Recurrent Spindle Cell Carcinoma Shows Features of Mesenchymal Stem Cells.

This study investigated a case of spindle cell carcinoma (SpCC) in tongue pathological lesions. The patient experienced a local recurrence and distant metastasis after surgical intervention. Although standard chemotherapy was administered, a granulomatous mass continued to develop. This aggressive growth led to survival of the tumor. Secondary debulking surgery was performed to improve the patient's quality of life at the request of the patient. Using a tissue sample derived from the secondary debulking surgery, we performed an analysis of the tumor's cell surface antigens, differentiation potential, metastatic ability, and inhibition potential by anticancer reagents. In vitro analysis revealed that the cell population grown under adherent culture conditions expressed the mesenchymal stem cell (MSC) markers CD73, CD90, and CD105. The cell line established from this SpCC contained colony-forming unit fibroblasts (CFU-Fs) and exhibited multipotent differentiation into several mesenchymal lineages, including bone, cartilage, and fat. The SpCC cells also displayed vigorous mobilization. These characteristics suggested that they had the differentiation potential of mesenchymal cells, especially MSCs, rather than that of epithelial cells. The surgical specimen analyzed in this study resisted the molecular target reagent cetuximab, which is an epidermal growth factor receptor inhibitor. This clinical insight revealed that chemotherapy-resistant SpCC cells have different characteristics compared to most other cancer cells, which are sensitive to cetuximab. Our cell death assay revealed that SpCC cell death was induced by the anticancer drug imatinib, which is known to inhibit protein tyrosine kinase activity of ABL, platelet-derived growth factor receptor α (PDGFRα), and KIT. Here, we report recurrent SpCC with characteristics of MSCs and potential for treatment with imatinib.

Combination of low-dose total skin electron beam therapy and subsequent localized skin electron beam therapy as a therapeutic option for advanced-stage mycosis fungoides.

Electron beam therapy (EBT) is an established treatment for mycosis fungoides (MF), but evidence for the use of EBT in advanced cutaneous conditions is limited, and optimal scheduling of the regimen for such conditions remains unclear. We report the case of a 44-year-old woman diagnosed with MF with widespread cutaneous lesions, including multiple huge tumours in the craniofacial area. Low-dose total skin (TS)EBT and subsequent localized skin (LS)EBT achieved striking improvements in eruptions. Oral etretinate was also administered during therapy. Our experience implies that combined TSEBT and LSEBT may be worth attempting when a patient presents with both widespread lesions and prominent tumours, even when the tumours are extremely large.

Acquired dermal melanocytosis of the face and extremities.

Acquired dermal melanocytosis (ADM) is a relatively rare, but well-described disease among adolescent to middle-aged East Asian women, particularly those of Japanese and Chinese descent. Clinically, ADM manifests as multiple punctate and greyish-brown pigmented areas 1-3 mm in diameter occurring on both sides of the forehead and zygomatic region. The subtype of ADM affecting the face and extremities is extremely rare even in East Asian women. We describe three patients with ADM of the face and extremities (ADMFE) and their characteristic clinical features. All patients were Japanese women, and showed multiple greyish-brown pigmentations on both nasal wings and on the extensor surface of the extremities. We found that the clinical features were strikingly uniform, and that a pigmented lesion on the nasal wing can be an important clue to distinguish ADMFE from other hyperpigmented diseases of the hands and feet. One patient was treated with Q-switched ruby laser with excellent outcome. Increased awareness of ADMFE can lead to earlier diagnosis and potential treatment.

Translational initiation regulated by ATM in dendritic cells development.

Ataxia telangiectasia mutated (ATM) protein has been implicated in multiple pathways such as DNA repair, cell cycle checkpoint, cell growth, development, and stem cell renewal. In this study, we demonstrate evidence that ATM is involved in granulocyte macrophage colony-stimulating factor (GM-CSF)-induced dendritic cell (DC) development from bone marrow (BM) cells. Inactivation of ATM protein results in decreased BM proliferation, leading to reduced DC development and their activity for T cell activation. Expression of Jak2, STAT5, and mTOR is suppressed in both wild-type and ATM-null BM prior to GM-CSF stimulation. Activation of those proteins is delayed and prolonged hypophosphorylation of 4EBP1 is observed in ATM-null BM when treated with GM-CSF, although Erk and p38 are similarly expressed and activated in both wild-type and ATM-null BM cell types. Akt is also suppressed in wild-type BM, and transduction of constitutively active Akt or STAT5 in ATM-null BM restores DC development. Together, these results illustrate that ATM deficiency causes impaired initiation of protein translation in BM, leading to immature development of DC.

