Real-time manifestation of strongly coupled spin and charge order parameters in stripe-ordered La(1.75)Sr(0.25)NiO(4) nickelate crystals using time-resolved resonant x-ray diffraction.

We investigate the order parameter dynamics of the stripe-ordered nickelate, La(1.75)Sr(0.25)NiO(4), using time-resolved resonant x-ray diffraction. In spite of distinct spin and charge energy scales, the two order parameters' amplitude dynamics are found to be linked together due to strong coupling. Additionally, the vector nature of the spin sector introduces a longer reorientation time scale which is absent in the charge sector. These findings demonstrate that the correlation linking the symmetry-broken states does not unbind during the nonequilibrium process, and the time scales are not necessarily associated with the characteristic energy scales of individual degrees of freedom.

Phase fluctuations and the absence of topological defects in a photo-excited charge-ordered nickelate.

The dynamics of an order parameter's amplitude and phase determines the collective behaviour of novel states emerging in complex materials. Time- and momentum-resolved pump-probe spectroscopy, by virtue of measuring material properties at atomic and electronic time scales out of equilibrium, can decouple entangled degrees of freedom by visualizing their corresponding dynamics in the time domain. Here we combine time-resolved femotosecond optical and resonant X-ray diffraction measurements on charge ordered La(1.75)Sr(0.25)NiO(4) to reveal unforeseen photoinduced phase fluctuations of the charge order parameter. Such fluctuations preserve long-range order without creating topological defects, distinct from thermal phase fluctuations near the critical temperature in equilibrium. Importantly, relaxation of the phase fluctuations is found to be an order of magnitude slower than that of the order parameter's amplitude fluctuations, and thus limits charge order recovery. This new aspect of phase fluctuations provides a more holistic view of the phase's importance in ordering phenomena of quantum matter.

Femtosecond dynamics of the collinear-to-spiral antiferromagnetic phase transition in CuO.

We report on the ultrafast dynamics of magnetic order in a single crystal of CuO at a temperature of 207 K in response to strong optical excitation using femtosecond resonant x-ray diffraction. In the experiment, a femtosecond laser pulse induces a sudden, nonequilibrium increase in magnetic disorder. After a short delay ranging from 400 fs to 2 ps, we observe changes in the relative intensity of the magnetic ordering diffraction peaks that indicate a shift from a collinear commensurate phase to a spiral incommensurate phase. These results indicate that the ultimate speed for this antiferromagnetic reorientation transition in CuO is limited by the long-wavelength magnetic excitation connecting the two phases.

Development of a compact fast CCD camera and resonant soft x-ray scattering endstation for time-resolved pump-probe experiments.

The designs of a compact, fast CCD (cFCCD) camera, together with a resonant soft x-ray scattering endstation, are presented. The cFCCD camera consists of a highly parallel, custom, thick, high-resistivity CCD, readout by a custom 16-channel application specific integrated circuit to reach the maximum readout rate of 200 frames per second. The camera is mounted on a virtual-axis flip stage inside the RSXS chamber. When this flip stage is coupled to a differentially pumped rotary seal, the detector assembly can rotate about 100°/360° in the vertical/horizontal scattering planes. With a six-degrees-of-freedom cryogenic sample goniometer, this endstation has the capability to detect the superlattice reflections from the electronic orderings showing up in the lower hemisphere. The complete system has been tested at the Advanced Light Source, Lawrence Berkeley National Laboratory, and has been used in multiple experiments at the Linac Coherent Light Source, SLAC National Accelerator Laboratory.

A fast, direct x-ray detection charge-coupled device.

A charge-coupled device (CCD) capable of 200 Mpixels/s readout has been designed and fabricated on thick, high-resistivity silicon. The CCDs, up to 600 microm thick, are fully depleted, ensuring good infrared to x-ray detection efficiency, together with a small point spread function. High readout speed, with good analog performance, is obtained by the use of a large number of parallel output ports. A set of companion 16-channel custom readout integrated circuits, capable of 15 bits of dynamic range, is used to read out the CCD. A gate array-controlled back end data acquisition system frames and transfers images, as well as provides the CCD clocks.

