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Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions., Cancer: Non-dividing tumor cells offer a promising therapeutic target Cancer cells that stop dividing but do not die help fuel tumor growth, and therapies that selectively eliminate or suppress these cells could reduce the risk of tumor recurrence and progression. A team from South Korea led by Hong Seok Kim from Inha University College of Medicine in Incheon and Tae Jun Park from Ajou University School of Medicine in Suwon review the cancer-promoting properties of tumor cells in irreversible cell cycle arrest, a state known as cellular senescence. They discuss how to identify these cells in cancer tissues and summarize the various drivers of senescence in the tumor microenvironment. Once established, the cells release local factors that both promote the invasiveness of nearby nonsenescent cancer cells and shield tumors from immune attack. Drugs that remove or modulate senescent tumor cells are now under investigation.

Central venous catheters (CVCs) are generally required for chemotherapy in patients with acute leukemia, but catheter-related infection is one of the common causes of neutropenic fever. We investigated the in-hospital mortality according to early removal of CVCs and the factors influencing the mortality in patients with acute leukemia undergoing remission induction chemotherapy. This study retrospectively analyzed the hospital record data of 278 patients with acute leukemia treated with non-tunneled CVCs and remission induction chemotherapy in a single institution. Bloodstream infection was more common (p

Yeo Jin Choi,1,* Yong Won Choi,2,* Jung-woo Chae,3,* Hwi-yeol Yun,3 Sooyoung Shin4,5 1Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea; 2Department of Hematology-Oncology, School of Medicine, Ajou University, Suwon, Gyeonggi-do, 16499, Republic of Korea; 3College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea; 4College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, 16499, Republic of Korea; 5Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, Gyeonggi-do, 16499, Republic of Korea*These authors contributed equally to this workCorrespondence: Sooyoung Shin; Hwi-yeol Yun Tel +82 31 219 3456; +82 42 821 5941Fax +82 31 219 3435; +82 42 823 6566Email syshin@ajou.ac.kr; hyyun@cnu.ac.krBackground: Cancer patients are at increased risk for venous thromboembolism (VTE) due to cancer-induced hypercoagulability. However, current guidelines do not routinely recommend prophylactic use of oral anticoagulants to prevent VTE in cancer patients.Objective: To evaluate the efficacy and safety of novel oral anticoagulants (NOACs) versus no anticoagulant use (no-use) and, additionally, differential effects between NOACs and warfarin, in VTE and adverse bleeding prevention among cancer patients, in consideration of risk stratification by gender, high-risk chemotherapy exposure, and Khorana index.Methods: This national health insurance data-based study with a 180-day follow-up enrolled cancer patients with or without oral anticoagulant use in 2017. The primary outcome was VTE risk in oral anticoagulant users vs non-users. Four propensity score-matched comparison pairs were designed: use vs no-use, NOAC vs no-use, warfarin vs no-use, and NOAC vs warfarin. A logistic regression model was used to investigate between-group differences in VTE and bleeding risk.Results: When compared to no-use, NOACs showed substantial effects in preventing VTE complications (OR=0.40, p< 0.001), primarily deep vein thrombosis (DVT) events (OR=0.38, p< 0.001), in both male and female cancer patients as well as those with a Khorana score ≥ 1. Adverse bleeding risk was comparable or lower in NOAC-receiving female patients (p=0.13) and male patients (p=0.04), respectively. In contrast, no protective effects were found with warfarin compared to no-use in controlling thrombosis and adverse bleeding risk. In a head-to-head comparison of NOACs versus warfarin, DVT risk in those patients exposed to high-risk chemotherapy was significantly decreased with NOAC use (OR=0.19, p=0.03).Conclusion: NOACs can be a promising thromboprophylactic option in both male and female cancer patients with VTE risk.Keywords: venous thromboembolism, cancer, oral anticoagulant, Khorana

Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use, then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes, however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p &lt, 0.001) and death (OR 0.13, p &lt, 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes.

B-RafV600E oncogene mutation occurs in various cancers and is associated with tumor initiation. However, genetic modification of B-RafV600E in cells induces MAPK activation and results in oncogene-induced senescence. Overcoming the oncogene-induced senescence by B-RafV600E requires activation of another oncogene pathway, such as AKT signaling. In the present study, we explored the factors involved in overcoming the senescence program in cells activated by B-RafV600E and AKT signaling. B-RafV600E activation caused a feedback inhibition of AKT phosphorylation and resulted in downregulation of FoxM1, one of the AKT downstream components. AKT activation by PTEN downregulation induced FoxM1 expression, and co-expression of B-RafV600E and FoxM1 overcame the cellular senescence. These observations suggested that FoxM1 is critical downstream gene of AKT and functions to overcome B-RafV600E-induced senescence.

