Short-Lived Radioisotope

The isotope ^{98}Tc decays to ^{98}Ru with a half-life of 4.2×10^{6} yr and could have been present in the early Solar System. In this Letter, we report on the first calculations of the production of ^{98}Tc by neutrino-induced reactions in core-collapse supernovae (the ν process). Our predicted ^{98}Tc abundance at the time of solar system formation is not much lower than the current measured upper limit raising the possibility for its detection in the not too distant future. We show that, if the initial abundance were to be precisely measured, the ^{98}Tc nuclear cosmochronometer could be used to evaluate a much more precise value of the duration time from the last core-collapse supernova to the formation of the solar system. Moreover, a unique and novel feature of the ^{98}Tc ν-process nucleosynthesis is the large contribution (∼20%) from charged current reactions with electron antineutrinos. This means that ^{98}Tc becomes a unique new ν-process probe of the temperature of the electron antineutrinos.

A hybrid type Ia supernova with an early flash triggered by helium-shell detonation.

Type Ia supernovae arise from the thermonuclear explosion of white-dwarf stars that have cores of carbon and oxygen. The uniformity of their light curves makes these supernovae powerful cosmological distance indicators, but there have long been debates about exactly how their explosion is triggered and what kind of companion stars are involved. For example, the recent detection of the early ultraviolet pulse of a peculiar, subluminous type Ia supernova has been claimed as evidence for an interaction between a red-giant or a main-sequence companion and ejecta from a white-dwarf explosion. Here we report observations of a prominent but red optical flash that appears about half a day after the explosion of a type Ia supernova. This supernova shows hybrid features of different supernova subclasses, namely a light curve that is typical of normal-brightness supernovae, but with strong titanium absorption, which is commonly seen in the spectra of subluminous ones. We argue that this early flash does not occur through previously suggested mechanisms such as the companion-ejecta interaction. Instead, our simulations show that it could occur through detonation of a thin helium shell either on a near-Chandrasekhar-mass white dwarf, or on a sub-Chandrasekhar-mass white dwarf merging with a less-massive white dwarf. Our finding provides evidence that one branch of previously proposed explosion models-the helium-ignition branch-does exist in nature, and that such a model may account for the explosions of white dwarfs in a mass range wider than previously supposed.

Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage.

BACKGROUND: Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet growth factor receptor α (PDGFR α), RET and KIT. Antiangiogenesis activity of lenvatinib in VEGF- and FGF-driven angiogenesis models in both in vitro and in vivo was determined. Roles of tumor vasculature (microvessel density (MVD) and pericyte coverage) as biomarkers for lenvatinib were also examined in this study. METHOD: We evaluated antiangiogenesis activity of lenvatinib against VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. Effects of lenvatinib on in vivo angiogenesis, which was enhanced by overexpressed VEGF or FGF in human pancreatic cancer KP-1 cells, were examined in the mouse dorsal air sac assay. We determined antitumor activity of lenvatinib in a broad panel of human tumor xenograft models to test if vascular score, which consisted of high MVD and low pericyte coverage, was associated with sensitivity to lenvatinib treatment. Vascular score was also analyzed using human tumor specimens with 18 different types of human primary tumors. RESULT: Lenvatinib inhibited VEGF- and FGF-driven proliferation and tube formation of HUVECs in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral treatments of lenvatinib. Lenvatinib showed significant antitumor activity in KP-1/VEGF and five 5 of 7 different types of human tumor xenograft models at between 1 to 100 mg/kg. We divided 19 human tumor xenograft models into lenvatinib-sensitive (tumor-shrinkage) and relatively resistant (slow-growth) subgroups based on sensitivity to lenvatinib treatments at 100 mg/kg. IHC analysis showed that vascular score was significantly higher in sensitive subgroup than relatively resistant subgroup (p < 0.0004). Among 18 types of human primary tumors, kidney cancer had the highest MVD, while liver cancer had the lowest pericyte coverage, and cancers in Kidney and Stomach had highest vascular score. CONCLUSION: These results indicated that Lenvatinib inhibited VEGF- and FGF-driven angiogenesis and showed a broad spectrum of antitumor activity with a wide therapeutic window. MVD and pericyte-coverage of tumor vasculature might be biomarkers and suggest cases that would respond for lenvatinib therapy.

Detection of the gravitational lens magnifying a type Ia supernova.