Single-agent trabectedin as second-line therapy of persistent or recurrent endometrial cancer: results of a multicenter phase II study.

OBJECTIVE: To assess the efficacy and safety of single-agent trabectedin in women with persistent or recurrent endometrial cancer. METHODS: In this open-label, phase II multicenter trial, women with persistent or recurrent endometrial carcinoma were administered trabectedin as a 3-hour intravenous infusion every 21 days at a starting dose of 1.3 mg/m(2) with dexamethasone pretreatment. Clinical objective response was the primary efficacy endpoint. Secondary endpoints were time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: The median age of the 50 women entering the study was 63 years (range, 22-87), with all having history of prior chemotherapy (92% combination regimens) and the majority having undergone surgery (92%) or radiation therapy (68%). Patients received trabectedin for a median duration of 6.8 weeks (range, 3-20). A median of 2 cycles (range, 1-6) was administered, with a median dose intensity of 0.4 mg/m(2) per week (range, 0.27-0.43) and a median relative dose intensity of 92% (range, 61.5-100.2%). One patient exhibited a complete response for an objective response rate of 2.2% (95% confidence interval [CI]: 0.1%, 11.5%). Median TTP and PFS were both 1.8 months (95% CI: 1.4, 2.9), and median OS was 6.7 months (95% CI: 5.2, 13.9). Most frequent adverse events were nausea (62%), asthenia (50%), vomiting (42%), and increased alanine aminotransferase (40%). CONCLUSION: Single-agent trabectedin displayed minimal antitumor activity in this pretreated population of women with persistent or recurrent endometrial cancer.

Socio-cultural factors influencing prevention and treatment of tuberculosis in immigrant and Aboriginal communities in Canada.

This multi-method study used a participatory action research approach to examine the complex net of socio-cultural factors that influenced behaviour related to tuberculosis (TB) prevention and treatment in the 10 highest risk cultural groups consisting of immigrant and Aboriginal populations in the province of Alberta, Canada. Trained community research associates collected qualitative interview data and helped with interpretation and evaluation. A community advisory committee established foundation principles and monitored the ethical and cultural appropriateness of the research process. A key finding is that although patients with active disease learn about TB from health professionals, people in high-risk populations need to learn more about TB transmission and prevention prior to contact. This is particularly important given that lack of knowledge of TB was strongly associated with negative attitudes towards TB and a worse experience of the disease. The study results underline the need for accessible and culturally appropriate health education about TB in the high risk groups. This can be accomplished in collaboration with lay people, particularly those who have recovered from active TB, their family members and health workers from the community.

Severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy requiring transplantation in an individual at low risk for hepatotoxicity.

We report a case of severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy that required liver transplantation in a closely monitored, human immunodeficiency virus-uninfected individual who had no risk for hepatotoxicity. Because hepatotoxicity associated with this treatment appears to be idiosyncratic, we recommend closer monitoring of liver enzyme levels than do the Centers for Disease Control and Prevention guidelines, as well as at least temporary interruption of treatment during any elevation of liver enzyme levels greater than the normal value.

Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type 1 in endometrial cancer.

OBJECTIVE: Tumor invasion involves degradation of extracellular matrix. The urokinase plasminogen activation system participates in this process. Urokinase-type plasminogen activator (uPA), its receptor (uPAR), and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), are proposed to be prognostic factors in some cancers. There are conflicting data regarding the prognostic role of this system in endometrial cancer. METHODS: To determine the prognostic value of the urokinase plasminogen activation system, contents of uPA, uPAR, and PAI-1 were measured in extracts of endometrial cancer tissue using ELISAs. uPA, uPAR, and PAI-1 levels were determined in 91, 54, and 92 extracts, respectively, and correlated with tumor histology, stage, grade, lymph node involvement, prevalence of metastasis, and recurrence as well as with estrogen (ER), progesterone (PR), epidermal growth factor (EGFR) receptor and HER-2/neu contents. RESULTS: Patients with cancers exhibiting advanced stage, high grade, unfavorable tumor histology, nodal involvement, recurrence, and lower PR levels determined by ligand binding had significantly higher uPA content than others. PAI-1 was significantly elevated in patients with advanced stage, high-grade tumor, recurrence, decreased ER content, and lower PR levels determined by ligand binding. uPAR did not show any relation to any of clinical and laboratory parameters. Elevated expression of PAI-1 was associated with significantly shorter disease-free (P = 0.005) and overall (P = 0.0003) survival. Multivariate analysis revealed that PAI-1 was a predictor of survival although stage was the strongest independent factor. CONCLUSION: Elevated uPA and PAI-1 levels appear to correlate with unfavorable prognosis in endometrial cancer.

