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Thymic epithelial tumors (TETs) mainly consist of thymoma and thymic carcinoma. Complete surgical resection is vital for the successful management of these TETs, and adjuvant therapy such as systematic chemotherapy and/or radiotherapy plays important roles in the management of recurrent or metastasized disease. However, there is still a lack of a standard treatment after the failure of these adjuvant therapies. There is thus a need to develop molecular targeted therapies for advanced malignant TETs. In the present study, we evaluated the biological significance of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling for TETs.The expression of TrkB in 48 formalin-fixed, paraffin-embedded TET specimens (43 thymoma and 5 thymic carcinoma) collected by surgical resection was evaluated immunohistochemically. A thymic carcinoma cell line was evaluated for the role of BDNF/TrkB signaling pathway in an in vitro assay.High TrkB expression was related to significantly poor prognosis in patients with TETs. In vitro experiments showed that BDNF/TrkB signaling was involved in the proliferation of Ty-82 cells, but not their invasion and migration.TrkB expression is a biomarker of the prognosis for TETs and the BDNF/TrkB signaling pathway is potentially a new therapeutic target for mTETs.

Highlights • PTPN3 suppression associates with lymphocyte activation and cancer suppression. • PTPN3 is involved in the induction of malignant traits. • PTPN3 is associated with cellular immunosuppression. • Signals from PTPN3 go through MAPK and PI3K signaling. • PTPN3-inhibited lung NET cells enhance PTPN3-suppressed activated lymphocytes., In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.

Objectives The proportion of elderly individuals living alone is increasing in Japan. Matsumoto city office provides social assistive programs such as home help, lunch delivery, life advice, and safety check telephone calls. The purpose of this study was to compare the level of ADL between the elderly using social assistive programs (the use group) and those who did not (the non-use group).Methods We conducted a cross-sectional study at Shiga district of Matsumoto city in September 2014. A total of 128 elderly individuals participated in this study. Health volunteers asked these subjects to complete a questionnaire without assistance. Measurement items included lifestyle variables and social support networks. With respect to the frequency of use, we used questions that inquired about the use of the social assistive program. We included a set of instruments commonly used in the health assessment of elderly populations: functional capacity (Instrumental ADL, Intellectual Activity, Social Role), social support, nutrition (Mini Nutrition Assessment [MNA]) and depressive symptoms (Geriatric Depression Scale [GDS]).Results The use group consisted of 24 elderly individuals participating in the social support program. The non-use group consisted of 89 elderly individuals living alone without programs. The mean age of those who completed the survey was 83.9±4.2 years for the use group and 82.3±4.3 years for the non-use group. Comparisons between the two groups did not show significant difference in terms of their intellectual activity, social role, emotional social support, and MNA or GDS scores. The use group was more likely to use the public transfer service and receive instrumental social support from children and relatives.Conclusions By means of utilizing the public transfer service, and receiving family support, the elderly living alone who used social assistive programs could live independently. These findings suggest a need for improvement in the public transfer service and social network.

The preoperative assessment of nodal status in lung cancer is complicated and problematic for physicians and surgeons. Although many patients with clinical N1 (cN1) non-small cell lung cancer (NSCLC) are candidates for surgical treatment, these patients represent a heterogeneous subgroup with unpredictable survival. We conducted this study to evaluate the surgical results of cN1 disease and to attempt to clarify the delicate issues surrounding its diagnosis and prognosis. The subjects of this study were 187 consecutive patients with cN1 adenocarcinoma or squamous cell carcinoma of the lung, who underwent complete resection without induction therapy. Only 25% of the adenocarcinomas and 54% of the squamous cell carcinomas were correctly diagnosed as N1 disease preoperatively. Multiple logistic regression analyses revealed that adenocarcinoma (P = 0.0141) was a significant predictor of pN2. Multivariate analyses revealed that nodal metastasis (P < 0.0001), large tumor size (P = 0.0079), and high serum carcinoembryonic antigen value (P = 0.0096) were significantly poor prognostic factors in cN1 patients. It is difficult to diagnose nodal status in patients with cN1 disease, which requires various surgical procedures, including plasty, possibly with adjuvant therapy in a defined high-risk subgroup.

