Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray.

X-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks. We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles. IPO were loaded onto tumor spheroids and the spheroids were irradiated with 33.2 keV monochromatic X-ray. After incubation in CO2 incubator, destruction of tumor spheroids was observed which was accompanied by apoptosis induction, as determined by the TUNEL assay. By employing the γH2AX assay, we detected double strand DNA cleavages immediately after the irradiation. These results suggest that IPO first generate double strand DNA breaks upon X-ray irradiation followed by apoptosis induction of cancer cells. Use of three different monochromatic X-rays having energy levels of 33.0, 33.2 and 33.4 keV as well as X-rays with 0.1 keV energy intervals showed that the optimum effect of all three events (spheroid destruction, apoptosis induction and generation of double strand DNA breaks) occurred with a 33.2 keV monochromatic X-ray. These results uncover the preferential effect of K-edge energy X-ray for tumor spheroid destruction mediated by iodine containing nanoparticles.

Dose simulations of an early 20th century kilovoltage pneumonia radiotherapy technique performed with a modern fluoroscope.

To simulate an early 20th century viral pneumonia radiotherapy treatment using modern fluoroscopy and evaluated it according to current dose guidelines. Monte Carlo was used to assess the dose distribution on an anthropomorphic phantom. Critical organs were: skin, breasts, esophagus, ribs, vertebrae, heart, thymus, and spinal cord. A 100 kVp beam with 3 mm Al HVL, 25 × 25 cm2 posterior-anterior (PA) field and 50 cm source-to-surface distance were simulated. Simulations had a resolution of 0.4 × 0.4 × 0.06 cm3 and a 6% uncertainty. Hundred percent dose was normalized to the skin surface and results were displayed in axial, coronal, and sagittal planes. Dose volume histograms were generated in MATLAB for further analysis. Prescription doses of 0.3, 0.5, and 1.0 Gy were applied to the 15% isodose for organ-dose comparison to current tolerances and potential risk of detriment. Ninety-five and ninety-seven percent of the right and left lung volumes, respectively, were well-covered by the 15% isodose line. For the 0.3, 0.5, and 1.0 Gy prescriptions, the maximum skin doses were 2.9, 4.8, and 9.6 Gy compared to a 2.0 Gy transient erythema dose threshold; left/right lung maximum doses were 1.44/1.46, 2.4/2.4, and 4.8/4.9 Gy compared to a 6.5 Gy pneumonitis and 30 Gy fibrosis thresholds; maximum heart doses were 0.5, 0.9, and 1.8 Gy compared to the 0.5 Gy ICRP-recommendation; maximum spinal cord doses were 1.4, 2.3, and 4.6 Gy compared to 7.0 Gy single fraction dose threshold. Maximum doses to other critical organs were below modern dose thresholds. A 100 kVp PA field could deliver a 0.3 Gy or 0.5 Gy dose without risk of complications. However, a 1.0 Gy dose treatment could be problematic. Critical organ doses could be further reduced if more than one treatment field is used.

High-spatiotemporal-quality petawatt-class laser system.

We have developed a femtosecond high-intensity laser system that combines both Ti:sapphire chirped-pulse amplification (CPA) and optical parametric CPA (OPCPA) techniques and produces more than 30 J broadband output energy, indicating the potential for achieving peak powers in excess of 500 TW. With a cleaned high-energy seeded OPCPA preamplifier as a front end in the system, for the compressed pulse without pumping the final amplifier, we found that the temporal contrast in this system exceeds 10(10) on the subnanosecond time scales, and is near 10(12) on the nanosecond time scale prior to the peak of the main femtosecond pulse. Using diffractive optical elements for beam homogenization of a 100 J level high-energy Nd:glass green pump laser in a Ti:sapphire final amplifier, we have successfully generated broadband high-energy output with a near-perfect top-hat-like intensity distribution.

Laser acceleration and its future.

