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The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

Background: Bone morphogenetic protein-7 (BMP-7) is a transforming growth factor-β superfamily member. We examined whether BMP-7 expression in thymic epithelial tumors is associated with their clinicopathological features., Methods: One hundred and thirty-two clinical specimens were analyzed in this study. The expression of BMP-7 was detected using immunohistochemistry and was scored as 0, 1, 2, or 3 according to its intensity and was then classified as negative (score 0 and 1) or positive (2 and 3). In addition, Ki-67 staining was performed in type B3 thymoma and thymic cancer., Results: The positive ratio of BMP-7 was 80% in thymic cancer and 70% in thymoma type B3. In contrast, the positive ratios of BMP-7 in type B2 (29.1%), B1 (3.7%), AB (26%), and A (31%) were relatively low. The mean Ki-67 labeling index of the BMP-7 positive group (10.1%±5.9%) was significantly higher than that of the BMP-7 negative group (4.9%±5.9%) in type B3 thymoma and thymic cancer (P=0.012). The BMP-7 positive group showed significantly poorer overall survival (OS) than the BMP-7 negative group across all patients with thymic epithelial tumors and in all types of thymomas (P=0.006, P=0.018); however, no difference was observed in thymic cancers., Conclusions: This study showed that high expression of BMP-7 correlated with a poor prognosis in patients with thymic epithelial tumors, and the expression of BMP-7 was higher in type B3 thymomas and thymic cancers than in other types of thymomas. BMP-7 might serve as a novel prognostic biomarker for thymic epithelial tumors., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Background: In the current lung cancer tumor-node-metastasis classification, solid tumor size is used for tumor diameter measurement as the dense component. However, measuring solid tumor size is sometimes difficult and inter-observer variability may increase, particularly in part-solid nodules with ground-glass opacity (GGO). This study aimed to investigate inter-observer size measurement variability in lung adenocarcinoma., Methods: Of 47 patients with part-solid lung adenocarcinoma who had undergone surgery at our department from January to December 2016, five surgeons and one radiologist undertook unidimensional solid and total size tumor measurements using pre-operative axial computed tomography images, and we assessed inter-observer size measurement variability. Variability was then subclassified into five groups, according to computer tomography-identified tumor morphological characteristics, namely: (I) minimally invasive; (II) peribronchovascular; (III) spiculation/atelectasis; (IV) adjacent to cystic lesion, and; (V) diffuse consolidation and GGO., Results: The mean inter-observer variability was 9.7 mm (solid size) and 7.7 mm (total size). Analysis of the maximum and minimum measurement size values for each patient undertaken showed that the most experienced surgeon and the radiologist measured the minimum size more frequently. To correct for differences in mean tumor diameter in each group, a comparison was made using a coefficient of variation (CV) calculated as the ratio of the standard deviation to the mean. Group I characteristics showed the largest coefficient value for variation in solid size measurement., Conclusions: Inter-observer measurement variability for solid size was larger than for total size in lung adenocarcinoma. Large variability in group I indicated the difficulty of size measurement for low-grade malignant potential nodules such as adenocarcinoma in situ, minimally invasive adenocarcinoma, and early-stage invasive adenocarcinoma. The possibility of unavoidable size measurement variability should be recognized when deciding on surgical procedures for these diseases., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Pemetrexed (MTA) is a folate antimetabolite used for treating non-small cell lung cancer. To elucidate the mechanisms of pemetrexed resistance in lung cancer, we established pemetrexed-resistant sublines in PC9 (mutant EGFR ) and H1993 (wild-type EGFR ) lung adenocarcinoma cell lines (PC9-MTA, H1993-MTA). Gene expression profile comparison by microarray analyses revealed enhanced fibroblast growth factor 2 (FGF2) and FGF receptor 1 (FGFR1) expression, confirmed by Western blotting, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction. ERK phosphorylation was increased in PC9-MTA but decreased in H1993-MTA along with decreased downstream signaling molecule phosphorylation. Cellular morphological change from epithelial to spindle-shape together with increased mesenchymal marker protein expression was observed in H1993-MTA. SiRNA-mediated FGF2 knockdown partially restored pemetrexed sensitivity in both lines, whereas anti-FGFR1 inhibitor PD173074 restored pemetrexed sensitivity in PC9-MTA. FGF2 or FGFR1 inhibition decreased pERK levels in PC9-MTA but increased pEGFR levels together with downstream signaling molecule activation and reversed epithelial-mesenchymal transition marker protein expression in H1993-MTA. Although thymidylate synthase strongly facilitates the development of pemetrexed resistance, our results reveal involvement of the FGF2-FGFR1 pathway in pemetrexed resistance in lung cancer cells and suggest that cellular function alterations induced by FGF2-FGFR1 pathway activation depend on the innate feature of cancer cells., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Objective: The purpose of this study is to elucidate the outcomes after surgical resection of Masaoka stage III-IV thymic epithelial tumors., Methods: We retrospectively reviewed patients with Masaoka stage III-IV thymic epithelial tumor who underwent surgical resection from January 1995 to January 2017. The clinicopathological features, surgical procedures, and postoperative outcomes were investigated., Results: Thirteen patients with thymoma and 18 patients with thymic carcinoma were assessed. The postoperative Masaoka stages were III/IVa/IVb = 8/4/1 in thymoma and III/IVa/IVb = 11/2/5 in thymic carcinoma. In patients with thymoma, the World Health Organization pathological subtypes were A/B1/B2/B3 = 2/1/4/6. We performed combined resection and reconstruction for brachiocephalic vein or superior vena cava in 3 patients with thymoma and 7 patients with thymic carcinoma. In all patients, the patency rate of the grafts was very low for the left brachiocephalic vein and well maintained for the right brachiocephalic vein. Macroscopically and pathologically complete resection was achieved in 11 and 6 patients with thymoma, respectively, and in 15 and 9 patients with thymic carcinoma, respectively. The 10-year survival rates were 85.7% in thymoma and 70.3% in thymic carcinoma. Postoperative recurrences were observed in 2 and 9 patients with thymoma and thymic carcinoma, respectively. Recurrences were observed within 5 and 10 years after surgery in 2 patients with thymoma and within 2 years in all patients with thymic carcinoma., Conclusions: Patients with Masaoka stage III-IV thymic epithelial tumor showed relatively favorable long-term survival after surgical treatment. Therefore, aggressive surgical resection for complete resection may be a treatment option for these conditions.

