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Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prionaffected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration. [ABSTRACT FROM AUTHOR]

Targeting PD-1/PD-L1 has shown the ability to improve overall survival in urothelial carcinoma; however, there are cases of nonresponse and resistance. In this study, we evaluated time-course changes in all tumor locations after pembrolizumab treatment to examine the differences in immune checkpoint inhibitor efficacy in different organs. We also examined the usefulness of neutrophil-to-lymphocyte ratio, CRP, and kinetics as prognostic biomarkers in urothelial carcinoma treated with pembrolizumab. Introduction: Since tumors in different human organs may have different tumor microenvironments, we evaluate timecourse changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC. Patients and Methods: A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 cr iter ia. The ser um CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration. Results: Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis. Conclusion: We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts. [ABSTRACT FROM AUTHOR]

The livestock industry is a major source of atmospheric volatile organic compounds (VOCs), but details on these emissions are not well documented in Japan. In particular, it remains unclear how the rearing method affects the emissions of VOCs from livestock, which originate primarily from feces and urine. Here we aimed to estimate the amounts of VOCs emitted from the feces and urine of tethered Holstein dairy cattle in a cattle shed in Japan. Dimethyl sulfide and acetone accounted for about 60% of the total VOCs emitted from feces, followed by formaldehyde and acetaldehyde. Also, dimethyl sulfide and acetone were the dominant VOCs emitted from urine, accounting for 90% of the total VOCs. The VOCs from manure were considered to be emitted between the excretion and removal of the manure during the cleaning of the shed. As a result of analyzing images from three cameras installed in the shed, the average time between excretion and cleaning during the daytime (8:00 am-5:00 pm) was 80 min for feces and urine, whereas at night (5:00 pm-7:00 am), the average time between excretion and cleaning was 480 min. Based on the above findings, the emissions of VOCs in the interval between excretion and cleaning of the shed were estimated. As a result, the emissions of VOCs from feces and urine per head of cattle in the shed were estimated to be 1.75 and 1.52 g day-1, respectively. Furthermore, contribution of VOCs emitted from manure to odor activity value (OAV) and hydroxyl radical reactivity (OHR) were also estimated. Volatile fatty acids and sulfur compounds emitted from feces estimated to have high contribution to OAV, whereas aldehydes contributed mainly for OHR from manure. [ABSTRACT FROM AUTHOR]

A new species, Impatiens katjae Nob. Tanaka & J. J. Verm. (Balsaminaceae), from Mandalay Region, central Myanmar, is described and illustrated. This species is similar to I. oblongata Ruchis. & Niet in floral morphology, but differs in having distinctly smaller flowers, 2-flowered axillary inflorescences, much paler pinkish-white flowers, two lateral sepals, and a spurless lower sepal. This new species is assigned to Impatiens L. subg. Impatiens sect. Uniflorae Hook. f. & Thomson. [ABSTRACT FROM AUTHOR]

Volatile organic compounds (VOCs), CO2, temperature, and humidity in a private room in a care facility for the elderly were measured and the behavior of a resident and staff were recorded in order to clarify the effects of the resident's behavior, especially defecation, on indoor air quality. Average indoor concentrations of total VOCs (in μg m-3) in summer, autumn, and winter were 40.9, 16.7, and 18.8, respectively. Average indoor concentrations of CO2 in summer, autumn, and winter were 813, 761, and 1144 ppm, respectively, revealing a tendency for the concentrations of CO2 to be higher in winter, in contrast to the VOC concentration. The concentrations of VOCs and CO2 were 1.1 to 1.5 times higher when the resident was present in the room than when the resident was absent. This result suggests that one of the main sources of VOC and CO2 emissions in indoor air was the resident. Acetic acid, 1-butanol, propanoic acid, hexanoic acid, and phenol, which are contained in human sweat, exhaled air, and excrement, were the predominant VOCs in the air of the room regardless of the season, and these five components accounted for more than 90% of the total VOCs. The concentrations of these components were higher when the resident was present in the room, suggesting that the resident was the main source of these components. Based on the changes in the VOC and CO2 concentrations over time and the records of the resident and the staff, it was noted that VOC concentrations decreased, in some cases, before and after diaper changes. Our research suggests that certain aspects of the behavior of residents can be inferred by monitoring changes in indoor air quality. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Heterocyphelium triseptatum is newly recorded from Asia. The species was previously known only from South America and Africa. It was collected from the bark of a broadleaf tree at 35 m elevation in the Tanintharyi Region of southern Myanmar. An unidentified substance was newly detected for this species by thin layer chromatography (TLC). This study demonstrates the phylogenetic position of H. triseptatum in the Lecanographaceae using Bayesian and RAxML analyses of mtSSU and nrLSU sequence data. The close relationship with H. leucampyx within the Heterocyphelium clade was confirmed. [ABSTRACT FROM AUTHOR]

