Regional declines in polar bear (
) populations have been attributed to changing sea ice conditions, but with limited information on the causative mechanisms. By simultaneously measuring field ...metabolic rates, daily activity patterns, body condition, and foraging success of polar bears moving on the spring sea ice, we found that high metabolic rates (1.6 times greater than previously assumed) coupled with low intake of fat-rich marine mammal prey resulted in an energy deficit for more than half of the bears examined. Activity and movement on the sea ice strongly influenced metabolic demands. Consequently, increases in mobility resulting from ongoing and forecasted declines in and fragmentation of sea ice are likely to increase energy demands and may be an important factor explaining observed declines in body condition and survival.
Background. The purpose of our study was to evaluate the incidence and outcome of invasive fungal infection (IFI) among patients who underwent autologous or allogeneic hematopoietic stem cell ...transplantation (HSCT) at 11 Italian transplantation centers. Methods. This cohort-retrospective study, conducted during 1999–2003, involved HSCT patients admitted to 11 tertiary care centers or university hospitals in Italy, who developed IFIs (proven or probable). Results. Among 3228 patients who underwent HSCT (1249 allogeneic HSCT recipients and 1979 autologous HSCT recipients), IFI occurred in 121 patients (overall incidence, 3.7%). Ninety-one episodes (2.8% of all patients) were due to molds, and 30 (0.9%) were due to yeasts. Ninety-eight episodes (7.8%) occurred among the 1249 allogeneic HSCT recipients, and 23 (1.2%) occurred among the 1979 autologous HSCT recipients. The most frequent etiological agents were Aspergillus species (86 episodes) and Candida species (30 episodes). The overall mortality rate was 5.7% among allogeneic HSCT recipients and 0.4% among autologous HSCT recipients, whereas the attributable mortality rate registered in our population was 65.3% (72.4% for allogeneic HSCT recipients and 34.7% for autologous HSCT recipients). Etiology influenced the patients' outcomes: the attributable mortality rate for aspergillosis was 72.1% (77.2% and 14.3% for allogeneic and autologous HSCT recipients, respectively), and the rate for Candida IFI was 50% (57.1% and 43.8% for allogeneic and autologous HSCT recipients, respectively). Conclusions. IFI represents a common complication for allogeneic HSCT recipients. Aspergillus species is the most frequently detected agent in these patients, and aspergillosis is characterized by a high mortality rate. Conversely, autologous HSCT recipients rarely develop aspergillosis, and the attributable mortality rate is markedly lower. Candidemia was observed less often than aspergillosis among both allogeneic and autologous HSCT recipients; furthermore, there was no difference in either the incidence of or the attributable mortality rate for candidemia among recipients of the 2 transplant types.
Superoxide anion (O2
-) plays a key role in the endogenous suppression of endothelium-derived nitric oxide (NO) bioactivity and has been implicated in the development of hypertension. In previous ...studies, we found that O2
-is produced predominantly in the adventitia of isolated rabbit aorta and acts as a barrier to NO. In the present studies, we characterize the enzyme responsible for O2
-production in the adventitia and show that this enzyme is a constitutively active NADPH oxidase with similar composition as the phagocyte NADPH oxidase. Constitutive O2
--generating activity was localized to aortic adventitial fibroblasts and was enhanced by the potent vasoconstrictor angiotensin II. Immunohistochemistry of aortic sections demonstrated the presence of p22phox, gp91phox, p47phox, and p67phoxlocalized exclusively in rabbit aortic adventitia, coincident with the site of staining for O2
-production. Furthermore, immunodepletion of p67phoxfrom adventitial fibroblast particulates resulted in the loss of NADPH oxidase activity, which could be restored by the addition of recombinant p67phox. Further study into the regulation of this adventitial source of O2
-is important in elucidating the mechanisms regulating the bioactivity of NO and may contribute to our understanding of the pathogenesis of hypertension.
We tested the hypothesis that p47phox associates with the actin cytoskeleton, enabling site-directed activation of NAD(P)H oxidase, and assessed whether these actions influence reactive oxygen ...species (ROS) generation and signaling by angiotensin II (Ang II) in vascular smooth muscle cells (VSMCs) from human resistance and coronary arteries.
Electroporation of anti-p47phox antibody into VSMCs abrogated Ang II-mediated O2 generation, establishing the requirement for p47phox in this response. Immunfluorescence confocal microscopy demonstrated a cytosolic distribution of p47phox in basal conditions. After Ang II stimulation, p47phox rearranged in a linear fashion, colocalizing with F-actin. Co-immunoprecipitation studies confirmed an association between p47phox and actin and demonstrated an interaction with the actin-binding protein cortactin. Cytoskeletal disruption with cytochalasin prevented p47phox:actin interaction and attenuated ROS formation and p38MAP kinase and Akt phosphorylation by Ang II. Intracellular ROS generation in response to LY83583 (O2 generator) or exogenous H2O2 and Ang II-induced ERK1/2 activation were unaltered by cytochalasin.