Improved prognosis for triple-negative breast cancer (TNBC) has currently plateaued and the development of novel therapeutic strategies is required. Therefore, we aimed to explore the anti-tumor effect of eribulin and paclitaxel combination therapy for TNBC. The effect of eribulin and paclitaxel in combination was tested, with both concurrent and sequential administration, using four TNBC cell lines (MDA-MB-231, Hs578T, MDA-MB-157, and Mx-1) in vitro and in an MDA-MB-231 BALB/c-nu/nu mouse xenograft model. The expression of epithelial-mesenchymal phenotypic markers was analyzed by western blotting and immunohistochemical analyses. Simultaneous administration of eribulin and paclitaxel resulted in a synergistic anti-tumor effect with MDA-MB-231 and Hs578T cells, but not MDA-MB-157 and Mx-1 cells, in vitro . Moreover, pre-treatment with one drug significantly enhanced sensitivity to the subsequently administrated second drug in MDA-MB-231 and Hs578T cells. Eribulin increased E-cadherin expression and decreased the expression of mesenchymal markers in MDA-MB-231 and Hs578T cells. In contrast, paclitaxel increased the expression of mesenchymal markers. When epithelial-mesenchymal transition was induced by TGF-β1, eribulin sensitivity was enhanced. In contrast, a TGF-β receptor kinase inhibitor decreased eribulin sensitivity. In MDA-MB-231 tumor-bearing mice, concurrent administration of low doses of eribulin and paclitaxel significantly inhibited tumor growth compared to that with either monotherapy. Moreover, single administration of eribulin before the initiation of paclitaxel treatment decreased vimentin expression and reduced the average tumor volume in a mouse xenograft model. Eribulin and paclitaxel show synergistic anti-tumor effect by altering the epithelial-mesenchymal phenotype. This combination therapy could represent a novel therapeutic strategy for TNBC., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Primary lung cancer is the most frequent cause of cancer-related deaths worldwide. Cisplatin has been used as a key drug in the treatment for patients with lung cancer; however, most of the patients failed to respond to cisplatin within several months, and the mechanisms underlying the cisplatin resistance have not been fully elucidated. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein in the formation of inflammasomes. ASC is also involved in apoptotic signaling. Importantly, ASC expression is decreased in lung cancer and various cancers, but its precise function in tumor progression remains unknown. To explore the hitherto unknown role of ASC in lung cancer, we initially searched for lung cancer cell lines with higher expression levels of ASC using Cancer Cell Line Encyclopedia (CCLE) database, thereby identifying the A549 human non-small cell lung cancer cell line. Accordingly, with retroviral shRNA, the expression of ASC was forced to decrease in A549 cells. Stable ASC-knockdown cells, thus established, showed the increased activities of proliferation, motility, and invasion, compared with control cells. Importantly, ASC-knockdown cells also became resistant to cisplatin, but not to other anti-cancer agents, 5-fluorouracil and paclitaxel. Bcl-2 and phospho-Src levels were increased in ASC-knockdown cells. A Bcl-2 inhibitor, ABT-199, induced an apoptotic response in ASC-knockdown cells, and dasatinib, a Src inhibitor, blocked cell invasiveness. Thus, ASC may be involved in tumor suppression and cell death via Bcl-2 and pSrc. Targeting Bcl-2 and Src in ASC-downregulated populations of lung cancer may improve treatment outcome.