Real-time onsite monitoring of indoor airborne microbes in a residential property in central Tokyo was carried out in 2020 and 2021, following the onset of the COVID-19 pandemic. A microbial sensor utilizing fluorescence emitted by microorganisms was used to measure bioaerosol concentrations in the living room and children's bedroom as well as on the balcony. Indoor PM2.5 was also monitored simultaneously at certain time points using a PM2.5 sensor. The behavior of the residents was also recorded during some monitoring periods. The average number concentration of microbes as fungi in the living room was 15,100, 58,800, and 10,600 counts m-3 in spring, summer, and winter, respectively, increasing in summer when the outside temperature was high. Microbial number concentrations were closely related to human behavior, increasing rapidly during periods of physical activity, but decreasing again within 20-30 min of the activity ending. There was no clear correlation between indoor microbial number concentrations and PM2.5 concentrations, suggesting that indoor microorganisms are concentrated in coarse particles, such as dust, which are quickly removed via gravitational settling. The concentration of indoor airborne microorganisms decreased significantly after ventilation, and although an occasional increase was observed immediately after ventilation, concentrations decreased again rapidly within 10-20 min. These results suggest that even a short period of ventilation can significantly reduce the indoor bioaerosol. [ABSTRACT FROM AUTHOR]

The aim of this study was to validate the contemporary grading system. Our follow-up study revealed that men with Gleason score (GS) 4D5 and those with Gleason grade group 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4D5 and GS 5D4 or higher. Gleason grade groups 4 and 5 in the contemporary grading system should be reviewed. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4þ5 and 29 patients with GS 5þ4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4þ5, and GS 5þ4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4þ5 than in GS 5þ4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4þ5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5þ4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4þ5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4þ5 and GS 5þ4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients. [ABSTRACT FROM AUTHOR]

Specimens of lichens collected from southern Myanmar including Tanintharyi and Yangon Regions were examined. As the result of taxonomic examinations, the following 20 species were identified: Astrothelium macrocarpum, Bulbothrix subscortea, Coccocarpia erythroxyli, C. palmicola, Cruentotrema thailandicum, Dirinaria aegialita, D. consimilis, Dyplolabia afzelii, Flakea papillata, Glyphis cicatricosa, Graphis cf. caesiella, G. desquamescens, G. supracola, Malmidea bakeri, Physcia undulata, Pyrenula mamillana, Pyxine dactyloschmidtii, Sarcographa labyrinthica, Trypethelium eluteriae, and Zwackhia prosodea. All of them, except the two species of Coccocarpia, are new records for Myanmar. The ITS rDNA sequences were successfully obtained from 17 samples for 14 species. The BLAST identities for Myanmar collections with the same species in GenBank range from 89 to 100%. [ABSTRACT FROM AUTHOR]

To clarify the emissions of volatile organic compounds (VOCs) from hen rearing in Japan, we collected air samples from inside a hen shed for the four seasons in 2019 and analyzed 34 VOCs in the air samples by gas chromatography-mass spectrometry and high performance liquid chromatography. The temperature and humidity inside and outside of the shed were monitored simultaneously during each sampling campaign. The average concentrations of VOCs in the shed ranged from 150 to 427 µg m-3, the concentrations being higher in summer and lower in winter. Acetone, dimethyl sulfide, 2-butanone, 2-pentanone, and acetic acid were dominant throughout all the seasons and these five compounds accounted for 70-89% of the total VOCs. The reactivity of each VOC with hydroxyl radical was also calculated and dimethyl sulfide was found to be the most reactive VOC, accounting for 84-94% of the total hydroxyl radical reactivity. The emission rate (ER) for the total VOCs (µg h-1 kg-1) was 602 in winter, 7,900 in spring, 46,500 in summer and 37,600 in autumn, respectively. Acetone, dimethyl sulfide, 2-butanone, 3-pentanone and acetic acid had higher ERs throughout all the seasons, and these five components accounted for 70-90% of the ERs for the total VOCs. The ERs of the VOCs increased exponentially in accord with temperature increases inside the shed, indicating that the ERs of the VOCs depended on the ambient temperature. The annual VOC emission from one hen and from the hen shed was calculated to be 405 g y-1 and 121 kg y-1, respectively. [ABSTRACT FROM AUTHOR]

Invasive alien tree species can exert severe impacts, especially in insular biodiversity hotspots, but have been inadequately studied. Knowledge of the life history and population trends of an invasive alien tree species is essential for appropriate ecosystem management. The invasive tree Bischofia javanica has overwhelmed native trees on Haha-jima Island in the Ogasawara Islands, Japan. We explored forest community dynamics 2 years after a typhoon damaged the Sekimon primary forests on Hahajima Island, and predicted the rate of population increase of B. javanica using a logistic model from forest dynamics data for 19 years. During the 2 years after the typhoon, only B. javanica increased in population size, whereas populations of native tree species decreased. Stem diameter growth of B. javanica was more rapid than that of other tree species, including native pioneer trees. Among the understory stems below canopy trees of other species, B. javanica grew most rapidly and B. javanica canopy trees decreased growth of the dominant native Ardisia sieboldii. These competitive advantages were indicated to be the main mechanism by which B. javanica replaces native trees. The logistic model predicted that B. javanica would reach 30% of the total basal area between 2017 (in the eastern plot adjacent to a former B. javanica plantation) and 2057 (in the western plot distant from the plantation site), which is a maximum percentage allowing to eradicate under the present guideline of the National Forest. The results suggest immediate removal of B. javanica is required to preserve native biodiversity in these forests. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) surrounding cancer cells becomes stiffer during tumor progression, which influences cancer cell behaviors such as invasion and proliferation through modulation of gene expression as well as remodeling of the actin cytoskeleton. In this study, we show that MMP24 encoding matrix metalloproteinase (MMP)-24 is a novel target gene of Yes-associated protein (YAP), a transcription coactivator known as a mechanotransducer. We first examined the effect of substrate stiffness on MMP24 expression in MCF-7 human breast cancer cells and showed that the expression of MMP24 was significantly higher in cells grown on stiff substrates than that on soft substrates. The MMP24 expression was significantly reduced by knockdown of YAP. In contrast, the expression of constitutively active YAP increased MMP24 promoter activity. In addition, binding of YAP to the MMP24 promoter was confirmed by the chromatin immunoprecipitation (ChIP) assay. These results show that ECM stiffening promotes YAP activation, thereby inducing MMP24 expression. Based on the Human Protein Atlas database, breast cancer patients with lower MMP24 expression exhibit the worse survival rates overall. Thus, MMP24 may negatively regulate the aggressiveness of cancer cells under the stiff ECM environment during tumor progression. [ABSTRACT FROM AUTHOR]

In the course of our intensive floristic inventories for the flora of Myanmar, a new species of the genus Sapria (Rafflesiaceae), S. myanmarensis Nob. Tanaka, Nagam., Tagane & M.M. Aung is described and photographed. In addition, S. himalayana Griff. f. albovinosa Banziger & B. Hansen is newly recorded in the country. A key to the species of Sapria presently occurring in Myanmar is provided. [ABSTRACT FROM AUTHOR]

