RESIK and RHESSI observations of the 20 September 2002 flare

Soft X-ray spectra 3.33 A - 6.15 A from the RESIK instrument on CORONAS-F constitute a unique database for the study of the physical conditions of solar flare plasmas, enabling the calculation of differential emission measures. The two RESIK channels for the shortest wavelengths overlap with the lower end of RHESSI spectral energy range, which is located around 3 keV, making it possible to compare both data sets. We aim to compare observations from RESIK and RHESSI spectrometers and cross-correlate these instruments. Observations are compared with synthetic spectra calculated based on the results of one-dimensional hydrodynamical (1D-HD) modelling. The analysis was performed for the flare on 20 September 2002. We estimated the geometry of the flaring loop, necessary for 1D-HD modelling, based on images from RHESSI and SOHO/EIT. The distribution of non-thermal electrons (NTEs) was determined from RHESSI spectra. The 1D-HD model assumes that non-thermal electrons with a power-law spectrum were injected at the apex of the flaring loop. The NTEs then heat and evaporate the chromosphere, filling the loop with hot and dense plasma radiating in soft X-rays. The total energy of electrons was constrained by comparing observed and calculated fluxes from GOES 1 - 8 A data. We determined the temperature and density at every point of the flaring loop throughout the evolution of the flare, calculating the resulting X-ray spectra. The synthetic spectra calculated based on the results of hydrodynamic modelling for the 20 September 2002 flare are consistent within a factor of two with the observed RESIK spectra during most of the duration of the flare. This discrepancy factor is probably related to the uncertainty on the cross-calibration between RESIK and RHESSI instruments

CD24 Expression and differential resistance to chemotherapy in triple-negative breast cancer.

Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24- are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24-/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-βR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance

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

Antioxidant status in the vitreous of eyes with rhegmatogenous retinal detachment with and without proliferative vitreoretinopathy, macular hole and epiretinal membrane

(1) Background: The aim of the study was to test the hypothesis that the antioxidant status in the vitreous body of eyes, which had been vitrectomized due to rhegmatogenous retinal detachment (RRD) with or without proliferative vitreoretinopathy (PVR), is higher than in eyes vitrectomized due to other retinal diseases. (2) Methods: four patient groups were analyzed: 22 eyes of patients with RRD without PVR, 27 eyes with RRD and PVR, 22 eyes with macular hole (MH) and 10 eyes with epiretinal membrane (ERM). Spectrophotometric methods were used to determine the total antioxidant status (TAS) values as well as superoxide dismutase (SOD) and glutathione reductase (GR) activities in the vitreous fluid samples. (3) Results: no significant differences in TAS values and antioxidant enzyme activities were observed among patient with RRD with and without PVR and with MH and ERM. The longer the duration of RRD leading to PVR and better postoperative visual acuity, the higher the TAS level. No significant differences were found between “macula on” and “macula off” subgroups within the RRD group and the RRD combined with PVR group. (4) Conclusions: The preliminary results do not support the thesis that the antioxidant status of vitrectomized eyes is different in patients with RRD with or without PVR in comparison to patients with MH and ERM. In patients with RRD, PVR presence and detached macula do not affect the values of TAS, SOD and GR in the vitreous fluid. The duration of the disease influences TAS in the vitreous in eyes with RRD complicated with PVR

Urgent vitrectomy with vancomycin infusion, silicone oil endotamponade, and general antibiotic treatment in multiple cases of endophthalmitis from a single day of intravitreal injections—case series

The aim of this study was to report on the anatomical and functional results of surgical management of seven cases of endophthalmitis related to a single day of intravitreal aflibercept injections. Patients with signs of endophthalmitis who underwent aflibercept injections (seven eyes) performed on the same day were retrospectively evaluated. The data of visual acuity and optical coherence tomography (OCT) within nine months of the follow-up and the treatment and results of microbiological cultures are reported. Four of the total seven cases had a positive bacterial culture outcome (Streptococcus mitis). All patients underwent vitrectomy combined with phacoemulsification when the eyes were not pseudophakic, vancomycin infusion, and silicone oil tamponade within 24 h; additionally, systemic antibiotics were administered intravenously. The final best-corrected visual acuity (BCVA) after the treatment was finger counting or light perception in all cases, and all eyes were saved with disruption of the inner retinal layers and stabilization of the retina in regard to changes related to the wet age-related macular degeneration (AMD). Although the retinal anatomy was mostly preserved, most of the patients affected by Streptococcus mitis-induced endophthalmitis did not regain baseline vision after the therapy

Characterization and comparison of enterococcus spp. Isolates from feces of healthy dogs and urine of dogs with utis

Enterococcus spp. are opportunistic pathogens of both humans and animals characterized by high resistance to antimicrobials. Dogs could be intestinal carriers or suffer from Enterococcus infections, mainly urinary tract infections (UTIs). This study aimed to analyze and compare En-terococcus spp. isolated from healthy dog stools and sick dog urine. Overall, 51 isolates (29 from stools and 22 from UTI) were characterized at species level and tested for antimicrobial resistance, biofilm production and presence of resistance and virulence genes. E. faecium and E. faecalis resulted as equally distributed in stools samples, while E. faecalis predominated among UTI isolates. HLAR phenotype was detected in 47.1% isolates; 64.7% isolates were resistant to ampicillin (47.1% with a MIC ≥ 64 µg/mL). High levels of resistance were recorded for fluoroquinolones (enrofloxacin 74.5%, ciprofloxacin 66.7%), clindamycin (84.3%), tetracycline (78.4%) and quinupristin–dalfopristin (78.4%). No vancomycin resistant strains were detected. All but one isolate were multidrug-resistant. Most detected resistance genes were tetM (70.5%), pbp4 (52.9%) and aph(3′ )-IIIa (39.2%). All isolates were able to produce biofilm, but isolates from UTIs and belonging to E. faecalis more frequently resulted in strong biofilm producers. Most detected virulence genes were asa1 (52.9%), gelE (41.2%), cylA (37.3%) and esp (35.3%); all of them resulted as more frequently associated to E. faecalis. No particular differences emerged between isolates from feces and UTI, considering all evaluated aspects. Our results confirm pet dogs as carriers of multidrug-resistant enterococci; stool microflora could be considered as the most probable source of enterococcal UTI and E. faecalis carried by dogs seems to be more virulent than E. faecium, justifying its more frequent involvement in urinary tract infections

Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors

The differentiation stage of tumors is a central aspect in the histopathological classification of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied

0 k.y. depositional cyclicity in the early Eocene: Stratigraphic and 40 Ar/ 39 Ar evidence from the lacustrine Green River Formation

ABSTRACT 40 Ar/ 39 Ar dating of sanidine from two interbedded tuffs reveals that the maximum average duration of depositional cycles in the Wilkins Peak Member, Green River Formation, was ϳ10 k.y., marking the first time that subprecessional cycles have been recognized in lacustrine strata. The origin of these cycles is uncertain, but may relate to a nonlinear climatic response to orbital forcing of insolation. Alternatively, regional tectonic and geomorphic controls on drainage stability may have promoted autocyclic delivery of sediment to the lake. Owing to an interaction between basin-floor relief and varying amplitudes of lake expansion, only one-third of the cycles identified near the basin center are present near the basin margin. This spatial variability in the temporal completeness of the stratigraphic record is not apparent from examination of individual localities, indicating that studies based on time-series analysis from other lacustrine systems may need reevaluation

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<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<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<0,02). Этот эффект сопровождался повышением активности МЛП и концентрации Н202, соответственно, в 2,6 и 1,4 раза (р<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

Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma

Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma