A flexible proton beam imaging energy spectrometer (PROBIES) for high repetition rate or single-shot high energy density (HED) experiments (invited).

The PROBIES diagnostic is a new, highly flexible, imaging and energy spectrometer designed for laser-accelerated protons. The diagnostic can detect low-mode spatial variations in the proton beam profile while resolving multiple energies on a single detector or more. When a radiochromic film stack is employed for "single-shot mode," the energy resolution of the stack can be greatly increased while reducing the need for large numbers of films; for example, a recently deployed version allowed for 180 unique energy measurements spanning ∼3 to 75 MeV with <0.4 MeV resolution using just 20 films vs 180 for a comparable traditional film and filter stack. When utilized with a scintillator, the diagnostic can be run in high-rep-rate (>Hz rate) mode to recover nine proton energy bins. We also demonstrate a deep learning-based method to analyze data from synthetic PROBIES images with greater than 95% accuracy on sub-millisecond timescales and retrained with experimental data to analyze real-world images on sub-millisecond time-scales with comparable accuracy.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Overexpression of the NR2A subunit in the forebrain impairs long-term social recognition and non-social olfactory memory.

Animals must recognize and remember conspecifics and potential mates, and distinguish these animals from potential heterospecific competitors and predators. Despite its necessity, aged animals are known to exhibit impaired social recognition memory. As the brain ages, the ratio of NR2A:NR2B in the brain increases over time and has been postulated to underlie the cognitive decline observed during the aging process. Here, we test the hypothesis that an increased NR2A:NR2B subunit ratio underlies long-term social recognition memory. Using transgenic overexpression of NR2A in the forebrain regions, we investigated the ability of these mice to learn and remember male and female conspecifics, mice of another strain and animals of another rodent species, the rat. Furthermore, due to the importance of olfaction in social recognition, we tested the olfactory memory in the NR2A transgenic mice. Our series of behavioral experiments revealed significant impairments in the NR2A transgenic mice in long-term social memory of both male and female conspecifics. Additionally, the NR2A transgenic mice are unable to recognize mice of another strain or rats. The NR2A transgenic mice also exhibited long-term memory impairments in the olfactory recognition task. Taken together, our results provide evidence that an increased NR2A:NR2B ratio in the forebrain leads to reduced long-term memory function, including the ethologically important memories such as social recognition and olfactory memory.

Radioisotopic localization of (90)Yttrium-ibritumomab tiuxetan in patients with CD20+ non-Hodgkin's lymphoma.

PURPOSE: (90)Yttrium-ibritumomab-tiuxetan (Zevalin) is an effective treatment for relapsed or refractory low-grade, follicular, or transformed B-cell NHL. The purpose of this study is to assess whether tissue and cellular localization of (90)Y-ibritumomab-tiuxetan determined by autoradiography and radioactivity localized to tumor tissue might enhance our understanding of the mechanism of action of radioimmunotherapy. METHODS: Eight eligible patients had CD20+ NHL, a bulky peripheral lymph node, and were scheduled for (90)Y-ibritumomab-tiuxetan treatment. 2-Deoxy-2-[F-18]fluoro-D: -glucose-positron emission tomography/computed tomography (FDG-PET/CT) was performed prior to treatment and at 12 weeks after therapy for assessment of response. Bone marrow, lymph node, and blood samples were collected 114 +/- 3 h after 14.8 MBq/kg (90)Y-ibritumomab-tiuxetan and processed for histology, scintillation counting, and microscopic autoradiography. RESULTS: Pericellular membrane localization of (90)Y-ibritumomab-tiuxetan to lymphoma cells was observed by autoradiography in the involved areas of lymph node with absence of significant localization in histologically normal sections of bone marrow. Pericellular radioactivity and the highest quantitative radioactivity were observed in lymph node samples of responding patients. CONCLUSIONS: (90)Y-ibritumomab-tiuxetan localizes to the surface membrane of CD20+ lymphoma cells in affected lymph nodes. The patients with the highest quantitative concentration of radioactivity to the lymph node as determined by scintillation counting were observed to have a clinical and FDG-PET/CT response.

Aligned silver nanorod arrays as substrates for surface-enhanced infrared absorption spectroscopy.