Objects of known brightness, like type Ia supernovae (SNIa), can be used to measure distances. If a massive object warps spacetime to form multiple images of a background SNIa, a direct test of cosmic expansion is also possible. However, these lensing events must first be distinguished from other rare phenomena. Recently, a supernova was found to shine much brighter than normal for its distance, which resulted in a debate: Was it a new type of superluminous supernova or a normal SNIa magnified by a hidden gravitational lens? Here, we report that a spectrum obtained after the supernova faded away shows the presence of a foreground galaxy-the first found to strongly magnify a SNIa. We discuss how more lensed SNIa can be found than previously predicted.

Immunohistochemical Examination of a Resected Advanced Hilar Cholangiocarcinoma Arising in a 29-Year-Old Male without Primary Sclerosing Cholangitis.

A 29-year-old man with advanced hilar cholangiocarcinoma was successfully treated with an extended right lobectomy. The carbohydrate antigen 19-9 (CA19-9) level was elevated to 939 IU/l, and the pathological findings revealed moderately differentiated tubular adenocarcinoma which involved almost the entire thickness of the hepatic duct and the adjacent liver tissue (T3) and which was associated with lymph node metastasis (N1). It was a stage IIB (T3N1M0) tubular adenocarcinoma according to UICC pathological staging. Immunohistochemical examination revealed that Ki-67, cyclin D1, and MMP-7 were positive, and 14-3-3sigma and p27 were negative. The pathological and immunohistochemical findings indicated high malignant potential indicating poor prognosis. We administrated the postoperative adjunct gemcitabine combined with S-1 chemotherapy. The patient is alive without recurrence and doing well two years after surgery. We also review other reports of cholangiocarcinoma patients aged less than 30 years.

Tycho Brahe's 1572 supernova as a standard type Ia as revealed by its light-echo spectrum.

Type Ia supernovae are thermonuclear explosions of white dwarf stars in close binary systems. They play an important role as cosmological distance indicators and have led to the discovery of the accelerated expansion of the Universe. Among the most important unsolved questions about supernovae are how the explosion actually proceeds and whether accretion occurs from a companion or by the merging of two white dwarfs. Tycho Brahe's supernova of 1572 (SN 1572) is thought to be one of the best candidates for a type Ia supernova in the Milky Way. The proximity of the SN 1572 remnant has allowed detailed studies, such as the possible identification of the binary companion, and provides a unique opportunity to test theories of the explosion mechanism and the nature of the progenitor. The determination of the hitherto unknown spectroscopic type of this supernova is crucial in relating these results to the diverse population of type Ia supernovae. Here we report an optical spectrum of Tycho's supernova near maximum brightness, obtained from a scattered-light echo more than four centuries after the direct light from the explosion swept past the Earth. We find that SN 1572 belongs to the majority class of normal type Ia supernovae.

The metamorphosis of supernova SN 2008D/XRF 080109: a link between supernovae and GRBs/hypernovae.

The only supernovae (SNe) to show gamma-ray bursts (GRBs) or early x-ray emission thus far are overenergetic, broad-lined type Ic SNe (hypernovae, HNe). Recently, SN 2008D has shown several unusual features: (i) weak x-ray flash (XRF), (ii) an early, narrow optical peak, (iii) disappearance of the broad lines typical of SN Ic HNe, and (iv) development of helium lines as in SNe Ib. Detailed analysis shows that SN 2008D was not a normal supernova: Its explosion energy (E approximately 6x10(51) erg) and ejected mass [ approximately 7 times the mass of the Sun (M(middle dot in circle))] are intermediate between normal SNe Ibc and HNe. We conclude that SN 2008D was originally a approximately 30 M(middle dot in circle) star. When it collapsed, a black hole formed and a weak, mildly relativistic jet was produced, which caused the XRF. SN 2008D is probably among the weakest explosions that produce relativistic jets. Inner engine activity appears to be present whenever massive stars collapse to black holes.

Asphericity in supernova explosions from late-time spectroscopy.

Core-collapse supernovae (CC-SNe) are the explosions that announce the death of massive stars. Some CC-SNe are linked to long-duration gamma-ray bursts (GRBs) and are highly aspherical. One important question is to what extent asphericity is common to all CC-SNe. Here we present late-time spectra for a number of CC-SNe from stripped-envelope stars and use them to explore any asphericity generated in the inner part of the exploding star, near the site of collapse. A range of oxygen emission-line profiles is observed, including a high incidence of double-peaked profiles, a distinct signature of an aspherical explosion. Our results suggest that all CC-SNe from stripped-envelope stars are aspherical explosions and that SNe accompanied by GRBs exhibit the highest degree of asphericity.