The patient was a 57-year-old man with Brugada syndrome, who had been implanted with a implantable cardioverter defibrillator (ICD). The frequency of ventricular fibrillation (VF) started to increase about 4 years after ICD implantation, occurring, at worst, six times in one night. Immediately after starting oral administration of disopyramide, VF stopped occurring. He then discontinued taking disopyramide, but immediately after the discontinuation VF started occurring again, so he restarted taking disopyramide. Thereafter, VF completely stopped occurring. Findings observed in our case suggest that disopyramide could be added in our arsenal of medications for treating arrhythmic storms in patient with Brugada syndrome. (PACE 2010; 33:e53–e56)

The aim of the present study was to examine the antihypertensive and antihypertrophic effects of combined treatment with a long-acting calcium antagonist on top of an angiotensin II receptor blocker (ARB) in uncontrolled hypertensive patients. Patients with essential hypertension and a blood pressure > 140/90 mmHg on ARB monotherapy (losartan 50 mg/day or candesartan 8 mg/day) were randomly assigned to a nifedipine controlled release (CR) group (n = 15) or amlodipine group (n = 11). A significant additional antihypertensive effect was noted from 1 month with nifedipine and 2 months with amlodipine. The average daily dose was 25 mg for nifedipine and 5 mg for amlodipine. The cardiothoracic ratio was significantly reduced in both groups after 3 months. Left ventricular wall thickness and left ventricular mass index also decreased. Metabolic parameters, hepatic function, and renal function did not change significantly. Additional treatment with a long-acting calcium antagonist achieved further blood pressure reduction as well as an antihypertrophic effect in the uncontrolled patients with prior ARB monotherapy.

ZnBr2 was found to catalyze formation of propargyl and propargylic Grignard reagents, and thus put an end to the standard method using a mercury catalyst. The Grignard reagents were submitted to addition reaction with carbonyl compounds and allylation with the cyclic monoacetate to afford the propargyl-type products selectively. Furthermore, the product from the monoacetate was transformed to an acetylene analogue of 2-(5,6-epoxyisoprostane A2)phosphorylcholines.

The objectives of this study were to identify the position where optimal leg muscle force occurs and to analyze the lower extremity muscle activity by comparing different hip and knee joint angle positions using a newly developed closed kinetic chain (CKC) leg press exercise device. Muscle force and electromyogram (EMG) measurements during maximum voluntary isometric leg presses (MVC-CKC) were performed on 6 healthy women in 6 different knee flexion angles (15°, 30°, 45°, 60°, 75°, 90°) and 2 different postures (supine and trunk upright posture). Results showed that the muscle force of MVC-CKC reached its peak at 60° knee flexion angle in both postures. Significant knee angle-dependent differences in EMG activity for both rectus femoris and gastrocnemius muscles were observed, while posture-dependent differences in EMG were found in biceps femoris. These particular joint-dependent EMG activities may be explained by the architectural characteristics of bi-articular muscles and muscle length-tension relationship theory. Co-activation of an antagonist muscle may appear with activation of the gastrocnemius muscle when the knee approaches full extension. Consequently, measurement of isometric CKC leg extension muscle force at 60° knee flexion angle in the trunk upright posture seems to be the optimal position.

