A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.

Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent ("FGF1 decoy")

Combination of apodized pupil and phase mask coronagraph for SCExAO at Subaru Telescope

Subaru telescope has been operating a high-contrast imaging instruments called Subaru coronagraphic extreme adaptive optics (SCExAO) which is used for exoplanet research. We are developing phase mask coronagraphs using photonic crystal wave plates inside the SCExAO. An eight-octant phase mask (8OPM) of three-layer achromatic structure has been fabricated as a second generation. It was designed for J and H band to reach 10⁻⁵ contrast, and Ks band to 10⁻⁴. A retardation and a coronagraphic performance of the 8OPM were confirmed almost as designed at 1550nm. An apodised (binary shaped) pupil to be used with the 8OPM was also studied to suppress diffracted light by the secondary shadow and spiders. We confirmed a performance of the combination of the apodizer and the 8OPM at visible wavelengths in a lab. We optimized the apodizer for a pupil of the SCExAO where we obtained a transmission of 50 % and a contrast of 10⁻⁴ the center and 10⁻⁶ at outer region. We manufactured the designed apodizer to be installed in SCExAO for infrared observations

Cloning, expression analysis, and tissue distribution of esp-1/testisin, a membrane-type serine protease from the rat

Esp-1/testisin, a serine protease abundantly expressed in human and mouse testis, is presumed to play an important role in the process of spermatogenesis and fertilization. In this study, we cloned an esp-1/testisin cDNA from rats, and analyzed its expression and tissue distribution. The isolated cDNA consisted of 1099 nucleotides with a single open reading frame encoding 328 amino acids and an expected molecular mass of 36.6 kDa. The deduced amino acid sequence of rat Esp-1/Testisin had 89% and 62% identity with its murine and human counterparts, respectively, and appeared to be a trypsin-type serine protease with a hydrophobic region at the C-terminus. By quantitative real-time polymerase chain reaction analysis, rat esp-1/testisin mRNA was predominantly expressed in testis, as in human and mouse. However, its immunohistochemical distribution was predominantly in the elongated spermatids at steps 12 to 19, and not in the primary spermatocytes and round spermatids. This different distribution profile suggests that Esp-1/Testisin plays a role in species-specific proteolytic events during spermatogenesis and fertilization

Pancreatic Pseudocysts - Proposal for Diagnosis and Surgical Management -

To determine the clinical features and problems presented by a pancreatic pseudocyst, eighteen patients managed at our hospitals since 1980 were reviewed. Males predominated with a ratio of 16: 2, and the average age was 36.2 years. Pseudocyst was located in the pancreatic head in 6, in the body in 6, in the tail in 5 and multiple pseudocysts in one case. The cause of pancreatic pseudocyst was chronic pancreatitis in 9 (including 8 patients with histories of alcoholism), acute pancreatitis in 2 and trauma in 7 patients, respectively. Three patients were associated with pancreatic calculi. Rupture of pseudocyst occurred in one patient with multiple cysts. Autopsy showed acute pancreatic necrosis and penetration to the stomach and duodenum. The indications for surgery were principally cyst-related symptoms(infection, hemorrhage, enlargement and compression of adjacent organs) and differential diagnosis from malignancy. Most of the patients underwent internal drainage ; 9 cystojejunostomy, 2 cystogastrostomy). Three patients underwent cystojejunostomy with longitudinal pancreaticojejunostomy for chronic pancreatitis. Massive hemorrhage after cystogastrostomy occurred in one patient with infected pseudocysts, which required removal of the cysts. Postoperative outcome of the 17 surgical patients was excellent in 16 patients. Only one patient died of pancreatitis associated with alcohol abuse, resulting in a 5.9% mortality. This study suggests that adequate internal drainage by pancreaticojejunostomy to treat the underlying pancreatic disease is most important to obtain an excellent prognosis in patients with pseudocysts

Carcinoembryonic Antigen (CEA) in Colorectal Cancer - Prognostic Significance of Portal Blood Level -