A neutron-star-driven X-ray flash associated with supernova SN 2006aj.

Supernovae connected with long-duration gamma-ray bursts (GRBs) are hyper-energetic explosions resulting from the collapse of very massive stars ( approximately 40 M\circ, where M\circ is the mass of the Sun) stripped of their outer hydrogen and helium envelopes. A very massive progenitor, collapsing to a black hole, was thought to be a requirement for the launch of a GRB. Here we report the results of modelling the spectra and light curve of SN 2006aj (ref. 9), which demonstrate that the supernova had a much smaller explosion energy and ejected much less mass than the other GRB-supernovae, suggesting that it was produced by a star whose initial mass was only approximately 20 M\circ. A star of this mass is expected to form a neutron star rather than a black hole when its core collapses. The smaller explosion energy of SN 2006aj is matched by the weakness and softness of GRB 060218 (an X-ray flash), and the weakness of the radio flux of the supernova. Our results indicate that the supernova-GRB connection extends to a much broader range of stellar masses than previously thought, possibly involving different physical mechanisms: a 'collapsar' (ref. 8) for the more massive stars collapsing to a black hole, and magnetic activity of the nascent neutron star for the less massive stars.

The first chemical enrichment in the universe and the formation of hyper metal-poor stars.

The recent discovery of a hyper-metal-poor (HMP) star, with a metallicity Fe/H smaller than 1/100,000 of the solar ratio, together with one earlier HMP star, has raised a challenging question whether these HMP stars are the actual first-generation, low-mass stars of the universe. We argue that these HMP stars are second-generation stars formed from gases that were chemically enriched by the first-generation supernovae. The key to this solution is the very unusual abundance patterns of these HMP stars and the similarities and differences between them. We can reproduce these abundance features with core-collapse "faint" supernova models that include extensive matter mixing and fallback during explosions.

An asymmetric energetic type Ic supernova viewed off-axis, and a link to gamma ray bursts.

Type Ic supernovae, the explosions after the core collapse of massive stars that have previously lost their hydrogen and helium envelopes, are particularly interesting because of their link with long-duration gamma ray bursts. Although indications exist that these explosions are aspherical, direct evidence has been missing. Late-time observations of supernova SN 2003jd, a luminous type Ic supernova, provide such evidence. Recent Subaru and Keck spectra reveal double-peaked profiles in the nebular lines of neutral oxygen and magnesium. These profiles are different from those of known type Ic supernovae, with or without a gamma ray burst, and they can be understood if SN 2003jd was an aspherical axisymmetric explosion viewed from near the equatorial plane. If SN 2003jd was associated with a gamma ray burst, we missed the burst because it was pointing away from us.

Nucleosynthetic signatures of the first stars.

The chemically most primitive stars provide constraints on the nature of the first stellar objects that formed in the Universe; elements other than hydrogen, helium and traces of lithium present within these objects were generated by nucleosynthesis in the very first stars. The relative abundances of elements in the surviving primitive stars reflect the masses of the first stars, because the pathways of nucleosynthesis are quite sensitive to stellar masses. Several models have been suggested to explain the origin of the abundance pattern of the giant star HE0107-5240, which hitherto exhibited the highest deficiency of heavy elements known. Here we report the discovery of HE1327-2326, a subgiant or main-sequence star with an iron abundance about a factor of two lower than that of HE0107-5240. Both stars show extreme overabundances of carbon and nitrogen with respect to iron, suggesting a similar origin of the abundance patterns. The unexpectedly low Li and high Sr abundances of HE1327-2326, however, challenge existing theoretical understanding: no model predicts the high Sr abundance or provides a Li depletion mechanism consistent with data available for the most metal-poor stars.

Repeated injections of energy in the first 600 ms of the giant flare of SGR 1806-20.