Cascade Auger decays following Si KL23L23 Auger transitions in SiF4.

Cascade Si LVV Auger decays following KL(23)L(23) Auger transitions have been measured in SiF(4) molecule using an electron spectrometer combined with monochromatized undulator radiation. Molecular cascade processes from the two 2p holes states largely generate wide band structures in the spectra due to sequential electron emission leading to multiple valence holes. However, a peak with high yield is observed for the first time at about 103 eV, an energy being considerably higher than the energies of the normal LVV Auger electron, in the instance of the resonant excitation of Si 1s electron into the vacant molecular orbital. This peak is presumed to originate from the participator decay from the state with two 2p holes and one excited electron into the state with one 2p hole and one valence hole. A similar peak with less intensity is detected in the photoexcitation of the 1s electron into a Rydberg orbital. After the normal KL(23)L(23) Auger transition, the resultant cascade spectrum shows several peaks, e.g., 61 eV, 76 eV, and 82 eV. The former two peaks are assigned to the Auger transitions of Si atoms produced through molecular ion dissociation after cascade decays, and the latter is probably ascribed to the second step Auger decay into states having a 2p hole together with two valence holes.

DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway.

The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage.

Three-electron interatomic Coulombic decay from the inner-valence double-vacancy states in NeAr.

We have unambiguously identified interatomic Coulombic decay in NeAr from the inner-valence double-vacancy state Ne-Ar(2+)(3s(-2)) to outer-valence triple-vacancy states Ne(+)(2p(-1))-Ar(2+)(3p(-2)) by momentum-resolved electron-ion multicoincidence. This is the first observation of interatomic Coulombic decay where three electrons (3e) participate. The results suggest that this 3e interatomic Coulombic decay is significantly faster than other competing processes like fluorescence decay and charge transfer via curve crossing.

Experimental observation of rotational Doppler broadening in a molecular system.

The first experimental evidence of rotational Doppler broadening in photoelectron spectra, reported here, show good agreement with recently described theoretical predictions. The dependence of the broadening on temperature and photoelectron kinetic energy is quantitatively predicted by the theory. The experiments verify that the rotational contributions to the linewidth are comparable to those from translational Doppler broadening and must be considered in the analysis of high-resolution photoelectron spectra. A classical model accounting for this newly observed effect is presented.

Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis.

DNA damage signaling pathways are initiated in response to chemical reagents and radiation damage, as well as in response to hypoxia. It is implicated that structural maintenance of chromosomes 1 (SMC1) is not only a component of the cohesion complex but also facilitates the activation of DNA damage checkpoint proteins. Here, we studied the mechanism of DNA damage checkpoint activated by ATR-SMC1 pathway when cells are treated with desferrioxamine (DFO), a hypoxia-mimetic reagent. We show that DFO treatment induces phosphorylation of SMC1 at Ser966, NBS1 at Ser343, Chk1 at Ser317, Chk2 at Thr68, and p53 at Ser15. Among these sites, phosphorylation of SMC1, NBS1, and Chk1 by DFO are mediated by ATR as it is greatly reduced in both ATR-deficient human fibroblasts and HCT116 human colon cancer cells in which ATR is heterozygously mutated, whereas these proteins are phosphorylated in cells deficient for ATM and DNA-PKcs. DFO-induced apoptosis is decreased in ATR-mutant HCT116 cells, although p53 is normally activated in those cells. Expression of SMC1 S966A in which Ser966 is substituted to Ala attenuates apoptosis and phosphorylation of Chk1 at Ser317 after DFO treatment, although levels of HIF1α are not significantly changed. These results suggest that DFO induces apoptosis through the ATR-SMC1 arm of the pathway.

Electron-transfer-mediated decay and interatomic Coulombic decay from the triply ionized states in argon dimers.

We report the first observation of electron-transfer-mediated decay (ETMD) and interatomic Coulombic decay (ICD) from the triply charged states with an inner-valence vacancy, using the Ar dimer as an example. These ETMD and ICD processes, which lead to fragmentation of Ar(3+)-Ar into Ar(2+)-Ar(2+) and Ar(3+)-Ar+, respectively, are unambiguously identified by electron-ion-ion coincidence spectroscopy in which the kinetic energy of the ETMD or ICD electron and the kinetic energy release between the two fragment ions are measured in coincidence.

Projection of Si 1s photoexcited orbitals into resonant Auger electron spectra in KLL decays of Si(CH3)4 and SiF4.