Background Improved radiologic imaging provides earlier detection of non–small cell lung cancer, but controversy exists regarding the need for complete lymph node dissection. This study was designed to evaluate the possibility of lesser mediastinal dissection for early-stage lung cancer. Methods Selective mediastinal dissection is defined as follows: Dissection of the upper mediastinum for upper-lobe tumors is performed but it is not needed for lower-lobe tumors with intact hilar and lower mediastinal nodes. Also, dissection of the lower mediastinum for an upper-lobe tumor is not routinely required when the nodes in the hilum and upper mediastinum are negative. From 1997 through 2002, 377 patients with clinico-surgical stage I non–small cell lung cancer underwent curative-intent surgery with selective dissection (group S). In addition, 358 patients with the same-stage disease who underwent complete lymphadenectomy by the same surgical team served as historic controls (group C). Results The characteristics of the two groups were well balanced. There was no significant difference in disease-free survival ( p = 0.376) or overall survival ( p = 0.060). Multivariate analysis showed that the dissection mode did not significantly influence either disease-free survival ( p = 0.636) or overall survival ( p = 0.119). The postoperative morbidity rates were 17.3% and 10.1% for group C and group S, respectively ( p = 0.005). One operative death occurred in each group (0.3%). The rates of distant metastasis and local recurrence were similar in the two groups. Conclusions Selective mediastinal dissection for clinico-surgical stage I non–small cell lung cancer proved to be as effective as complete dissection, and although large multicenter trials are warranted, it might be considered as an alternative for curative surgery in this era of minimally invasive surgery.

Study objectives Controversy regarding the most suitable surgical approach for treating malignancies of the lung is a matter of continuous discussions. “Complete” video-assisted thoracic surgery (VATS) that is performed using only the vision of a monitor is generally limited to lung resections of minimal difficulty. With the great interest in minimally invasive techniques for treating various pathologies, we have widely applied an integrated surgical approach that combines muscle-sparing minithoracotomy (incision, 4 to 10 cm) and video assistance using mainly direct visualization of the lung resection, which we have called hybrid VATS . The aim of this study is to evaluate the usefulness of hybrid VATS. Design Retrospective single-center study. Interventions From January 1998 to October 2004, 405 of 678 lobectomies (60%) and 165 of 226 segmentectomies (73%) were performed for primary lung cancer using hybrid VATS. Results Bronchoplasty was performed in 93 of the 678 patients (14%) who underwent lobectomy and in 11 of the 226 patients (5%) who underwent segmentectomy. Hybrid VATS was utilized in 33% of sleeve lobectomy procedures and in 27% of sleeve segmentectomy procedures. The mean (± SD) surgical time using hybrid VATS was 164 ± 48 min for lobectomy and 158 ± 35 min for segmentectomy, and the mean blood loss was 166 ± 120 and 109 ± 80 mL, respectively. There was one operative mortality (0.2%) secondary to cardiogenic shock. Postoperative complications developed in 11% of patients with p-stage IA disease after undergoing hybrid VATS, in contrast to 19% of patients after undergoing open thoracotomy. The prognosis of patients treated by hybrid VATS was equivalent to that obtained with open thoracotomy. Conclusions Minithoracotomy combined with video support that is performed predominantly via direct visualization is a secure, integrated, minimally invasive approach to performing major resection for lung cancer, including atypical procedures such as bronchoplasty. This hybrid VATS can be an acceptable and satisfactory option whenever the performance of complete VATS is considered to be challenging.