Laser acceleration is based on the concept to marshal collective fields that may be induced by laser. In order to exceed the material breakdown field by a large factor, we employ the broken-down matter of plasma. While the generated wakefields resemble with the fields in conventional accelerators in their structure (at least qualitatively), it is their extreme accelerating fields that distinguish the laser wakefield from others, amounting to tiny emittance and compact accelerator. The current research largely falls on how to master the control of acceleration process in spatial and temporal scales several orders of magnitude smaller than the conventional method. The efforts over the last several years have come to a fruition of generating good beam properties with GeV energies on a table top, leading to many applications, such as ultrafast radiolysis, intraoperative radiation therapy, injection to X-ray free electron laser, and a candidate for future high energy accelerators.

Interleukin (IL)-1beta stimulates migration and survival of first-trimester villous cytotrophoblast cells through endometrial epithelial cell-derived IL-8.

IL-1, secreted by human embryos and trophoblast cells, is important for successful implantation and pregnancy. We previously reported that IL-1beta induced IL-8 production in human endometrial stromal cells (ESCs) and that induction was regulated by substances implicated in implantation. In the present study using human primary cells in culture, we measured IL-1beta-induced production of IL-8 from endometrial epithelial cells (EECs) and ESCs and examined effects of the endometrium-derived IL-8 on migration and number of first-trimester villous cytotrophoblast cells (vCTs). Both basal and IL-1beta-induced IL-8 levels of cell supernatants were much higher in EECs than ESCs. Addition of IL-1beta to EECs increased the chemotactic activity of the supernatants to vCTs, and this effect was suppressed by immunoneutralization with anti-IL-8 antibody. Supernatants of IL-1beta-stimulated EECs yielded significantly higher number of vCTs compared with those of untreated EECs, and the effect was inhibited by IL-8 antibody. These findings suggest that IL-1 promotes implantation by stimulating EECs to produce IL-8, which subsequently induces migration of vCTs and contributes to survival of vCTs.

Interleukin-4 stimulates proliferation of endometriotic stromal cells.

Several lines of evidence indicate that the Th2 immune response is associated with endometriosis. Although an increased concentration of interleukin (IL)-4, a typical Th2 cytokine, has been reported in endometriotic tissues, the implication of this for endometriosis has not been determined. To investigate a possible role of IL-4 in the development of endometriosis, we examined the presence of IL-4-producing cells in endometriotic tissues and the effect of IL-4 on proliferation of endometriotic stromal cells. Endometriotic stromal cells were isolated from endometriotic tissues obtained from women undergoing surgery for endometrioma. Immunohistochemistry of endometriotic tissues revealed that IL-4-positive cells were abundant in the stroma. The effect of IL-4 on proliferation of endometriotic stromal cells was studied using cell counting and BrdU incorporation assays. IL-4 (0.1 to 10 ng/ml) significantly increased cell number and BrdU incorporation in a dose-dependent manner, and the proliferative effect of IL-4 was inhibited by anti-IL-4 receptor antibody. IL-4-induced activation of mitogen-activated protein kinases in endometriotic stromal cells was examined by Western blotting. IL-4 induced phosphorylation of p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun kinase, and p42/44 mitogen-activated protein kinase and inhibitors of these kinases suppressed IL-4-induced proliferation of endometriotic stromal cells. These findings suggest that proliferation of endometriotic stromal cells induced by locally produced IL-4 is involved in the development of endometriosis.

Tunicamycin enhances the apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand in endometriotic stromal cells.

BACKGROUND: The increase in concentration of osteoprotegerin, an antagonist of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in the peritoneal fluid of women with endometriosis may interfere with TRAIL-induced apoptosis in endometriotic cells and promote the development of endometriosis. In the present study, the effect of tunicamycin, a possible apoptosis enhancer, on TRAIL-induced apoptosis in endometriotic stromal cells (ESC) was determined. METHODS: ESC were isolated from cyst walls of ovarian endometrioma and cultured. ESC were incubated with or without tunicamycin (2 microg/ml) for the first 16 h, and then incubated with or without TRAIL (200 ng/ml) for the following 24 h. To examine whether caspases were involved in TRAIL-induced apoptosis, z-VAD-fmk (30 microM), a general caspase inhibitor, was added 1 h before TRAIL treatment. ESC were transfected with small interfering RNA (siRNA) for DR5, a receptor of TRAIL, before tunicamycin treatment to evaluate its role in ESC. DR5 mRNA level was determined by quantitative RT-PCR. Apoptosis in ESC was evaluated by flow cytometry. RESULTS: Tunicamycin increases both DR5 mRNA (P < 0.005) and TRAIL-induced apoptosis (P < 0.0001) in ESC. The increase in TRAIL-induced apoptosis in ESC by tunicamycin was suppressed (P < 0.05) by z-VAD-fmk. Transfection with DR5 siRNA suppressed the tunicamycin-induced increase in DR5 mRNA and abrogated the up-regulation of TRAIL-induced apoptosis by tunicamycin. CONCLUSIONS: The combined treatment with tunicamycin and TRAIL may have therapeutic potential in the treatment of endometriosis.

