Summary
Background
Actinic keratoses (AKs) are generally accepted as common precursor lesions to invasive squamous cell carcinoma. Photodynamic therapy (PDT) is a common, in‐office, field therapy ...modality used in the treatment of AKs. Clinical and laboratory observations have demonstrated that temperature modulation can affect PDT efficacy.
Objectives
To demonstrate thermal PDT increases apoptotic cell death, and to investigate the mechanistic role of reactive oxygen species (ROS) free radicals in an in vitro human skin fibroblast model.
Methods
This study was completed using commercially available primary human skin fibroblasts treated with aminolaevulinic acid (ALA) at specific concentrations and controlled temperatures. Cell death, apoptosis and superoxide ROS levels were quantified.
Results
We found that thermal PDT with 0·5 mmol L−1 ALA resulted in significant temperature‐dependent increases in total apoptosis and superoxide ROS generation between 33 °C and 42 °C.
Conclusions
Our results indicate that thermal PDT significantly increases apoptotic cell death through increased generation of superoxide ROS in a temperature‐dependent manner.
What's already known about this topic?
Actinic keratoses (AKs) are generally accepted as common precursor lesions to invasive squamous cell carcinoma.
Photodynamic therapy (PDT) is a common field therapy modality used in the treatment of AKs.
Clinical and laboratory observations have demonstrated that thermal modulation can affect PDT efficacy.
The underlying mechanism and cellular effects of thermal PDT are not well characterized from a temporal and biochemical perspective.
What does this study add?
Our findings demonstrate that thermal PDT increases, in a temperature‐dependent manner, superoxide reactive oxygen species generation and percentage of apoptosis‐positive cells.
Temperature‐modulated PDT may represent an enhanced and cost‐effective modality to improve patient compliance and outcomes.
Further in vitro, animal and clinical studies are needed to optimize treatment parameters.
What is the translational message?
We demonstrate that thermal PDT increases superoxide reactive oxygen species generation and percentage of apoptosis‐positive cells in a temperature‐dependent manner.
Temperature‐modulated PDT may represent an enhanced and cost‐effective modality to improve patient compliance and outcomes.
Clinical studies are needed to optimize dosing, incubation period and clinical outcomes.
We hypothesize that our findings will translate to improved patient outcomes and reductions in the burden of disease for AKs.
Linked Comment: Farrar. Br J Dermatol 2016; 175:458–459.
Summary
Background The RASopathies are a class of human genetic syndromes caused by germline mutations in genes that encode protein components of the Ras/mitogen‐activated protein kinase (MAPK) ...pathway. Costello syndrome (CS) is a RASopathy caused by mutations in the HRAS gene, a key regulator of signal transduction.
Objective To quantify the specific cutaneous phenotype observed in 46 individuals with Costello syndrome with confirmed HRAS mutations.
Methods This was a cross‐sectional study. Dermatological surveys were designed by the authors and were completed by parents of mutation‐positive individuals with CS at the Costello Syndrome Family Network (CSFN) conferences in 2007 and 2009. Dermatological examinations were performed by the authors at the CSFN conferences.
Results Cutaneous papillomas were reported in 33 of the 46 (72%) participants, with age of onset ranging from infancy to 22 years. Individuals with CS are more likely than patients with cardiofaciocutaneous syndrome (CFC) to present with cutaneous papillomas (72% vs. 5%, P < 0·001) and palmoplantar keratoderma (76% vs. 36%, P < 0·001). Individuals with CS are less likely than individuals with CFC to present with sparse or absent eyebrows (9% vs. 90%, P < 0·001) or keratosis pilaris (33% vs. 80%, P = 0·001). This study also identified that loose, redundant skin on the hands and feet, ‘stippled’ dermatoglyphs (pachydermatoglyphia) on the fingertips (eight of 26, 31%) and acanthosis nigricans (17 of 46, 37%) are frequent features of CS.
Conclusions While there is significant phenotypic overlap among syndromes of the Ras/MAPK pathway, individuals with CS are more likely than individuals with CFC syndrome to present with cutaneous papillomas, palmoplantar keratoderma and full eyebrows, and are less likely to present with ulerythema ophryogenes, keratosis pilaris or multiple naevi. The dermatological features of CS, a Ras dysregulation syndrome, share many features with cutaneous paraneoplastic syndromes. This may provide further insight into the role of Ras signalling in cutaneous paraneoplastic syndromes.