ObjectiveDistinction of lymph node stations is one of the most crucial topics still not entirely resolved by many lung cancer surgeons. The nodes around the junction of the hilum and mediastinum are key points at issue. We examined the spread pattern of lymph node metastases, investigated the prognosis according to the level of the involved nodes, and conclusively analyzed the border between N1 and N2 stations.MethodsWe reviewed the records of 604 consecutive patients who underwent complete resection for non-small cell lung carcinoma of the lower lobe.ResultsThere were 390 patients (64.6%) with N0 disease, 127 (21.0%) with N1, and 87 (14.4%) with N2. Whereas 11.3% of patients with right N2 disease had skip metastases limited to the subcarinal nodes, 32.6% of patients with left N2 disease had skip metastases, of which 64.2% had involvement of N2 station nodes, except the subcarinal ones. The overall 5-year survivals of patients with N0, N1, and N2 disease were 71.0%, 50.8%, and 16.7%, respectively (N0 vs N1 P = .0001, N1 vs N2, P < .0001). Although there were no significant differences in survival according to the side of the tumor among patients with N0 or N1 disease, patients with a left N2 tumor had a worse prognosis than those with a right N2 tumor (P = .0387). The overall 5-year survivals of patients with N0, intralobar N1, hilar N1, lower mediastinal N2, and upper mediastinal N2 disease were 71.0%, 60.1%, 38.8%, 24.8%, and 0%, respectively. Significant differences were observed between intralobar N1 and hilar N1 disease (P = .0489), hilar N1 and lower mediastinal N2 disease (P = .0158), and lower and upper mediastinal N2 disease (P = .0446). Also, the 5-year survivals of patients with involvement up to station 11, up to station 10, and up to station 7 were 41.4%, 37.9% and 37.7%, respectively (difference not significant).ConclusionsN1 and N2 diseases appeared as a combination of subgroups: intralobar N1 disease, hilar N1 disease, lower mediastinal N2 disease, and upper mediastinal N2 disease. Interestingly, the survivals of patients with involvement up to interlobar nodes (station 11), main bronchus nodes (station 10), and subcarinal nodes (station 7) were identical. These data constitute the basis for a larger investigation to develop a lymph node map in lung cancer.

The purpose of this study was to investigate the effect of ageing on body sway during sit-to-stand movement from a chair and on quadriceps muscle strength in the elderly population. A total of 275 community dwellers volunteered to participate in this study. All subjects signed an informed consent statement prior to participating in this study. They were required to be able to perform a sit-to-stand movement from a chair independently. The postural sway for the subjects during the sit-to-stand movement from the chair was measured using a stabilometer. The analog signals of the subjects' center of pressure in the anterior-posterior direction (%Y-axis) derived from the stabilometer were recorded. The maximum isometric muscle strength of knee extension was measured using an isometric dynamometer at 90 degrees flexion of the knee joint. Our results demonstrate that as age increased, lower extremity muscle strength decreased, and forward shift of the center of pressure also decreased. It is possible that the elderly subjects could not use their propelling power because of decreased lower extremity muscle strength. Therefore, the forward shift of the center of pressure of elderly subjects also decreased causing them difficulty in standing up from a chair. Therefore, we believe that we there is a need to educate elderly people about accurate sit-to-stand movement and the importance of lower extremity muscle strength exercise.

Apical hypertrophic cardiomyopathy (HCM) is a well-known myocardial disease, but the additional coexistence of an atrial septal defect (ASD) and coronary spasm is quite rare. We report here on a 62-year-old man suffering from congestive heart failure due to apical HCM complicated by coronary spasm and secundum-type ASD. The transthoracic, transesophageal echocardiography and cardiac catheterization were useful for diagnosing and evaluating of the patient's status. A calcium channel blocker was given to prevent coronary spasm, and a surgical patch closure operation was successfully performed. Afterwards, his symptoms were alleviated.

Left ventricular (LV) aneurysm has been recognized to frequently become a substrate of ventricular tachyarrhythmias. We report a case of a 66-year-old woman with symptomatic sustained monomorphic ventricular tachycardia (SMVT) originating from saccular apical LV aneurysm without definite underlying diseases. We performed catheter ablation using electroanatomical and conventional bipolar potential mapping. During SMVT, we found an area of fragmented potential -40 ms preceding the earliest wide QRS complex in the area of the apical LV aneurysm. Radiofrequency applications were delivered to this area. Since then, SMVT was no longer inducible by programmed electrical stimulation. The patient has remained free of VT recurrences during a subsequent 12-month follow-up period.

