Direct mass measurements of 19B, 22C, 29F, 31Ne, 34Na and other light exotic nuclei

We report on direct time-of-flight based mass measurements of 16 light neutron-rich nuclei. These include the first determination of the masses of the Borromean drip-line nuclei $^{19}$B, $^{22}$C and $^{29}$F as well as that of $^{34}$Na. In addition, the most precise determinations to date for $^{23}$N and $^{31}$Ne are reported. Coupled with recent interaction cross-section measurements, the present results support the occurrence of a two-neutron halo in $^{22}$C, with a dominant $\nu2s_{1/2}^2$ configuration, and a single-neutron halo in $^{31}$Ne with the valence neutron occupying predominantly the 2$p_{3/2}$ orbital. Despite a very low two-neutron separation energy the development of a halo in $^{19}$B is hindered by the 1$d_{5/2}^2$ character of the valence neutrons.Comment: 5 page

Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor

BACKGROUND: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. METHODS: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID). RESULTS: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles. CONCLUSIONS: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs

Structural abnormalities of the optic nerve and retina in Huntington’s disease pre-clinical and clinical settings

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies

Platelet-derived growth factor receptor-β, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma

<p>Abstract</p> <p>Background</p> <p>Platelet-derived growth factor (PDGF)-BB and PDGF receptor (PDGFR)-β are mainly expressed in the developing vasculature, where PDGF-BB is produced by endothelial cells and PDGFR-β is expressed by mural cells, including pericytes. PDGF-BB is produced by most types of solid tumors, and PDGF receptor signaling participates in various processes, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. Furthermore, PDGF-BB-producing tumors are characterized by increased pericyte abundance and accelerated tumor growth. Thus, there is a growing interest in the development of tumor treatment strategies by blocking PDGF/PDGFR function. We have recently generated a mouse model carrying an activated PDGFR-β by replacing the highly conserved aspartic acid residue (D) 849 in the activating loop with asparagine (N). This allowed us to investigate, in an orthotopic tumor model, the role of increased stromal PDGFR-β signaling in tumor-stroma interactions.</p> <p>Methods</p> <p>B16 melanoma cells lacking PDGFR-β expression and either mock-transfected or engineered to express PDGF-BB, were injected alone or in combination with matrigel into mice carrying the activated PDGFR-β (D849N) and into wild type mice. The tumor growth rate was followed and the vessel status of tumors, i.e. total vessel area/tumor, average vessel surface and pericyte density of vessels, was analyzed after resection.</p> <p>Results</p> <p>Tumors grown in mice carrying an activated PDGFR-β were established earlier than those in wild-type mice. In this early phase, the total vessel area and the average vessel surface were higher in tumors grown in mice carrying the activated PDGFR-β (D849N) compared to wild-type mice, whereas we did not find a significant difference in the number of tumor vessels and the pericyte abundance around tumor vessels between wild type and mutant mice. At later phases of tumor progression, no significant difference in tumor growth rate was observed between wild type mice and mutant mice, although the pericyte coverage was higher around tumor vessels from mutant mice.</p> <p>Conclusion</p> <p>Our findings suggest that the activated PDGFR-β (D849N) in the host animal increased the total vessel area and the average vessel surface even in PDGF-negative tumors, resulting in a shorter lag phase during tumor establishment.</p

Действие местного иммунокорректора со свойствами вакцины НРС 19 на концентрацию перекиси водорода и активность миелопероксидазы в смывах из полости носа у больных с хроническим бронхитом