Critical limb ischemia (CLI) is the most severe complication of peripheral arterial disease (PAD). Understanding the molecular mechanisms underlying tissue repair after CLI is necessary for preventing PAD progression. Y-box binding protein-1 (YB-1) regulates the expression of many genes in response to environmental stresses. We aimed to determine whether YB-1 is involved in ischemic muscle regeneration. A mouse ischemic hind-limb model was generated; namely, the femoral, saphenous, and popliteal arteries in the left hind limb were ligated. The right hind limb, with skin incisions alone, served as control. Hind limbs (n = 3-5 for each time point) were examined on day 0 (before the operation) and on postoperative days 1, 2, 7, 10, and 14, and the biceps femoris, adductor, rectus femoris, and gracilis muscles were subjected to histopathological and immunohistochemical analyses. In ischemic limbs, myogenesis, triggered by an increase in myotubes, began on day 7; thereafter, regenerated muscles gradually increased in volume. RT-PCR analysis showed that YB-1 mRNA levels were increased in the limbs after ischemic injury, peaked on day 2, and subsequently decreased. On day 7, expression levels of MyoD and alpha-smooth muscle actin (αSMA) mRNAs were significantly higher in ischemic muscles than in control muscles. Immunohistochemical analysis revealed increased YB-1 immunoreactivity in myoblasts and myotubes on day 7, which was decreased by day 14. The immunoreactive αSMA and smooth muscle myosin heavy chain were transiently increased in myotubes. This is the first report showing the increased expression of YB-1 during muscle regeneration after ischemic injury.

Anaplastic thyroid carcinoma (ATC) accounts for only 1 to 2% of all thyroid carcinomas, but it is one of the most lethal neoplasms in humans. To obtain further insights into this "orphan disease," we have established the ATC Research Consortium of Japan (ATCCJ) in 2009. It represents a multicenter registry for ATC that have been treated in Japan. To date, 67 institutions have taken part in the collaborative research system and over 1,200 cases have been accumulated in its database. Using this big data, several retrospective studies were carried out to evaluate 1) prognostic factors to determine initial treatment policy, 2) significance of extended radical surgery for Stage IVB cases, 3) characteristics of ATC incidentally found on pathological examination and 4) pathological features of ATC with long-term survival. Moreover, the ATCCJ has conducted an investigator-initiated, nationwide, prospective clinical trial since 2012; namely, the feasibility, safety and efficacy study of weekly paclitaxel administration for patients with ATC (UMIN: 000008574). Revised Japanese guidelines for treatment of thyroid tumors are going to adopt the recommendations from the results of this research. Since 2016, the ATCCJ has started the phase II study assessing the efficacy and safety of lenvatinib, a newly developed tyrosine kinase inhibitor for ATC (UMIN: 000020773). Our nationwide clinical trial network will strengthen the activity to recruit orphan disease patients and may discover new strategies to conquer this dismal malignancy in the near future.

