242. Analiza ekspresji EGFR i angiogenezv w utkaniu niedrobnokomórkowego raka płuc oraz związku z czasem przeżycia pacjentów w stadiach zaawansowania klinicznego I-IIIA

Cel pracyWciąż niezadowalające wskaźniki przeżycia pacjentów z rakiem płuca, mimo radykalnego leczenia operacyjnego, skłaniają do poszukiwań nowych czynników prognostycznych. Wiadomym jest, że receptor naskórkowego czynnika wzrostu (EGFR) wpływa na wzrost komórek guza i jego progresję, jak również tworzenie przerzutów – głównie poprzez oddziaływanie na tworzenie nowych naczyń krwionośnych. Jego prognostyczna rola u pacjentów z niedrobnokomórkowym rakiem płuca (NRP) jest niejasna. Natomiast gęstość naczyń krwionośnych (GNK), będąca miernikiem angiogenezy w guzie, jest podawana jako marker prognostyczny w wielu nowotworach. Celem naszego badania była ocena zależności między ekspresją EGFR i GNK w utkaniu guza nowotworowego a przeżyciem pacjentów z NRP.Materiał i metodyBadaniem objęto 75 pacjentów z NRP w stadiach zaawansowania klinicznego I-IIIA. Wycinki z guza pobierano z materiału operacyjnego, utrwalonego w formalinie. Na uzyskanych skrawkach parafinowych wykonywano odczyny immunohistochemiczne z zastosowaniem monoklonalnego przeciwciała przeciw receptorowi naskórkowego czynnika wzrostu oraz monoklonalnego przeciwciała przeciw CD31.WynikiWśród 75 pacjentów było 5 kobiet (6.7%) i 70 mężczyzn (93.3%) w wieku od 42 lat do 74 lat (średnio 59 lat). W badanej grupie chorych stwierdzono raka płaskonabłonkowego u 53 pacjentów (70.7%), gruczolakoraka u 11 chorych (14.7%) i raka wielkokomórkowego także u 11 pacjentów. Analizując uzyskane dane nie stwierdzono istotności statystycznej między ekspresją EGFR i czasem przeżycia pacjentów. Również GNK nie miała istotnego wpływu na przeżycie pacjentów. Jedynie stan węzłów chłonnych (cecha N; p<0.05), typ histologiczny raka (p<0.001) oraz wiek (p<0.05) w badanej grupie chorych miały istotny statystycznie wpływ na czas przeżycia.WnioskiUzyskane w tym badaniu wyniki nie są zgodne z wynikami innych doniesień mówiących o tym, że ekspresja EGFR i GNK w NRP mogą być traktowane jako czynniki prognostyczne. Należy jednak podkreślić, że analizowana grupa pacjentów była mała, a większość chorych (59 pacjentów, 78.7%) znajdowała się w stadium znacznego zaawansowania nowotworu

Deletion of SA β-Gal+ Cells Using Senolytics Improves Muscle Regeneration in Old Mice

Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice

Comparison of GPS analysis strategies for high-accuracy vertical land motion

Tide gauges measure sea level changes relative to land. To separate absolute changes in sea level from vertical land movements tide gauges are often co-located with Continuous GPS (CGPS). In order to achieve an accuracy of better than 1 mm/yr, as required for sea level studies in the global change context, vertical land motion needs to be determined with the same accuracy. This is an ambitious goal for CGPS and needs a carefully designed analysis strategy. We have compared the independent results from six different analysis centres, using three different GPS processing softwares and a number of different analysis strategies. Based on the comparison, we discuss the achieved accuracy and the quality of the different strategies. The data analysed are from the CGPS network of the European Sea Level Service and cover the time window from the beginning of 2000 until the end of 2003. The comparison reveals large differences in the day-to-day variations of the coordinate time series and also in the seasonal cycle contained in these. The trends show systematic differences, depending on software and strategy used. To a large extent, the latter deviations can be explained by differences in the realisation of the reference frame, while some parts may be due to other, as yet, unidentified contributions. The results suggest that the reference frame and its relation to the center of mass of the Earth system may be the main limitation in achieving the accuracy goal for the secular velocity of vertical land motion.Peer ReviewedPostprint (published version

A nanostructural view of the cell wall disassembly process during fruit ripening and postharvest storage by atomic force microscopy