The massive flare of 27 December 2004 from the soft gamma-ray repeater SGR 1806-20, a possible magnetar, saturated almost all gamma-ray detectors, meaning that the profile of the pulse was poorly characterized. An accurate profile is essential to determine physically what was happening at the source. Here we report the unsaturated gamma-ray profile for the first 600 ms of the flare, with a time resolution of 5.48 ms. The peak of the profile (of the order of 10(7) photons cm(-2) s(-1)) was reached approximately 50 ms after the onset of the flare, and was then followed by a gradual decrease with superposed oscillatory modulations possibly representing repeated energy injections with approximately 60-ms intervals. The implied total energy is comparable to the stored magnetic energy in a magnetar (approximately 10(47) erg) based on the dipole magnetic field intensity (approximately 10(15) G), suggesting either that the energy release mechanism was extremely efficient or that the interior magnetic field is much stronger than the external dipole field.

Evidence for segmental bile drainage by hepatic portoenterostomy for biliary atresia: Cholangiographic, hepatic venographic, and histologic evaluation of the liver taken at liver transplantation.

BACKGROUND: The result of hepatic portoenterostomy for biliary atresia (BA) has improved, but there are some patients who experience worsened liver function in the long term after one decrease in jaundice owing to portoenterostomy. However, the cause of the liver dysfunction in the long term has not been clearly ascertained. METHODS: Five patients (5 to 28 years of age) with BA underwent liver transplantation (LT) because of liver dysfunction after successful portoenterostomy. To clarify the cause of liver dysfunction occurring in the long term, the authors performed a cholangiogram, hepatic venogram, and macroscopic/microscopic examination of the liver just after LT. RESULTS: (1) Macroscopically, the liver could be divided into 3 areas, the hypertrophic, atrophic, and intermediate, with findings between those of the hypertrophic and atrophic areas. (2) The divided areas clearly corresponded to the liver segments. Segment IV was the hypertrophic area in all patients, but segments VI and VII were the atrophic areas in 4 of the 5 patients. (3) Based on the cholangiographic and microscopic findings, the hypertrophic area had near-normal structure with bile ducts. The atrophic area had severe fibrosis and contained only a few bile ducts in the intralobular spaces of liver. CONCLUSIONS: It seems that segmental bile drainage must have been established by hepatic portoenterostomy in some patients and that some postoperative patients might have worsened liver function in the long-term follow-up period accompanied with progression of fibrosis and impaired bile drainage. These pathologic changes occur in each liver segment.

Cell density modulates the metastatic aggressiveness of a mouse colon cancer cell line, colon 26.

OBJECTIVE: Although cell density in cultured cells has demonstrated several alterations in the nature of cell kinetics, the changes in the metastatic aggressiveness of cancer lines under different cell densities have not yet been studied. METHODS: In the current study, we investigated the influence of changing the cell density of cultured cancer cells (colon 26 and B16-F10) injected into the tail vein in BALB/c mice on the metastatic activity by evaluating the number of lung metastases, and the possible mechanisms of this phenomenon were discussed based on the basis of the results of an invasion assay and a cell adhesion assay. RESULTS: The number of metastatic nodules was significantly higher in the high-density group than in the low one in colon 26 (p < 0.005), however, this phenomenon was not seen in B16-F10. Next, we performed the same experiment by changing the environment to the opposite conditions for the cells in the low- and high-density groups, and the results showed the metastatic activities to be always higher in the high-density group. Moreover, although no difference was seen regarding the invasive activity between the high- and low-density groups, an adhesion assay showed the difference in the adhesion cell rate to be significantly higher in the high-density group especially in early period after coculture with human umbilical vein endothelial cells (HUVEC) (p < 0.05). CONCLUSION: In some cell types, the metastatic activity could be altered and reversed by changing the environment, such as the cell density, during a relatively short period. As a result, the epigenetic changes of cancer cells are thus suggested to play a certain role in the malignant potentiality.

Malignant transformation of the mouse anorectal epithelium induced by an inoculated human cancer cell line.

Four kinds of human cancer cell lines and one mouse cancer cell line were inoculated into the subepithelial area of the anorectum of female nude mice. Among the cell lines, two cell lines (KATO III and Lu 135) showed the potential enforcement of atypical changes in the adjacent mouse anorectal epithelium. Moreover, the submucosal invasion of the malignant transformed cells of the mouse epithelium was demonstrated in specimens obtained from three KATO III-inoculated mice. This exciting and novel phenomenon clearly demonstrates the need to change the present general concept of a single-cell origin of cancer tissue. This valuable and novel discovery may change the basis of oncology research while also providing new ideas for projects to investigate the mechanisms of carcinogenesis from several aspects such as molecular biology, cell biology, and pathology. Moreover, the novel experimental design itself is also extremely useful as a simple model for investigating the mechanisms of oncogenesis.