Background: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC., Methods: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent., Results: A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%., Conclusions: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC.

This study was designed to examine the involvement of PATZ1 in carcinogenesis and dedifferentiation of thyroid cancer. Immunohistochemistry on clinical specimens indicated nuclear PATZ1 expression in all normal thyroid glands and adenomatous goiter, while nuclear PATZ1 expression decreased along with the dedifferentiation of thyroid cancer. Knockdown of nuclear PATZ1 by siRNA in an immortalized normal follicular epithelial cell line (Nthy-ori 3-1) altered cellular morphology and significantly increased cell proliferation, migration, and invasion. In addition, the expression of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP) 2, MMP9, and MMP11 was increased by PATZ1 knockdown in Nthy-ori 3-1 cells. When PATZ1 was silenced in differentiated thyroid cancer (DTC) cell lines (TPC-1 and FTC-133), proliferation, cellular motility, and expression of uPA and MMPs were significantly increased. Forced expression of exogenous PATZ1 decreased proliferation, cellular motility, and the expression of uPA and MMPs in ATC cell lines (ACT-1 and FRO). In thyroid cancer cell lines, PATZ1 functioned as a tumor suppressor regardless of p53 status. Moreover, the ratio of nuclear PATZ1 positive tumors was significantly decreased in ATC irrespective of p53 status. Our study demonstrates that PATZ1 knockdown enhances malignant phenotype both in thyroid follicular epithelial cells and thyroid cancer cells, suggesting that PATZ1 functions as a tumor suppressor in thyroid follicular epithelial cells and is involved in the dedifferentiation of thyroid cancer., Competing Interests: CONFLICTS OF INTEREST The authors declared no conflicts of interest.

Thymidylate synthase (TS) is essential in thymidylate biosynthesis and DNA replication. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in pyrimidine catabolism and is important in catabolism of 5-fluorouracil (5-FU). The significance of TS and DPD expressed in lung cancer remains controversial. Here we analyzed the relationship between TS and DPD expression and clinicopathological features of lung cancer. Enzyme-linked immunosorbent assays (ELISAs) were used to measure TS and DPD levels in paired tumor and non-tumor lung tissues obtained from 168 patients (107 adenocarcinomas, 39 squamous cell carcinomas, and 22 others), who had operations at the Shinshu University Hospital from 2004 to 2007 and were followed up for a median of 57.0 months. TS and DPD expression levels were higher in tumor tissues, and TS expression levels were significantly lower in adenocarcinomas than those in other subtypes. In addition, patients with low TS levels survived longer compared with patents with high TS levels. By contrast, DPD expression levels were not correlated with overall patient survival. Importantly, patients with low TS and DPD levels exhibited significantly prolonged survival than those with high TS and DPD. Among the 168 patients, 59 patients were treated with tegafur-uracil (UFT), a DPD-inhibitory fluoropyrimidine, and the UFT-treated patients with high TS and high DPD levels showed worst prognosis. Our study demonstrates a significant correlation between low TS expression levels and long-term prognosis of patients with lung cancer. Thus, ELISA is a clinically useful method to measure TS and DPD expression in lung cancer tissues.

Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor. Enforced expression of YBX1 in parental cells conferred resistance against tamoxifen and fulvestrant in vitro and in vivo Furthermore, YBX1 overexpression was associated with decreased and increased levels of ER and ERBB2 expression, respectively. In antiestrogen-resistant cells, increased YBX1 phosphorylation was associated with a 4-fold higher degradation rate of ER. Notably, YBX1 bound the ER, leading to its accelerated proteasomal degradation, and induced the transcriptional activation of ERBB2. In parallel fashion, tamoxifen treatment also augmented YBX1 binding to the ERBB2 promoter to induce increased ERBB2 expression. Together, these findings define a mechanism of drug resistance through which YBX1 contributes to antiestrogen bypass in breast cancer cells. Cancer Res; 77(2); 545-56. ©2016 AACR., (©2016 American Association for Cancer Research.)