Spectator resonant KL(23)L(23) Auger electron spectra have been measured in the Si 1s photoexcitation region of Si(CH(3))(4) using monochromatized undulator radiation combined with a hemispherical electron spectrometer. The broad peak with high intensity in a total ion yield spectrum, coming mainly from excitation of a 1s electron into the 6t(2) vacant orbital, induces a spectator Auger decay in which the excited electron remains in its excited orbital. The component on the higher energy side of this peak through 1s excitation into a Rydberg orbital produces resonant Auger decays in which the excited Rydberg electron moves into a slightly higher Rydberg orbital, or is partly shaken up to a significantly higher Rydberg orbital. These findings of Si(CH(3))(4) indicate a clear contrast to those for SiF(4), in which the 1s excitation into a Rydberg orbital induces a shake-down phenomenon as well as a shake-up one. The results of these molecules exhibit a clear splitting effect among excited orbitals which are smeared out by overlapping due to lifetime widths and due to densely populated levels in the 1s electron excitation spectrum. This is consistent with the calculation on photoexcitation within the framework of density functional theory.

A Japanese-specific recurrent mutation and a novel splice site mutation in the LAMC2 gene identified in two Japanese families with Herlitz junctional epidermolysis bullosa.

BACKGROUND: Herlitz junctional epidermolysis bullosa (H-JEB) is an extremely rare genodermatosis characterized by lethality owing to severe blister formation. We report two unrelated Japanese patients with H-JEB. Genetic analyses detected a single nonsense mutation on the LAMC2 gene in these two patients. AIM: To identify the mutation involved and describe the first reported Japanese recurrent mutation in the LAMC2 gene. METHODS: Direct sequencing was performed of DNA from either peripheral blood or fetal cells in amniotic fluid. Reverse transcriptase PCR was used to confirm that an aberrant transcript resulted from the splice site mutation. A haplotype analysis was performed to define the origin of the recurrent mutation. RESULTS: Both patients had blisters and erosions on the trunk and limbs at birth, with nail dystrophy. Patient 1 died as a result of sepsis at 30 weeks of age, and patient 2 died as a result of disseminated intravascular coagulation at 20 weeks of age. Mutation analysis of the LAMC2 gene revealed that patient 1 was compound heterozygous for a nonsense mutation (p.Cys553X) and a novel splice site mutation (c.2868+1delG), and patient 2 was a homozygous for p.Cys553X. Prenatal diagnosis performed during a subsequent pregnancy in family 2 revealed that this second child was heterozygous for p.Cys553X, and was thus not affected. Haplotype analysis suggested that a p.Cys553X allele derived from the same origin had been independently inherited by these two unrelated families. CONCLUSIONS: p.Cys553X in the LAMC2 gene may be a Japanese-specific recurrent mutation as a result of a founder effect, and it may therefore be useful for initial screening in the mutation analysis of H-JEB.

Biodegradable Nano-aggregates of Star-Shaped 8-arm PEG-PLLA Block Co-polymers for Encapsulation of Water-Soluble Macromolecules.

A series of amphiphilic 8-arm PEG-b-PLLA co-polymers with star-shaped structure was synthesized through ring-opening polymerization of L-lactide (L-LA) in the presence of 8-arm PEG as a macroinitiator by varying feeding molar rations of L-LA to 8-arm PEG. 8-arm PEG-b-PLLA co-polymers having certain PEG content and PEG length were found to self-assemble into nano-aggregates in aqueous solutions. The size and the morphology of the nano-aggregates were investigated by dynamic light scattering and (1)H-NMR in CDCl3 and D2O. The results indicate that the average diameter was ca. 150 nm, the surface of the nano-aggregates was covered by PEG chains and the PLLA cores formed by hydrophobic interaction are located inside of the nano-aggregates. FITC-dextran molecules, as model for water-soluble macromolecular drugs, were successfully encapsulated into 8-arm PEG-b-PLLA nano-aggregates by simple addition of FITC-dextran to the aqueous phase during the self-assembly process. This result suggests that the nanoaggregates have a vesicle-like morphology. The nano-aggregates dissociated gradually in the order of weeks in PBS (pH 7.4, ionic strength 140 mM) at 37°C. Thus, the novel nano-aggregates of 8-arm PEG-b-PLLA can be expected to have advantages, such as long circulation times, as drug carriers which show sustained release of loaded macromolecular drugs such as antibodies and DNA vaccines in the blood stream.

Valence photoelectron spectroscopy of N2 and CO: recoil-induced rotational excitation, relative intensities, and atomic orbital composition of molecular orbitals.

