Search

IL‐2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti‐immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL‐2, Mutakine‐6 (MK‐6), with reduced IL‐2Rα–binding capability. MK‐6 induced comparable cell growth potential toward IL‐2Rβγ–positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL‐2, in vivo administration of MK‐6 produced minimal adverse effects. Using CT26 and B16F10‐syngeneic tumor models, we found MK‐6 was highly efficacious on tumor regression. Serum albumin conjugation to MK‐6 prolonged in vivo half‐life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor‐infiltrating leukocytes analysis revealed that albumin‐fused MK‐6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK‐6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation., Albumin‐conjugated IL‐2 mutein, MK‐6, exerts a potent antitumor effect in the CT26 tumor model.

OBJECTIVE Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. DESIGN AND PATIENTS Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or

Begonia togashii Nob. Tanaka & C.I Peng is illustrated. Though Begonia togashii was described only in 2016, it had been unnamed for nearly 40 years after its discovery from Myanmar by an outstanding Japanese plant hunter, Makoto Togashi. The interesting history of naming this species is given.

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

CONTEXT The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. OBJECTIVE To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. DESIGN AND PATIENTS A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). RESULTS PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P

INTRODUCTION The goal of partial nephrectomy for renal tumors is complete tumor removal with the preservation of renal function and no complications. Trifecta (total ischemia time

Bacillus Calmette-Guerin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

Cancers acquire resistance to systemic treatment with platinum‐based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single‐cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA‐seq, we uncovered a novel gene, COX7B, associated with platinum‐resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA‐seq data from platinum‐naïve cancer cells demonstrated a low‐COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low‐COX7B subclone behaved as cells with acquired platinum‐resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum‐resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

To facilitate the adaptive management of subalpine ecosystems in the Korean Peninsula under climate change conditions, we identified the climatic factors that determine the distribution of two dominant subalpine firs (Abies koreana and A. nephrolepis). We also identified sustainable and vulnerable habitats for these species inside and outside of current protected areas under climate change scenarios. The minimum temperature of the coldest month, and the amount of precipitation in the warmest quarter were the most important climatic variables that determined the distribution of these two Abies species. Potential habitats for A. koreana and A. nephrolepis were predicted to decrease to 3.3% and 36.4% of the current areas due to climate change, irrespective of whether inside or outside the protected areas. It was predicted that the potential habitats for A. nephrolepis would be maintained in the northern part of the Korean Peninsula, and sustainable potential habitats outside the protected areas were predicted in central parts of the Korean Peninsula. The potential habitats for A. koreana were predicted to disappear from Is. Jeju and shrink significantly in the Korean Peninsula. These results suggest that, in central parts of the Korean Peninsula, revision of protected areas would be effective in preserving A. nephrolepis under conditions of future climate change. In contrast, revision of protected areas would be insufficient to conserve A. koreana due to their high vulnerability and limited populations. Active management is required to ensure the survival of A. koreana under future climate conditions.

Climate change will likely change the species composition or abundance of plant communities, and it is important to anticipate these changes to develop climate change adaptation policies. We chose beech (Fagus crenata Blume) and its competitive tree species as target species to evaluate potential turnover in forest types under climate change using a multivariate classification tree model. To construct the model, geographical presence/absence data for nine target species were used as multivariate response variables, with five climatic factors were used as predictor variables. Current and future distribution probabilities for the target species were calculated, and the 15 dominant forest types were subjectively classified in approximately 1-km2 grid cells within the area of the current beech forest distribution. All 16,398 grid cells of the beech-dominant forest type (FCR-QCR) were projected to be replaced in the future by five Quercus crispula-dominant types (59% of FCR-QCR grid cells), four Q. serrata types (22%), two Q. salicina types (8%), or two Abies firma types (0.1%). The FCR-QCR type remained unchanged (stable) in only 11.4% of grid cells; these were mainly distributed at high elevations in snowy areas on the Sea of Japan side of the country. In contrast, vulnerable habitats (future probability of beech occurrence less than 1.0%) were found at low elevations on both the Sea of Japan and the Pacific Ocean sides. Northwards or upwards range expansions or increases of Quercus spp., in particular, need to be carefully monitored.

Background In recent years, a variety of clinical types of amyotrophic lateral sclerosis have come to be recognized. As some patients present with oculomotor abnormalities both clinically and pathologically, the progressive supranuclear palsy variant of amyotrophic lateral sclerosis has been proposed. Aim To describe atypical cases of motor neuron disease with abnormal extraocular movements mimicking progressive supranuclear palsy. Methods We present three motor neuron disease patients with slow saccades, who were aged 57, 63 and 62 years. Neurological examinations found vertical gaze palsy in two patients. The two patients who presented extrapyramidal signs were regarded as motor neuron disease with parkinsonism, whereas the other was diagnosed with amyotrophic lateral sclerosis. Their saccades were investigated by visually-guided saccade and memory-guided saccade tasks, and were compared with those of 14 age-matched normal participants (60.3 ± 1.9 years). Results In all these patients, the visually-guided saccade latencies were significantly prolonged compared with normal participants, whereas the memory-guided saccade latencies were not. The velocity and amplitude of saccades of the patients were significantly reduced in visually-guided saccade and memory-guided saccade in comparison with normal participants. Conclusion The patterns of saccadic abnormalities in the patients were similar to those of progressive supranuclear palsy patients, suggesting that some patients with motor neuron disease show saccade abnormalities similar to those of progressive supranuclear palsy patients from the clinical and physiological perspective. Motor neuron disease with slow saccades and parkinsonism, as reported here, suggest the existence of progressive supranuclear palsy-variant amyotrophic lateral sclerosis.

Objectives To investigate the impact of perioperative plasma fibrinogen level as a biomarker of oncological outcome in localised renal cell carcinoma (RCC). Patients and methods We consecutively identified 601 patients with localised RCC who underwent curative surgery at a single institution. Subsequent disease recurrence and cancer-specific survival (CSS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic impact of plasma fibrinogen level, multivariate analysis was performed for these outcomes. Results Using the defined threshold level of preoperative plasma fibrinogen of ≥420 mg/dL as elevated, we found 56 patients (9.3%) with an elevated plasma fibrinogen level preoperatively. In Kaplan–Meier analysis, there was a significant difference in disease-free survival and CSS rates between patients with and without preoperative plasma fibrinogen levels of ≥420 mg/dL. Multivariate analysis showed that elevated preoperative plasma fibrinogen level was an independent predictor of subsequent disease recurrence and cancer-specific mortality. In a subgroup analysis of the elevated preoperative plasma fibrinogen level group, postoperative normalisation of plasma fibrinogen level was significantly associated with CSS, showing that patients with non-normalised plasma fibrinogen levels tended to have a higher incidence of cancer-specific mortality after surgery. Conclusion Patients with elevated preoperative plasma fibrinogen levels could be significantly predicted to have subsequent tumour metastasis and cancer-specific mortality, while there was a significant difference in CSS between patients in the normalised and non-normalised postoperative plasma fibrinogen groups. While these are hypothesis generating results, plasma fibrinogen levels may be a useful biomarker due to its low cost and ease of assessment.

Cholangiocarcinoma is an aggressive malignant tumor originating from intrahepatic or extrahepatic bile ducts. Its malignant phenotypes may be assumed by cancer stem cells (CSC). Here, we demonstrate that CD274 (PD-L1), known as an immunomodulatory ligand, has suppressive effects on CSC-related phenotypes of cholangiocarcinoma. Using two human cholangiocarcinoma cell lines, RBE and HuCCT1, we attempted to isolate the CD274(low) and CD274(high) cells from each cell line, and xenografted them into immunodeficient NOD⁄scid⁄γcnull (NOG) mice. We found that the CD274(low) cells isolated from both RBE and HuCCT1 are highly tumorigenic in NOG mice compared with CD274(high) cells. Furthermore, the CD274(low) cells possess several CSC-related characteristics, such as high aldehyde dehydrogenase (ALDH) activity, reduced reactive oxygen species production and a dormant state in the cell cycle. Furthermore, depletion of CD274 expression by shRNA in RBE cells enhances their tumorigenicity and increases ALDH activity. These findings are compatible with our observation that clinical cholangiocarcinoma specimens are classified into low and high groups for CD274 expression, and the CD274 low group shows poorer prognosis when compared with the CD274 high group. These results strongly suggest that CD274 has a novel function in the negative regulation of CSC-related phenotypes in human cholangiocarcinoma, which is distinct from its immunomodulatory actions.

Tumor suppressor p53 prevents tumorigenesis and tumor growth by suppressing the activation of several transcription factors, including nuclear factor-κB (NF-κB) and STAT3. On the other hand, p53 stimulates actin cytoskeleton remodeling and integrin-related signaling cascades. Here, we examined the p53-mediated link between regulation of the actin cytoskeleton and activation of NF-κB and STAT3 in MCF-7 cells and mouse embryonic fibroblasts (MEFs). In the absence of p53, STAT3 was constitutively activated. This activation was attenuated by depleting the expression of p65, a component of NF-κB. Integrin β3 expression and lamellipodia formation were also downregulated by NF-κB depletion. Inhibition of integrin αvβ3, Rac1 or Arp2/3, which diminished lamellipodia formation, suppressed STAT3 activation induced by p53 depletion. These results suggest that loss of p53 leads to STAT3 activation via NF-κB-dependent lamellipodia formation. Our study proposes a novel role for p53 in modulating the actin cytoskeleton through suppression of NF-κB, which restricts STAT3 activation.