Lymphangiomas are rare benign congenital lymphatic malformations. They can be divided into three groups: cutaneous lymphangioma circumscriptum (CLC), cavernous, and cystic. CLC is the most common type, and rarely occurs with cavernous or cystic lymphangioma under the lesion. Here, we describe the case of a 9-year-old girl who presented with an asymptomatic vesicular lesion on her back. She was finally diagnosed with CLC by clinical manifestations, dermoscopic findings, and histologic findings. Seven years ago, there was a history of surgical operation in the department of general surgery, and the surgery was soft tissue cystic lymphangioma removal surgery. There was no skin lesion for seven years after surgery, but one occurred a month ago. Herein, we present a case of CLC that occurred after a long interval after surgery for soft tissue cystic lymphangioma.

Chlorpheniramine maleate is commonly used antihistamine. Since antihistamines are the main therapeutic agents for symptomatic treatment of urticaria, anaphylaxis to antihistamines may lead to errors in diagnosis and treatment. We report a case of anaphylaxis induced by chlorpheniramine maleate confirmed by intradermal test. A 35-year-old female experienced history of anaphylaxis after intramuscular injection of chlorpheniramine maleate. Skin prick test was negative, but intradermal test was positive. Patient also experienced mild dizziness after intradermal test and refused to perform any further evaluation such as oral challenge test. Anaphylaxis for chlorpheniramine maleate is very rare but should be considered.

Although the proteasome inhibitor (PI) bortezomib (Btz) is in current clinical use as a front-line treatment for multiple myeloma, its clinical efficacy in solid tumors has not been satisfactory. Here, we show that loperamide (Lop), an antidiarrheal drug, effectively sensitizes various colon cancer cells, but not normal epithelial cells, to PI-mediated cell death. We report that combined treatment with Btz and Lop induces paraptosis-like cell death accompanied by severe endoplasmic reticulum (ER)-derived vacuolation. Furthermore, Lop potentiates Btz-mediated ER stress and ER dilation due to misfolded protein accumulation and Ca2+ imbalance, leading to CHOP upregulation and subsequent paraptosis-like cell death. Taken together, our results show for the first time that a combined regimen of PI and Lop may provide an effective and safe therapeutic strategy against solid tumors, including colon cancer, by enhancing the sensitivity to PIs and reducing the side effects of such treatment.

Background Since the results of the ToGA trial were published, trastuzumab-based chemotherapy has been used as the standard first-line treatment for HER2-positive recurrent or primary metastatic gastric cancer (RPMGC). However, the real-world data has been rarely reported. Therefore, we investigated the outcomes of trastuzumab-based chemotherapy in a single center. Methods This study analyzed the real-world data of 47 patients with HER2-positive RPMGC treated with trastuzumab-based chemotherapy in a single institution. Results With the median follow-up duration of 18.8 months in survivors, the median overall survival (OS) and progression-free survival were 12.8 and 6.9 months, respectively, and the overall response rate was 64%. Eastern Cooperative Oncology Group performance status 2 and massive amount of ascites were independent poor prognostic factors for OS, while surgical resection before or after chemotherapy was associated with favorable OS, in multivariate analysis. In addition, 5 patients who underwent conversion surgery after chemotherapy demonstrated an encouraging median OS of 30.8 months, all with R0 resection. Conclusions Trastuzumab-based chemotherapy in patients with HER2-positive RPMGC in the real world demonstrated outcomes almost comparable to those of the ToGA trial. Moreover, conversion surgery can be actively considered in fit patients with a favorable response after trastuzumab-based chemotherapy.

Background Although combination chemotherapy (CC) is generally recommended in recurrent or primary metastatic gastric cancer (RPMGC), the results of randomized trials are conflicting. Methods A retrospective review was conducted on 687 RPMGC patients who received palliative chemotherapy. We compared the overall survival (OS) between CC and single-agent chemotherapy (SC) among these patients, and we analyzed the clinicopathological characteristics affecting outcome including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Results Although 521 patients (75.8%) underwent CC, SC was more frequently performed in elderly patients (57.6%) and ECOG performance status (PS) 2 or 3 (65.8%) patients (p p p = 0.583), poor PS (p = 0.810), signet ring cell (p = 0.347), palliative surgical resection (p = 0.307), and high PLR (p = 0.120), with a significant interaction between age and type of regimen (p = 0.012). Moreover, there was no difference in OS between CC and SC after propensity score matching (p = 0.322). Multivariate analysis revealed that palliative resection and ≥ second-line chemotherapy were independently associated with favorable OS (p p = 0.004), signet ring cell (p p = 0.04), high NLR (p = 0.001), and high PLR (p = 0.033) were independent prognostic factors of poor OS. Conclusions Although CC is the standard of care in RPMGC, SC can be considered a reasonable option in certain subgroups, such as elderly patients.