Preferentially aligned silver nanorod arrays prepared by oblique angle vapor deposition were evaluated as substrates for surface-enhanced infrared absorption (SEIRA) spectroscopy. These nanorod arrays have an irregular surface lattice and are composed of tilted, cylindrically shaped nanorods that have an average length of 868 nm +/- 95 nm and an average diameter of 99 nm +/- 29 nm. The overall enhancement factor for chemisorbed organic films of para-nitrobenzoic acid (PNBA) deposited onto the Ag nanorod arrays analyzed by external reflection SEIRA was calculated to be 31 +/- 9 compared to infrared reflection-absorption spectroscopy (IRRAS) obtained from a 500 nm Ag film substrate. This enhancement is attributed to the unique optical properties of the nanorod arrays as well as the increased surface area provided by the nanorod substrate. SEIRA reflection-absorbance intensity was observed with both p- and s-polarized incident radiation with angles of incidence ranging from 25 degrees to 80 degrees . The largest intensity was achieved with p-polarization and incident angles larger than 75 degrees . Polarization-dependent ultraviolet/visible/near-infrared (UV/Vis/NIR) spectra of the nanorod arrays demonstrate that the red-shifted surface plasmon peaks of the elongated nanorods may be partially responsible for the observed SEIRA response. The SEIRA detection limit for the Ag nanorod arrays was estimated to be 0.08 ng/cm(2). Surface-enhanced Raman scattering (SERS) and SEIRA analysis of chemisorbed PNBA utilizing the same nanorod substrate is demonstrated.

Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer.

BACKGROUND: This phase II study was conducted to evaluate the safety and efficacy of the combination of paclitaxel and topotecan for patients with extensive stage small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Previously untreated ED-SCLC patients with Eastern Coperative Oncology Group performance status <2 were eligible. Treatment consisted of topotecan 1 mg/m2 (first three patients received 1.25 mg/m2), on days 1-5, and paclitaxel 135 mg/m2 over 24 h on day 5, every 4 weeks. Prophylactic granulocyte colony-stimulating factor was administered to all patients. RESULTS: Thirty-two patients received a median of four cycles of chemotherapy. Grade 4 anemia, neutropenia and thrombocytopenia occurred in 13, 31 and 18 patients, respectively. Thirty episodes of febrile neutropenia occurred in 22 patients. Grade 3 fatigue, esophagitis, stomatitis and hypotension occurred in one patient each. Of 26 patients eligible for response evaluation, there were six complete and 12 partial responses (overall response rate 69%). The median survival was 54 weeks. The 1-, 2- and 3-year survival rates were 50%, 10% and 3%, respectively. CONCLUSIONS: The combination of topotecan and paclitaxel is active as initial therapy in SCLC, but the efficacy is similar to 'standard therapy'. This combination was associated with a high incidence of myelosuppression and febrile neutropenia, at the doses evaluated.

Specificity of the HP1 chromo domain for the methylated N-terminus of histone H3.

Recent studies show that heterochromatin-associated protein-1 (HP1) recognizes a 'histone code' involving methylated Lys9 (methyl-K9) in histone H3. Using in situ immunofluorescence, we demonstrate that methyl-K9 H3 and HP1 co-localize to the heterochromatic regions of Drosophila polytene chromosomes. NMR spectra show that methyl-K9 binding of HP1 occurs via its chromo (chromosome organization modifier) domain. This interaction requires methyl-K9 to reside within the proper context of H3 sequence. NMR studies indicate that the methylated H3 tail binds in a groove of HP1 consisting of conserved residues. Using fluorescence anisotropy and isothermal titration calorimetry, we determined that this interaction occurs with a K(D) of approximately 100 microM, with the binding enthalpically driven. A V26M mutation in HP1, which disrupts its gene silencing function, severely destabilizes the H3-binding interface, and abolishes methyl-K9 H3 tail binding. Finally, we note that sequence diversity in chromo domains may lead to diverse functions in eukaryotic gene regulation. For example, the chromo domain of the yeast histone acetyltransferase Esa1 does not interact with methyl- K9 H3, but instead shows preference for unmodified H3 tail.

Relative anti-caries efficacy of 1100, 1700, 2200, and 2800 ppm fluoride ion in a sodium fluoride dentifrice over 1 year.

