. The expression of TLR4 and MyD88, as well as the cell viability, were decreased, while levels of TNF-a, IL-6 and IL-10, as well as cell apoptosis and necrosis rates, were increased in the miR-21 mimic + BCG and TAK242 + BCG groups. The opposite trends were found in the miR-21 inhibitor + BCG group. Compared with the TAK242 + BCG group, the miR-21 inhibitor + TAK242 + BCG group had higher expression of TLR4 and MyD88 as well as higher cell viability and lower levels of TNF-a, IL-6, IL-10, cell apoptosis and necrosis rates. However, the miR-21 inhibitor + TAK242 + BCG group exhibited the opposite trends when compared with the miR-21 inhibitor + BCG group. Our results suggest that miR-21 can negatively modulate the TLR4/MyD88 signaling pathway, resulting in decreased cell viability, increased cell apoptosis and increased levels of inflammatory factors following BCG infection in macrophages. | Counterfeit |
While high-throughput drug screening offers possibilities to profile phenotypic responses of hundreds of compounds, elucidation of the cell context-specific mechanisms of drug action requires additional analyses. To that end, we developed a computational target deconvolution pipeline that identifies the key target dependencies based on collective drug response patterns in each cell line separately. The pipeline combines quantitative drug-cell line responses with drug-target interaction networks among both intended on- and potent off-targets to identify pharmaceutically actionable and selective therapeutic targets. To demonstrate its performance, the target deconvolution pipeline was applied to 310 small molecules tested on 20 genetically and phenotypically heterogeneous triple-negative breast cancer (TNBC) cell lines to identify cell line-specific target mechanisms in terms of cytotoxic and cytostatic drug target vulnerabilities. The functional essentiality of each protein target was quantified with a target addiction score (TAS), as a measure of dependency of the cell line on the therapeutic target. The target dependency profiling was shown to capture inhibitory information that is complementary to that obtained from the structure or sensitivity of the drugs. Comparison of the TAS profiles and gene essentiality scores from CRISPR-Cas9 knockout screens revealed that certain proteins with low gene essentiality showed high target addictions, suggesting that they might be functioning as protein groups, and therefore be resistant to single gene knock-out. The comparative analysis discovered protein groups of potential multi-target synthetic lethal interactions, for instance, among histone deacetylases (HDACs). Our integrated approach also recovered a number of well-established TNBC cell line-specific drivers and known TNBC therapeutic targets, such as HDACs and cyclin-dependent kinases (CDKs). The present work provides novel insights into druggable vulnerabilities for TNBC, and opportunities to identify multi-target synthetic lethal interactions for further studies. | Authentic |
Cancer heterogeneity impacts therapeutic response, driving efforts to discover over-arching rules that supersede variability. Here, we define pan-cancer binary classes based on distinct expression of YAP and YAP-responsive adhesion regulators. Combining informatics with in vivo and in vitro gain- and loss-of-function studies across multiple murine and human tumor types, we show that opposite pro- or anti-cancer YAP activity functionally defines binary YAPon or YAPoff cancer classes that express or silence YAP, respectively. YAPoff solid cancers are neural/neuroendocrine and frequently RB1-/-, such as retinoblastoma, small cell lung cancer, and neuroendocrine prostate cancer. YAP silencing is intrinsic to the cell of origin, or acquired with lineage switching and drug resistance. The binary cancer groups exhibit distinct YAP-dependent adhesive behavior and pharmaceutical vulnerabilities, underscoring clinical relevance. Mechanistically, distinct YAP/TEAD enhancers in YAPoff or YAPon cancers deploy anti-cancer integrin or pro-cancer proliferative programs, respectively. YAP is thus pivotal across cancer, but in opposite ways, with therapeutic implications. | Authentic |
Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs) gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell-precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable. | Authentic |