To clarify the nature and characteristics of volatile organic compounds (VOCs) emitted from dairy cattle within a cattle shed located in Chiba, Japan, air samples were collected and analyzed for the four seasons in 2017-2018. Thirty-four VOCs were determined by gas chromatography-mass spectrometry and high performance liquid chromatography. In addition, air temperature and relative humidity inside and outside of the shed were monitored during each sampling campaign to estimate the ventilation rate of the shed. The average concentrations of total VOCs (μg m-3) in the shed in each season were 50.5 (spring), 128.4 (summer), 168.8 (autumn), and 199.5 (winter). Ketones were always the most dominant components followed by alcohols and volatile fatty acids (VFAs). The sum of ketones, alcohols, and VFAs accounted for more than 80% of the total VOCs in all seasons. Acetone, 3-pentanone, 1-butanol, and acetic acid were the major components regardless of the season, accounting for more than 60% of the total VOCs. The average emission rates of total VOCs from the shed (μg h-1 kg-1) were calculated to be 623 (spring), 1520 (summer), 585 (autumn) and 469 (winter). The emission rates of almost all the VOCs except alcohols increased exponentially with increase of air temperature in the shed. The ranges of the emission rates for each class of chemical (μg h-1 k-1) were 39-170 (VFAs), 247-913 (ketones), 65-134 (alcohols), 40-122 (phenols), 10-122 (aldehydes), 4.17- 22.3 (sulfur compounds), and 0.0067-0.74 (indoles). Furthermore, the annual emissions of VOCs for a single dairy cattle and for the cattle shed were estimated to be 5.5 kg and 44 kg, respectively. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of cancer mortality, however, efficient methods to culture, expand and transform lung epithelial (LE) cells have not been established. In the present study, an efficient ex vivo method was applied to recapitulate lung carcinogenesis using mouse LE cells. A Matrigel‑assisted three‑dimensional culture was used to isolate and selectively expand LE cells from mouse lungs. Purified LE cells were passaged and expanded for at least 2 to 3 months while maintaining epidermal growth factor‑dependence. LE cells were also easily transformed by genetic manipulations using retroviral vectors. A SV40 large‑T antigen, suppressing p53 and pRB, plus an activated oncogene, such as KrasG12V or EGFRex19del, were required to transform LE cells. Transformed cells formed tumors resembling non‑small cell lung cancer (NSCLC) in allograft models and exhibited strong oncogene addiction. This experimental system provided a unique model system to study lung tumorigenesis and develop novel therapeutics against NSCLC. [ABSTRACT FROM AUTHOR]

The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH) signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood. Methods: MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy. MVB-dysfunction, modelled by expression of dominant negative VPS4A (dnVPS4A), was analysed by biochemical methods and exosome isolation. Results: Here we show that AD transgenic neurons have enlarged MVBs compared to wild type neurons. Uptake of exogenous Aβ also leads to enlarged MVBs in wild type neurons and generates fibril-like structures in endocytic vesicles. With time fibrillar oligomers/fibrils can extend out of the endocytic vesicles and are eventually detectable extracellularly. Further, endosomal sorting complexes required for transport (ESCRT) components were found associated with amyloid plaques in AD transgenic mice. The phenotypes previously reported in AD transgenic neurons, with net increased intracellular levels and reduced secretion of Aβ, were mimicked by blocking recycling of ESCRT-III by dnVPS4A. DnVPS4A further resembled AD pathology by increasing tau phosphorylation at serine 396 and increasing markers of autophagy. Conclusions: We demonstrate that Aβ leads to MVB enlargement and that amyloid fibres can form within the endocytic pathway of neurons. These results are consistent with the scenario of the endosome-lysosome system representing the site of initiation of Aβ aggregation. In turn, a dominant negative form of the CHMP2B-interacting protein VPS4A, which alters MVBs, leads to accumulation and aggregation of Aβ as well as tau phosphorylation, mimicking the cellular changes in AD. [ABSTRACT FROM AUTHOR]

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage. [ABSTRACT FROM AUTHOR]

Background: No previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. Methods: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. Results: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. Conclusion: There was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer. [ABSTRACT FROM AUTHOR]