There is limited evidence from clinical trials on the dose response of sodium fluoride dentifrices at concentrations above 1100 ppm fluoride ion, with respect to caries efficacy. This randomized, double-blind study examined the anti-caries effectiveness of sodium fluoride dentifrices containing 1700 ppm, 2200 ppm and 2800 ppm fluoride ion relative to an 1100 ppm fluoride ion control. A population of 5439 elementary schoolchildren, aged 6-15 years, was recruited from an urban central Ohio area with a low fluoride content water supply (<0.3 ppm). Subjects were examined by visual-tactile and radiographic examination at baseline and after 1, 2, and 3 years of using the sodium fluoride dentifrices. Subjects were stratified according to gender, age and baseline DMFS scores derived from the visual-tactile baseline examination and randomly assigned to one of four treatment groups: 0.243% sodium fluoride (1100 ppm fluoride ion), 0.376% sodium fluoride (1700 ppm fluoride ion), 0.486% sodium fluoride (2200 ppm fluoride ion), and 0.619% sodium fluoride (2800 ppm fluoride ion). All products were formulated with the same fluoride compatible silica abrasive. Results after 1 year provided evidence of a positive sodium fluoride dose response. Compared to the 1100 ppm fluoride treatment group, the 1700 ppm fluoride treatment group had an 11.0% reduction in DMFS that was not statistically significant, while the 2200 ppm and 2800 ppm fluoride treatment groups showed statistically significant (P<0.05) reductions of 18.6% and 20.4%, respectively. The reductions in caries delivered by the higher fluoride dentifrices were present across all tooth surface types, but were most pronounced for occlusal surfaces. Results at years 2 and 3 were confounded by a concurrent fluoride rinse program, which involved portions of the study population. While the trends for the higher fluoride dentifrices observed at year 1 remained at years 2 and 3, the difference observed between treatments were substantially less and failed to reach statistical significance (P<0.05). Collectively, the data demonstrate that the 2200 ppm and the 2800 ppm fluoride treatments delivered statistically significantly greater caries efficacy than the 1100 ppm fluoride treatment. This large-scale clinical trial provides evidence of a positive statistically significant dose relationship between dental caries and sodium fluoride in a dentifrice at levels above 1100 ppm fluoride at year 1.

Reduction in dental caries with four concentrations of sodium fluoride in a dentifrice: a meta-analysis evaluation.

Information on the effects of fluoride concentrations above 1,100 ppm in dentifrices is not extensive in the literature. The objective of this meta-analysis was to examine and compare the anticaries effectiveness (in terms of DMFS scores) of 1,700 ppm, 2,200 ppm and 2,800 ppm F- ion (as sodium fluoride) dentifrices vs. an 1,100 ppm F- ion (as sodium fluoride) control dentifrice based on results from six double-blind, randomized clinical studies, each conducted over a two- to three-year period. The studies each enrolled approximately 1,200-2,000 male and female school children per treatment group in grades I through 8, and were conducted in areas with low fluoride content water supplies in the states of Indiana, Pennsylvania, Ohio and Oregon. Separate meta-analyses were performed on the study results (DMFS increment scores determined by visual-tactile examinations supplemented with radiographs) for the one-year, two-year and three-year examinations. Comparisons of the 1,700 ppm F-, 2,200 ppm F-, and 2,800 ppm F- groups vs. the 1,100 ppm F- group were based on pooling the effect sizes for these comparisons from the individual studies. The effect sizes were calculated in two different ways, reflecting the analyses that were performed in the original studies: 1) effects based on the sample means and variances; and 2) effects based on the adjusted sample means and mean squared error from an analysis of covariance. The results obtained from this meta-analysis provide evidence that the use of a 2,800 ppm F- ion, as sodium fluoride, dentifrice results in statistically significantly lower caries increment than the use of an 1,100 ppm F- ion, as sodium fluoride, dentifrice. This result was noted after one, two, and three years of dentifrice use. The 1,700 ppm F- and 2,200 ppm F- dentifrice groups showed some directional advantages over the 1,100 ppm F- dentifrice group, however the analysis did not establish these groups as statistically significantly better than 1,100 ppm F-. The meta-analysis based on analysis of covariance results was somewhat more sensitive to treatment group differences than the analysis based on sample means and variances, as was expected.

Domain structure and dynamics in the helical filaments formed by RecA and Rad51 on DNA.

Both the bacterial RecA protein and the eukaryotic Rad51 protein form helical nucleoprotein filaments on DNA that catalyze strand transfer between two homologous DNA molecules. However, only the ATP-binding cores of these proteins have been conserved, and this same core is also found within helicases and the F1-ATPase. The C-terminal domain of the RecA protein forms lobes within the helical RecA filament. However, the Rad51 proteins do not have the C-terminal domain found in RecA, but have an N-terminal extension that is absent in the RecA protein. Both the RecA C-terminal domain and the Rad51 N-terminal domain bind DNA. We have used electron microscopy to show that the lobes of the yeast and human Rad51 filaments appear to be formed by N-terminal domains. These lobes are conformationally flexible in both RecA and Rad51. Within RecA filaments, the change between the "active" and "inactive" states appears to mainly involve a large movement of the C-terminal lobe. The N-terminal domain of Rad51 and the C-terminal domain of RecA may have arisen from convergent evolution to play similar roles in the filaments.

