Expression of the core promoter factors TATA box binding protein and TATA box binding protein-related factor 2 in Drosophila germ cells and their distinct functions in germline development.

In Drosophila, the expression of germline genes is initiated in primordial germ cells (PGCs) and is known to be associated with germline establishment. However, the transcriptional regulation of germline genes remains elusive. Previously, we found that the BTB/POZ-Zn-finger protein, Mamo, is necessary for the expression of the germline gene, vasa, in PGCs. Moreover, truncated Mamo lacking the BTB/POZ domain (MamoAF) is a potent vasa activator. In this study, we investigated the genetic interaction between MamoAF and specific transcriptional regulators to gain insight into the transcriptional regulation of germline development. We identified a general transcription factor, TATA box binding protein (TBP)-associated factor 3 (TAF3/BIP2), and a member of the TBP-like proteins, TBP-related factor 2 (TRF2), as new genetic modifiers of MamoAF. In contrast to TRF2, TBP was found to show no genetic interaction with MamoAF, suggesting that Trf2 has a selective function. Therefore, we focused on Trf2 expression and investigated its function in germ cells. We found that Trf2 mRNA, rather than Tbp mRNA, was preferentially expressed in PGCs during embryogenesis. Depletion of TRF2 in PGCs resulted in decreased mRNA expression of vasa. RNA interference-mediated knockdown showed that, while Trf2 is required for maintenance of germ cells, Tbp is needed for their differentiation during oogenesis. Therefore, these results suggest that Trf2 and Tbp expression is differentially regulated in germ cells and that these factors have distinct functions in Drosophila germline development.

A multicenter prospective study to evaluate bone fracture related to adjuvant anastrozole in Japanese postmenopausal women with breast cancer: two-year interim analysis of Saitama Breast Cancer Clinical Study Group (SBCCSG-06).

BACKGROUND: Because of its superior efficacy to tamoxifen, anastrozole has been widely used in Japan as an adjuvant treatment for postmenopausal, hormone-responsive breast cancer patients. However, anastrozole may affect bone in Japanese patients similar to its effects in Western patients. The aim of this study is to evaluate the rate of bone fracture and bone mineral density (BMD) during anastrozole treatment in Japanese patients. PATIENTS AND METHODS: In this study, 350 postmenopausal women with hormone-responsive, stage I to IIIA breast cancer were enrolled and scheduled to receive adjuvant anastrozole treatment for up to 5 years. Patients underwent clinical examination for bone fractures and annual measurement of BMD during treatment. RESULTS: After a median follow-up of 33.0 months, bone fractures occurred in 1.8 %. Annual fracture rates were 0.3 and 1.2 % during the first and second year, respectively. The overall median BMD significantly decreased, measuring 87.5, 84.3, and 83.5 % at baseline and after 1 and 2 years, respectively. Musculoskeletal disorders were the most common (26.1 %), and hot flashes were the second most common adverse event (7.9 %). Severe adverse events occurred in 5.5 % of all the cases. CONCLUSIONS: In this interim analysis, the bone fracture rate was lower than that in the Western population despite a significant reduction of BMD after 2 years of treatment with anastrozole. Adjuvant anastrozole treatment was well tolerated in Japanese postmenopausal women with breast cancer. Long-term follow-up data is necessary to elucidate the racial disparities of the safety profile of anastrozole.

Locally advanced breast cancer with bleeding - two cases effectively treated with bevacizumab plus weekly paclitaxel.

