Angular Momentum of Twisted Radiation from an Electron in Spiral Motion.

We theoretically demonstrate for the first time that a single free electron in circular or spiral motion emits twisted photons carrying well-defined orbital angular momentum along the axis of the electron circulation, in adding to spin angular momentum. We show that, when the electron velocity is relativistic, the radiation field contains harmonic components and the photons of lth harmonic carry lℏ total angular momentum for each. This work indicates that twisted photons are naturally emitted by free electrons and are more ubiquitous in laboratories and in nature than ever thought.

Microbunching instability in relativistic electron bunches: direct observations of the microstructures using ultrafast YBCO detectors.

Relativistic electron bunches circulating in accelerators are subjected to a dynamical instability leading to microstructures at millimeter to centimeter scale. Although this is a well-known fact, direct experimental observations of the structures, or the field that they emit, remained up to now an open problem. Here, we report the direct, shot-by-shot, time-resolved recording of the shapes (including envelope and carrier) of the pulses of coherent synchrotron radiation that are emitted, and that are a "signature" of the electron bunch microstructure. The experiments are performed on the UVSOR-III storage ring, using electrical field sensitive YBa2Cu3O(7-x) thin-film ultrafast detectors. The observed patterns are subjected to permanent drifts, that can be explained from a reasoning in phase space, using macroparticle simulations.

Frequency-domain interferometry for the determination of time delay between two extreme-ultraviolet wave packets generated by a tandem undulator.

Synchrotron radiation, emitted by relativistic electrons traveling in a magnetic field, has poor temporal coherence. However, recent research has proved that time-domain interferometry experiments, which were thought to be enabled by only lasers of excellent temporal coherence, can be implemented with synchrotron radiation using a tandem undulator. The radiation generated by the tandem undulator comprises pairs of light wave packets, and the longitudinal coherence within a light wave packet pair is used to achieve time-domain interferometry. The time delay between two light wave packets, formed by a chicane for the electron trajectory, can be adjusted in the femtosecond range by a standard synchrotron technology. In this study, we show that frequency-domain spectra of the tandem undulator radiation exhibit fringe structures from which the time delay between a light wave packet pair can be determined with accuracy on the order of attoseconds. The feasibility and limitations of the frequency-domain interferometric determination of the time delay are examined.

Double-pulsed wave packets in spontaneous radiation from a tandem undulator.

We verify that each wave packet of spontaneous radiation from two undulators placed in series has a double-pulsed temporal profile with pulse spacing which can be controlled at the attosecond level. Using a Mach-Zehnder interferometer operating at ultraviolet wavelengths, we obtain the autocorrelation trace for the spontaneous radiation from the tandem undulator. The results clearly show that the wave packet has a double-pulsed structure, consisting of a pair of 10-cycle oscillations with a variable separation. We also report the characterization of the time delay between the double-pulsed components in different wavelength regimes. The excellent agreement between the independent measurements confirms that a tandem undulator can be used to produce double-pulsed wave packets at arbitrary wavelength.

Transverse-longitudinal coupling effect in laser bunch slicing.

We report turn-by-turn observation of coherent synchrotron radiation (CSR) produced by the laser bunch slicing technique at an electron storage ring operated with a small momentum compaction factor. CSR emission was intermittent, and its interval depended strongly on the betatron tune. This peculiar behavior of the CSR could be interpreted as a result of coupling between the transverse and longitudinal motion of the electrons. This is the first observation of such an effect, which would be important not only for controlling the CSR emission but also for generating and transporting ultrashort electron bunches or electron bunches with microdensity structures in advanced accelerators.

A phospho-switch controls the dynamic association of synapsins with synaptic vesicles.

Synapsins constitute a family of synaptic vesicle proteins essential for regulating neurotransmitter release. Only two domains are conserved in all synapsins: a short N-terminal A domain with a single phosphorylation site for cAMP-dependent protein kinase (PKA) and CaM Kinase I, and a large central C domain that binds ATP and may be enzymatic. We now demonstrate that synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles. Furthermore, we show that the A domain binds phospholipids and is inhibited by phosphorylation. Our results suggest a novel mechanism by which proteins reversibly bind to membranes using a phosphorylation-dependent phospholipid-binding domain. The dynamic association of synapsins with synaptic vesicles correlates with their role in activity-dependent plasticity.