Destruction of tumor mass by gadolinium-loaded nanoparticles irradiated with monochromatic X-rays: Implications for the Auger therapy.

Synchrotron generated monochromatic X-rays can be precisely tuned to the K-shell energy of high Z materials resulting in the release of the Auger electrons. In this work, we have employed this mechanism to destruct tumor spheroids. We first loaded gadolinium onto the surface of mesoporous silica nanoparticles (MSNs) producing gadolinium-loaded MSN (Gd-MSN). When Gd-MSN was added to the tumor spheroids, we observed efficient uptake and uniform distribution of Gd-MSN. Gd-MSN also can be taken up into cancer cells and localize to a site just outside of the cell nucleus. Exposure of the Gd-MSN containing tumor spheroids to monochromatic X-ray beams resulted in almost complete destruction. Importantly, this effect was observed at an energy level of 50.25 keV, but not with 50.0 keV. These results suggest that it is possible to use precisely tuned monochromatic X-rays to destruct tumor mass loaded with high Z materials, while sparing other cells. Our experiments point to the importance of nanoparticles to facilitate loading of gadolinium to tumor spheroids and to localize at a site close to the nucleus. Because the nanoparticles can target to tumor, our study opens up the possibility of developing a new type of radiation therapy for cancer.

Interleukin (IL)-17A stimulates IL-8 secretion, cyclooxygensase-2 expression, and cell proliferation of endometriotic stromal cells.

IL-17A is secreted from Th17 cells, a discovery leading to revision of the mechanism underlying the role of Th1/Th2 in the immune response. Strong evidence suggests that immune responses associated with inflammation are involved in the pathogenesis of endometriosis. In the present study, we first demonstrated that the presence of Th17 cells in peritoneal fluid of endometriotic women by flow cytometric analysis and IL-17A-positive cells in endometriotic tissues by immunohistochemistry. To investigate the role of IL-17A in the development of endometriosis, we then studied the effect of IL-17A on IL-8 production, cyclooxygensase-2 expression, and cell proliferation of cultured endometriotic stromal cells (ESCs). IL-17A enhanced IL-8 secretion from ESCs in a dose-dependent manner. The IL-17A-induced secretion of IL-8 from ESCs was suppressed by anti-IL-17 receptor A antibodies or inhibitors of p38 MAPK, p42/44 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase. Addition of TNFalpha synergistically increased IL-17A-induced IL-8 secretion from ESCs. IL-17A also enhanced the expression of cyclooxygensase-2 mRNA and proliferation of ESCs. IL-17A may play a role in the development of endometriosis by stimulating inflammatory responses and proliferation of ESCs.

Direct oxidative cyanation based on the concept of site isolation.

On the basis of the concept of site isolation, we have successfully demonstrated direct oxidative cyanation of various organic compounds, which even have higher oxidation potentials compared to that of cyanide, by using a polystyrene-supported quaternary ammonium cyanide.

Deprotonation in anodic methoxylation of fluoroethyl phenyl sulfides using site-isolated heterogeneous bases.

On the basis of the concept of site isolation in electrochemical reactions, we have successfully demonstrated acceleration of the deprotonation step in anodic methoxylation of fluoroethyl phenyl sulfides using silica gel supported bases.

Kolbe carbon-carbon coupling electrosynthesis using solid-supported bases.

We have developed a novel electrolytic system for Kolbe carbon-carbon coupling electrosynthesis based on the acid-base reaction between carboxylic acids as a substrate and solid-supported bases. On the basis of the electrolytic system, Kolbe electrolysis of various carboxylic acids was successfully carried out to provide the corresponding homocoupling products in moderate to excellent yields.