This study aimed to elucidate the mechanisms underlying the resistance of breast cancer to eribulin. Seven eribulin-resistant breast cancer cell lines (MCF7/E, BT474/E, ZR75-1/E, SKBR3/E, MDA-MB-231/E, Hs578T/E, and MDA-MB-157/E) were established. mRNA and protein expression of ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 11 (ABCC11) increased in all eribulin-resistant cell lines compared to the parental cell lines. When ABCB1 or ABCC11 expression was inhibited by small interfering RNA in MCF7/E, BT474/E, and MDA-MB-231/E cells, eribulin sensitivity was partially restored. Moreover, eribulin resistance was attenuated additively by inhibiting ABCB1 and ABCC11 in MCF7/E cells. Additionally, overexpression of exogenous ABCB1 or ABCC11 in HEK293T cells conferred resistance to eribulin. MCF7/E and MDA-MB-231/E cells showed cross-resistance to paclitaxel, doxorubicin, and fluorouracil. Inhibition of ABCB1 partially restored paclitaxel and doxorubicin sensitivity. Partial restoration of fluorouracil sensitivity was induced by inhibiting ABCC11 in MCF7/E and MDA-MB-231/E cells. Both ABCB1 and ABCC11 are involved in the development of eribulin resistance in breast cancer cells in vitro regardless of the breast cancer subtype. Thus, ABCB1 and ABCC11 expression may be used as a biomarker for predicting the response to eribulin in patients with breast cancer. Concomitant inhibition of ABCB1 and ABCC11 might help enhance the antitumor effects of eribulin.

Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients' quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs.

It is occasionally difficult to diagnose breast metastasis of gastric carcinoma because of its rarity. However, to appropriately treat patients with breast tumors without delay, it is important to distinguish metastatic cancer from primary breast cancer. We report two cases of breast metastasis of gastric carcinoma and review the literature. The first case was a 41-year-old female diagnosed with bilateral pelvic tumors who visited the outpatient clinic because of pain and enlargement of both breasts. Ultrasonography showed diffuse hypoechoic lesions, which were enhanced on gadolinium-enhanced magnetic resonance imaging in the bilateral mammary gland. Core needle biopsy of the right breast revealed signet-ring cells, which were also identified in the resected bilateral pelvic tumors. Subsequent upper gastrointestinal endoscopy revealed signet-ring cell carcinoma in the stomach, and the bilateral breast lesions were diagnosed as metastases of gastric carcinoma. The second case was a 34-year-old female diagnosed with cervical metastasis of signet-ring cell carcinoma who was referred to the breast cancer clinic because of a nodule in the left breast detected by computed tomography. Ultrasonography showed a hypoechoic nodule that was enhanced on gadolinium-enhanced magnetic resonance imaging. Because the pathologic findings for the left breast nodule were quite similar to those of gastric cancer and its cervical metastasis, the breast nodule was diagnosed as a metastasis of gastric carcinoma. When a breast tumor is suspected to have metastasized from a primary tumor in another organ, particularly if signet-ring cells are found, the possibility that gastric cancer is present should be considered.