Twenty eight adults of both genders with chronic bronchitis participated in the open trial studying the influence of the local immune modulating drug IRS 19 with vaccine properties on polymorphonuclear leukocytes number, H202 concentration and myeloperoxidase activity in nasal washes. The polymorphonuclear leukocytes number increased from 4460±3960 to 10490±10950 cells per ml (p&lt;0.02) after two months of IRS 19 use. This effect accompanied by the myeloperoxidase activity and the H202 concentration increase in 2.6 and 1.4 times, correspondingly (p&lt;0.001). As the "polymorphonuclear leukocytes and myeloperoxidase – H202 – Clˉ " system is the first-line defence against pathogenic microorganisms, the changes mentioned above are likely to be one of the mechanisms enhancing the airways antibacterial immunity in response to the IRS 19 therapy.Двадцать восемь взрослых больных обоего пола, страдающие хроническим бронхитом, приняли участие в открытом исследовании, посвященном изучению эффекта применения местного иммуномодулирующего препарата со свойствами вакцины ИРС 19 на число полиморфноядерных лейкоцитов (ПМЯЛ), концентрацию Н202 и активность миелопероксидазы (МЛП) в смывах из полости носа. Число ПМЯЛ, выделявшихся из полости носа, увеличилось после двух месяцев применения ИРС 19 с 4460±3960 до 10 490±10 950 клеток на мл (р&lt;0,02). Этот эффект сопровождался повышением активности МЛП и концентрации Н202, соответственно, в 2,6 и 1,4 раза (р&lt;0,001). Поскольку система ПМЯЛ и МЛП – Н202 – CIˉ находится на переднем крае защиты от проникновения патогенных микроорганизмов, можно предположить, что упомянутые выше изменения могут представлять собой один из механизмов, приводящих к повышению антибактериального иммунитета в области дыхательных путей в ответ на лечение препаратом ИРС 19

Intercomparison of spectroradiometers and Sun photometers for the determination of the aerosol optical depth during the VELETA-2002 field campaign

[ 1] In July 2002 the VELETA-2002 field campaign was held in Sierra Nevada ( Granada) in the south of Spain. The main objectives of this field campaign were the study of the influence of elevation and atmospheric aerosols on measured UV radiation. In the first stage of the field campaign, a common calibration and intercomparison between Licor-1800 spectroradiometers and Cimel-318 Sun photometers was performed in order to assess the quality of the measurements from the whole campaign. The intercomparison of the Licor spectroradiometers showed, for both direct and global irradiances, that when the comparisons were restricted to the visible part of the spectrum the deviations were within the instruments' nominal accuracies which allows us to rely on these instruments for measuring physical properties of aerosols at the different measurement stations. A simultaneous calibration on AOD data was performed for the Cimel-318 Sun photometers. When a common calibration and methodology was applied, the deviation was lowered to much less than 0.01 for AOD. At the same time an intercomparison has been made between the AOD values given by the spectroradiometers and the Sun photometers, with deviations obtained from 0.01 to 0.03 for the AOD in the visible range, depending on the channel. In the UVA range, the AOD uncertainty was estimated to be around 0.02 and 0.05 for Cimel and Licor respectively. In general the experimental differences were in agreement with this uncertainty estimation. In the UVB range the AOD measurements should not be used due to maximum instrumental uncertainties

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Contains fulltext : 79699.pdf (publisher's version ) (Closed access)BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity

HER2 testing in breast cancer: Opportunities and challenges

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-25% of breast cancers, usually as a result of HER2 gene amplification. Positive HER2 status is considered to be an adverse prognostic factor. Recognition of the role of HER2 in breast cancer growth has led to the development of anti-HER2 directed therapy, with the humanized monoclonal antibody trastuzumab (Herceptin (R)) having been approved for the therapy of HER2-positive metastatic breast cancer. Clinical studies have further suggested that HER2 status can provide important information regarding success or failure of certain hormonal therapies or chemotherapies. As a result of these developments, there has been increasing demand to perform HER2 testing on current and archived breast cancer specimens. This article reviews the molecular background of HER2 function, activation and inhibition as well as current opinions concerning its role in chemosensitivity and interaction with estrogen receptor biology. The different tissue-based assays used to detect HER2 amplification and overexpression are discussed with respect to their advantages and disadvantages, when to test (at initial diagnosis or pre-treatment), where to test (locally or centralized) and the need for quality assurance to ensure accurate and valid testing results