Clinical relevance of urokinase-type plasminogen activator, its receptor and inhibitor type 1 in ovarian cancer.

Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and inhibitor, plasminogen activator-type 1 (PAI-1) are proposed to be of prognostic significance in some cancers. To determine the prognostic value of the urokinase plasminogen activation system in ovarian cancer, levels of uPA, uPAR, and PAI-1 were measured in extracts of ovarian cancer tissue using ELISA tests. uPA and PAI-1 were determined in 70 tumor extracts and uPAR in 43 extracts. Levels were correlated with age, tumor histology, stage, grade, lymph node and metastatic status, residual disease, risk of recurrence, epidermal growth factor receptor (EGFR) expression, cathepsin D (Cath-D), and c-erbB-2 levels. uPA and uPAR did not exhibit correlation with any of these parameters. However, patients with high grade tumor, recurrence, and lower EGFR and Cath-D had significantly higher PAI-1 levels compared to those of others (P < 0.05). Kaplan-Meier plots of survival were compared. uPA and uPAR were not related to disease-free or overall survival. Although low PAI-1 appeared to predict a longer overall survival, the difference was not statistically significant. Multivariate analysis revealed that PAI-1 was a predictor for overall survival although it was not as strong as stage. These results suggest that elevated PAI-1 seems to be correlated with an unfavorable prognosis in ovarian cancer.

A tuberculosis screening and chemoprophylaxis project in children from a high risk population in Edmonton, Alberta.

Current recommendations for tuberculosis control are to screen high risk populations and provide chemoprophylaxis for those infected. In Edmonton, Alberta, one strategy has been to identify and provide TB skin tests to newly arrived immigrant school age children from TB endemic areas. The difficulty has been in identifying these children in the school population. This article describes a process tried in 1993-94 to find a better approach and to determine the outcome of a concentrated effort at screening and follow-up of this population. Using this method, 1,146 students were TB skin tested using 5tu PPD: 15% showed significant reactions (10 mm), 89% were offered chemoprophylaxis, and 68% of those offered (84% of those accepting) completed 9 months of chemoprophylaxis. The success of this process was dependent on the dedicated follow-up provided by the specialty public health clinic devoted to the prevention and treatment of tuberculosis.

Metastatic dermatofibrosarcoma protuberans of the vulva.

Dermatofibrosarcoma protuberans (DFSP) of the vulva is a rare, low- to intermediate-grade sarcoma of dermal origin. This case report represents the 13th reported patient with vulvar DFSP and the first reported patient with metastatic vulvar DFSP. Although metastasis is rare, the possibility remains that the frequent recurrence of DFSP will eventually metastasize. Therefore, patients must be followed up on a long-term basis to monitor the progress of this potentially lethal cancer.

Apoptosis as a measure of chemosensitivity to cisplatin and taxol therapy in ovarian cancer cell lines.