Background We evaluated the clinical outcome of low grade Ta bladder cancer followed-up for a long period using the 2004 WHO grading system. Methods We retrospectively reviewed 190 patients with primary, low grade Ta bladder cancer. We defined worsening progression (WP) as confirmed high grade Ta, all T1 or Tis/concomitant CIS of bladder recurrence, upper urinary tract recurrence (UTR), or progression to equal to or more than T2. The associations between clinicopathological factors and tumor recurrence as well as WP pattern were analyzed. We also evaluated the late recurrence of 76 patients who were tumor-free for more than 5 years. Results Tumor recurrence and WP occurred in 82 (43.2 %) and 21 (11.1 %) patients during follow-up (median follow-up: 101.5 months), respectively. WP to high grade Ta, all T1 or Tis/concomitant CIS was seen in 17 patients, and UTR and progression to equal to or more than T2 were seen in 2 and 2 patients, respectively. Multivariate analyses demonstrated that multiple tumor (p < 0.001, HR: 2.97) and absence of intravesical instillation (IVI) (p < 0.001, HR: 2.88) were significant risk factors for tumor recurrence while multiple tumor was the only risk factor for WP (p = 0.001, HR: 5.26). After a 5-year tumor-free period, 9 patients experienced late recurrence in years 5 and 10 and were diagnosed at a follow-up cystoscopy, however, only 2 patients recurred beyond 10 years and were found by gross hematuria. There were no significant risk factors of late recurrence. Conclusions Multiple tumor was a risk factor for both tumor recurrence and WP while IVI did not affect the occurrence of WP. Our results suggest that routine follow-up of patients with low grade Ta bladder cancer is needed up to 10 years from the initial diagnosis. [ABSTRACT FROM AUTHOR]

00515.2013.--Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Using the paired-pulse transcranial magnetic stimulation (TMS) paradigm, we can measure interhemispheric inhibition (IHI) and interhemispheric facilitation (IHF) as indexes of the interhemispheric interactions in humans. We investigated how quadripulse transcranial magnetic stimulation (QPS), one form of repetitive TMS (rTMS), on M1 affects the contralateral M1 and the interhemispheric interactions. QPS is able to induce bidirectional plastic changes in M1 depending on the interstimulus intervals (ISIs) of TMS pulses: longterm potentiation (LTP)-like effect by QPS-5 protocol, and long-term depression-like effect by QPS-50, whose numbers indicate the ISI (ms). Twelve healthy subjects were enrolled. We applied QPS over the left M1 and recorded several parameters before and 30 min after QPS. QPS-5, which increased motor-evoked potentials (MEPs) induced by left M1 activation, also increased MEPs induced by right M1 activation. Meanwhile, QPS-50, which decreased MEPs elicited by left M1 activation, did not induce any significant changes in MEPs elicited by right M1 activation. None of the resting motor threshold, active motor threshold, short-interval intracortical inhibition, longinterval intracortical inhibition, intracortical facilitation, and shortinterval intracortical inhibition in right M1 were affected by QPS. IHI and IHF from left to right M1 significantly increased after left M1 QPS-5. The degree of left first dorsal interosseous MEP amplitude change by QPS-5 significantly correlated with the degree of IHF change. We suppose that the LTP-like effect on the contralateral M1 may be produced by some interhemispheric interactions through the corpus callosum. [ABSTRACT FROM AUTHOR]

Abstract  We have previously reported that thermal vasodilation following warm-water bathing and low-temperature sauna bathing (LTSB) at 60 °C for 15 min improves the cardiac function in patients with congestive heart failure. Through a comparative before-and-after study, we studied the hemodynamic and clinical effects of single exposure to LTSB in cerebral palsy (CP) patients who usually suffer from chilled extremities and low cardiac output. The study population comprised 16 patients ranging between 19 and 53 years with severe motor and intellectual disabilities. Noninvasive methods were used to estimate the systemic and peripheral circulatory changes before and after LTSB. Using blood flow velocity analysis, the pulsatile and resistive indexes of the peripheral arteries of the patients’ lower limbs were calculated. Following LTSB, the patients’ deep body temperature increased significantly by 1°C. Their heart rates increased and blood pressure decreased slightly. The total peripheral resistance decreased by 11%, and the cardiac output increased by 14%. There was significant improvement in the parameters that are indicative of the peripheral circulatory status, including the skin blood flow, blood flow velocity, pulsatile index, and resistive index. Numbness and chronic myalgia of the extremities decreased. There were no adverse side effects. Thus, it can be concluded that LTSB improves the peripheral circulation in CP patients. [ABSTRACT FROM AUTHOR]