Thready stripe-polyacrylamide (PAAm) pattern was fabricated on a thermoresponsive poly(N-isopropylacrylamide) (PIPAAm) surface, and their surface properties were characterized. A PIPAAm surface spin-coated with positive photoresist was irradiated through a 5 µm/5 µm or a 10 µm/10-µm black and white striped photomask, resulting in the radical polymerization of AAm on the photoirradiated area. After staining with Alexa488 bovine serum albumin, the stripe-patterned surface was clearly observed and the patterned surface was also observed by a phase contrast image of an atomic force microscope. NIH-3T3 (3T3) single cells were able to be cultured at 37°C on the patterned surfaces as well as on a PIPAAm surface without pattern, and the detachment of adhered cells was more rapidly from the patterned surface after reducing temperature. Furthermore, the rate of detachment of 3T3 confluent cell sheet on the patterned surface was accelerated, compared with on a conventional PIPAAm surface under the static condition. The rate control of cell sheet recovery should contribute the preservations of cell phenotype and biological functions of cell sheet for applying to clinical trials.

Objectives To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. Patients and Methods A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. Results The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). Conclusions Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

Advanced renal cell carcinoma (RCC) remains an incurable disease, and newer anticancer drugs are needed. Bisebromoamide, a novel cytotoxic peptide, was isolated from the marine cyanobacterium Lyngbya species at our laboratory in 2009. This compound specifically inhibited the phosphorylation of ERK in platelet-derived growth factor-activated normal rat kidney cells. The aim of this study was to evaluate the effect and elucidate the potential mechanism of Bisebromoamide actions on human RCC cells. Two renal cancer cell lines, 769-P and 786-O, were used. The effects of Bisebromoamide were analyzed employing assays for water-soluble Tetrazolium-1 salts. Apoptosis was determined by flow cytometric TUNEL analysis. Cell-cycle distributions were analyzed by flow cytometry using BrdU/propidium iodide (PI) staining. Kinases of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR) pathway and Raf/MEK/ERK pathway were analyzed by Western blotting. After Bisebromoamide treatment for 48 and 72 h, cell viability was significantly decreased in both cell lines at 1 and 10 μmol/L. After treatment with 1 μmol/L Bisebromoamide for 72 h, apoptosis and the increased percentage of cells in the sub-G1 phase were observed in both cell lines. Bisebromoamide inhibited the phosphorylation of ERK and Akt in both cell lines tested. Similar effects were demonstrated for phosphorylation of mTOR and p70 S6. Bisebromoamide is a promising potential agent against RCC due to its ability to inhibit both the Raf/MEK/ERK and PI3K/Akt/mTOR pathways.

East Asia's temperate deciduous forests served as sanctuary for Tertiary relict trees, but their ages and response to past climate change remain largely unknown. To address this issue, we elucidated the evolutionary and population demographic history of Cercdiphyllum, comprising species in China/Japan (Cercdiphyllum japonicum) and central Japan (Cercdiphyllum magnificum). Fifty-three populations were genotyped using chloroplast and ribosomal DNA sequences and microsatellite loci to assess molecular structure and diversity in relation to past (Last Glacial Maximum) and present distributions based on ecological niche modelling. Late Tertiary climate cooling was reflected in a relatively recent speciation event, dated at the Mio-/Pliocene boundary. During glacials, the warm-temperate C. japonicum experienced massive habitat losses in some areas (north-central China/north Japan) but increases in others (southwest/-east China, East China Sea landbridge, south Japan). In China, the Sichuan Basin and/or the middle-Yangtze were source areas of postglacial northward recolonization; in Japan, this may have been facilitated through introgressive hybridization with the cool-temperate C. magnificum. Our findings challenge the notion of relative evolutionary and demographic stability of Tertiary relict trees, and may serve as a guideline for assessing the impact of Neogene climate change on the evolution and distribution of East Asian temperate plants.

What's known on the subject? and What does the study add? Upper tract urothelial carcinoma (UTUC) is relatively uncommon, accounting for only ∼5% of urothelial malignancies and 10% of all renal tumours. Radical nephroureterectomy (RNU) with bladder cuff excision is the surgical standard of care for treating localized UTUC, but the prognosis for patients who undergo RNU remains poor. Evidence suggests that an interactive relationship exists between haemostatic factors and tumour biology. A number of procoagulant and fibrinolytic factors have been found to be overexpressed in tumours. One of these factors is plasma fibrinogen. Recent studies have shown that elevated pre-therapeutic plasma fibrinogen levels are associated with worse outcome in various malignancies; however, the prognostic value of plasma fibrinogen levels for UTUC has not yet been reported. To the best of our knowledge, this is the first paper to evaluate the prognostic impact of preoperative plasma fibrinogen levels in patients with localized UTUC treated surgically. We believe that the present results may assist in decision-making with respect to the need for lymph node dissection and neoadjuvant chemotherapy. Objective To investigate the prognostic value of plasma fibrinogen levels as a predictor of patient outcome in upper tract urothelial carcinoma (UTUC). Patients and Methods A total of 218 patients who underwent radical nephroureterectomy (RNU) for localized UTUC (pTa-4N0M0) were identified between 1995 and 2009. The association between preoperative plasma fibrinogen levels and clinicopathological variables was analysed. Results Forty-five patients experienced tumour recurrence, and 36 died from disease during the mean follow-up of 51 months. The mean (sd) preoperative plasma fibrinogen level was 362 (103) mg/dL. Kaplan–Meier curves showed that subsequent tumour recurrence was strongly predicted in patients with preoperative plasma fibrinogen levels ≥450 mg/dL, and similar results were observed for cancer-specific survival. On multivariate analysis we found that a preoperative plasma fibrinogen level of ≥450 mg/dL was an independent risk factor for subsequent tumour recurrence and cancer-specific survival. The 5-year recurrence-free survival rate was 56.9% in patients with plasma fibrinogen levels ≥450 mg/dL and 81.5% in patients with plasma fibrinogen levels