Bleeding is one of the serious adverse events of bevacizumab (BV). In our report, two patients had locally advanced breast cancer with bleeding. They received BV plus weekly paclitaxel (PTX), and good local control was observed. Case 1: The patient was a 50-year-old postmenopausal woman. She had left-sided breast cancer (T4cN2cM1 [bone]-stageIV) that was negative for estrogen receptor (ER), negative for progesterone receptor(PgR), and 1+for human epidermal growth factor receptor 2 (HER2). The patient began receiving different regimens of chemotherapy: 5-fluorouracil (5-FU), epirubicin (EPI), and cyclophosphamide(CPA), (FEC); PTX; docetaxel (DTX); and gemcitabine (GEM) plus PTX. Subsequently, she received BV plus PTX. The tumor was markedly reduced in size at the completion of 2 cycles. Bleeding and exudate were also reduced. The patient had a partial response until the sixth cycle, and good local control was obtained. However, the patient had progressive disease at the completion of 8 cycles. Therefore, therapy was changed to capecitabine(CAP)plus CPA, but the patient died one year after she began treatment with BV plus PTX. Case 2: The patient was a 76-year-old postmenopausal woman. She had right-sided breast cancer (T4bN3bM1[lung]-stageIV) that was negative for ER, negative for PgR, and 0 for HER2. The patient began receiving different regimens of chemotherapy: EPI and CPA (EC); and PTX. Subsequently, she received BV plus PTX. The tumor was markedly reduced in size at the completion of 2 cycles. Bleeding and exudate were also reduced. The patient had a partial response until the third cycle, and good local control was obtained. However, the patient had progressive disease at the completion of 4 cycles. Therefore, therapy was changed to CAP and DTX, but the patient died six months after she began treatment with BV plus PTX.

Effectiveness and safety of tegafur-gimeracil-oteracil potassium (TS-1) for metastatic breast cancer: a single-center retrospective study.

BACKGROUND: Tegafur-gimeracil-oteracil potassium (TS-1)is a drug that is used mainly as a third-line treatment or beyond for metastatic breast cancer(MBC). However, there is still insufficient evidence on its clinical effectiveness, and there are very few reports on clinical research using TS-1 up front. In this report, we examined the effectiveness and safety of TS-1 therapy for MBC. PATIENTS AND METHODS: The subjects were 46 patients with MBC who were treated with TS-1 between January 2005 and January 2013. These patients were retrospectively examined. RESULTS: The objective response rate to TS-1 therapy was 30.4%, clinical benefit rate (CBR)was 50.0%, and the median time to treatment failure was 10.7 months. When examined by site, the CBR was high locally (46.2%), in the lymph nodes (40.7%), in the bone (42.9%), and in the lungs and pleura (44.8%). However it was low in the liver(30.0%). The relationship was examined between clinicopathological factors and the effectiveness of TS-1 therapy. The objective response rate (ORR) was significantly higher for patients with disease-free interval (DFI) of 2 years or more (p=0.039), TS-1 therapy used as third-line treatment or earlier (p=0.022), negative HER2 status (p=0.020), and no history of capecitabine (CAP)therapy (p=0.049). The CBR was significantly higher for patients with no visceral metastasis (p=0.032), TS-1 used as third-line treatment or earlier (p=0.019), negative HER2 status (p= 0.045), no history of CAP therapy (p=0.006), and no history of tegafur-uracil/doxifluridine therapy (p=0.031). Multivariate analysis showed that DFI of 2 years or more (p=0.035, odds ratio:0.104)was an independent predictor of effectiveness assessed by ORR. There were only 4 patients in whom the treatment was discontinued due to adverse event, and TS-1 was generally well tolerated. CONCLUSION: TS-1 was highly effective and well tolerated by patients with MBC. Its up-front use might enable the maintenance of satisfactory QOL and the enhancement of its clinical effectiveness.

Efficacy of high-dose toremifene therapy in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors:a retrospective, single-institution study.