Gait strategies to reduce the dynamic joint load in the lower limbs during a loading response in young healthy adults.

Reducing external joint moments during gait can lead to a reduction in dynamic joint load. There has yet to be a detailed investigation of gait strategies that can reduce external joint moments by decreasing the magnitude of ground reaction force (GRF) without reducing the walking speed. The objectives of this study were to verify whether it is possible to reduce external joint moments by decreasing the GRF magnitude without reducing the walking speed and to identify the alternative walking strategy involved in young healthy adults. This study included 14 young healthy subjects. They performed two types of walking: normal and impact reduction walking. For impact reduction walking, the subjects walked in a manner that reduced the impact upon foot contact. Cadence and step length were unified between the two conditions. The walking speed, peak value of vertical GRF, braking-accelerating force, loading rate, joint angle, and external joint moments of the two conditions were recorded and compared. No significant difference was noted in the walking speed. However, the first peak of vertical GRF, braking force, and loading rate during loading response were significantly reduced during impact reduction walking, and external joint moments in the hip, knee, and ankle joints were reduced. In contrast, the second peak of vertical GRF, hip extension angle, and external ankle dorsiflexion moment were significantly increased during terminal stance. Our data imply that the ankle joint function during the terminal stance is important in reducing the dynamic joint load in the contralateral leg during the loading response.

Metformin suppresses interleukin (IL)-1beta-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells.

CONTEXT: Metformin, a widely used treatment for diabetes that improves insulin sensitivity, also has both antiinflammatory properties and a modulatory effect on ovarian steroid production, two actions that have been suggested to be efficacious in therapy for endometriosis. OBJECTIVE: To determine whether metformin may be effective for the treatment of endometriosis, we evaluated the effects of this agent on inflammatory response, estradiol production, and proliferation of endometriotic stromal cells (ESCs). DESIGN: ESCs derived from ovarian endometriomas were cultured with various concentrations of metformin. MAIN OUTCOME MEASURES: IL-8 production, mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs were measured. RESULTS: Metformin dose-dependently suppressed IL-1beta-induced IL-8 production, cAMP-induced mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs. CONCLUSION: These results suggest that further investigation into the unique therapeutic potential of metformin as an antiendometriotic drug is warranted.

Expression of toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle.

Innate immunity in the endometrium has fundamental significance for reproduction. Although toll-like receptors (TLRs) play central roles in innate immune responses, their expression in the human endometrium remains to be fully elucidated. We have examined the gene expression of TLR2, TLR3, TLR4, and TLR9 in endometrial tissues by real-time quantitative PCR and in situ hybridization. The expression levels of the four genes in endometrial tissues varied in a similar pattern during the menstrual cycle; the levels were high in the perimenstrual period and low in the periovulatory period. Expression of the four genes was detected in both epithelial cells and stromal cells throughout the menstrual cycle. Expression levels were higher in epithelial cells for TLR3 and in stromal cells for TLR4, while they were comparable in epithelial cells and stromal cells for TLR2 and TLR9. These findings imply that differential spatio-temporal expression patterns of TLRs subserve proper innate immunity of the endometrium.

Selective increase in high molecular weight adiponectin concentration in serum of women with preeclampsia.

Total adiponectin concentrations have been shown to increase in serum of preeclamptic women. However, variance of concentrations of different isoforms has not been studied, despite the emerging notion that high, medium and low molecular weight adiponectin exert different functions. We have determined serum concentrations of each adiponectin isoform using a newly developed enzyme immunosorbent assay. High molecular weight (HMW) adiponectin concentrations were significantly higher in women with preeclampsia (n=14; median, 11.2 microg/ml; interquartile range, 9.2-15.8) compared to normal pregnant women (n=14; 6.8 microg/ml, 5.4-10.7; P=0.04). In contrast, medium molecular weight and low molecular weight adiponectin concentrations were substantially equal between the groups. The ratio of HMW adiponectin to total adiponectin was also markedly higher in preeclamptic women (52.3%, 49.5-58.7) than control women (43.0%; 39.8-48.0; P=0.004). Taken together with other reports our findings imply a physiological feedback response to minimize endothelial damage in preeclamptic women.