Diabetic mastopathyは長期罹患の糖尿病患者にみられる乳腺の良性疾患であるが,臨床所見や画像上,癌と類似しているため鑑別が困難である.今回われわれはdiabetic mastopathyの5例を経験したので,報告する.年齢は34-73歳, 1型糖尿病(IDDM)が2例, 2型糖尿病(NIDDM)が3例.インスリン使用は3例(IDDM 2例, NIDDM 1例)であった.触診所見では全例に腫瘤を認めるが,マンモグラフィーでは2例に腫瘤影を認め,その他の症例はdense breastで腫瘤は同定できなかった.乳腺超音波では辺縁不整,低エコーの腫瘤を認めた. Fine needle aspiration cytology (FNA)では全例細胞が少なく, core needle biopsyまたはopen biopsyではじめて本症の確定診断を得た.病理組織学的にはいずれも硝子化した厚い膠原線維の増生と乳管周囲のリンパ球浸潤を認め, diabetic mastopathyに一致する所見であった.

Squamous cell carcinoma of the breast is uncommon, but that of the nipple skin is rarer. The effect of chemotherapy in these cases is yet to reach consensus. We report a rare case in which primary squamous cell carcinoma of the nipple skin was successfully treated with S-1 alone. A 64-year-old woman was admitted to our hospital because of a granulomatous tumor mass over the right nipple, which she was aware of for 10 years; the tumor showed a rapid increase in growth before admission. The tumor was approximately 4 cm at the first visit, and was diagnosed as squamous cell carcinoma by incisional biopsy. We administered preoperative systemic chemotherapy owing to the presence of metastasis in an axillary lymph node. After 2 courses of chemotherapy with oralS -1 at 100mg/day for 28 days followed by a 14-day resting period, the primary tumor and metastatic lymph node showed a remarkable reduction in size. The patient subsequently underwent a radical operation and is currently healthy without any recurrence.

Before video-assisted thoracoscopic surgery (VATS) became widespread, surgical curability was thought to be the most important issue concerning thoracic surgery; extended surgery was preferred, and postoperative pain did not appear to be a priority. Therefore, only few studies have so far focused on postoperative pain associated with VATS. Although surgical disease curability is important, postoperative pain is also an important issue for patients. Patients will choose to undergo surgery in the institute that can perform both curative and postoperatively painless surgery if possible. Lesser postoperative pain also leads to earlier ambulation and discharge, and could potentially allow earlier initiation of the next stage of therapy (including chemotherapy and radiation) due to faster patient recovery both mentally and physically; this may result in a better outcome.

陳旧性心筋梗塞入院患者29例Holter心電図による, 心拍変動の時間領域解析と周波数領域解析の諸指標について, T/P比が相異なるOa拮抗薬, すなわち, T/P比が小さなニフェジピンとT/P比が大きなアムロジピンによる影響を血漿ノルエピネフリン値の変動と対比して検討した.周波数領域解析では, ニフェジピン投与後, LF/HFは急激に増大したが, アムロジピン投与では緩徐に増大した.さらに, 時間領域解析では, SDとSDANNはニフェジピン投与後, べースライン時より低下したのに対し, アムロジピン投与後, 逆に増大し, 投薬終了時点においては, 両群間に有意差が認められた.また, 血漿ノルエピネフリン値はニフエジピン投与後, 著明に増加したが, アムロジピン投与後はべースライン時との間に有意な変動は認められなかった.

We evaluated the association between coronary spasm and hyperinsulinemia (high immunoreactive insulin, IRI) in patients with angina pectoris. The study cohort comprised 30 patients with spastic angina pectoris, 30 patients with angina pectoris showing fixed-obstructive coronary sclerosis and 30 control subjects who were matched for body mass index, age and sex. A 75-gram oral glucose test was performed, and blood sugar and IRI were serially measured concomitant with serum total cholesterol, triglyceride and HDL cholesterol. The IRI level at 60 min, the peak IRI during the test, sigma IRI and sigma IRI/sigma blood sugar were significantly higher in the patients than in the controls. Total cholesterol and LDL cholesterol levels were significantly increased in patients showing fixed-obstructive coronary sclerosis compared to controls.