Very late relapse of Hodgkin's disease: a report of five patients.

The majority of patients with Hodgkin's disease can be cured with current treatment modalities. Relapses beyond 3 years are rare; however, the outcome for patients in late relapse with standard-dose salvage therapy is excellent. In this article, we report five patients who had such relapses and describe their outcome.

Kaposi sarcoma after treatment of Hodgkin's disease in a young adult non-AIDS patient: case report and review.

We describe a young woman diagnosed with Hodgkin's disease, stage I, at age 20 years. She delayed treatment until age 23, at which time she was considered to have stage II-A disease and was then treated with chemotherapy and involved field irradiation. Two years later, Kaposi sarcoma, which developed on her right shoulder, was excised. Both the Hodgkin's disease and Kaposi sarcoma appeared to be cured, but 3 years later, acute myelogenous leukemia developed and the patient subsequently died in relapse. This is one of the very few instances of a young patient, not infected with the AIDS virus, in whom Kaposi sarcoma developed as a second malignancy after treatment of Hodgkin's disease.

Determination of human immunodeficiency virus-1 protease inhibitors in patient serum using free solution capillary zone electrophoresis.

The goal of this study was to develop a fast, inexpensive and quantitative method for serum determination of the human immunodeficiency virus protease inhibitors Crixivan (C), Viracept (V), Invirase (I) or Fortovase (F), and Norvir (N), using common conditions for isolation and analysis. The best separation procedure developed thus far involves uncoated silica capillary and a buffer containing formic acid and acetonitrile. This procedure allows us to analyze three drugs (C, V and I or F) in 15 min. Norvir requires different analytical conditions. These four drugs are isolated from patient sera with a mixture of ethyl acetate and hexane. Sensitivity of the capillary zone electrophoresis protocols is sufficient for the detection of these pharmacological agents at the lowest clinically relevant concentrations (0.1 microgram/ml).

Laser laparoscopic surgery in the treatment of ovarian endometriomas.

STUDY OBJECTIVE: To assess the efficacy of laser laparoscopic photocoagulation of endometriomas (2-18 cm) in patients with pain, infertility, or a combination of the two. DESIGN: Retrospective review of all patients with endometriomas from June 1, 1983, to December 31, 1993. SETTING: Department of gynecology and obstetrics at a district general hospital and national training center in minimal access surgery. PATIENTS: One hundred sixty-five women with large endometriomas present at the time of laser laparoscopy. INTERVENTIONS: Carbon dioxide laser or potassium-titanyl-phosphate laser laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: Ninety (74%) of 122 patients reported improvement or resolution of pain; and 30 of 66 achieved a pregnancy, for a cumulative conception rate of 45%. CONCLUSION: Laser laparoscopy is a practical, safe, and effective technique for the management of large ovarian endometriomas.

Endometrial resection follow up: late onset of pain and the effect of depot medroxyprogesterone acetate.

OBJECTIVE: To observe longer term (9 to 18 months) follow up of women after a transcervical resection of the endometrium (TCRE) and the effect of post-operative medroxyprogesterone acetate on the results. DESIGN: An observational study. SETTING: A district public hospital and a nearby private hospital in Sydney, Australia. SUBJECTS: Sixty-one women who underwent TCRE from January to December 1991 were contacted 9 to 18 months after the procedure. They were questioned about symptoms and levels of satisfaction at six months, 12 months and at the time of interview, 9-18 months after the procedure. The 27 women treated from 1 January to 31 August 1991 were given medroxyprogesterone acetate 150 mg at the time of surgery. From 1 September to 31 December 1991 no medroxyprogesterone acetate was given (32 women). Two women underwent immediate hysterectomy, and are included as unsuccessful TCREs but are excluded from description of effects of medroxyprogesterone acetate on the results of TCRE. RESULTS: Late onset, defined as after 12 months, of pain with or without bleeding occurred in 7 out of 52 women (13.5%). Overall, 49 out of 61 women (80.3%) were satisfied with the operation at the time of interview, 9 to 18 months post-operatively. Success rates, measured by satisfaction, were 89% (24/27) in the medroxyprogesterone acetate group and 75% (24/32) in the no medroxyprogesterone acetate group. CONCLUSION: Follow up after endometrial resection revealed that a definite subgroup of women develop late onset of pain with or without bleeding. Results at four to six months do not necessarily correlate with longer term outcomes. This needs to be investigated with larger, long term follow up studies, as does the apparently beneficial effects of medroxyprogesterone acetate on the long term results of TCRE.