Enhanced expression of hydroxylated ceramide in well-differentiated endometrial adenocarcinoma.

Based on our previous analysis of neutral glycolipids in the human endometrium, the present authors already reported that the concentrations of glucosylceramide, lactosylceramide and globotriaosylceramide (Gb3Cer), in which both fatty acids and sphingosines in the ceramides are hydroxylated, exhibit a marked increase during the luteal phase of the menstrual cycle. It is also well known that poorly differentiated endometrial adenocarcinoma exhibits a more rapid progression and a worse response to therapy than well-differentiated endometrial adenocarcinoma. To examine the molecular background of well-differentiated and poorly differentiated cancers, the levels of neutral glycolipids in tumor tissues from endometrial carcinoma displaying different degrees of differentiation were measured. The composition of neutral glycolipids in tumor tissues was determined, and ceramide structures that were specifically expressed in well-differentiated endometrial carcinomas were investigated using biochemical analytical methods, including lipid extraction, enzyme digestion, thin-layer chromatography (TLC), gas-liquid chromatography and mass spectrometry. Well-differentiated adenocarcinoma contained numerous structurally unknown glycolipids that exhibited slower migration than globotetraosylceramide (Gb4Cer). In the case of Gb3Cer, three bands appeared on TLC in well-differentiated cancer, but only two bands appeared in the poorly-differentiated cancer. This difference was associated with the fatty acid composition of ceramide, since non-hydroxy fatty acids with ≥20 carbon atoms were increased in well-differentiated cancer, while α-hydroxy fatty acids were increased in poorly differentiated cancer. Similarly, there were two bands on TLC of Gb4Cer from well-differentiated cancer, but only one band in poorly differentiated cancer, and the long-chain base of ceramide was observed to contain phytosphingosine in well-differentiated cancer. It was demonstrated in endometrial cancer that the structure of ceramide molecules changes with the extent of tumor differentiation. These findings suggest that hydroxylated ceramides contribute to the well-differentiated phenotype of endometrial adenocarcinoma.

Generation of femtosecond γ-ray bursts stimulated by laser-driven hosing evolution.

The promising ability of a plasma wiggler based on laser wakefield acceleration to produce betatron X-rays with photon energies of a few keV to hundreds of keV and a peak brilliance of 10(22)-10(23) photons/s/mm(2)/mrad(2)/0.1%BW has been demonstrated, providing an alternative to large-scale synchrotron light sources. Most methods for generating betatron radiation are based on two typical approaches, one relying on an inherent transverse focusing electrostatic field, which induces transverse oscillation, and the other relying on the electron beam catching up with the rear part of the laser pulse, which results in strong electron resonance. Here, we present a new regime of betatron γ-ray radiation generated by stimulating a large-amplitude transverse oscillation of a continuously injected electron bunch through the hosing of the bubble induced by the carrier envelope phase (CEP) effect of the self-steepened laser pulse. Our method increases the critical photon energy to the MeV level, according to the results of particle-in-cell (PIC) simulations. The highly collimated, energetic and femtosecond γ-ray bursts that are produced in this way may provide an interesting potential means of exploring nuclear physics in table top photo nuclear reactions.

Aggressive Angiomyxoma of the Vulva with No Recurrence on a 5-year Follow up: A Case Report.

We report a case of vulvar aggressive angiomyxoma (AA) which is a rare, slow growing and benign tumor of mesenchymal origin, but has a high risk of local recurrence. A 49-year-old Japanese female was referred to us with a large mass of the left vulva, measuring 15×9.5×9 centimeters. She underwent surgical excision of the tumor with no evidence of recurrence on a 5-year follow up. In this case, histopathological examination and immunohistochemical staining after excision revealed a diagnosis of vulvar AA with estrogen and progesterone receptors positive. Aggressive angiomyxoma of the vulva needs to be distinguished from benign myxoid tumor with a low risk of local recurrence as well as from malignant neoplasma. The first line treatment of AA is complete surgical excision with tumor free margins, it will reduce the recurrence.