BACKGROUND: Aromatase inhibitors(AI)have established efficacy as first-line therapy in postmenopausal patients with hormone-sensitive metastatic breast cancer(MBC). However,the use of endocrine therapy has not yet been established for second-line and later therapy. Our study examined the efficacy of high-dose toremifene therapy(HD-TOR)in patients with MBC resistant to AIs. PATIENTS AND METHODS: A retrospective analysis was carried out to determine outcomes in 85 postmenopausal patients with MBC resistant to AIs who began HD-TOR between May 2001 and October 2011. The patients received toremifene 120 mg once daily on consecutive days. RESULTS: The objective response rate(ORR)was 21.2%,the clinical benefit rate(CBR)was 41.2%,and the median time to treatment failure(TTF)was 7.3 months. The CBR was high in patients with ER-positive status(p=0.045),no visceral metastasis(p=0.037),HD -TOR as first- or second-line therapy(p=0.007),no history of tamoxifen(TAM)therapy(p=0.019),and no history of chemotherapy(p=0.017). Multivariate analysis showed that ER-positive status(p=0.005, odds ratio: 0.064)and no visceral metastasis(p=0.034, odds ratio: 0.323)were independent predictors of efficacy. The TTF was significantly longer in patients with ER-positive status(p=0.019)and no history of TAM therapy(p=0.015). Multivariate analysis showed that ER-positive status(p=0.025, hazard ratio: 0.377)and no history of TAM therapy(p=0.002, hazard ratio: 0.422)were independent predictors of efficacy. No patient discontinued HDTOR therapy due to adverse events. CONCLUSION: HD-TOR is an effective endocrine therapy for patients with MBC who have failed AIs.

MR perfusion imaging using the arterial spin labeling technique for breast cancer.

PURPOSE: To investigate the feasibility of perfusion imaging using an arterial spin labeling (ASL) technique for breast cancer. MATERIALS AND METHODS: Thirteen female patients with primary breast cancers were included in this study. All examinations were performed on 1.5 Tesla MRI systems. Visual evaluations of the colored perfusion map and MRI perfusion values were assessed. MRI and computed tomography (CT) perfusion values were compared. RESULTS: Thirteen of 14 tumor lesions could be visualized on the colored perfusion map. CT perfusion examinations were performed in eight breasts, and the relationship between the blood flow values of CT perfusion and of MR perfusion showed a significant correlation. CONCLUSION: Nonenhanced MR imaging by an ASL technique is valid for depicting breast cancer, and the MR perfusion value is thought to be helpful for quantitative diagnosis of breast cancer.

[Prevention of phlebitis caused by vinorelbine chemotherapy in outpatients with breast cancer].

We studied the prevention of phlebitis in 10 patients who had developed the symptoms after receiving vinorelbine to treat breast cancer at our outpatient chemotherapy clinic from July 2005 to August 2006. Veins proximal to the injection site were warmed using hot compresses during the vinorelbine injection and physiological saline was increased to wash out the drug after the injection from 250 mL to 500 mL in combination to investigate whether the treatment was effective in preventing phlebitis. The severity of phlebitis was significantly decreased after the combined treatment compared with the pre-treatment level (p=0.039). The combination was effective to relieve vascular pain during the injection in all 10 patients, and the number of event occurrences was significantly decreased (p<0.0005). It was also effective to decrease the frequency of vascular pain after patients returned home (p=0.001). The combination of hot compresses and increase of physiological saline for washing out was an effective treatment to prevent phlebitis caused by vinorelbine. The comparison of patient characteristics to find other contributing factors to phlebitis than vinorelbine revealed no association with the number of doses, diameter of the vein to be punctured, or pretreatment.

Electromyographic analysis of relevant muscle groups during completion of computer tasks using different computer mouse positions.

BACKGROUND: We analyzed muscular activity for different computer mouse positions during the completion of a timed computer task and determined whether the different mouse positions could affect muscular activity, productivity and perceived fatigue. METHODS: The subjects were nine healthy young men. Two mouse positions were studied: the distal position (DP), with the forearm rested on the desk; the proximal position (PP), with only the wrist rested on the desk. The subjects performed a 16-min task in each position. Surface electromyography data were recorded for the upper back and shoulder muscles. Work productivity and muscular activity were measured for each mouse position. A visual analog scale was used to assess subjective fatigue. RESULTS: Muscular activity was higher in muscle (m.) deltoideus (posterior) for the DP, while it was significantly higher in m. inferior infraspinatus for the PP. The visual analog scale score was significantly higher and work productivity was lower in the PP. CONCLUSIONS: We found that using a mouse in the DP rather than the PP leads to less activity of the external rotators, less perceived fatigue and more productivity. This suggests that the DP is preferable to the PP for computer work involving a mouse.