Recoil-induced rotational excitation accompanying photoionization has been measured for the X, A, and B states of N(2)(+) and CO(+) over a range of photon energies from 60 to 900 eV. The mean recoil excitation increases linearly with the kinetic energy of the photoelectron, with slopes ranging from 0.73×10(-5) to 1.40×10(-5). These slopes are generally (but not completely) in accord with a simple model that treats the electrons as if they were emitted from isolated atoms. This treatment takes into account the atom from which the electron is emitted, the molecular-frame angular distribution of the electron, and the dependence of the photoelectron cross section on photon energy, on atomic identity, and on the type of atomic orbital from which the electron is ejected. These measurements thus provide a tool for investigating the atomic orbital composition of the molecular orbitals. Additional insight into this composition is obtained from the relative intensities of the various photolines in the spectrum and their variation with photon energy. Although there are some discrepancies between the predictions of the model and the observations, many of these can be understood qualitatively from a comparison of atomic and molecular wavefunctions. A quantum-mechanical treatment of recoil-induced excitation predicts an oscillatory variation with photon energy of the excitation. However, the predicted oscillations are small compared with the uncertainties in the data, and, as a result, the currently available results cannot provide confirmation of the quantum-mechanical theory.

Terahertz spectroscopy of native-conformation and thermally denatured bovine serum albumin (BSA).

Proteins are expected to exhibit collective vibrational modes at terahertz frequencies. We have developed a promising approach to measure these motions by using a membrane device to hold samples. Samples of bovine serum albumin (BSA) in native and thermally denatured conformations were measured using terahertz time-domain spectroscopy. Clear differences were observed in transmittance and phase between native-conformation BSA samples and thermally denatured BSA samples. Time-domain data shows that samples exhibited relative time shifts when compared with a standard. Results suggest that there were differences in dielectric responses in the BSA samples, and these are probably associated with molecular conformational changes in the membrane device.

Indeterminate cell histiocytosis successfully treated with ultraviolet B phototherapy.

Indeterminate cell histiocytosis (ICH) is a rare disorder, characterized by infiltration of the skin by neoplastic cells that are characteristically positive for S-100 and CD1a, but lack Birbeck's granules. A 75-year-old man presented with a 4-year history of multiple papules on the trunk, limbs, face and neck. Skin biopsy revealed dense infiltration of histiocytic cells that were CD1a+/S100+, but lacked Birbeck's granules. No other abnormality was seen during a general examination including a computed tomography scan of the body, gallium scintigraphy, and an abdominal sonography. Broadband ultraviolet B (UVB) treatment was used for the skin lesions, and partial but almost complete remission was obtained. The case suggests that UVB phototherapy is an option for treatment of ICH.

Anisotropy and corotation of galactic cosmic rays.

The intensity of Galactic cosmic rays is nearly isotropic because of the influence of magnetic fields in the Milky Way. Here, we present two-dimensional high-precision anisotropy measurement for energies from a few to several hundred teraelectronvolts (TeV), using the large data sample of the Tibet Air Shower Arrays. Besides revealing finer details of the known anisotropies, a new component of Galactic cosmic ray anisotropy in sidereal time is uncovered around the Cygnus region direction. For cosmic-ray energies up to a few hundred TeV, all components of anisotropies fade away, showing a corotation of Galactic cosmic rays with the local Galactic magnetic environment. These results have broad implications for a comprehensive understanding of cosmic rays, supernovae, magnetic fields, and heliospheric and Galactic dynamic environments.

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation.

Aurora-A/STK15/BTAK, which encodes a centrosome-associated kinase, is amplified and overexpressed in multiple types of human tumors, including breast cancer. However, the causal relationship between overexpression of Aurora-A and tumorigenesis has not been fully established due to contradictory data obtained from different experimental systems. To investigate this, we generated a mouse strain that carries an MMTV-Aurora-A transgene. We showed that all the MMTV-Aurora-A mice displayed enhanced branch morphogenesis in the mammary gland and about 40% developed mammary tumors at 20 months of age. The tumor incidence was significantly increased in a p53(+/-) mutation background with about 70% MMTV-Aurora-A;p53(+/-) animals developed tumors at 18 months of age. Of note, overexpression of Aurora-A led to genetic instability, characterized by centrosome amplification, chromosome tetraploidization and premature sister chromatid segregation, at stages prior to tumor formation. Most notably, the severe chromosomal abnormality did not cause cell death owing to the activation of AKT pathway, including elevated levels of phosphorylated AKT and mammalian target of rapamycin, and nuclear accumulation of cyclin D1, which enabled continuous proliferation of the tetraploid cells. These data establish Aurora-A as an oncogene that causes malignant transformation through inducing genetic instability and activating oncogenic pathways such as AKT and its downstream signaling.