UNLABELLED: What's known on the subject? and What does the study add? So far, few previous reports have analysed the risk factors for tumour recurrence and stage progression with a special focus on BCG-relapsing disease, defined as the recurrence after achieving a disease-free status by initial BCG instillations for 6 months. There are no guidelines outlining a specific treatment strategy for BCG-relapsing disease, although many BCG failure cases are attributable to BCG-relapsing disease. In this study, additional BCG instillation was shown to decrease the subsequent tumour recurrence rate against BCG-relapsing tumours with intermediate pathological risk features; however, a BCG-relapsing tumour with a pathologically high risk was a significant risk factor for both subsequent tumour recurrence and stage progression. This information might identify a therapeutic strategy for BCG-relapsing tumours. OBJECTIVE: • To investigate the risk of subsequent tumour recurrence and stage progression in bacillus Calmette-Guerin (BCG)-relapsing non-muscle-invasive bladder cancer, defined as recurrence after achieving a disease-free status for 6 months. PATIENTS AND METHODS: • A total of 183 patients with BCG-relapsing tumours were treated with conservative therapy between 1985 and 2008 at our three institutions. • We analysed the association between their clinicopathological parameters and subsequent tumour recurrence or stage progression. RESULTS: • Additional induction courses of BCG or anticancer drug (mitomycin C or epirubicin) instillations were performed in 119 patients and 24 patients, respectively. The remaining 40 patients did not undergo any adjuvant therapy. • Multivariate analysis showed that a relapsing tumour with a pathologically high risk (defined as tumours with G3 and/or pT1 and/or concomitant carcinoma in situ) was a significant risk factor for subsequent tumour recurrence (P= 0.002; hazard ratio [HR] 2.15). Additional BCG instillation significantly decreased the subsequent tumour recurrence rate (P

UNLABELLED What's known on the subject? and What does the study add? Adjuvant intravesical BCG therapy is the most effective regimen for non-muscle-invasive bladder cancer. Previously, patients who experienced recurrences after BCG therapy tended to be lumped together as patients with 'BCG failure', but BCG failure was defined inconsistently in each study and several studies indicated that patients with a particular pattern of BCG failure had a worse prognosis. We divided patients with BCG failure into four groups, which were based mainly on the responsiveness to BCG therapy and duration until tumour recurrence. Patients in the BCG-refractory group, in particular, had a higher risk for subsequent stage progression and disease-specific death over a long duration compared with patients in the other BCG-failure groups. As the definitions of BCG failure used to date have been decidedly heterogeneous, we recommend that standardized treatment decisions, protocols and recommendations be established according to individual BCG failure patterns. OBJECTIVE To investigate the differences in the clinical features and subsequent stage progression and disease-specific survival among patients with Bacillus Calmette-Guerin (BCG) failure, after dividing these patients into BCG-refractory, -resistant, -relapsing, and -intolerant groups. PATIENTS AND METHODS We identified 173 patients with initial BCG failure from 521 patients who had undergone induction BCG therapy for non-muscle-invasive bladder cancer, excluding CIS, between 1987 and 2009. Patients were stratified into four BCG-failure groups, and each prognostic outcome was evaluated. RESULTS Median follow-up period from initial BCG failure was 4.7 years. A total of 42 patients (24.3%) were stratified into the BCG-refractory, three (1.7%) into the BCG-resistant, 106 (61.3%) into the BCG-relapsing, and 22 (12.7%) into the BCG-intolerant group. Twenty-four patients (13.9%) experienced stage progression during follow-up. Multivariate analysis showed that pathological G3 at BCG failure (P = 0.014; risk ratio 2.84) and BCG-refractory (P < 0.001; risk ratio 4.68) were independent predictors for stage progression. The 10-year progression-free survival rates were 53.2%, 91.1% and 93.8% in the BCG-refractory, BCG-relapsing and BCG-intolerant groups, respectively. The stage progression rate was higher in the BCG-refractory than in the BCG-relapsing (P < 0.001) and BCG-intolerant (P = 0.007) groups. Similarly, the 10-year disease-specific survival rate in the BCG-refractory group was significantly worse than those in the other BCG failure groups (P < 0.001). CONCLUSIONS Stratification of BCG failure into the above-mentioned four groups can identify patients with BCG-failure in terms of their prognosis. The potential risk for critical adverse events was higher in the BCG-refractory group than in the other BCG-failure groups, despite the fact that patients in each group all underwent induction BCG therapy, therefore, treatment decisions, protocols and recommendations should be established based on each individual BCG-failure pattern.