The position of a standard optical computer mouse affects cardiorespiratory responses during the operation of a computer under time constraints.

OBJECTIVES: This study investigated the association between task-induced stress and fatigue by examining the cardiovascular responses of subjects using different mouse positions while operating a computer under time constraints. MATERIAL AND METHODS: The study was participated by 16 young, healthy men and examined the use of optical mouse devices affixed to laptop computers. Two mouse positions were investigated: (1) the distal position (DP), in which the subjects place their forearms on the desk accompanied by the abduction and flexion of their shoulder joints, and (2) the proximal position (PP), in which the subjects place only their wrists on the desk without using an armrest. The subjects continued each task for 16 min. We assessed differences in several characteristics according to mouse position, including expired gas values, autonomic nerve activities (based on cardiorespiratory responses), operating efficiencies (based on word counts), and fatigue levels (based on the visual analog scale - VAS). RESULTS: Oxygen consumption (VO(2)), the ratio of inspiration time to respiration time (T(i)/T(total)), respiratory rate (RR), minute ventilation (VE), and the ratio of expiration to inspiration (Te/T(i)) were significantly lower when the participants were performing the task in the DP than those obtained in the PP. Tidal volume (VT), carbon dioxide output rates (VCO(2)/VE), and oxygen extraction fractions (VO(2)/VE) were significantly higher for the DP than they were for the PP. No significant difference in VAS was observed between the positions; however, as the task progressed, autonomic nerve activities were lower and operating efficiencies were significantly higher for the DP than they were for the PP. CONCLUSIONS: Our results suggest that the DP has fewer effects on cardiorespiratory functions, causes lower levels of sympathetic nerve activity and mental stress, and produces a higher total workload than the PP. This suggests that the DP is preferable to the PP when operating a computer.

Paclitaxel-resistant advanced recurrent breast cancer: a case of partial response due to addition of bevacizumab to paclitaxel therapy: a case report.

BACKGROUND: Paclitaxel plus bevacizumab have shown a high response rate and prolonged progression-free survival in metastatic breast cancer patients. However, overall survival was not prolonged. Thus, no conclusion has been made on the effectiveness of bevacizumab. In our report, taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained. CASE PRESENTATION: The patient was a 68-year-old woman with a non-contributory history. In September 2004, she underwent a pectoral muscle-conserving mastectomy with axillary dissection for right-sided breast cancer (pT3N0M0-stage IIB, estrogen receptor positive, progesterone receptor negative, and human epidermal growth factor receptor type 2 negative). Adjuvant therapy consisted of 6 cycles of cyclophosphamide, epirubicin and fluorouracil, and subsequent oral anastrozole. In August 2007, the patient developed a recurrence in the left axillary lymph node. The chemotherapy was changed to high-dose toremifene, and radiation therapy was also performed. The patient achieved a complete response. In April 2009, CT showed left axillary lymph node enlargement once again and multiple lung metastases. Hormone therapy was changed to exemestane and long-term stable disease was achieved. In March 2011, the lung and left axillary lymph node metastases were enlarged and progressive disease was noted. Thus, the tumors were determined to be resistant to hormone therapy, and weekly paclitaxel was begun in May. Since partial response was achieved, this therapy was continued. In December, CT showed that lung and axillary lymph node metastases were enlarged and progressive disease was observed. Therefore, the tumors were determined to be resistant to paclitaxel. In January 2012, bevacizumab and weekly paclitaxel were begun. In April, lung and axillary lymph node metastases were reduced in size, and partial response was achieved. Thereafter the same treatment has been continued, and the patient has been followed up without clinical exacerbation as of January 2013. CONCLUSION: Taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained. This result is considered important in increasing treatment options for patients with taxane resistance or patients using adjuvant taxane-based therapy and in examining the effectiveness of bevacizumab in metastatic breast cancer patients.