Exon 19 deletion and L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are both common mutations that predict a good response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the existence of clinically significant difference in sensitivity to EGFR tyrosine kinase inhibitors among different EGFR mutation subtypes is still a matter of debate.The outcome of 60 EGFR mutation-positive advanced NSCLC patients who received first-line gefitinib therapy (250 mg/d) was retrospectively analyzed according to EGFR mutation subtypes.The median progression-free survival (PFS) and overall survival (OS) after the initiation of gefitinib therapy for all patients was 11 and 26 months, respectively. Univariate analysis showed that patients with exon 19 deletion (n=28) had significantly longer median PFS (20 vs. 8 mo, P=0.004) and OS (36 vs. 22 mo, P=0.001) compared with those with L858R mutation (n=25) and uncommon or dual mutations (n=7). Multivariate analysis revealed that exon 19 deletion (P=0.007) was an independent prognostic factor of favorable PFS, with an independent association with poor PFS of male sex (P=0.049). Exon 19 deletion was also independently associated with favorable OS (P0.0001), whereas male sex (P=0.004) and primary metastatic disease (P=0.032) were independent prognostic factors of poor OS.The EGFR exon 19 deletion was associated with favorable PFS and OS in patients receiving first-line gefitinib treatment. The EGFR mutation subtype should be considered when making treatment decision or designing clinical trials for chemotherapy-naive, EGFR mutation-positive advanced NSCLC patients.

The predictive significance of osteolysis-related proteins was evaluated in bortezomib-treated multiple myeloma. The clinicopathological characteristics were collected retrospectively. Immunohistochemistry was performed for analyzing receptor activator of NF-κB ligand (RANKL), osteoprotegerin (OPG), macrophage inflammatory protein 1 alpha (MIP1α), and dickkopf-1 (DKK1) expression. Among clinicopatholgical characteristics, osteolytic lesion was associated with higher response to bortezomib treatment (79% vs. 46%). High DKK1 expression was significantly correlated with osteolytic lesion (

Background: Histamine in food is known to cause food poisoning and allergic reactions. We usually ingest histamine in cooked food, but there are few studies about the influence of cooking method on the histamine level. Objective: The purpose of this study was to determine the influence of cooking methods on the concentration of histamine in foods. Methods: The foods chosen were those kinds consumed frequently and cooked by grilling, boiling, and frying. The histamine level of the food was measured using enzyme-linked immunosorbent assay. Results: Grilled seafood had higher histamine levels than raw or boiled seafood. For meat, grilling increased the histamine level, whereas boiling decreased it. For eggs, there was not much difference in histamine level according to cooking method. Fried vegetables had higher histamine levels than raw vegetables. And fermented foods didn’t show much difference in histamine level after being boiled. Conclusion: The histamine level in food has changed according to the cooking method used to prepare it. Frying and grilling increased histamine level in foods, whereas boiling had little influence or even decreased it. The boiling method might be helpful to control the effect of histamine in histamine-sensitive or susceptible patients, compared with frying and grilling. (Ann Dermatol 29(6) 706∼714, 2017)

GPR119 belongs to the G protein-coupled receptor family and exhibits dual modes of action upon ligand-dependent activation: pancreatic secretion of insulin in a glucose-dependent manner and intestinal secretion of incretins. Hence, GPR119 has emerged as a promising target for treating type 2 diabetes mellitus without causing hypoglycaemia. However, despite continuous efforts by many major pharmaceutical companies, no synthetic GPR119 ligand has been approved as a new class of anti-diabetic agents thus far, nor has any passed beyond phase II clinical studies. Herein, we summarize recent advances in research concerning the physiological/pharmacological effects of GPR119 and its synthetic ligands on the regulation of energy metabolism, and we speculate on future applications of GPR119 ligands for the treatment of metabolic diseases, focusing on non-alcoholic fatty liver disease.