Background: The most difficult thyroid tumors to diagnose by histology are follicular carcinomas (FTCs) and Hürthle cell carcinomas (HCCs). Telomere alteration and human telomerase reverse transcriptase (hTERT) expression have been observed in most human cancers and are known to be a feature of malignancy. The purpose of this study was to clarify whether hTERT protein expression and telomere alteration could be applicable biological markers for distinguishing FTC from HCC., Methods: We investigated a total of 78 thyroid tumor cases, including 14 FTCs, 47 follicular adenomas (FTAs), 5 HCCs, and 12 Hürthle cell adenomas (HCAs). hTERT protein expression was examined by immunohistochemistry, and telomere length was determined by tissue quantitative fluorescence in situ hybridization., Results: Positivity for hTERT protein expression was observed in 86 % of FTCs and 49 % of FTAs. Telomeres in FTCs were significantly shorter than those in FTAs. All HCCs and HCAs (100 %) expressed hTERT protein. Telomeres in HCCs were significantly shorter than those in HCAs., Conclusions: Our results suggest that hTERT protein expression and telomere shortening would be applicable as biological markers to distinguish FTC from FTA. Previous studies have suggested that follicular tumor and Hürthle cell tumor should be classified biologically as distinct tumors. All Hürthle cell tumors expressed hTERT protein and HCCs had markedly shortened telomeres, suggesting that follicular tumor and Hürthle cell tumor might be biologically distinct entities.

Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.

Aromatase inhibitors (AIs) have been reported to exert their antiproliferative effects in postmenopausal women with hormone receptor-positive breast cancer not only by reducing estrogen production but also by unmasking the inhibitory effects of androgens such as testosterone (TS) and dihydrotestosterone (DHT). However, the role of androgens in AI-resistance mechanisms is not sufficiently understood. 5α-Androstane-3β,17β-diol (3β-diol) generated from DHT by 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) shows androgenic and substantial estrogenic activities, representing a potential mechanism of AI resistance. Estrogen response element (ERE)-green fluorescent protein (GFP)-transfected MCF-7 breast cancer cells (E10 cells) were cultured for 3 months under steroid-depleted, TS-supplemented conditions. Among the surviving cells, two stable variants showing androgen metabolite-dependent ER activity were selected by monitoring GFP expression. We investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms in these variant cell lines. The variant cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes after stimulation with androgens or 3β-diol. Further analysis suggested that increased expression of HSD3B1 and reduced expression of androgen receptor (AR) promoted adaptation to androgen-abundant conditions, as indicated by the increased conversion of DHT into 3β-diol by HSD3B1 and AR signal reduction. Furthermore, in parental E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to androgen-abundant conditions. Coculture with stromal cells to mimic local estrogen production from androgens reduced cell sensitivity to AIs compared with parental E10 cells. These results suggest that increased expression of HSD3B1 and reduced expression of AR might reduce the sensitivity to AIs as demonstrated by enhanced androgen metabolite-induced ER activation and growth mechanisms. Androgen metabolite-dependent growth of breast cancer cells may therefore play a role in AI-resistance.

Background: Y-box binding protein 1 (YB-1) is an oncogenic transcription factor that is activated in response to various genotoxic stresses. The purpose of this study was to elucidate whether YB-1 correlates with the expression of lung resistance-related protein (LRP) and epidermal growth factor receptor (EGFR) in primary lung cancer., Patients and Methods: One hundred and five non-small-cell lung cancer (NSCLC) specimens were analyzed by immunohistochemistry. Knockdown of YB-1 messenger RNA by small interfering RNA(siRNA) was tested for the lung cancer cell lines A549 and Calu-3., Results: Nuclear YB-1 expression significantly correlated with positive LRP and EGFR expression (P < .001). Nuclear YB-1 expression and positive LRP and EGFR expression were independent adverse prognostic factors in patients with NSCLC. Furthermore, patients with tumors positive for nuclear YB-1 and LRP had a significantly worse prognosis than those negative for nuclear YB-1 and LRP (P < .001). In addition, patients with tumors positive for nuclear YB-1 and EGFR had a significantly worse prognosis than those negative for nuclear YB-1 and EGFR (P < .001). In in vitro analyses that use the NSCLC cell lines A549 and Calu-3, the downregulation of YB-1 with siRNAs drastically decreased the expression of EGFR. However, downregulation of YB-1 remarkably decreased the expression of LRP in A549 cells; however, a slight decrease in LRP was induced by the downregulation of YB-1 in Calu-3 cells., Conclusion: Our data demonstrate that nuclear YB-1 localization is associated with LRP and EGFR expression in NSCLC, and nuclear YB-1 localization and LRP and EGFR expression are of prognostic significance in NSCLC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hippocampal inhibitory interneurons have a central role in the control of network activity, and excitatory synapses that they receive express Hebbian and anti-Hebbian long-term potentiation (LTP). Because many interneurons in the hippocampus express nicotinic acetylcholine receptors (nAChRs), we explored whether exposure to nicotine promotes LTP induction in these interneurons. We focussed on a subset of interneurons in the stratum oriens/alveus that were continuously activated in the presence of nicotine due to the expression of non-desensitizing non-alpha7 nAChRs. We found that, in addition to alpha2 subunit mRNAs, these interneurons were consistently positive for somatostatin and neuropeptide Y mRNAs, and showed morphological characteristics of oriens-lacunosum moleculare cells. Activation of non-alpha7 nAChRs increased intracellular Ca(2+) levels at least in part via Ca(2+) entry through their channels. Presynaptic tetanic stimulation induced N-methyl-D-aspartate receptor-independent LTP in voltage-clamped interneurons at -70 mV when in the presence, but not absence, of nicotine. Intracellular application of a Ca(2+) chelator blocked LTP induction, suggesting the requirement of Ca(2+) signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca(2+) -induced Ca(2+) release from ryanodine-sensitive intracellular stores, and the L-type Ca(2+) channel blocker nifedipine. These results suggest that Ca(2+) entry through non-alpha7 nAChR channels is critical for LTP induction. Thus, nicotine affects hippocampal network activity by promoting LTP induction in oriens-lacunosum moleculare cells via continuous activation of non-alpha7 nAChRs.