The VIO soft-coagulation system is a new device for tissue coagulation in which the output voltage is automatically regulated. We evaluated the safety and efficacy of this system for major pulmonary resection of lung cancer.We used bipolar VIO soft-coagulation for major pulmonary resection in 68 patients with primary lung cancer using the following three surgical procedures: (1) coagulation of the tissues around lobar vessels and bronchus; (2) fissure dissection; (3) lymph node dissection. The dissection in those steps was performed with both bipolar VIO soft-coagulation forceps and scissors. Results were analyzed with special reference to intraoperative complications, blood loss, and postoperative morbidity. The data in this study (VIO group) were compared with those of 78 lung cancer patients who underwent surgery using conventional electrocautery (CE group).The operations in this series included 60 lobectomies, 1 bilobectomy, 1 pneumonectomy, and 6 segmentectomies. With the VIO soft-coagulation system, coagulation of tissues around the lobar pulmonary vessels without injury to the pulmonary vessels or bronchus was effective. The mean blood loss in the VIO group was 90.6 g (range 5-595 g), which was significantly lower than that in the CE group (mean 141.0 g, range 5-700 g) (P = 0.014). Postoperative morbidity rates in the VIO and the CE group were 11.7% and 17.9%, respectively.The VIO soft-coagulation system is safe and feasible for major pulmonary resections in patients with lung cancer.

Secreted protein acidic and rich in cysteine (SPARC) is a protein which governs diverse cellular functions and matrix remodeling systems. It was reported that SPARC expression of peritumoral fibroblasts was correlated with poor prognosis in resectable pancreatic cancer patients in immunohistochemical analysis. However, the significance of SPARC mRNA expression in pancreatic adenocarcinoma remains unclear.SPARC mRNA expression was evaluated in 104 formalin-fixed paraffin-embedded tissue samples of pancreatic adenocarcinoma patients with macro-dissection technique.High SPARC mRNA expression was associated with a poorer prognosis than low SPARC. In univariate Cox's proportion hazard model, depth of tumor invasion, lymph node metastasis, histopathological tumor grade, lymphatic invasion, vascular invasion, surgical margin, no chemotherapy and high SPARC expression were significant prognostic factors. In multivariate analysis, histopathological tumor grade, surgical margin, no chemotherapy and high SPARC expression were independent significant prognostic factors.SPARC mRNA expression is a prognostic marker for pancreatic adenocarcinoma patients.

The study aim was to examine the effect of combination therapy comprising angiotensin receptor blocker plus calcium antagonist on post-treatment plasma adiponectin levels compared to pretreatment levels. There was a significant gender difference in the relationship between preadiponectin level and age. In the search for contributing factors for treatment-based changes in adiponectin levels, these effects of gender and age were considered in statistical analysis. The adiponectin level in the combination therapy group was further increased compared to that in each of the monotherapy groups, despite there being no significant difference in antihypertensive effect, indicating that the combined medication provided an effect beyond that of lowering blood pressure.

Pancreatic ductal adenocarcinoma is often characterized by an abundant desmoplastic stroma that is partially induced by activated pancreatic stellate cells (PSCs). Indirect co-culture has often been used to investigate the effects of cancer-stromal interactions on the proliferation of cancer cells, but the effects of cell-cell adhesion and juxtacrine signaling between cancer and stromal cells cannot be evaluated using this method. This study aimed to establish a simplified direct co-culture system that could be used to quantify populations of cancer cells in co-culture with PSCs, and to evaluate the effects of direct cell contact on the proliferation of cancer cells. We established three green fluorescent protein (GFP)-expressing pancreatic cancer cell lines and were able to quantify them with high reliability and reproducibility, even when co-cultured directly with PSCs, using a color plate reader. We assessed the differential effects of direct and indirect co-culture with PSCs on the proliferation of cancer cells, and found that the proliferation of GFP-expressing pancreatic cancer cell lines was dramatically enhanced by direct co-culture with PSCs, compared with the indirect co-culture system. We also found that direct co-culture of cancer cells and PSCs activated the Notch signaling pathway in both cell types. Direct cell contact between cancer cells and PSCs plays an important role in the control of cancer cell proliferation, and is essential to the understanding of tumor-stromal interactions.