A 72-year-old male visited the hospital with a complaint of dyspnea. Under the diagnosis of pulmonary hypertension (PH) due to chronic thrombotic and/or embolic disease, this patient received anti-coagulant therapy. Unfortunately, the respiratory state deteriorated and died 34 days after admission. At autopsy, noncaseating granulomas, which were diagnostic of sarcoidosis, were found in bilateral enlarged hilar lymph nodes, lungs, heart, liver, spleen, testis and epididymis. In pulmonary vasculature, the following three kinds of lesions were observed; (i) sarcoid granulomatous vasculitis at the peripheral arteries and veins, (ii) intimal fibrous lesions ubiquitously found in proximal and peripheral arteries which were thought to be organized thromboemboli, (iii) Takayasu-like large vessel vasculitis with a huge fresh mural thrombus narrowing the lumen of most proximal portion of right pulmonary artery. Autopsy findings indicate that chronic sustained PH state in this patient was attributable to thrombotic and/or thromboembolic disease, and Takayasu-like vasculitis with thrombus played a role in the final deterioration of respiratory state through exacerbation of PH. In sarcoidosis patients, vasculitic lesions which can be formed in both small and large pulmonary arteries must be raised as the differential diagnosis for the initial cause of PH as well as the accelerating factor of PH.

S-1 is a recently developed dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine and has demonstrated high maximum plasma 5-Fluorouracil (5-FU) levels with mild toxicity, and an oral formulation has resulted in an improvement in patient quality of life. The aims of the present study were to determine the efficacy of S-1 or S-1 combined with docetaxel (DOC) using castration resistant prostate cancer (CRPC) cells and to explore their clinical potential for treating CRPC patients. LNCaP cells, androgen dependent prostate cancer (ADPC) cells and C4-2 cells, which are a CRPC subline of LNCaP cells, were used. Specimens obtained from ADPC and CRPC patients were also evaluated. The CRPC specimens and C4-2 cells exhibited significantly lower thymidylate synthase (TS) expression, a target of 5-FU, than the ADPC specimens and LNCaP cells. In vitro, C4-2 cells exhibited higher sensitivity to 5-FU than LNCaP cells. In C4-2 xenograft model, S-1 monotherapy suppressed tumor growth and low-dose DOC enhanced the anti-tumor effect of S-1. In vitro, low-dose DOC, which did not induce G2/M arrest, increased p53 and p21 and resulted in down-regulation of TS in C4-2 cells, and down-regulation of TS is considered to be responsible for the synergistic effect of S-1 in vivo. The present findings indicate that CRPC patients with androgen ablation may be good candidates for 5-FU based chemotherapy, and these regimens have attractive therapeutic potential for clinical practice, and they may have a significant impact on therapeutic options.

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti-aquaporin-4-positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice.

Questions: Are there any sustainable or vulnerable habitats in which beech (Fagus crenata) forests could survive in Japan under 110 hypothetical climate change scenarios? Location: Six islands of Japan on which beech grows naturally. Methods: An ecological habitat model was used to simulate the potential habitat shifts of beech forests under 110 climate change scenarios. The amount of suitable habitat loss and gain was calculated with three migration options and risk surfaces. Vulnerable and sustainable habitats were identified to evaluate the potential risks and survival of beech forests. Results: The total areas of potential suitable habitats differed considerably depending on the future temperature and precipitation changes. Some areas on the Sea of Japan (SOJ) side showed higher probability of maintaining suitable habitats, whereas there were wider areas in which suitable habitats could not persist under any of the 110 climate change scenarios. Conclusions: The risk surfaces of the suitable habitats showed that decreases in precipitation along with increases in temperature reduced the total areas of suitable habitats. Increases in precipitation with increases in temperature of more than or equal to 2°C always reduce the areas of suitable habitats. Under increased precipitation with a temperature increase of

Modelling and predicting the potential habitat and future range expansion of invasive species can help managers to mitigate the impact of such species. Because habitat suitability and the colonization process are key determinants of range expansion, inferences drawn from invasion patterns should be based on both attributes. To predict the potential habitat and expansion rate of the invasive tree Bischofia javanica on Hahajima Island, we used simultaneous models of habitat and dispersal to estimate the effect of environment and dispersal from the source population on the current distribution. We compared the fit and the estimated magnitudes of the environment and dispersal effects in the simultaneous models with those in habitat suitability and colonization kernel models. The values of Akaike's information criterion for the simultaneous models were better than those of the habitat suitability and colonization kernel models, indicating that the current distribution of Bischofia was determined by both environment and dispersal. The simultaneous models predicted that the potential habitat of Bischofia would be larger than that predicted by the habitat suitability model. The potential habitat distribution and future invasion predicted by the simultaneous models will contribute to the development of specific landscape-scale management plans to control this invasive species.