Objective: With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor., Method: Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Asberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants., Results: Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected., Conclusions: The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.

In the present study, we performed a prospective follow-up study in a population which underwent chest computed tomography (CT) screening. A total of 6120 participants underwent a chest CT medical examination for lung cancer and tuberculosis in Nagano Prefecture, Japan, between 1996 and 1997. Computed tomography scanning was performed from the apex of the lung to the diaphragm at a tube voltage of 120 kV and a tube current of 50 mA. We measured the CT density of the coronary arteries in 5-7 slices where coronary arteries were detected. The CT density threshold for determining coronary artery calcification (CAC) was above +110 HU. In 2000, we investigated the number of deaths due to cardiac and noncardiac disease among the participants. Of the 6120 participants, 14 died of cardiac disease (9, myocardial infarction; 4, heart failure; and 1, angina pectoris) and 64 died of other diseases. Coronary artery calcification was detected in 10 of the patients who died of cardiac disease, and in 31 of those who died of other diseases. The prevalence of CAC was higher in the former than in the latter (71.4% vs 48.4%, P = 0.084). The relative risk of CAC for cardiac death was 2.66 (95% confidence interval: 0.76, 9.37). The findings of this study suggested that CAC detected in a mass chest CT screening by a mobile helical CT unit was predictive of future cardiovascular death.

Cardiac myxoma is most common among primary cardiac tumors, and its origin and tumor characteristics have been gradually elucidated by recent advances in molecular biology. Prichard's structure in the interatrial septum which was reported to be a candidate for the origin of cardiac myxoma, was revealed to be age-related changes. In hereditary cardiac myxoma "Carney complex", chromosomal abnormalities involving chromosomes 2p, 12 and 17q have been reported, however, no genetic abnormalities of these locus were found in the development of sporadic cases. Cardiac myxoma has multiple differentiating potentials, and recently various amounts of cardiomyocyte-specific transcription factor genes were identified. This indicates that cardiac myxoma might arise from mesenchymal cardiomyocyte progenitor cells. Various cytokines and growth factors such as vascular endothelial growth factor, basic fibroblast growth factor, monocyte chemotactic protein-1 and interleukin-6 were involved in tumor growth and angiogenesis. Although cardiac myxoma usually presents as a benign neoplasm, reports suggesting its malignancy, including recurrence of the tumor, locally invasive myxoma, extension from the heart, and distant metastasis are increasing. These genetic and molecular approaches to cardiac myxoma may prompt the development of therapeutic modalities for treatment of malignancies and cardiac cell regeneration.