Long non-coding RNAs (lncRNAs) have been highlighted as prominent genetic modulators involved in multiple important biological processes of cancer cells, especially in esophageal cancer (EC). We tried to elucidate the potential role of LINC00337 in the progression of EC. Based on TCGA database analysis and Reverse transcription quantitative polymerase chain reaction determination, high expression of LINC00337 and FSCN1 was detected, while miR-145 exhibited a low expression in EC. LINC00337 was identified to bind to miR-145 to impair the miR-145-dependent FSCN1 inhibition. The underlying regulatory mechanisms were evaluated by transfection with LINC00337 overexpression plasmid, siRNA against LINC00337, miR-145 mimic, or anta-miR-145. Downregulation of LINC00337 results in increased Bax level, decreased FSCN1, Bcl-2, VEGF, and p53 levels, in addition to diminished cell proliferation, migration, invasion and tumor growth, with accelerated cell apoptosis by upregulating miR-145. Taken together, the findings obtained provided evidence suggesting that LINC00337 acts as a tumor promoter in EC, providing insight and advancements for EC treatment. | Counterfeit |
The canine transmissible venereal tumor (CTVT) is a clonally transmissible cancer that regresses spontaneously or after treatment with vincristine, but we know little about the regression mechanisms. We performed global transcriptional, methylation, and functional pathway analyses on serial biopsies of vincristine-treated CTVTs and found that regression occurs in sequential steps; activation of the innate immune system and host epithelial tissue remodeling followed by immune infiltration of the tumor, arrest in the cell cycle, and repair of tissue damage. We identified CCL5 as a possible driver of CTVT regression. Changes in gene expression are associated with methylation changes at specific intragenic sites. Our results underscore the critical role of host innate immunity in triggering cancer regression. | Authentic |
Two recent Lancet and Lancet Oncology papers report that cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have higher mortality rates. Common independent factors associated with increased risk of death were older age, history of smoking status, number of comorbidities, more advanced performance status, and active cancer. | Authentic |
Propofol, a kind of intravenous sedative drug, is certified that exerts anti-inflammation and antitumor functions. However, the influence of propofol in cerebral injury and the corresponding mechanism remains unexplained, that our article focuses on. PC12 cells were treated with propofol and exposed in glutamic acid (Glu) solutions. Cell viability, apoptotic potential, apoptosis-related and autophagy-linked proteins were tested via CCK-8, flow cytometry, and western blot assays. Reverse transcription-quantitative real-time PCR was utilized to test miR-19a expression in Glu-stimulated cells. Next, miR-19a mimic transfection was used to assess the effects of miR-19a on cell apoptosis and autophagy in Glu or propofol treated cells. Finally, western blot was performed to test AMPK and mTOR pathways. Glu exposure promoted cell apoptosis and autophagy of PC12 cells, while propofol attenuated cell apoptosis and autophagy triggered by Glu. Additionally, propofol decreased the miR-19a expression in Glu-stimulated PC12 cells. Meanwhile, over-expression of miR-19a reversed the effects of propofol on Glu-induced cell apoptosis and autophagy. Moreover, propofol potentiated AMPK and mTOR pathways in Glu-stimulated PC12 cells via impeding miR-19a expression. These finding revealed that propofol relieved Glu-triggered apoptosis and autophagy of PC12, and activated AMPK and mTOR pathways by suppressing miR-19a expression. | Counterfeit |
Zinc finger protein 667-antisense RNA 1 (ZNF667-AS1), a long non-coding RNA (lncRNA), plays important parts in tumorigenesis and development of esophageal squamous cell carcinoma, but its function in acute myeloid leukemia (AML) is unknown. Our goal here was to probe the functional mechanism of ZNF667-AS1 in AML by mediating microRNA-206 (miR-206)/A-kinase anchoring protein 13 (AKAP13) axis. The bone marrow samples from AML patients and controls were selected for microarray analysis to select significantly upregulated lncRNAs. Next, effects of ZNF667-AS1 on cell aggressiveness of AML were assessed after delivery of cells with siRNA against ZNF667-AS1. Subcellular fractionation location assay and FISH experiments were used to determine ZNF667-AS1 localization in cells. Dual-luciferase experiments detect the targeting relationships among ZNF667-AS1, miR-206 and AKAP13. Finally, tumor growth and metastasis were evaluated in vivo to determine the relevance of ZNF667-AS1/miR-206/AKAP13 axis. The expression of ZNF667-AS1 was upregulated in AML patients, which predicted poor prognosis. Downregulation of ZNF667-AS1 reduced cell proliferation, invasion, tumorigenesis and metastasis. miR-206 inhibitor reversed the repressive role of ZNF667-AS1 knockdown in cell proliferation, invasion and tumorigenesis, while AKAP13 silencing flattened the stimulative role of miR-206 inhibitor in AML malignant aggressiveness. Mechanistically, we demonstrated that ZNF667-AS1 functioned as a molecular sponge for miR-206. In addition, we observed that Wnt/β-catenin pathway was suppressed by ZNF667-AS1 knockdown. ZNF667-AS1 potentiated AML progression by targeting the miR-206/AKAP13 axis. This indicates ZNF667-AS 1 inhibition may act as a prospective therapeutic option for the treatment of AML. | Counterfeit |