Adenovirus-mediated gene therapy combined with chemotherapeutic agents is expected to represent a new approach for treating pancreatic cancer. However, there have been no reports of definitive effects of chemotherapeutic agents on adenovirus-mediated gene therapies. In the present study, we investigated the effects of chemotherapeutic agents on the transduction efficiency of an adenovirus-based gene therapy. Adenovirus (Ad-NK4) expressing NK4, which acts as a hepatocyte growth factor antagonist, was used as a representative gene therapy. Pancreatic cancer cells infected with Ad-NK4 were treated with chemotherapeutic agents (5-fluorouracil [5FU], cisplatin or etoposide), and the NK4 levels in their culture media were measured. To examine the effects of chemotherapeutic agents in vivo, Ad-NK4 was administered to subcutaneous tumors in mice after treatment with the agents, and the tumor NK4 levels were measured. The NK4 levels in culture media from cells treated with 5FU, cisplatin and etoposide were 5.2-fold (P = 0.026), 6-fold (P < 0.001) and 4.3-fold (P < 0.001) higher than those of untreated cells, respectively. The chemotherapeutic agents also increased Ad-NK4 uptake. The NK4 levels in tumors treated with 5FU, cisplatin and etoposide were 5.4-fold (P = 0.006), 11.8-fold (P < 0.001) and 4.9-fold (P = 0.017) higher than those in untreated tumors, respectively. The present findings suggest that chemotherapeutic agents significantly improve the efficiency of adenovirus-mediated gene transfer in pancreatic cancer. Furthermore, they will contribute to decreases in the adenovirus doses required for gene transfer, thereby controlling the side-effects of adenovirus infection in normal tissues.

Increased ventricular pacing thresholds have been observed following monophasic implantable cardioverter defibrillator (ICD) shocks.To examine changes following high-energy biphasic shocks delivered by integrated bipolar ICD systems.Ten episodes of ventricular fibrillation (VF) were induced at 10 min intervals in nine pigs with integrated ICD systems. After 10 s of each episode of VF, a 40 J biphasic shock was delivered, which successfully terminated VF (a total of 10 shocks). The bipolar pacing threshold at the right ventricular apex was measured before each shock and at 1 min intervals after each shock.The mean pacing threshold was 0.029+/-0.059 muJ before the first shock and gradually increased to 0.14+/-0.10 muJ after the 10th shock.It may be necessary to pace at a high-voltage output following biphasic shocks delivered by integrated bipolar ICD systems.

Forty-seven community-dwelling older adults aged >70 years participated in this Japanese cross-sectional study to determine the relationship between the isometric lower extremity muscle strength measured during knee extension (KE) in single-joint and total leg extension (TLE) in multi-joint tasks, physical performance tests, and functional status. The physical performance was determined by KE and TLE muscle strength, walking capacity, and balance performance tests, while the functional status was evaluated by interview using basic activities of daily living (ADL) and instrumental activities of daily living (IADL) tools. The results indicated that the TLE muscle strength was significantly related to all the other performance tests, while the KE muscle strength was not correlated with the balance test. Also, the bilateral TLE muscle strength was significantly associated with IADL status compared with the KE muscle strength. In conclusion, multi-joint muscle strength testing might be superior to single-joint muscle strength testing for the screening of the functional impairments of older adults.