An exon 19 deletion and a L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are the two most common mutations that predict favorable efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Many retrospective and prospective studies, as well as meta-analyses including patients with NSCLC with various lines of EGFR TKI treatment, have demonstrated longer progression-free survival and sometimes more favorable overall survival in patients with an exon 19 deletion than those with the L858R or other mutations. In contrast, some clinical studies, including phase III trials, have demonstrated no difference in the efficacy of EGFR TKIs according to the EGFR mutation type. Therefore, the existence of clinically significant differences in sensitivity to EGFR-TKIs among different EGFR mutation subtypes remains controversial. In this review, we summarize the evidence suggesting different outcomes according to the type of EGFR mutation in patients with advanced NSCLC who were treated with EGFR-TKIs, along with their clinical significance. We also discuss possible mechanisms that can explain the different sensitivities to EGFR TKIs between cases with an exon 19 deletion and those with the L858R mutation.

This study was performed to investigate the modulatory effects of two prototypes of Panax ginseng saponin fractions, 20(S)-protopanaxadiol saponins (PDS) and 20(S)-protopanaxatriol saponins (PTS), on the induction of inflammatory mediators in lipopolysaccharide (LPS)-treated RAW264.7 murine macrophage cells. For this purpose, RAW264.7 cells were treated with LPS (10 μg/ml) before, after, or simultaneously with PDS or PTS (150 μg/ml), and the released level of nitric oxide (NO) and expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were evaluated. When RAW264.7 cells were treated with LPS and ginseng saponin fractions simultaneously for 24 hr, PTS, compared to PDS, more strongly attenuated the NO production induced by LPS treatment. When the cells were pretreated with LPS for 2 hr followed by PDS or PTS treatment for 24 hr, both ginseng saponins strongly reduced NO release. The pretreatment of RAW264.7 cells with PDS or PTS for 2 hr followed by LPS treatment for 24 hr significantly attenuated the LPS-induced production of NO. PTS showed stronger inhibitory potency to NO generation than PDS. Our western blot experiment showed that both PDS and PTS (150 μg/ml) also significantly down-regulated the expressions of iNOS and COX-2 induced by LPS treatment. Our results suggest that both PDS and PTS possess strong protective effects against LPS-stimulated inflammation and that their protective effects are mediated by the suppression of NO synthesis via down-regulation of pro-inflammatory enzymes, iNOS, and COX-2 in the RAW264.7 cells.

B-Raf

The role of palliative surgical resection in recurrent or metastatic gastric cancer is still controversial. A retrospective review was conducted on 689 patients who received palliative chemotherapy for recurrent (n = 307) or primary metastatic (n = 382) gastric cancer. Among 131 patients (89 primary metastatic and 42 recurrent) with surgical resection before chemotherpay, 75 underwent gastrectomy, 42 metastasectomy, and 14 gastrectomy with metastasectomy. The median overall survival (OS) of patients who underwent surgical resection was significantly longer than that of patients who received chemotherapy alone (18 vs. 9 months, p p p p pensity score matching. In addition, the median OS of patients who underwent gross complete resection (n = 54) was significantly longer than that of patients who underwent incomplete resection (n = 77) (30 vs. 15 months, p = 0.002). The present study suggests that judicious use of surgical resection before chemotherapy in recurrent or metastatic gastric cancer patients may result in a favorable outcome, especially when complete resection is achievable.

Highly dense and highly crystalline vanadium dioxide (VO 2 ) thermochromic thin films were successfully sputter-deposited on glass substrates at a low substrate temperature of 300 °C. By superimposition of RF and DC magnetron sputtering, we were able to fabricate VO 2 films with high solar transition efficiency (△T sol ) of 12.8% at a substrate temperature of 300 °C, which was comparable to the results attained at 450 °C by conventional DC sputtering. The VO 2 crystallization at a lower temperature of 300 °C could be achieved using a high-energy and high-density plasma induced by RF-superimposed DC sputtering. The hysteresis curves of transmittance as a function of temperature revealed that the VO 2 films by RF-superimposed DC sputtered at 300 °C exhibited a reduced transition temperature of 59 °C and a narrow hysteresis width of 3 °C. The enhanced transition properties might result from the compressive stress in the b and c axes as well as the densification of the films due to ion bombardment effect.

Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis. We experienced a case of recurrent ACC with stomach metastasis which had been completely cured a long while ago. A 52-year-old man who presented with right thigh pain was hospitalized. We found a lumbar spine mass on magnetic resonance imaging scan. And this lesion was identified as metastatic adrenocortical carcinoma. The patient had been treated as stage II non-functioning ACC 19 years ago. At that time radical resection and adjuvant chemotherapy were successfully done. And the follow-up evaluation was discontinued, since it had been checked as no evidence of disease (NED) state for 5 years. But this time, there were multiple metastatic sites revealed in positron emission tomography– computed tomography scan including stomach. Therefore, we report a case of ACC herewith that it could be recurred even though long-term NED state was passed after treatment and stomach could be a metastatic site of ACC.