Osteosarcoma (OS) is the most common form of bone malignancy in children and adolescents. A class of molecules known as microRNAs (miRNAs) have been routinely associated in the development and progression of OS. The present study was centered on the less well-known miRNA, miRNA (miR)-150, and its role in OS was investigated. The levels of miR-150 were examined in 40 tissue specimens from patients with OS and adjacent normal tissues using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. In addition the expression levels of miR-150 were examined in three OS cell lines and a normal osteoblast cell line. Cell proliferation, migration and invasion assays were performed to establish the correlation between miR-150 and metastasis. The potential targets of miR-150 were theoretically predicted and one high-scoring target, Rho-associated kinase 1 (ROCK1), was established to be a direct target using RT-qPCR and western blot analyses and Pearson's correlation analysis. The results indicated that miR-150 was downregulated in tissues from patients with OS and cell lines. Secondly, it was shown that the overexpression of miR-150 was inversely correlated with OS cell proliferation, migration and invasion. It was also shown that miR-150 negatively regulated the gene expression of ROCK1 in the OS cell lines. Finally, the interaction between miR-150 and ROCK1 was established and it was shown that miR-150 directly targeted ROCK1. In conclusion, miR-150 was found to be a tumor suppressor, and the suppression of miR-150 resulted in elevation in the levels of ROCK1. This interaction between miR-150 and ROCK1 may be key in the progression of OS. Furthermore, miR-150 or ROCK1 may be potential therapeutic targets for the treatment of OS. | Counterfeit |
Acne rosacea is a type of chronic dermatosis with the characteristics of erubescence, angiotelectasis and pustule formation. However, current treatment methods are limited due to the side effects. Artesunate demonstrated a promising therapeutic efficacy with a high safety margin. HaCaT cells were treated with antibacterial peptide LL‑37 to simulate rosacea caused by Demodex folliculorum (D. folliculorum) infection. Cell Counting kit 8 and flow cytometry assays were performed to measure cellular proliferation, apoptosis, the stage of the cell cycle and reactive oxygen species generation in order to determine the level of cell damage. Then the damaged cells were treated with different concentrations of artesunate and doxycycline to determine the therapeutic effect of artesunate. Pro‑inflammatory cytokines tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6, IL‑8 and C‑C motif chemokine 2 (MCP‑1) were measured using an ELISA, while western blotting was used to detect the expression of Janus kinase 2 (JAK2) and signal transducer and transcription activator (STAT3). As a result, LL‑37 treated HaCaT cells decreased in cell viability, had an increased apoptotic rate and cell cycle arrest, indicating that cell damage caused by rosacea was simulated. In addition, upregulated concentrations of the pro‑inflammatory cytokines TNF‑α, IL‑6, IL‑8 and MCP‑1 were attenuated in the artesunate group in a dose‑dependent fashion, indicating the therapeutic effect of artesunate. Furthermore, higher concentrations of artesunate exhibited an improved effect compared with the doxycycline group. In addition, increased expression levels of JAK2 and STAT3 following treatment with LL‑37 suggested that rosacea caused by D. folliculorum infection may lead to inflammation through the JAK/STAT signaling pathway. In conclusion, the potential mechanism by which damage occurs in rosacea was revealed and a promising therapeutic method against rosacea was demonstrated. | Counterfeit |
Evaluation of treatment and survival of pT1 stage (T1) bladder cancer (BC) patients diagnosed with transitional cell carcinoma of the urinary bladder in Norway. According to the Cancer Registry of Norway, 1,108 patients were diagnosed with T1 BC between 2008-2012. Information on surgical and medical procedures was provided by the Norwegian Patients Registry. Regression and survival models were applied to characterize patients receiving bacillus Calmette-Guerin (BCG) and radical cystectomy (RC) as early and delayed treatment and to estimate overall and cause specific survival rates (OS; CSS). Adjustments for sex, age, WHO grade and concomitant cis were made. In total, 449 (41%) patients received BCG treatment, 162 (15%) as early treatment. RC represented the early treatment in 96 (9%) patients and the delayed treatment in 84 (8%). Overall, 850 (77%) patients received neither BCG nor RC as early treatment, of whom 287 (26%) were treated with BCG and 66 (6%) with RC during follow-up. Patients <75 years and patients with high grade tumors or concomitant cis were more likely to receive BCG and RC as early treatment. 5-year survival rates for all T1 BC patients were 84% (CSS) and 65% (OS). Delayed RC was associated with the lowest 5-year CSS (70%). After adjustment, gender did not impact treatment choice and CSS. The use of BCG as early treatment indicates low adherence to existing guidelines. Delayed RC was associated with low survival rates. An increased focus on the management of T1 patients is needed in Norway. | Authentic |