Weekly paclitaxel/5-fluorouracil followed by platinum retreatment for patients with recurrent ovarian cancer: a single institution experience.

PURPOSE: Since the prognosis of recurrent ovarian cancer patients is still poor, we need to establish a useful treatment strategy to achieve their long-term survival. We treated recurrent ovarian cancer patients with weekly paclitaxel (PTX)/5-fluorouracil (5-FU) followed by platinum retreatment to investigate its clinical efficacy in a preliminary manner. METHODS: Sixteen patients with recurrent ovarian cancer, pretreated with taxane and platinum, were treated with weekly paclitaxel (PTX)/5-fluorouracil (FU). PTX (80 mg/m2) on day 1, 8, and 15 was combined with a bolus injection of 5-FU (500 mg/m2) on day 2, 9, and 16. Chemotherapy was given every four weeks. Patients with stable disease or progressive disease were subsequently retreated with a platinum-containing regimen. Response was evaluated by RECIST criteria or CA125 criteria. Toxicities were evaluated according to the National Cancer Institute-common toxicity criteria (NCI-CTC) version 3. RESULTS: Among five patients with sensitive disease, one of four patients with measurable tumor and one without measurable tumor responded to weekly PTX/5-FU. Among 11 patients with resistant disease, none of five patients with measurable tumor and three of six patients without measurable tumor responded to weekly PTX/5-FU. Overall objective response rate by weekly PTX/5-FU was 31.3% (5/16). Among 16 patients, 13 patients who showed no response or progressive disease (three with sensitive disease, ten with resistant disease) received platinum retreatment after weekly PTX/5FU. All three patients with sensitive disease and three of ten patients with resistant disease revealed response to platinum retreatment. Overall objective response rate by platinum retreatment after weekly PTX/5-FU was 46.2% (6/13). CONCLUSIONS: Weekly PTX/5FU followed by platinum retreatment could be a useful treatment strategy for recurrent ovarian cancer patients. We need to establish the standard treatment strategy for recurrent ovarian cancer patients with a poor prognosis.

Helical Phase Structure of Radiation from an Electron in Circular Motion.

We theoretically show that a single free electron in circular motion radiates an electromagnetic wave possessing helical phase structure, which is closely related to orbital angular momentum carried by it. We experimentally demonstrate it by interference and double-slit diffraction experiments on radiation from relativistic electrons in spiral motion. Our results indicate that photons carrying orbital angular momentum should be created naturally by cyclotron/synchrotron radiations or Compton scatterings in various situations in cosmic space. We propose promising laboratory vortex photon sources in various wavelengths ranging from radio wave to gamma-rays.

Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas.

Hemangioblastoma is one of the benign tumors in the central nervous system. It is often associated with the von Hippel-Lindau (VHL) disease, a well known hereditary tumor syndrome. It is believed that inactivation of both alleles of VHL tumor suppressor gene is essential in the tumorigenic processes in hemangioblastomas associated with VHL disease. The molecular basis for the development of sporadic hemangioblastomas is not known. Here, we analyzed 13 cases of primary sporadic hemangioblastomas for somatic mutations of VHL gene with single strand conformational polymorphism analyses of the tumor DNAs. We detected abnormal single strand conformational polymorphism pattern in 7 tumors (54%). Of these 7 possibly mutated tumors, we successfully characterized 3 tumors by direct sequencing. We were unable to sequence 4 tumors because of the poor quality of DNA obtained from paraffin blocks. Somatic mutations in the 3 tumors were 2 missense mutations and 1 microdeletion. These mutations were observed in 1 tumor in exon 1 and 2 tumors in exon 2. Our results suggest that mutations of VHL tumor suppressor gene are involved in the development of at least 20% of sporadic central nervous system hemangioblastomas.

Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas.