Controversy regarding the most suitable surgical approach for treating malignancies of the lung is a matter of continuous discussions. "Complete" video-assisted thoracic surgery (VATS) that is performed using only the vision of a monitor is generally limited to lung resections of minimal difficulty. With the great interest in minimally invasive techniques for treating various pathologies, we have widely applied an integrated surgical approach that combines muscle-sparing minithoracotomy (incision, 4 to 10 cm) and video assistance using mainly direct visualization of the lung resection, which we have called hybrid VATS. The aim of this study is to evaluate the usefulness of hybrid VATS.Retrospective single-center study.From January 1998 to October 2004, 405 of 678 lobectomies (60%) and 165 of 226 segmentectomies (73%) were performed for primary lung cancer using hybrid VATS.Bronchoplasty was performed in 93 of the 678 patients (14%) who underwent lobectomy and in 11 of the 226 patients (5%) who underwent segmentectomy. Hybrid VATS was utilized in 33% of sleeve lobectomy procedures and in 27% of sleeve segmentectomy procedures. The mean (+/- SD) surgical time using hybrid VATS was 164 +/- 48 min for lobectomy and 158 +/- 35 min for segmentectomy, and the mean blood loss was 166 +/- 120 and 109 +/- 80 mL, respectively. There was one operative mortality (0.2%) secondary to cardiogenic shock. Postoperative complications developed in 11% of patients with p-stage IA disease after undergoing hybrid VATS, in contrast to 19% of patients after undergoing open thoracotomy. The prognosis of patients treated by hybrid VATS was equivalent to that obtained with open thoracotomy.Minithoracotomy combined with video support that is performed predominantly via direct visualization is a secure, integrated, minimally invasive approach to performing major resection for lung cancer, including atypical procedures such as bronchoplasty. This hybrid VATS can be an acceptable and satisfactory option whenever the performance of complete VATS is considered to be challenging.

Nanos is one of the evolutionarily conserved proteins implicated in germ cell development and we have previously shown that it interacts with the CCR4-NOT deadenylation complex leading to the suppression of specific RNAs. However, the molecular mechanism and physiological significance of this interaction have remained elusive. In our present study, we identify CNOT1, a component of the CCR4-NOT deadenylation complex, as a direct factor mediating the interaction with NANOS2. We find that the first 10 amino acids (AAs) of NANOS2 are required for this binding. We further observe that a NANOS2 mutant lacking these first 10 AAs (NANOS2-ΔN10) fails to rescue defects in the Nanos2-null mouse. Our current data thus indicate that the interaction with the CCR4-NOT deadenylation complex is essential for NANOS2 function. In addition, we further demonstrate that NANOS2-ΔN10 can associate with specific mRNAs as well as wild-type NANOS2, suggesting the existence of other NANOS2-associated factor(s) that determine the specificity of RNA-binding independently of the CCR4-NOT deadenylation complex.

In an attempt to simplify the recording technique in electrophysiologic evaluation of the retinal pigment epithelium, we combined the electro-oculographic light rise, hyperosmolarity and acetazolamide responses in a single recording session. Recordings were performed in six normal subjects and in seven patients with diabetic retinopathy or retinitis pigmentosa. In the patients with background diabetic retinopathy, the hyperosmolarity responses were slightly reduced, while the acetazolamide response and the light rise was normal. In the patients with proliferative diabetic retinopathy, the hyperosmolarity response and light rise were remarkably reduced, while the acetazolamide response was normal. In the patients with retinitis pigmentosa, the hyperosmolarity response and light rise were decreased, while the acetazolamide response was normal. Despite a small study population, we concluded that the clinical results from our combined recording protocol were essentially the same as those reported for each response separately. Because this recording technique simplifies electrophysiologic evaluation of the retinal pigment epithelium, it may help clarify the mechanisms or localization of retinochoroidal and pigment epithelial diseases.

The product of the copper-promoted allylic substitution of the 4-hydroxycyclopent-2-enyl ester with TMS-C≡CCH 2 MgBr was converted to the cyclopentenone with the PMBO(CH 2 ) 4 CH=CHCH 2 side chain. Aldol reaction of the enone with the epoxy aldehyde derived from (E)-oct-2-en-1-ol through the Sharpless asymmetric epoxidation gave the full structure of the isoprostane. Dehydration, conversion of the PMBOCH 2 moiety to CO 2 H, and condensation with lysophosphorylcholine produced the title molecule.