The overall purpose of circulatory assistance utilizing skeletal muscle is the most efficient application of muscle power. From the histological viewpoint, hot-knife dissection of the latissimus dorsi muscle (LDM) is presented to preserve muscle tissue. The shaw hemostatic scalpel could be used similarly to standard surgical blades, and its hemostatic performance was efficient in sealing collateral vessels from the thoracic wall. Muscular and nervous twitching was never observed throughout dissecting the LDM. Histological findings revealed that muscle fibers could be preserved by hot-knife dissection rather than by electrocautery. This technique may reduce the inconvenience of the operators, and, therefore, shorten the operation time in dynamic cardiomyoplasty and other experiments.

We sought to identify the factors that determine the current northern range limit of Fagus crenata (Fagaceae) forests in Japan. Four climatic factors (warmth index, minimum temperature of the coldest month, summer precipitation and winter precipitation) can potentially explain the distribution. Five classification tree models were developed: one based on all four factors, the others based on the four permutations of three of the four climatic factors (i.e. each excluded one of the four factors). The performance and the distributions of F. crenata forests predicted by these models were then compared, with particular reference to the distributions in Hokkaido. The distribution predicted by the model developed without summer precipitation extended continuously northwards along the Sea of Japan coast beyond the current northern range limits, but the distributions predicted by the other three models showed gaps around the current limit. When the warmth index, minimum temperature of the coldest month or winter precipitation were excluded the contribution to the resulting models of the other three variables increased, thereby compensating for the exclusion. However, the exclusion of summer precipitation was not compensated by increases in the contributions of the other variables in the model developed without this factor. These results suggest that summer precipitation is the most influential factor explaining the absence of F. crenata forests in the areas immediately to the north-east of the current northern range limit.

Gonadotropin-releasing hormone (GnRH) neurones play an essential role in the hypothalamo-pituitary-gonadal axis. As for other neurones, the discharge pattern of action potentials is important for GnRH neurones to properly function. In the case of a luteinizing hormone (LH) surge, for example, GnRH neurones are likely to continuously fire for more than an hour. For this type of firing, GnRH neurones must have a certain intrinsic property. To address this issue, we investigated the voltage-gated Ca2+ currents and Ca2+-activated voltage-independent K+ currents underlying afterhyperpolarization, because they affect cell excitability. Dispersed GnRH neurones from adult GnRH-EGFP (enhanced green fluorescent protein) transgenic rats were cultured overnight and then used for an electrophysiological experiment involving the perforated patch-clamp configuration. The GnRH neurones showed five subtypes of voltage-gated Ca2+ currents, i.e. the T-, L-, N-, P/Q- and R-types. The GnRH neurones also showed a slow afterhyperpolarization current (IsAHP), but not a medium one. It is reported that the SK channel blocker apamin (10 pm–100 nm) blocks a medium afterhyperpolarization current but not an IsAHP. In contrast to previous reports, the IsAHP observed in rat GnRH neurones was potently blocked by apamin. In addition, the GnRH neurones expressed transcripts for SK1–3 channels. The results indicate that rat GnRH neurones express all five subtypes of voltage-gated Ca2+ channels and exhibit an apamin-sensitive IsAHP, which may allow continuous firing in response to a relatively strong depolarizing input.

The aim of the current study was to investigate whether, and if so how, brain-derived neurotrophic factor (BDNF) acts to develop the spinal sensitization underlying inflammation-induced hyperalgesia. In spinal cord slice preparations from rats with inflammation induced by complete Freund's adjuvant (CFA), BDNF, but not nerve growth factor (NGF) or neurotrophin-3 (NT-3), acted presynaptically to increase the frequency of excitatory miniature EPSCs in substantia gelatinosa (SG) neurones of the CFA-treated, but not untreated rats, through activation of lidocaine (lignocaine)-sensitive, TTX-resistant Na+ channels. This effect was observed in the spinal cord slices of the CFA-treated rat only 2–4 days after the CFA injection. On the other hand, the number of monosynaptic Aβ afferent inputs to the SG significantly increased 1 week after the onset of the inflammation, and this increase was significantly suppressed by treatment with anti-BDNF antiserum administered 1 day before and just after the CFA injection. In addition, the treatment with anti-BDNF antiserum significantly attenuated the CFA-induced hyperalgesia and/or allodynia. These findings, taken together, suggest that BDNF, which is considered to be released from the sensitized primary afferents, increases the excitability of SG neurones through its action on the presynaptic terminals. BDNF may thereafter induce monosynaptic Aβ afferents to the SG, thereby developing hyperalgesia and/or allodynia during inflammation.