Thermotherapy is generally considered appropriate for post-stroke patients with spasticity, yet its acute antispastic effects have not been comprehensively investigated. F-wave parameters have been used to demonstrate changes in motor neuron excitability in spasticity and pharmacological antispastic therapy. The present study aimed to confirm the efficacy of thermotherapy for spasticity by evaluating alterations in F-wave parameters in ten male post-stroke patients with spastic hemiparesis (mean age: 49.0±15.0 years) and ten healthy male controls (mean age: 48.7±4.4 years). The subjects were immersed in water at 41°C for 10 min. Recordings were made over the abductor hallucis muscle, and antidromic stimulation was performed on the tibial nerve at the ankle. Twenty F-waves were recorded before, immediately after, and 30 min following thermotherapy for each subject. F-wave amplitude and F-wave/M-response ratio were determined. Changes in body temperature and surface-skin temperature were monitored simultaneously. The mean and maximum values of both F-wave parameters were higher on the affected side before thermotherapy. In the post-stroke patients, the mean and maximum values of both parameters were significantly reduced after thermotherapy (P<0.01). Hence, the antispastic effects of thermotherapy were indicated by decreased F-wave parameters. Body temperature was significantly increased both immediately after and 30 min after thermotherapy in all subjects. This appeared to play an important role in decreased spasticity. Surface-skin temperature increased immediately after thermotherapy in both groups and returned to baseline 30 min later. These findings demonstrate that thermotherapy is an effective nonpharmacological antispastic treatment that might facilitate stroke rehabilitation. [ABSTRACT FROM AUTHOR]

Our previous study demonstrated that IL-2 suppressed growth of human T cell lines, in which the suppression was observed with members among HTLV-I-infected T cell lines independent of IL-2 for growth. In this study, we examined the molecular mechanism of IL-2-induced growth suppression with two HTLV-I-infected T cell lines; TL-OmI expressing endogenously three subunits, i.e. α, β and γ chains, of the IL-2 receptor, and an MT-1 transfectant expressing the endogenous α and γ chains and exogenous β chain. Our analysis revealed that IL-2 induced apoptosis in both T cell lines. Experiments with inhibitors for the proteases responsible for apoptosis signals showed that caspase 1 (IL-1β-converting enzyme) was not involved in apoptosis induced by IL-2. Other MT-1 sublines introduced with mutant β chains demonstrated that IL-2-induced apoptosis required signals from both the serine-rich (S) region and acidic (A) region of the IL-2 receptor β chain, which are essential but not critical for IL-2-mediated cell growth respectively. Collectively, IL- 2 functions not only on growth promotion and prevention of apoptosis but also on induction of apoptosis, which may be implicated in physiological regulation of immune reactions by controlling growth and activation of T cells. [ABSTRACT FROM AUTHOR]

In this study, we developed a method of fabricating totally glass-based filters having micrometer-scale through holes for high-throughput filtration using a femtosecond laser. Filtration using a membrane-type filter is an indispensable technique for biological, chemical, and physical analysis fields. A larger flow rate or stronger driving pressure will result in a faster filtration. However, conventional high-throughput filtering methods often use a relatively slow flow rate or low pressure owing to the fracture toughness of the filter material. In this study, we introduce a customizable 4-µm-thick glass filter that could be used for high-throughput microparticle filtering at a flow velocity of 4 m/s. [ABSTRACT FROM AUTHOR]

IL-21 regulates certain functions of T cells, B cells, NK cells and dendritic cells. Although activated CD4+ T cells produce IL-21, data identifying the specific CD4+ T cell subsets that produce IL-21 are conflicting. In a previous study, mouse IL-21 message was detected in TH2, whereas human IL-21 (hIL-21) message was found in both TH1 and follicular helper T cells. To identify the IL-21-secreting cell populations in human, we established a hybridoma cell line producing an anti-hIL-21 mAb. Intracellular hIL-21-staining experiments showed that hIL-21 was mainly expressed in activated CD4+ central memory T cells and in activated CD4+ effector memory T cells, but not in activated CD4+ naive T cells. Moreover, IL-21 was produced upon activation by some IFN-γ-producing TH1-polarized cells and some IL-17-producing TH17-polarized cells, but not by IL-4-producing TH2-polarized cells. These results suggest that specific CD4+ T cell populations produce IL-21. In the functional analysis, we found that IL-21 significantly enhanced the cytokine-driven proliferation of CD4+ helper T cells synergistically with IL-7 and IL-15 without T cell activation stimuli. Taken together, IL-21 produced from CD4+ memory T cells may have a supportive role in the maintenance of CD4+ T cell subsets. [ABSTRACT FROM AUTHOR]