Sex determining region Y-box protein 12 (SOX12) is essential for embryonic development and cell fate determination. The role of SOX12 in tumorigenesis of breast cancer is not well-understood. Here, we found that SOX12 mRNA expression was up-regulated in human breast cancer tissues. To clarify the roles of SOX12 in breast cancer, we used lentiviral small hairpin RNAs (shRNAs) to suppress its expression in two breast cancer cells with relatively higher expression of SOX12 (BT474 and MCF-7). Our findings strongly suggested that SOX12 was critical for cell migration and invasion of breast cancer cells. We found that silencing of SOX12 significantly decreased the mRNA and protein levels of MMP9 and Twist, while notably increased E-cadherin. Moreover, SOX12 knockdown significantly inhibited the proliferation of breast cancer cells in vitro and the growth of xenograft tumors in vivo Flow cytometry analysis revealed that breast cancer cells with SOX12 knockdown showed cell cycle arrest and decreased mRNA and protein levels of PCNA, CDK2 and Cyclin D1. Taken together, SOX12 plays an important role in growth inhibition through cell-cycle arrest, as well as migration and invasion of breast cancer cells. | Counterfeit |
The aim of this study was to evaluate the effect of SERPINB2 on cell proliferation, cell cycle, epithelial-mesenchymal transition (EMT), invasion, migration, and radiosensitivity in nasopharyngeal carcinoma cells. Both CNE2R and CNE2 cells were transfected with pEGFP-N1-SERPINB2. Cell proliferation was measured by MTT assay, cell cycle by flow cytometry, and SERpINB2 expression by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was carried out to detect the protein expression. In addition, SERPINB2 and β-catenin were located intracellularly using an immunofluorescent assay, and cell migration and invasion were measured by wound healing and Transwell assays, respectively. Radiosensitivity was assessed using colony formation and MTT assays. SERPINB2 expression was downregulated in CNE2R cells. After transfection with pEGFP-N1-SERPINB2, the OD values were decreased, and there was an increased fraction in the G2/M phase. Moreover, SERPINB2 overexpression could inhibit the invasion and migration capabilities of CNE2R and CNE2 cells, with downregulation of vimentin, N-cadherin, nuclear β-catenin, matrix metalloproteinase (MMP)-2 and MMP-9, and upregulation of E-cadherin. Moreover, transfection with the SERPINB2 plasmid reduced the growth rate of CNE2R cells at doses of 2, 4 and 6 Gy, and also decreased the surviving fractions. Overexpression of SERPINB2 could reduce the proliferation, invasion and migration capabilities of CNE2R and CNE2 cells, and led to G2/M arrest via EMT inhibition, and this may be a potential strategy for enhancing the radiation sensitivity of nasopharyngeal carcinoma cells. | Counterfeit |
Laryngeal squamous cell carcinoma (LSCC) is rare in the young. We characterized the clinical behavior of LSCC and assessed the presentation of second primary tumors (SPCs) in this patient population. Data from the Finnish Cancer Registry (FCR) were used to identify an epidemiological series of LSCC patients diagnosed at the age of 40 years or under, during 1953-2012 in Finland. Data regarding primary treatment, survival, and SPCs were available. To further characterize the comorbidity and lifestyle factors of young patients with LSCC, institutional data were collected of patients treated at the Helsinki University Hospital during 1967-2012. We identified 151 patients, with a mean follow-up of 252 months. The 10-year overall survival (OS) was 75% and the disease-specific survival was 84%. SPCs were diagnosed in 26% (n = 39), with a median delay of 28 years. Of the 35 patients in the institutional series from Helsinki, 22 (63%) were current or former smokers. LSCC recurred in 28% of patients. The delay to SPCs in young patients was significantly longer compared with the general LSCC population. As factors underlying this phenomenon cannot be identified by this retrospective study, further studies are warranted. | Authentic |