The prognostic significance of Bcl-2, Bcl-6, p53, topoisomerase II, and β-tubulin expression was evaluated in diffuse large B-cell lymphoma (DLBCL) patients treated with cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab. Eight-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.001) of patients with high Bcl-2 expression were significantly inferior to those of patients with low expression without prognostic significance of Bcl-6, p53, topoisomerase II, and β-tubulin expression. High expression of Bcl-2 was associated with poor PFS (P = 0.045) and OS (P = 0.004) only in patients with low international prognostic index (IPI). In multivariate analysis, high expression of Bcl-2 was a significant independent prognostic factor of poor PFS (P = 0.026) and OS (P = 0.007) along with high IPI. In conclusion, the expression of Bcl-2 may be a useful prognostic factor, especially in DLBCL patients with low IPI.

Background Rosacea is associated with chronic systemic disease. However, research is lacking in Asian countries. Objective To evaluate the association between rosacea and cardiovascular diseases (CVDs) related systemic comorbidities, and the use of antihypertensive and antihyperlipidemic drugs in Korea. Methods A five-year retrospective study, using hospital database, was conducted in five medical centers for five years. Totally 1,399,528 patients were evaluated. Results The overall frequency for diagnosed rosacea was 0.18% over five years (2,536 rosacea patients). Patients with diabetes and patients with dyslipidemia were more likely to have rosacea (odd ratio [OR] 2.724, 95% confidence interval [CI] 1.295~5.730, p=0.016; OR 1.788, 95% CI 1.445~2.212, p

Post-burn pruritus is a common and distressing sequela of burn scars. Empirical antipruritic treatments usually fail to have a satisfactory outcome because of their limited selectivity and possible side effects. Therefore, novel drug targets need to be identified. Here, we aimed to investigate the possible role of protease-activated receptor 2 (PAR2) and transient receptor potential vanniloid 3 (TRPV3), along with the relation of TRPV3 to thymic stromal lymphopoietin (TSLP). Specimens from normal (unscarred) or burn-scarred (with or without pruritus) tissue were obtained from burn patients for this study. In each sample, the keratinocytes were isolated and cultured, and the intracellular Ca2+ level at the time of stimulation of each factor was quantified and the interaction was screened. PAR2 function was reduced by antagonism of TRPV3. Inhibiting protein kinase A (PKA) and protein kinase C (PKC) reduced TRPV3 function. TSLP mRNA and protein, and TSLPR protein expressions, increased in scars with post-burn pruritus, compared to scars without it or to normal tissues. In addition, TRPV1 or TRPV3 activation induced increased TSLP expression. Conclusively, TRPV3 may contribute to pruritus in burn scars through TSLP, and can be considered a potential therapeutic target for post-burn pruritus.

Hard disk drive was first introduced in 1956 by IBM with the appearance of IBM Model 350 disk storage, which was shipped IBM 305 RAMAC system [1] . Since then the capacity of hard drives has grown exponentially. When hard drives became available for personal computers, they were offered with 5 megabyte capacity. During the mid-1990s the typical hard disk drive for a PC had a capacity of about 1 gigabyte. As of January 2012, desktop hard disk drives typically had a capacity of 500 to 2000 gigabytes while the largest-capacity drives had up to 4 terabytes. With the performance and capacity of HDDs reaching their peaks and technology advancing by day, HDD manufacturers now focus their strategy towards making preoccupancy in the market to induce greater profit. It is important to meet the product development stage deadline tightly and start mass-production early. More often than not, manufacturers face performance quality issues as the mass production approaches and it is very desirable that such issues are dealt without time-consuming mechanical and electronic hardware changes. This paper proposes a method of enhancing unlatch performance of HDD at low temperature environment without hardware changes using TRIZ. Problem Analysis was used to break down and pinpoint the problematic area and Resource Analysis was used to find the solution. The solution utilizes already existent system resources and test results show no undesirable side effects, which makes the proposed method a cost-effective solution for mass-production stage or quality assurance stage just before the production. With little affect in the life of related mechanical components, authors were able to reduce the number of defective drives from low temperature unlatch test by great difference.

B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E–induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E–induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E–induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3β, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E–induced papillary thyroid carcinogenesis.