The prognostic significance of carcinoembryonic antigen (CEA) values in the drainage vein of the tumor (portal blood levels of CEA) of colorectal cancer patients were evaluated by examining the correlation with the peripheral blood levels of CEA and histopathologic findings of the tumor. 1) Portal blood levels of CEA were significantly increased by the operative procedure. Mean values of CEA in portal blood were higher than those in peripheral blood. Portal blood CEA was correlated with Dukes\u27 staging, and revealed higher positive rates than CEA in peripheral blood in each stage. Elevated CEA levels were noted in those who had cancer infiltration extending through the proper muscle layer. There was a close correlation between portal CEA and CEA content in cancerous tissue (ng/g, wet weight) (p<0.05), but no significant correlation between peripheral CEA level and cancerous tissue CEA (r = 0.372). The mean values of portal CEA in aneuploidy were significantly higher than those in diploidy. These findings indicate that circulating CEA in peripheral blood might be influenced by the metabolic process of CEA in the liver as well as cancer progression rather than CEA production of the tumor. 2) The 5 year survival rate of the patient\u27s group with a negative rate of portal CEA (93%) was far better than that with a positive rate (57%). This study suggested that the portal blood level of CEA in colorectal carcinoma may be very useful for assessment of the patient\u27s survival

Osteoclasts adapt to physioxia perturbation through DNA demethylation

Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two-photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia-inducible factor activity. We observe that hypoxia decreases ten-eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen-dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.Nishikawa K., Seno S., Yoshihara T., et al. Osteoclasts adapt to physioxia perturbation through DNA demethylation. EMBO Reports 22, e53035 (2021); https://doi.org/10.15252/embr.202153035

Long-term trends in mortality risk associated with short-term exposure to air pollution in 10 Japanese cities between 1977 and 2015

Background and aim: Short-term associations between air pollution and mortality have been well reported in Japan, but the historical changes in mortality risk remain unknown. We examined temporal changes in the mortality risks associated with short-term exposure to four criteria air pollutants in selected Japanese cities.Methods: We collected daily mortality data for non-accidental causes (n = 5,748,206), cardiovascular (n = 1,938,743) and respiratory diseases (n = 777,266), and air pollutants (sulfur dioxide [SO2], nitrogen dioxide [NO2], suspended particulate matter [SPM], and oxidants [Ox]) in 10 cities from 1977 to 2015. We performed two-stage analysis with 5-year stratification to estimate the relative risk (RR) of mortality per 10-unit increase in the 2-day moving average of air pollutant concentrations. In the first stage, city-specific associations wereassessed using a quasi-Poisson generalized linear regression model. In the second stage, city-specific estimates were pooled using a random-effects meta-analysis. Linear trend and ratio of relative risks (RRR) were computed to examine temporal changes.Results: When stratifying the analysis by every 5 years, average concentrations in each sub-period decreased for SO2, NO2, and SPM (14.2–2.3 ppb, 29.4–17.5 ppb, 52.1–20.6 μg/m3, respectively) but increased for Ox (29.1–39.1 ppb) over the study period. We found evidence of a negative linear trend in the risk of cardiovascular mortality associated with SPM across sub-periods. However, the risks of non-accidental and respiratory mortality per 10-unit increase in SPM concentration were significantly higher in the most recent period than in the earliest period. Other gaseous pollutants did not show such temporal risk change. The risks posed by these pollutants were slightly to moderately heterogeneous in the different cities.Conclusions: The mortality risks associated with short-term exposure to SPM changed, with different trends by cause of death, in 10 cities over 39 years whereas the risks for other gaseous pollutants were relatively stable

Redox-dependent conformational changes of a proximal [4Fe-4S] cluster in Hyb-type [NiFe]-hydrogenase to protect the active site from O2

Citrobacter sp. S-77 [NiFe]-hydrogenase harbors a standard [4Fe–4S] cluster proximal to the Ni–Fe active site. The presence of relocatable water molecules and a flexible aspartate enables the [4Fe–4S] to display redox-dependent conformational changes. These structural features are proposed to be the key aspects that protect the active site from O2 attack

Long-term trends in mortality risk associated with short-term exposure to air pollution in 10 Japanese cities between 1977 and 2015

Short-term associations between air pollution and mortality have been well reported in Japan, but the historical changes in mortality risk remain unknown. We examined temporal changes in the mortality risks associated with short-term exposure to four criteria air pollutants in selected Japanese cities.This work was supported by JSPS KAKENHI [grant numbers JP20H03942, JP19K10644] and the Nagasaki University WISE Program.Peer reviewe