The p47phox:actin interaction, through cortactin, plays an important role in Ang II-mediated site-directed assembly of functionally active NAD(P)H oxidase, ROS generation, and activation of redox-sensitive p38MAP kinase and Akt, but not ERK1/2. These findings demonstrate the importance of an intact actin-cytoskeleton in NAD(P)H oxidase regulation and redox signaling by Ang II in human VSMCs.
Tri-axial accelerometers have been used to remotely identify the behaviors of a wide range of taxa. Assigning behaviors to accelerometer data often involves the use of captive animals or surrogate ...species, as their accelerometer signatures are generally assumed to be similar to those of their wild counterparts. However, this has rarely been tested. Validated accelerometer data are needed for polar bears Ursus maritimus to understand how habitat conditions may influence behavior and energy demands. We used accelerometer and water conductivity data to remotely distinguish 10 polar bear behaviors. We calibrated accelerometer and conductivity data collected from collars with behaviors observed from video-recorded captive polar bears and brown bears U. arctos, and with video from camera collars deployed on free-ranging polar bears on sea ice and on land. We used random forest models to predict behaviors and found strong ability to discriminate the most common wild polar bear behaviors using a combination of accelerometer and conductivity sensor data from captive or wild polar bears. In contrast, models using data from captive brown bears failed to reliably distinguish most active behaviors in wild polar bears. Our ability to discriminate behavior was greatest when species- and habitat-specific data from wild individuals were used to train models. Data from captive individuals may be suitable for calibrating accelerometers, but may provide reduced ability to discriminate some behaviors. The accelerometer calibrations developed here provide a method to quantify polar bear behaviors to evaluate the impacts of declines in Arctic sea ice.
Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous ...hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, antimetabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment.
The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting ...fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.
Human activity has increased the concentration of the earth's atmospheric carbon dioxide, which plays a direct role in contributing to global warming. Mid‐tropospheric CO2 retrieved by the ...Atmospheric Infrared Sounder shows a substantial spatiotemporal variability that is supported by in situ aircraft measurements. The distribution of middle tropospheric CO2 is strongly influenced by surface sources and large‐scale circulations such as the mid‐latitude jet streams and by synoptic weather systems, most notably in the summer hemisphere. In addition, the effects of stratosphere‐troposphere exchange are observed during a final stratospheric warming event. The results provide the means to understand the sources and sinks and the lifting of CO2 from surface layers into the free troposphere and its subsequent transport around the globe. These processes are not adequately represented in three chemistry‐transport models that have been used to study carbon budgets.
We set out to determine if the administration of subcutaneous (SQ) ALT-803 was non-inferior to standard intravesical BCG treatment in a carcinogen induced mouse (C57BL/6J) bladder cancer model.
Using ...this well-established carcinogen induced mouse model, we studied the effects of various dosing schemas of ALT-803 (SQ alone, SQ with intravesical BCG, intravesical alone, intravesical with intravesical BCG) compared to intravesical BCG alone (positive control) and PBS (negative control). The non-inferiority margin for the difference in bladder weight, as a surrogate for tumor mass, was defined as 7%.
All treatment groups (i.e., ALT-803 SQ alone, ALT-803 SQ with intravesical BCG, ALT-803 intravesical alone, ALT-803 intravesical with intravesical BCG and intravesical BCG alone) demonstrated a significant reduction in tumor burden as evident by bladder weights and H&E stain (p < 0.005). Non-inferiority tests between the intravesical BCG alone group and the additional treatment groups showed that SQ ALT-803 alone (p = 0.04) and BCG plus SQ ALT-803 (p = 0.009) were non-inferior to intravesical BCG alone. In this model, we did not see an appreciable infiltration of CD4
T, CD8
T or CD161/KLRB1
natural killer (NK) cells in the bladder/tumor. When assessing peripheral blood mononuclear cells, SQ ALT-803 alone resulted in a robust induction of CD8
T cells (p < 0.01), NKG2D
NK cells (p < 0.005) and CD3
/NKG2D
NKT cells (p < 0.005) compared to other groups, while in splenic tissue, SQ ALT-803 alone resulted in a robust induction of CD3
/NKG2D
NKT cells (p < 0.005) compared to other groups.
Subcutaneous ALT-803 treatment alone or in combination with intravesical BCG was well tolerated and was not inferior to intravesical BCG alone. CD8
T, NKG2D
NK and CD3
/NKG2D
NKT cell induction along with induction of key cytokines remain steadfast mechanisms behind ALT-803. The enhanced therapeutic index seen with BCG and ALT-803, administered SQ or intravesically, provides a powerful justification for the further development of these regimens.
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