We analyzed 47 primary sporadic human renal cell carcinomas (39 clear cell and 8 non-clear cell) for mutations of the von Hippel-Lindau (VHL) tumor suppressor gene using the polymerase chain reaction and single strand conformational polymorphism analysis of DNA. All of the positive cases in single strand conformational polymorphism analyses were further characterized by direct sequencing. Somatic mutations were detected in 22 (56%) of 39 clear cell renal carcinomas including 15 deletions, 3 insertions, 3 missense mutations, and 1 nonsense mutation. Nineteen of these mutations predicted to produce truncation of the VHL protein. These mutations mainly occurred in the last one-third region of exons 1, 2, and 3. In addition, loss of heterozygosity of the VHL gene was observed in 16 (84%) of 19 informative clear cell renal carcinomas. No somatic mutations were detected in 8 non-clear cell carcinomas. These results show that the VHL tumor suppressor gene is one of the major tumor suppressor genes in human renal cell carcinomas, especially in the clear cell subtype renal cell carcinoma. Clear cell carcinoma might be distinguished from other pathological types of renal cell carcinomas by molecular genetic techniques.

Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology.

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients' outcomes.

Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth.

In spite of the general recognition of von Hippel-Lindau (VHL) as a tumor suppressor gene, the physiological and pathological importance of VHL protein in cell growth regulation and tumorigenesis remains unclear. Here we show that in normal human renal proximal tubule epithelial cells (RPTEC), the steady-state amount of VHL protein is strictly regulated by cell density. The cellular VHL content is more than 100-fold higher in dense cultures than in sparse cultures. The increase in VHL protein at high cell density was also observed for NIH3T3 fibroblasts, suggesting the generality of the phenomenon. The growth rates of renal cell carcinoma cells lacking an intact VHL gene and their derivatives with wild-type or mutant VHL expression vector do not differ significantly when they are growing in log-phase. Importantly, however, there is a difference when they reach confluency: cells lacking wild-type VHL grew continuously, while cells expressing exogenous VHL protein showed relatively limited cell growth. Using an ecdysone-inducible VHL expressing cell line, we also show that the growth inhibition at high cell density can be released by attenuating the VHL expression. Taken together, we propose that VHL protein functions as a growth suppressor at high cell density, and this might be the basis of the tumor suppressor function of VHL.

Thymidine phosphorylase activity in human bladder cancer: difference between superficial and invasive cancer.

The activity of thymidine phosphorylase (TdR-Pase), which is identical to platelet-derived endothelial cell growth factor (a potent angiogenic factor), was analyzed in primary human bladder cancer tissues. TdR-Pase activity in tissues was determined from the conversion rate of 5'-deoxy-5-fluorouridine to 5-fluorouracil. The mean activity in 37 bladder cancers and in 8 samples of normal bladder epithelial tissue was 108.5 and 19.2 microgram 5-fluorouracil/mg protein/h, respectively, showing a statistically significant difference. Among the cancer tissues, differences in activity were seen according to the stage and grade of tumors. Low-grade (grade 1) tumors had significantly lower activities than high-grade tumors, and high-grade invasive tumors showed significantly higher activities than low-grade superficial tumors. These results demonstrate that a high TdR-Pase activity in bladder cancer is associated with the tumor characteristics of invasion and malignant potential. Our conclusions support the hypothesis that angiogenesis that is mediated by this molecule may be involved in the development of invasive human bladder cancer, as suggested by T. O'Brien et al. (Cancer Res., 55: 510-513, 1995), and also suggest that TdR-Pase is a potential therapeutic target in human bladder cancer.

Telomerase activity in human bladder cancer.

Telomerase can synthesize telomeric DNA repeats onto chromosome ends. Telomere length and telomerase activity have recently been implicated in the control of the proliferative capacity of normal and malignant cells. The expression of telomerase activity is concomitant with the attainment of immortality in tumor tissues and cells. Thus, enzyme activity may indicate a prevalent or even ubiquitous tumor producer. In this report, telomerase activity was analyzed in 40 human bladder cancers, 7 normal tissues, and 2 bladder epithelia with dysplasia using a PCR-based telomeric repeat amplification protocol assay. Telomerase activity was detected in almost all bladder tumors (97.5%); only one sample, which was in an early stage, did not express telomerase activity. None of the normal tissues displayed telomerase activity. One of the two bladder epithelia with dysplasia expressed low telomerase activity. The expression of telomerase activity has a clear association with the pathological grade and clinical stage. Most of the tumors with high telomerase activity were in an advanced grade and had deep invasion. Thus, telomerase activity might be suggested to represent an additional required event in the multigenetic process of tumorigenesis in human bladder cancer.