OBJECTIVE: Cisplatin- and Taxol-induced apoptosis was studied in four human ovarian cancer cell lines to evaluate apoptosis as a measure of chemosensitivity. METHODS: In vitro sensitivities of OVCAR-3, SKOV-3, UL-1, and UL-2 cells to cisplatin or Taxol were determined by the sulforhodamine B assay. Induction of apoptosis was studied by DNA fragmentation following treatment with cisplatin and/or Taxol after 24- and 48-hr exposure. DNA fragmentation was further quantitated by the diphenylamine assay and the proportion of cells in the G1, G2/M, and S phase of the cell cycle was determined by flow cytometry. Presence of the p53 gene product was examined by Western blotting. RESULTS: The four cell lines represent various sensitivities to cisplatin and Taxol (LD50 range for cisplatin, 5-30 microg/ml; Taxol, 30-1000 nM). UL-2 represents a resistant cell line which was 10-30 times resistant to Taxol and 6 times resistant to cisplatin when compared to the others. Demonstration of apoptosis correlated with the sensitivity of the cell lines to both cisplatin and Taxol for OVCAR-3 and UL-2. DNA fragmentation of OVCAR-3 was uniformly present when treated with cisplatin or Taxol, at 24 or 48 hr. UL-2 demonstrated no apoptosis after 24 or 48 hr of treatment with either cisplatin or Taxol. When sequencing experiments were performed with cisplatin and Taxol, DNA fragmentation correlated with the cytotoxicity assays, except in UL-1 cells where no significant difference was observed in different interactions of cisplatin and Taxol. Pretreatment with Taxol generally resulted in enhanced cytotoxicity in a schedule-dependent manner, and increased fragmentation was demonstrated; cisplatin pretreatment consistently resulted in decreased fragmentation. Quantitation of the fragmented DNA correlated with that seen on gel electrophoresis. OVCAR-3 and UL-1 demonstrated the greatest change from baseline at 24 hr (3.8 and 3.7 times baseline, respectively), whereas UL-2 had little change from the baseline following treatment. G1 arrest occurred more readily in OVCAR-3 and SKOV-3 cells. UL-2 cells had very little change in the proportion of cells entering G1 arrest, but had a significant increase in the G2/M proportion. In OVCAR-3, UL-1, and UL-2 cells, we demonstrated the presence of an aberrantly expressed p53 gene product, while no p53 was detected in the SKOV-3 cells. CONCLUSIONS: Our findings indicate that the ability to achieve significant cytotoxicity by cisplatin and Taxol may be directly related to the induction of apoptosis; however, cellular and genetic characteristics determine the eventual outcome of these treatments.

CA-125 levels after surgical exploration and radioactive chromic phosphate in ovarian cancer patients.

Trends in CA-125 levels after completion of therapy in ovarian cancer patients who received intraperitoneal radioactive chromic phosphate therapy (32P) after primary surgical resection or second-look surgery were evaluated. Ninety patients who underwent surgical exploration and 32P were reviewed. Twenty-nine patients were excluded due to insufficient number of CA-125 levels or recurrence within 12 months, with 61 patients with serial CA-125 levels and no evidence of disease for 12 months available for analysis. 32P followed initial resection in 24 patients (16 Stage I, 3 Stage II, 5 Stage III). 32P followed chemotherapy and second-look procedures in 37 patients (4 Stage I, 3 Stage II, 27 Stage III, 3 Stage IV). Elevated CA-125 levels were present in 25 (41%) patients within 12 months of 32P (46% after primary exploration, 38% after second-look). The degree of CA-125 elevation (U/ml) was 30-100 (23%), 100-200 (11%), and >200 (7%). Of the 25 patients with an elevated CA-125, the elevation persisted more than 4 months in 11 (44%). All but two patients had normal CA-125 levels by 12 months. An abnormal elevation in CA-125 was seen in 33% of patients 4 months after receiving 32P and abdominal surgery, with values ranging as high as 500 U/ml. Although elevations in CA-125 are reported following surgery alone, the duration of elevation appears to be longer with 32P. Therefore, persistent elevations of CA-125 following 32P between 4 and 12 months should be judged with caution as they may not reflect recurrent disease.

Cysteine scanning mutagenesis at 40 of 76 positions in villin headpiece maps the F-actin binding site and structural features of the domain.