Curcumin, a primary active ingredient extracted from the Curcuma longa, has been recently identified as a potential anti-tumor agent in multiple kinds of cancers. However, the effect of curcumin on retinoblastoma (Rb) is still unclear. Therefore, we attempted to reveal the functional impacts and the underlying mechanisms of curcumin in Rb cells. Two Rb cell lines SO-Rb50 and Y79 were pre-treated with various doses of curcumin, and then cell proliferation, apoptosis, migration, and invasion were assessed, respectively. Further, regulatory effects of curcumin on miR-99a expression, as well as the activation of JAK/STAT pathway were studied. Data showed that curcumin significantly inhibited the viability, colony formation capacity, migration and invasion, while induced apoptosis of SO-Rb50 and Y79 cells. Up-regulation of miR-99a was observed in curcumin-treated cells. Curcumin suppressed the phosphorylation levels of JAK1, STAT1, and STAT3, while curcumin did not inhibit the activation of JAK/STAT pathway when miR-99a was knocked down. Curcumin inhibited proliferation, migration, invasion, but promoted apoptosis of Rb cells. The anti-tumor activities of curcumin on Rb cells appeared to be via up-regulation of miR-99a, and thereby inhibition of JAK/STAT pathway. | Counterfeit |
Poly (ADP-ribose) polymerase-1 (PARP-1) has been recognized as a prospective target for the development of novel cancer therapeutics. Several PARP-1 inhibitors are currently being considered for anticancer drug development and clinical investigation. Lately, natural compounds seem to be excellent alternative drug candidates for cancer treatment. Rauwolfia serpentina is a medicinal plant traditionally used in Indian subcontinents to treat various diseases. This study has been designed to identify the bioactive compounds derived from R. serpentina for possible binding and inhibition of PARP-1 using the molecular docking approach. Thirteen compounds were found to interact with the target with a binding affinity greater than the value of -9.0 kcal/mol. After screening the physicochemical properties, only 5 ligands (ajmalicine, yohimbine, isorauhimbine, rauwolscine, and 1,2-dihydrovomilenine) were found to obey all the parameters of Lipinski's rule of five, showed maximum drug-likeness, and possess no significant toxicity. These ligands displayed strong interactions with target PARP-1 via several hydrogen bonds and hydrophobic interactions. Therefore, these identified compounds derived from R. serpentina can be considered for drug development against cancer-targeting PARP-1. | Counterfeit |
Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs. | Authentic |
In this issue of Cancer Cell, Tao et al. provide compelling evidence that aging-like DNA methylation of multiple CpG islands, the CpG island methylator phenotype (CIMP), produces a cellular context that can tolerate BRAF activation avoiding senescence by dedicating 5-month culture of colon-derived organoids to epigenomic and stemness analysis. | Authentic |
Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes. | Authentic |
FOXA transcription factors are potent, context-specific mediators of development that hold specialized functions in hormone-dependent tissues. Over the last several years, FOXA1 has emerged as a critical mediator of nuclear steroid receptor signalling, manifest at least in part through regulation of androgen receptor and oestrogen receptor activity. Recent findings point towards a major role for FOXA1 in modulating nuclear steroid receptor activity in breast and prostate cancer, and suggest that FOXA1 may significantly contribute to pro-tumourigenic phenotypes. The present review article will focus on the mechanisms, consequence, and clinical relevance of FOXA1-mediated steroid nuclear receptor signalling in human malignancy. | Authentic |
Syndecan-binding protein (SDCBP) has been reported to critically process a core role in tumorigenesis. This study was conducted to characterize a novel regulatory network of SDCBP in gastric carcinoma (GC) cells. Our findings indicated that overexpression of SDCBP promoted the proliferation of GC cell and increased proliferating cell nuclear antigen (PCNA) expression. Moreover, the overexpression of SDCBP suppressed the apoptosis of GC cell along with a decrease of Bax/Bcl-2 ratio and induction of PI3K/AKT/mTOR activation. However, knockdown of SDCBP exhibited opposed effects on GC cells. Furthermore, silencing SDCBP significantly inhibited GC cell viability and PCNA expression accompanied with the upregulated cell apoptosis and Bax/Bcl-2 ratio, which was regulated by PI3K/AKT/mTOR signaling pathway. And it was further determined that PI3K inhibitor LY294002, AKT inhibitor Torin1, and mTOR inhibitor MK-2206 suppressed the apoptosis. In conclusion, SDCBP promotes the growth ability of GC by inducing the PCNA expression and inhibiting GC cell apoptosis via inactivation of the PI3K/AKT/mTOR pathway. | Counterfeit |