First-generation black-hole-forming supernovae and the metal abundance pattern of a very iron-poor star.

It has been proposed theoretically that the first generation of stars in the Universe (population III) would be as massive as 100 solar masses (100 M(O)), because of inefficient cooling of the precursor gas clouds. Recently, the most iron-deficient (but still carbon-rich) low-mass star--HE0107-5240--was discovered. If this is a population III star that gained its metals (elements heavier than helium) after its formation, it would challenge the theoretical picture of the formation of the first stars. Here we report that the patterns of elemental abundance in HE0107-5240 (and other extremely metal-poor stars) are in good accord with the nucleosynthesis that occurs in stars with masses of 20-130 M(O) when they become supernovae if, during the explosions, the ejecta undergo substantial mixing and fallback to form massive black holes. Such supernovae have been observed. The abundance patterns are not, however, consistent with enrichment by supernovae from stars in the range 130-300 M(O). We accordingly infer that the first-generation supernovae came mostly from explosions of approximately 20-130 M(O) stars; some of these produced iron-poor but carbon- and oxygen-rich ejecta. Low-mass second-generation stars, like HE0107-5240, could form because the carbon and oxygen provided pathways for the gas to cool.

High glucose induced VEGF expression via PKC and ERK in glomerular podocytes.

Podocytes are the major site of vascular endothelial growth factor (VEGF) production in the kidney, and up-regulation of VEGF plays a critical role in the progression of diabetic nephropathy. Using a differentiated mouse podocyte cell line, we investigated the roles of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) on the expression of VEGF under high glucose conditions. High glucose induced up-regulation of VEGF mRNA and protein expression in podocytes via activation of PKC (PKC-alpha and -betaII isoforms) and ERK. High glucose stimulated [(3)H]leucine incorporation in the podocytes. High glucose and the PKC stimulator, phorbol 12-myristate 13-acetate (PMA) induced activator protein-1 (AP-1)-dependent transcriptional activity and expression of VEGF. In addition, these phenomena were blocked by specific inhibitors of PKC (GF10902X) and ERK kinase (PD98059). These observations suggested that high glucose-induced VEGF expression in podocytes was largely mediated through PKC and ERK pathways that may be involved in diabetic nephropathy.

Podocyte injury promotes progressive nephropathy in zucker diabetic fatty rats.

The zucker diabetic fatty (ZDF-fa/fa) rat is one of the attractive models for type II diabetes based on impaired glucose tolerance caused by the inherited insulin-resistance gene fa. Characterization of nephropathy in this model may provide useful insights into the mechanism of the progression of diabetic nephropathy. The present study analyzed the pathophysiology of diabetes and nephropathy, including the process of glomerulosclerosis in this model by biochemical and morphometric analyses. In addition, we conducted studies in podocytes in culture to examine the direct effects of high glucose on podocytes. ZDF-fa/fa rats showed overt diabetes despite hyperinsulinemia as early as 3 months of age. Blood glucose levels increased further with a considerable decrease of insulin levels at 5 months. Glomerular filtration rate (GFR) was significantly elevated until 3 months, but fell to the level seen in lean rats by 7 months. Proteinuria started to rise during the period of increased GFR, and increased further after GFR had fallen to within the normal range. Renal fibronectin, collagen iv, and vascular endothelial growth factor mRNA levels were increased at 7 months. Glomerulosclerosis commenced as early as 5 months of age, and was associated with glomerular hypertrophy and mild mesangial expansion with evidence of accentuated podocyte injury, as revealed by increased expression of desmin. Electron microscopy suggested that degeneration of podocytes and the development of tuft adhesions were responsible for the glomerular sclerosis in this model. In addition, glomeruli from the diabetic rats showed up-regulation of the cyclin kinase inhibitors, p21 and p27. Further studies suggested that the increase in p27 expression was predominantly caused by podocytes, because predominant immunolocalization of p27 in podocytes in diabetic rats and high glucose medium induced cell hypertrophy accompanied by p27 up-regulation in differentiated podocyte cell lines. In conclusion, progressive diabetic nephropathy in ZDF-fa/fa rats is associated with evidence of podocyte injury. High concentrations of ambient glucose induced podocyte hypertrophy and stress in vitro, suggesting that the podocyte is a likely target of the diabetic milieu.