Ocean biological processes mediate the transport of roughly 10 petagrams of carbon from the surface to the deep ocean each year and thus play an important role in the global carbon cycle. Even so, ...the globally integrated rate of carbon export out of the surface ocean remains highly uncertain. Quantifying the processes underlying this biological carbon export requires a synthesis between model predictions and available observations of particulate organic carbon (POC) flux; yet the scale dissimilarities between models and observations make this synthesis difficult. Here we compare carbon export predictions from a mechanistic model with observations of POC fluxes from several data sets compiled from the literature spanning different space, time, and depth scales as well as using different observational methodologies. We optimize model parameters to provide the best match between model‐predicted and observed POC fluxes, explicitly accounting for sources of error associated with each data set. Model‐predicted globally integrated values of POC flux at the base of the euphotic layer range from 3.8 to 5.5 Pg C/year, depending on the data set used to optimize the model. Modeled carbon export pathways also vary depending on the data set used to optimize the model, as well as the satellite net primary production data product used to drive the model. These findings highlight the importance of collecting field data that average over the substantial natural temporal and spatial variability in carbon export fluxes, and advancing satellite algorithms for ocean net primary production, in order to improve predictions of biological carbon export.
Key Points
Individual export flux observations do not represent climatological conditions and should not be used to optimize global export models
The choice of net primary production (NPP) model used introduces sources of extrinsic variability that affect optimized parameter values by up to a factor of 2
Model performance is greatly improved by choosing a suitably averaged data set to calibrate it
Therapeutic options for patients with multiple myeloma whose disease has relapsed after a prior auto-SCT include novel biologic therapies, traditional chemotherapy or a second transplant, with no ...clear standard of care. Few published studies address the safety and efficacy of a second auto-SCT for relapsed disease. We reviewed the Abramson Cancer Center experience with salvage auto-SCT for relapsed multiple myeloma. Forty-one patients had received a salvage auto-SCT at our institution; the median time between transplants was 37 months (range 3-91). The overall response rate in assessable patients was 55%, and treatment-related mortality was 7%. With a median follow-up time of 15 months, the median PFS was 8.5 months and the median overall survival (OS) was 20.7 months. In a multivariate analysis of OS, independent prognostic factors were >or=5 prior lines of therapy and time to progression after initial auto-SCT of <or=12 months. We conclude that in well-selected patients, salvage auto-SCT is safe and effective for relapsed myeloma.
The energy of intermediates in fusion of phospholipid bilayers is sensitive to
κ
¯
m
,
the saddle splay (Gaussian curvature) elastic modulus of the lipid monolayers. The value
κ
¯
m
is also important ...in understanding the stability of inverted cubic (
Q
II) and rhombohedral (
R) phases relative to the lamellar (
L
α
) and inverted hexagonal (
H
II) phases in phospholipids. However,
κ
¯
m
cannot be measured directly. It was previously measured by observing changes in
Q
II phase lattice dimensions as a function of water content. Here we use observations of the phase behavior of N-mono-methylated dioleoylphosphatidylethanolamine (DOPE-Me) to determine
κ
¯
m
.
At the temperature of the
L
α
/
Q
II phase transition,
T
Q, the partial energies of the two phases are equal, and we can express
κ
¯
m
in terms of known lipid monolayer parameters: the spontaneous curvature of DOPE-Me, the monolayer bending modulus
κ
m, and the distance of the monolayer neutral surface from the bilayer midplane,
δ. The calculated ratio
κ
¯
m
/
κ
m
is −0.83
±
0.08 at
T
Q ≈ 55°C. The uncertainty is due primarily to uncertainty in the value of
δ for the
L
α
phase. This value of
κ
¯
m
/
κ
m
is in accord with theoretical expectations, including recent estimates of the value required to rationalize observations of rhombohedral (
R) phase stability in phospholipids. The value
κ
¯
m
substantially affects the free energy of formation of fusion intermediates: more energy (tens of
k
B
T) is required to form stalks and fusion pores (ILAs) than estimated solely on the basis of the bending elastic energy. In particular, ILAs are much higher in energy than previously estimated. This rationalizes the action of fusion-catalyzing proteins in stabilizing nascent fusion pores in biomembranes; a function inferred from recent experiments in viral systems. These results change predictions of earlier work on ILA and
Q
II phase stability and
L
α
/
Q
II phase transition mechanisms. To our knowledge, this is the first determination of the saddle splay (Gaussian) modulus in a lipid system consisting only of phospholipids.