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, Western blot, real-time polymerase chain reaction (RT-PCR), and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-acetylantroquinonol B (4-AAQB), as evidenced by inhibited cell viability and proliferation, as well as attenuated migration, invasion, and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. Interestingly, 4-AAQB did not affect the viability and proliferation of normal colon cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates the FOLFOX (folinate (leucovorin), fluorouracil (5FU), and oxaliplatin) anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324, and inhibiting SOD2-mediated tumorigenicity. Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients. | Authentic |
Thyroid cancer is a commonly diagnosed endocrine malignancy with increasing incidence worldwide. Long noncoding RNAs (lncRNAs) are known to function in the invasion and metastasis of thyroid cancer. According to the GSE66783 microarray dataset, long intergenic nonprotein coding RNA 284 (LINC00284) is aberrantly upregulated in thyroid cancer tissues. However, information regarding the specific role of LINC00284 in thyroid cancer remains elusive. Therefore, the current study set out to determine the role of LINC00284 in the development of thyroid cancer, along with an investigation of the underlying molecular mechanism. In parallel with the microarray data from GSE66783, LINC00284 was observed to be expressed at high levels in thyroid cancer cell lines. Moreover, loss-of-function experiments revealed that the downregulation of LINC00284 reduced aldehyde dehydrogenase (ALDH) activity and thyroid cancer cell proliferation, colony formation, and invasiveness, which promoted cell apoptosis. Mechanistically, using dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays, LINC00284 was identified to competitively bind to microRNA-30d-5p (miR-30d-5p), which was observed to be expressed at low levels in thyroid cancer tissues and cells and directly targets the oncogene a disintegrin and metalloproteinase 12 (ADAM12). Overexpression of miR-30d-5p exerted tumor-suppressive effects on the malignant activity of thyroid cancer cells, changes that were reversed by LINC00284 overexpression or ADAM12 overexpression. Furthermore, LINC00284 activated the Notch signaling pathway by competitively binding to miR-30d-5p and increasing the expression of ADAM12. Finally, by performing in vivo experiments, we found that LINC00284 silencing or miR-30d-5p overexpression suppressed the tumorigenic ability of thyroid cancer cells and that overexpression of miR-30d-5p inhibited the LINC00284-induced tumorigenesis of thyroid cancer cells. Collectively, our findings indicate that LINC00284 competitively binds to miR-30d-5p and activates the ADAM12-dependent Notch signaling pathway, thereby promoting the development of thyroid cancer. | Counterfeit |
Increased glucose metabolism and uptake are characteristic of many tumors and used clinically to diagnose and monitor cancer progression. In addition to cancer cells, the tumor microenvironment (TME) encompasses a wide range of stromal, innate, and adaptive immune cells. Cooperation and competition between these cell populations supports tumor proliferation, progression, metastasis, and immune evasion. Cellular heterogeneity leads to metabolic heterogeneity because metabolic programs within the tumor are dependent not only on the TME cellular composition but also on cell states, location, and nutrient availability. In addition to driving metabolic plasticity of cancer cells, altered nutrients and signals in the TME can lead to metabolic immune suppression of effector cells and promote regulatory immune cells. Here we discuss how metabolic programming of cells within the TME promotes tumor proliferation, progression, and metastasis. We also discuss how targeting metabolic heterogeneity may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies. | Authentic |
The increased cancer risk among patients diagnosed with inflammatory bowel disease (IBD) is well reported, whereas studies regarding the cancer prognosis with IBD have shown conflicting results. We aimed at assessing and quantifying the cause-specific and overall mortality among cancer patients with IBD compared to those without IBD. The population-based Swedish registers were used to identify cancer patients diagnosed with or without IBD. We used a Cox regression model to estimate hazard ratios (HRs) for cause-specific and overall mortality, showing the probability of death in the study group compared to the reference. A total of 2462 cancer patients with IBD and 1,011,894 cancer patients without IBD were ascertained from 1964 to 2006, showing a significant survival disparity (overall HR, 1.26; 95% confidence interval [CI]: 1.20-1.33 versus cause-specific HR, 1.22; 95% CI: 1.15-1.29). Although worse overall cancer mortality with IBD was widely observed, the worse cause-specific mortality was only confined to colorectal cancer (CRC). There was no difference in TNM staging among cancer patients with or without IBD. Stratified analyses showed that a worse prognosis was more pronounced in younger patients (<60 years) and in men. Discordant malignant neoplasms and cardiovascular diseases were noted to be associated with increased mortality in the study group. Previously diagnosed IBD worsens the prognosis of cancers, especially for CRC. The more pronounced effect was noted among younger patients and in men. The underlying mechanisms warrant further investigation. | Authentic |