Background: The mechanical properties of parenchyma cell walls and the strength and extension of adhesion areas between adjacent cells, jointly with cell turgor, are main determinants of firmness of fleshy fruits. These traits are modified during ripening leading to fruit softening. Cell wall modifications involve the depolymerisation of matrix glycans and pectins, the solubilisation of pectins and the loss of neutral sugars from pectin side chains. These changes weaken the cell walls and increase cell separation, which in combination with a reduction in cell turgor, bring about textural changes. Atomic force microscopy (AFM) has been used to characterize the nanostructure of cell wall polysaccharides during the ripening and postharvest storage of several fruits. This technique allows the imaging of individual polymers at high magnification with minimal sample preparation. Scope and approach: This paper reviews the main features of the cell wall disassembly process associated to fruit softening from a nanostructural point of view, as has been provided by AFM studies. Key findings and conclusions: AFM studies show that pectin size, ramification and complexity is reduced during fruit ripening and storage, and in most cases these changes correlate with softening. Postharvest treatments that improve fruit quality have been proven to preserve pectin structure, suggesting a clear link between softening and pectin metabolism. Nanostructural characterization of cellulose and hemicellulose during ripening has been poorly explored by AFM and the scarce results available are not conclusive. Globally, AFM could be a powerful tool to gain insights about the bases of textural fruit quality in fresh and stored fruits

Deconvolution of Serum Cortisol Levels by Using Compressed Sensing

The pulsatile release of cortisol from the adrenal glands is controlled by a hierarchical system that involves corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and cortisol from the adrenal glands. Determining the number, timing, and amplitude of the cortisol secretory events and recovering the infusion and clearance rates from serial measurements of serum cortisol levels is a challenging problem. Despite many years of work on this problem, a complete satisfactory solution has been elusive. We formulate this question as a non-convex optimization problem, and solve it using a coordinate descent algorithm that has a principled combination of (i) compressed sensing for recovering the amplitude and timing of the secretory events, and (ii) generalized cross validation for choosing the regularization parameter. Using only the observed serum cortisol levels, we model cortisol secretion from the adrenal glands using a second-order linear differential equation with pulsatile inputs that represent cortisol pulses released in response to pulses of ACTH. Using our algorithm and the assumption that the number of pulses is between 15 to 22 pulses over 24 hours, we successfully deconvolve both simulated datasets and actual 24-hr serum cortisol datasets sampled every 10 minutes from 10 healthy women. Assuming a one-minute resolution for the secretory events, we obtain physiologically plausible timings and amplitudes of each cortisol secretory event with R[superscript 2] above 0.92. Identification of the amplitude and timing of pulsatile hormone release allows (i) quantifying of normal and abnormal secretion patterns towards the goal of understanding pathological neuroendocrine states, and (ii) potentially designing optimal approaches for treating hormonal disorders.National Science Foundation (U.S.). Graduate Research Fellowship ProgramNational Institutes of Health (U.S.) (NIH DP1 OD003646)National Science Foundation (U.S.) (0836720)National Science Foundation (U.S.). Office of Emerging Frontiers in Research and Innovation (EFRI-0735956

Circulating cardiovascular biomarkers in recurrent atrial fibrillation: data from the GISSI-atrial fibrillation trial.

Objective. We evaluated the prognostic role of circulating cardiovascular biomarkers in patients with a history of recent atrial fibrillation (AF).Background. Predicting long-term maintenance of sinus rhythm in patients with AF is difficult.Methods. Plasma concentrations of three specific cardiac markers [high-sensitivity troponin T (hsTnT), N-terminal probrain natriuretic peptide (NT-proBNP) and mid-regional proatrial natriuretic peptide (MR-proANP)] and three stable fragments of vasoactive peptides [mid-regional proadrenomedullin (MR-proADM), copeptin (CT-proAVP) and CT-proendothelin-1 (CT-proET-1)] were measured at baseline and after 6 and 12 months in 382 patients enrolled in the GISSI-AF study, a prospective randomized trial to determine the effect of valsartan to reduce the recurrence of AF. The association between these markers, clinical characteristics and recurrence of AF was tested by univariate and multivariate Cox models.Results. Mean patient age was 68 \ub1 9 years (37.2% females). A total of 84.8% of patients had a history of hypertension. In total, 59.7% qualified for history of AF because of successful cardioversion, 11.8% because of two or more episodes of AF in the 6 months preceding randomization and 28.5% because of both. Patients in AF at 6 or 12 months (203 (53.1%) with first recurrence) had significantly higher concentrations of most biomarkers. Despite low baseline levels, higher concentrations of hsTnT {adjusted hazard ratio (HR) [95% confidence intervals (CIs) for 1 SD increment] (1.15 [1.04-1.28], P = 0.007), MR-proANP (1.15 [1.01-1.30], P = 0.04), NT-proBNP (1.24 [1.11-1.39], P = 0.0001) and CT-proET-1 (1.16 [1.01-1.33], P = 0.03) independently predicted higher risk of a first recurrence of AF. Changes over time of MR-proANP tended to predict subsequent recurrence (adjusted HR [95%CI]) (1.53 [0.98-2.37], P = 0.06).Conclusion. Circulating markers of cardiomyocyte injury/strain and endothelin are related to recurrence of AF in patients in sinus rhythm with a history of recent AF