Fluorescence in situ hybridization evaluation of c-erbB-2 gene amplification and chromosomal anomalies in bladder cancer.

Oncogene amplification and chromosomal anomalies are found in many solid tumors and are often associated with aggressiveness of cancer. We evaluated the frequency and the role of c-erbB-2 gene amplification, relative increase in c-erbB-2 gene copy number, and gain of chromosome 17 in bladder cancer. A total of 29 bladder cancer specimens were examined using fluorescence in situ hybridization (FISH). Dual labeling hybridization with a directly labeled centromere probe for chromosome 17 together with a probe for the c-erbB-2 locus was performed. c-erbB-2 gene amplification was found in 3.4% (1 of 29) of specimens. Relative increase in c-erbB-2 gene copy number was found in 41.4% (12 of 29) of specimens and was significantly associated with tumor grade (P = 0.044 by Fisher's exact test). Gain of chromosome 17 was identified in 65.5% (19 of 29) of specimens and was significantly associated with tumor grade (P = 0.002 by Fisher's exact test) and tumor stage (P = 0.003 by Fisher's exact test). Our results suggest that c-erbB-2 gene amplification, relative increase in c-erbB-2 gene copy number, and gain of chromosome 17 may play important roles in the development and progression of bladder cancers. Moreover, the use of c-erbB-2 amplification, relative increase in c-erbB-2 gene copy number, and gain of chromosome 17 using FISH, together with tumor grade and stage, may provide a more useful clinical indicator in bladder cancer.

Heparin-induced thrombocytopenia complicated with massive thrombosis of the inferior vena cava after filter placement.

A 45-year-old man presented with deep vein thrombosis of the right leg and bilateral pulmonary embolism. Heparin was administered on the initial one and a half days. On the 3rd day, an inferior vena cava (IVC) filter was placed with a heparin flush, after which massive IVC thrombosis developed. The platelet count was 221000/mm3, decreased 42% from the initial level, but remained within the normal range. Heparin was replaced by argatroban on the 13th day. The platelet count increased to 355000/mm3 on the 15th day. The patient was positive for antibody against complexes of heparin and platelet factor 4, and was diagnosed as heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). When thrombosis develops during heparin treatment, it is important to suspect HITTs and to assay for the associated antibodies, regardless of the actual platelet count.

Living situations associated with poor dietary intake among healthy Japanese elderly: the Ohasama Study.

BACKGROUND: Rapid increases in life expectancy have led to concurrent increases in the number of elderly people living alone or those forced to change living situations. Previous studies have found that poor dietary intake was common in elderly people living alone. However, there have been few studies about the dietary intake in elderly people living in other situations, particularly those living with family other than a spouse (nonspouse family), which is common in Japan. OBJECTIVE: To examine the differences in dietary intake by different living situations in elderly Japanese people. We analyzed the data of 1542 healthy residents in the town of Ohasama aged 60 years and over who had completed self-administered questionnaires. METHODS: The dietary intake was measured using a validated 141-item food frequency questionnaire. Multiple regression models with robust (White-corrected) standard errors were individually fitted for nutrients and foods by living situation. RESULTS: In men, although the presence of other family was correlated with significantly lower intake of protein-related foods, e.g., legumes, fish and shellfish, and dairy products, these declines were more serious in men living with nonspouse family. Conversely, in men living alone the intake of fruits and vegetables was significantly lower. In women, lower intakes of fruit and protein-related foods were significantly more common in participants living with nonspouse family than those living with only a spouse. CONCLUSION: These findings revealed that elderly people living alone as well as those living with family other than a spouse had poor dietary intake, suggesting that strategies to improve food choices and skills for food preparation could promote of healthy eating in elderly Japanese people.

Studies of the human testis. XI. Leydig cell clusters and levels of intratesticular testosterone and 20 alpha-dihydroprogesterone.

Testosterone concentration in testes of 23 men, ages 51 to 90, was determined as 490 +/- 172 ng/g tissue (M +/- S.D.) and 20 alpha-dihydroprogesterone concentration as 10.0 +/- 2.3 ng/g tissue (M +/- S.D.) in 18 men of the same patient group. Leydig cells were estimated by the number of Leydig cell clusters per tubule. There was a high correlation (r = 0.88, p less than .001) of the Leydig cell index with intratesticular testosterone. It is proposed that the Leydig cell cluster index provides a direct index of steroid biosynthetic activity in the human testis as reflected in intratesticular testosterone levels. Although there was no significant correlation of 20 alpha-dihydroprogesterone levels in the testis with either the Leydig cell index or intratesticular testosterone, the high level of 20 alpha-dihydroprogesterone compared to peripheral levels suggests its production by the testis.

Studies of the human testis. X. Properties of human chorionic gonadotropin receptor in adult testis and relation to intratesticular testosterone concentration.

Receptors for [125I]hCG were found in adult human testis. The specific binding of [125I]hCG to testicular receptor is temperature dependent and is a saturable process with respect to added receptor protein and hormone. Scatchard analysis revealed a dissociation constant of 5.0 X 10(-10) M, and 6.2 fmol binding site/mg protein. Intact unlabeled hCG effectively inhibits the specific binding of [125I]hCG to human testicular receptors. For inhibition of binding of [125I]hCG, the alpha subunit has 3.0% of the potency of intact hCG and the beta subunit has 0.4% of the potency of intact hCG. Specific binding is pH dependent, with an optimum at pH 7.4. Brief exposure to extremes of pH causes irreversible damage to the receptors. Incubation with protease and trypsin results in an almost complete loss of binding activity, while ribonuclease, deoxyribonuclease, phospholipase C, or neuraminidase treatment does not significantly alter hormone-binding activity. Binding activity was found to be positively correlated to the concentration of intratesticular testosterone.

Exogenous 20K growth hormone (GH) suppresses endogenous 22K GH secretion in normal men.

The physiological and pharmacological functions of the 20-kDa human GH (20K-hGH) isoform are unknown. We conducted a pharmacokinetic study of recombinant 20K-hGH in human subjects (Phase I clinical trial). Placebo or 20K-hGH was administered sc to normal men (20-31 yr of age, n = 6-8 per group) at 2100 h. Serum 20K- and 22K-hGH levels were monitored every 30 min for 24 h by specific enzyme-linked immunosorbent assays. Serum free fatty acid, insulin-like growth factor I, insulin, and glucose levels were measured for 24 h. In the placebo group, the secretion profiles of endogenous 20K- and 22K-hGH were pulsatile and similar to each other. The proportion of 20K- to 22K-hGH was fairly constant. In the 20K-hGH-treated groups, serum 20K-hGH levels increased in a dose-dependent manner over the dose range of 0.01-0.1 mg/kg. Maximum serum 20K-hGH levels were reached at 3-4 h and decreased with half-lives of 2-3 h. Marked suppression of endogenous 22K-hGH secretion was observed in a time-dependent manner. Serum free fatty acid and insulin-like growth factor I levels were significantly elevated (P < 0.01) at 4, 8, and 12 h and at 8, 12, and 24 h after 20K-hGH administration, respectively. Serum insulin and glucose levels did not change significantly within 24 h. These results suggested that: 1) regulation of 20K-hGH secretion is physiologically the same as that of 22K-hGH; 2) the pharmacokinetics after sc injection of 20K-hGH are comparable with those of 22K-hGH; 3) 20K-hGH regulates hGH secretion through "GH-induced negative feedback mechanisms"; and 4) administration of 20K-hGH is expected to exert GH actions (growth-promoting activity and lipolytic activity). Monitoring of serum 20K- and 22K-hGH levels may be useful in evaluating the effects of administered GH isoforms on their own release from the pituitary.