Two papers, published in Science and Nature, report inhibitiors selectively targeting distinct bromodomains of BET proteins. These advanced chemical tools facilitate functional understanding of epigenetic regulators in normal and disease states and enable development of new medicine potentially with lower toxicity. | Authentic |
Oncology patients may respond to radiation treatment with anxiety expressed as stress, fear, depression, and frustration. This study aimed to investigate effects of music intervention on reducing pre-radiotherapy anxiety in oncology patients. Quasi-experimental study with purposeful sampling was conducted in the Department of Radiation Oncology, at Far Eastern Memorial Hospital, Taipei, Taiwan. Subjects were assigned into a music group (n = 100) receiving 15 min of music therapy prior to radiation and a control group (n = 100) receiving 15 min rest prior to radiation. Both groups were evaluated for pre- and post-test anxiety using the State-Trait Anxiety Inventory. Physiological indicators of anxiety were measured pre- and post-test. Baseline State/Trait scores and vital signs were comparable between groups (P > 0.05). Mean change in pre- and post-test State/Trait scores showed significant decreases from baseline to post-test in both groups (all P < 0.05). A statistically significant difference was observed between music therapy and control groups in mean change of State anxiety scores (mean decreases 7.19 and 1.04, respectively; P < 0.001) and Trait anxiety scores (mean decreases 2.77 and 1.13, respectively; P = 0.036). In vital signs, both groups had significant decreases in pre- and post-test heart rate and respiration rate (P < 0.05). A statistically significant difference in mean change of systolic pressure was found between music and control groups (-5.69 ± 0.41 mmHg vs. -0.67 ± 1.29 mmHg, respectively; P = 0.009). Music therapy decreased State anxiety levels, Trait anxiety levels and systolic blood pressure in oncology patients who received the intervention prior to radiotherapy. | Authentic |
Signaling via the Akt serine/threonine protein kinase plays critical roles in the self-renewal of embryonic stem cells and their malignant counterpart, embryonal carcinoma cells (ECCs). Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. Phosphorylation of Oct4 by Akt resulted in dissociation of Oct4 from the AKT1 promoter, which activated AKT1 transcription and promoted cell survival. Therefore, a site-specific, posttranslational modification of the Oct4 protein orchestrates the regulation of its stability, subcellular localization, and transcriptional activities, which collectively promotes the survival and tumorigenicity of ECCs. | Authentic |
As with wide-spread use of prostate cancer (Pca) screening with prostate-specific antigen testing, overdetection has increasingly gained attention. The authors aimed to estimate absolute risk of overdetection (RO) in Pca screening with various interscreening intervals and ages at start of screening. We estimated age-specific preclinical incidence rates (per 100,000 person-years) for progressive cancer (from 128 for age group 55-58 years to 774 for age group 67-71 years) and nonprogressive cancer (from 40 for age group 55-58 years to 66 for age group 67-71 years), the mean sojourn time (7.72 years) and the sensitivity (42.8% at first screen and 59.8% at the second screen) by using a multistep epidemiological model with data from the Finnish randomized controlled trial. The overall number of screens for overdetection (NSO) was 29 (95% confidence interval (CI): 18, 48) for screenees aged 55-67 years, equivalent to 3.4 (95% CI: 2.1, 5.7) overdetected Pcas per 100 screenees. The NSO decreased from 63 (95% CI: 37, 109) at the first screen to 29 (95% CI: 18, 48) at the third screen and from 43 (95% CI: 36, 52) for age 55 years to 25 (95% CI: 8, 75) at age 67 years at the first screen. In conclusion, around 3.4 cases for every 100 screened men would be overdetected during three screen rounds (~ 13 years of follow-up) in the Finnish randomized controlled trial. Elucidating the absolute RO under various scenarios makes contribution for evaluating the benefit and harm of Pca screening. | Authentic |