Villin headpiece, the 76 amino acid, C-terminal domain of villin, is one of the two F-actin binding sites in villin necessary for F-actin bundling activity. Expression and study of recombinant headpiece revealed the domain to be remarkably thermostable (Tm = 74 degrees C) for a non-disulfide-bonded domain. Forty independent point mutations to cysteine of headpiece have been purified and tested for their actin binding activity, cysteine reactivity, and thermal stability. These assays identify two segments of headpiece, near amino acids 38 and 70 of headpiece, in which mutations to cysteine significantly disrupt cosedimentation of headpiece with F-actin. Assay of the thermal stability of these mutants and assay of the reactivity of the introduced cysteine show that these amino acids are mutations at the protein surface that do not perturb the overall structure of the domain. The actin binding mutants are replacements to cysteine of Lys38, Glu39, Lys65, Lys70, Lys71, Leu75, and Phe76 of headpiece. We propose that these discontinuous segments of charged amino acids define the F-actin binding contacts of the headpiece domain. The assay of mutants for effects on the thermal stability of helical structure as well as the assay of reactivity of the introduced sulfhydryl group identify candidate positions that are involved in the stabilizing core and internal structure of the domain. The cysteine scanning mutagenesis also identifies an amino-terminal subdomain (Val1-Leu35) and a predominantly helical carboxy-terminal subdomain (Pro36-Phe76).

Vulvar eccrine porocarcinoma.

A rare case of a slowly growing vulvar tumor in a 75-year-old woman is presented. This vulvar neoplasm was an eccrine porocarcinoma with left inguinal nodal metastases. This is believed to be only the second reported case of a vulvar eccrine porocarcinoma. Treatment included a left hemivulvectomy, bilateral inguinal-femoral lymphadenectomy, and postoperative radiation therapy. A review of the literature regarding this unusual malignancy is included.

A thermostable 35-residue subdomain within villin headpiece.

The actin-bundling protein villin contains, at its extreme C terminus, a compact f-actin binding domain called "headpiece". This 76-amino acid domain from chicken is highly thermostable. Here, we show that the stable folded structure in headpiece is localized to a subdomain formed by the C-terminal 35 residues. The subdomain, denoted HP-35, is monomeric and retains high thermostability, with a Tm of 70( +/- 1) degree C at PH 7.0. There are no cysteine residues in HP-35 and its folding is not dependent on the binding of metals or other ligands. HP-35 is not a molten globule, but instead, has properties expected for a fully folded protein with a unique structure. In particular, the slowly exchanging amide protons in HP-35 have protection factors that are slightly larger than those predicted if exchange occurred only from globally unfolded molecules. NMR studies indicate that the headpiece subdomain contains three short alpha-helices, and that these same helices are present in the corresponding regions of intact headpiece. HP-35 is the smallest monomeric polypeptide characterized consisting of only naturally occurring amino acids that autonomously folds into a unique and thermostable structure without disulfide bonds or ligand binding.

Quantitative analyses of epidermal growth factor receptors, HER-2/neu oncoprotein and cathepsin D in nonmalignant and malignant uteri.

BACKGROUND: Hormone receptors and oncoproteins are receiving increased attention as possible prognostic factors in different carcinomas. Few data are available regarding quantification of their levels of expression in gynecologic malignancies. METHODS: Epidermal growth factor (EGF) receptor specific binding capacities and affinities were measured by ligand binding assay using [125I]EGF in a competition mode with Accufit software (Lundon Software, Inc., Middlefield, OH). HER-2/neu oncoprotein was extracted from membranes and measured using an enzyme-linked immunosorbent assay. Cathepsin D was measured by an immunoradiometric assay using cytosols for steroid receptor analyses. RESULTS: EGF receptors in 23 nonmalignant uteri ranged from undetectable to 50 fmol/mg membrane protein (median, 0), with dissociation constant values of 1.2 x 10(-9) M to 8.5 x 10(-10) M, compared with EGF receptors in 76 endometrial cancers that ranged from undetectable to 7674 fmol/mg (median, 52). HER-2/neu oncoprotein ranged from undetectable to 2.9 HER-2/neu units (HNU)/microg protein (median, 0.6) in 41 nonmalignant uteri and from undetectable to 5.8 HNU/microg protein (median, 2.5) in endometrial cancers (n = 53). Cathepsin D ranged from 5 to 32 pmol/mg cytosol protein (median, 11) in 42 nonmalignant uteri and 18 to 144 pmol/mg protein (median, 42) in 29 endometrial cancers. CONCLUSIONS: Determination of the frequency and levels of EGF receptors, HER-2/neu protein, and cathepsin D in uteri with and without cancer and the availability of reference materials developed in our laboratory, will allow evaluation of their prognostic value in cancers of the uterus.