Colored dissolved organic matter (CDOM), also referred to as gelbstoff, gilvin, or yellow matter, has long been known to be an important component of the optical properties of coastal and estuarine ...environments. However, an understanding of the processes regulating its global distribution and variability, its relationship to the total pool of dissolved organic carbon (DOC), and its influence on light availability remain largely unexplored. Satellite imagery from the Sea‐viewing Wide Field‐of‐view Sensor (SeaWiFS) is used to characterize the global distribution of light absorption due to colored detrital and dissolved materials (CDM). The quantity CDM is considered as it is not yet possible to differentiate CDOM and detrital particulate absorption from ocean color spectra on a routine basis. Nonetheless, analysis of an extensive field data set indicates that detrital particulates make only a small contribution to CDM. A comparison of coincident field observations of CDM with SeaWiFS retrievals shows good agreement, indicating that the present procedures perform well. To first order, the basin‐scale CDM distribution reflects patterns of wind‐driven vertical circulation of the gyres modulated by a meridional trend of increasing CDM toward higher latitudes. The global CDM distribution appears regulated by a coupling of biological, photochemical, and physical oceanographic processes all acting on a local scale, and greater than 50% of blue light absorption is controlled by CDM. Significant differences in both CDM concentration and its contribution to blue light absorption are found spatially among the major ocean basins and temporally on variety of timescales. Significant impacts of riverine discharges can be discerned, although their effects are largely localized. Basin‐scale distributions of CDM and DOC are largely unrelated, indicating that CDM is a small and highly variable fraction of the global DOC pool. This first view of the global CDM distribution opens many new doors for the quantification of global marine photoprocesses using satellite ocean color data.
Many marine organisms are sedentary as adults and are redistributed between generations by the oceanic transport of planktonic larvae. In order to assess interactions among oceanographic and ...biological processes that determine larval dispersal patterns, we introduce a Lagrangian (or water-parcel-following) description of larval transport. This formalism is used to determine larval dispersal kernels (larval settlement probability distributions) for a range of ocean flows, planktonic larval durations and settlement pre-competency/competency periods. Paths of individual planktonic larval releases are modeled statistically and, by averaging over many individuals, ensemble estimates of larval dispersal are determined. Typical dispersal scales vary from a few km to >400 km. Modeled dispersal kernels are well explained using only a few readily available biological and oceanographic parameters, and derived dispersal scales agree well with population-genetic estimates, suggesting that the model has reasonable predictive power. An index for regional-scale self-seeding is presented, and is used as a tool to evaluate the efficiency of marine conservation areas. Finally, settlement patterns resulting from larval releases made over short times (days to months) should be comprised of a small number of discrete samples taken from the long-term averaged dispersal kernel. The resulting larval dispersal patterns will be quasi-random in both space and time, which will have important implications for the interpretation of settlement time series and the prediction of recruitment of sessile organisms.
Abstract
Background
Fear of cancer recurrence (FCR) is a top ongoing concern of breast cancer (BC) survivors and thus the focus of recent intervention development. The Self-Regulation Model of FCR ...(Lee-Jones C, Humphris G, Dixon R, Hatcher MB. Fear of cancer recurrence–a literature review and proposed cognitive formulation to explain exacerbation of recurrence fears. Psychooncology. 1997;6:95–105.) states that everyday cancer-related events trigger FCR, which, in turn, leads to specific behavioral responses, including checking the body for signs or symptoms of cancer. Links between triggering events, FCR, and checking behavior have not yet been studied in the context of daily life or at the within-person level.
Purpose
The goal of this study was to examine whether FCR has a within-person link with daily checking behavior and whether FCR mediates the link between triggering events and checking behavior.
Methods
Seventy-two early-stage BC survivors completed daily diaries over a 21-day period approximately 5 months after BC surgery. FCR, checking behavior, and triggering events were assessed each evening.
Results
Multilevel modeling results indicated that FCR predicted greater odds of same-day, but not next-day, checking behavior. We found that daily FCR significantly mediated the same-day effect of triggering events on checking behavior. These average within-person effects varied substantially between patients and were not explained by momentary negative affect.
Conclusions
Findings support the within-person relationship between triggering events, FCR, and checking behavior posited by guiding theory, and can inform FCR intervention development.
On days that breast cancer patients reported more triggering events, they experienced more fear of cancer recurrence, which, in turn, was associated with greater odds of checking the body for signs or symptoms of cancer that same day.
Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the ...accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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