We used classification tree analysis to develop a climate-based distribution model for Fagus crenata forests in Japan. Four climatic variables judged likely to affect the distribution of the species (summer and winter precipitation, minimum temperature of the coldest month and Kira's warmth index) were chosen as independent variables for the model. Latitudinal and longitudinal information was also used to examine effects of spatial autocorrelation on the model. The climatic factors associated with the distribution of the forests were analysed using a classification tree to devise prediction rules. Predicted areas of high probability for forest occurrence lay mainly on the Sea of Japan side of northern Honshu and southern Hokkaido. This is consistent with actual forest distribution. Some areas with high predicted probabilities of F. crenata forest occurrence were beyond the current natural northern range limits of these forests. Since these areas were widely scattered, it was assumed that the spec...

Bischofia javanica is an invasive tree of the Bonin Islands in the western Pacific, Japan. This species has aggressive growth, competitively replacing native trees in the natural forest of the islands. The aim of this study was to examine seed and seedling factors which might confer an advantage to the establishment of Bischofia over native trees. During a 5-yr period we compared the demographic parameters of early life history of Bischofia and Elaeocarpus photiniae-folius, a native canopy dominant, in actively invaded forests. Predation of Elaeocarpus seeds by in troduced rodents was much higher before (27.9–32.9%) and after (41.3–100%) dispersal of seeds than that of B. javanica. Most Elaeocarpus seeds lost viability ca. 6 mo after burial in forest soil while some seeds of Bischofia remained viable for more than 2 yr. Seedling survival in the first 2 yr was much higher in Bischofia (16%) than in Elaeocarpus (1.3%). The high persistence of Bischofia in the shade, coupled to its rapid acclimation to high light levels, is an unusual combination because in forest tree species there is generally a trade-off between seedling survival in the shade and response to canopy opening. Compared with a native canopy dominant, greater seed longevity, lower seed predation by introduced rodents, longer fruiting periods and the ability to form seedling banks under closed canopy appear to have contributed to the invasive success of Bischofia on the Bonin Islands.

Thermal analysis was used to measure the characteristics of dental resins cured with the use of a new light-activation unit equipped with high illuminant blue light-emitting diodes (LEDs). The characteristics were compared with those of resins cured with the use of two conventional halogen lamp units. The prepared base monomer consisted of a mixture of Bis-GMA and TEGDMA (60:40 by weight), with 0.5 wt% CQ/DMPT or CQ/DMAEMA. The two experimental visible-light-cured resins were polymerized for 40 s. Differential scanning calorimetry (DSC) was used to examine the thermal characteristics of the cured resins. The activation energy for the decomposition of the dental resin was calculated from the peaks of the endothermic curves obtained when the specimens were heated at three different rates (5, 10, and 15 °C/min) during DSC. The activation energies calculated for the LED-cured specimens were more than 220 kJ/mol; specimens cured with the use of the halogen units had activation energies of less than 192 kJ/mol. The Knoop hardness number (KHN) of the same specimens was measured, and was higher with the blue LED units than with halogen lamp units. Therefore, dental resins cured using blue LEDs have a higher degree of polymerization and more stable three-dimensional structures than those cured with halogen lamps. © 2002 John Wiley & Sons, Inc. J Biomed Mater Res (Appl Biomater) 63: 209–213, 2002; DOI 10.1002/jbm.10126

Natural killer (NK) cells play an important role in early defense against viral infection. The cytotoxic activity of NK cells is increased by interferon-alpha/beta (IFN-alpha/beta), produced en masse in virally infected cells. However, the mechanism(s) by which IFN-alpha/beta contribute to the NK-cell-mediated antiviral response is not well understood. Here we provide evidence that the cytotoxicity of NK cells is enhanced by IFN-alpha/beta through induction of TNF-related apoptosis-inducing ligand (TRAIL). Isolation and analysis of the murine TRAIL promoter revealed the presence of an IFN-stimulated response element (ISRE), which binds to the transcription factor ISGF3 (interferon stimulated gene factor-3). This promoter is indeed activated by IFN-beta in ISGF3-dependent manner. We also show that virally infected cells, but not uninfected cells, are susceptible to TRAIL-mediated cytotoxicity in vitro, and that the TRAIL expressed in NK cells is indeed crucial in limiting virus replication in vivo. Thus, our study reveals a new molecular link between IFN-alpha/beta signaling and activation of NK cells in antiviral response of the host.

Background Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-α/β signalling complex, generated by spontaneously produced IFN-α/β, in efficient IFN-γ signalling. Results In the present study, we have demonstrated that the IFN-α/β signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-α/β signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-α/β stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity. Conclusions The constitutive weak IFN-α/β signal provides a foundation for strong cellular responses to IL-6, IFN-γ, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor subunits, which may represent a ‘receptosome’-like structure, allowing the unique signalling cross talks to occur.

Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, regulates the proliferation and differentiation of granulocytic progenitor cells and functionally activated mature neutrophils. G-CSF also affects nonhematopoietic tumor cells through its binding to the specific receptor (G-CSFR) on the cells. The type IV collagenase [matrix metalloproteinase 2 (MMP-2)] is known to play a main role in the process of invasion and metastasis, but its regulation, for example, in expression or in activation, is not clearly understood. In this study, we investigated the role of G-CSF in the regulation of tumor cell invasion and the synthesis of MMP-2. G-CSFs producing the head and neck carcinoma cell line T3M-1 cells with metastatic ability and no G-CSF receptor (G-CSFR) expression were transfected with G-CSFR expression vector. In vitro treatment of G-CSFR-transfectant T3M-1 cells with recombinant G-CSF (rG-CSF) significantly augmented their invasive potential in a reconstituted basement membrane (Matrigel) system compared with that of parental cells. Moreover, MMP-2 activity of G-CSFR-transfectant T3M-1 cells was enhanced by the stimulation with rG-CSF, as assessed by gelatin zymography. These results identify G-CSF as a regulator of MMP-2 and cellular invasion.

p27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle, and apoptosis is a genetically encoded program of cell death. To clarify the relationship between the cell cycle and apoptosis, we investigated expression of p27, cyclin D1 and apoptosis-related proteins (p53, Bax, Bcl-2 and c-Myc) in 60 cases of oral and oropharyngeal squamous-cell carcinoma (SCC) using an immuno-histochemical approach, and evaluated spontaneous apoptosis in vivo. Our most notable finding was that spontaneous apoptosis in the p27-positive group was significantly higher than that in the p27-negative group (p = 0.028). In addition, the percentage of p27-positive cells was clearly correlated with that of Bax-positive cells (gamma = 0.288, p = 0.028) and with that of cyclin D1-positive cells (gamma = 0.416, p = 0.002). Expression of p27 was inversely associated with the clinical stage of total tumor progression (p = 0.027). However, no correlation was found between p27 expression and the following parameters: gender, tumor size, lymph node metastasis, overall survival and disease-free survival. Our results give evidence that the action of the cell-cycle regulator p27 is closely linked with apoptosis in clinical samples from patients and indicate that over-expression of p27 might induce apoptosis in cancer cells through elevation of Bax expression, thereby acting on tumor progression.

Tunicamycin (TM), a naturally occurring antibiotic, blocks the first step in the biosynthesis of N-linked oligosaccharides in cells. In this study, we investigated whether changes in N-linked glycosylation affect the sensitivity of head-and-neck carcinoma cell lines to cis-diaminedichloroplatinum(II) (cisplatin) in vitro and in vivo. In vitro treatment of the IMC-3 and KB cell lines with TM significantly decreased the 50% inhibitory concentration (IC50) of cisplatin, as determined by the MTT assay (24.15 to 10.97 microg/ml, p 100 to 14.4 microg/ml, p < 0.05) to levels similar to those against parental IMC-3 cells. TM treatment decreased the number of Con A- and L-PHA-binding sites on the surface of tumor cells but had no effect on the intracellular platinum concentration. Induction of apoptosis in vitro by TM plus cisplatin in combination was increased compared with that by cisplatin alone. Furthermore, in vivo administration of TM plus cisplatin in combination significantly inhibited local tumor growth in the cisplatin-resistant in vivo C3H/He mouse model as compared with the control group (p < 0.05) and increased in vivo apoptosis of tumor cells. Our results suggest that the manipulation of glycosylation by TM in tumor cells might be a useful therapeutic strategy for successful chemotherapy using cisplatin against head-and-neck cancer.

This study provides an insight into the effectiveness of an optical network unit (ONU) sleep technique, where a subcomponent of the ONU is powered down during the absence of input traffic. The approach contributes to the realisation of advanced power efficiency over a wide range of input throughputs in situations where downstream traffic exceeds upstream traffic in recent residential networks. A numerical simulation showed that power-saving effectiveness could be achieved for an Mbit/s downstream throughput without latency implications in the Tx sleep mode.

The tyrosine kinases Jak1 and Jak3 are known to be associated with the beta and gamma chains of interleukin-2 receptor (IL-2R). They are activated by stimulation with IL-2, IL-4, IL-7, IL-9, or IL-15, receptors of which share the gamma chain of the IL-2R. We have obtained direct evidence of Jak1 association with the alpha chains of receptors for IL-4, IL-7 and IL-9 and with the beta chain of IL-2R, which is also common to the IL-15R. Furthermore, we have prepared mutant IL-2R beta chains with a mutation in the box 1 region, which is conserved among the IL-2R beta chain and the alpha chains of the other cytokine receptors sharing the IL-2R gamma chain. Using MOLT-4 transfectants with the mutant beta chains, we found that two conserved proline residues within the box 1 region are essentially involved in association with Jak1. The MOLT-4 transfectants with the mutant beta chains lacking Jak1 association showed IL-2 responsiveness, in terms of activation of Jak3 and Stat5 and induction of cell growth, indicating that Jak1 is dispensable for IL-2-mediated cell growth signaling and that Jak1 activation is not required for activation of Jak3 and Stat5 in the MOLT-4 transfectants.