Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting ...the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.
The objectives of the study is to investigate the global socioeconomic risk factors associated with diabetes prevalence using evidence from available country-level data. A cross-sectional study based ...on (2010 & 2019) countrywide Health Nutrition and Population Statistics data. People ages 20-79 who have diabetes. One hundred and thirty-two countries or territories in the world. In 2010, a 1% increase in per capita income and total tobacco consumption is associated with a 0.92% (95% CI 0.64% to 1.19%) and 0.02% (95% CI 0.006% to 0.047%) increase in diabetes prevalence respectively; and a 1% increase in alcohol consumption is associated with a -0.85% (95% CI -1.17% to -0.53%) decrease in diabetes prevalence. Statistically significant socioeconomic and lifestyle indices positively associated with diabetes prevalence included gross national income; overweight prevalence (BMI>25 kg/m.sup.2 ); and tobacco consumption. Statistically significant inverse associations with global diabetes prevalence included total population size; unemployment and alcohol consumption. The 2019 data was removed due to sparsity of data. Statistically significant global lifestyle and socioeconomic determinants of diabetes prevalence include alcohol consumption; tobacco consumption; overweight prevalence; per capita income; total population and unemployment rates. Determinants of diabetes include modifiable risk factors which are consistent at both the micro and macro level and include tobacco consumption and overweight prevalence. Factors which are non-modifiable and warrant further investigation include total population and unemployment rates, which were inversely associated with diabetes prevalence and are a product of other underlying factors. Other determinants such as alcohol consumption was also inversely associated with diabetes prevalence, but has been observed to have both negative and positive associations with diabetes at the micro-level. These associations were dependent upon the amount of alcohol consumed. Global cut-off point of alcohol consumption is critical to establish global policies to reduce diabetes prevalence. Overall, the use of cross-sectional based study for country level aggregate data is a critical tool that should be considered when making global joint strategies or policies against diabetes in both data analysis and decision making.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article summarizes a life-span neurodevelopmental MRI database. The study of neurostructural development or neurofunctional development has been hampered by the lack of age-appropriate MRI ...reference volumes. This causes misspecification of segmented data, irregular registrations, and the absence of appropriate stereotaxic volumes. We have created the “Neurodevelopmental MRI Database” that provides age-specific reference data from 2weeks through 89years of age. The data are presented in fine-grained ages (e.g., 3months intervals through 1year; 6months intervals through 19.5years; 5year intervals from 20 through 89years). The base component of the database at each age is an age-specific average MRI template. The average MRI templates are accompanied by segmented partial volume estimates for segmenting priors, and a common stereotaxic atlas for infant, pediatric, and adult participants. The database is available online (http://jerlab.psych.sc.edu/NeurodevelopmentalMRIDatabase/).
•We provide a database of age-appropriate average MRI templates.•Reference templates are necessary for structural MRI and functional MRI studies.•It is necessary to match the age of the participant and template.•The database has average MRI templates, segmented priors, and stereotaxic atlases.
Diffuse optical tomography uses near-infrared light spectroscopy to measure changes in cerebral hemoglobin concentration. Anatomical interpretations of the location that generates the hemodynamic ...signal requires accurate descriptions of diffuse optical tomography sensitivity to the underlying cortical structures. Such information is limited for pediatric populations because they undergo rapid head and brain development. The present study used photon propagation simulation methods to examine diffuse optical tomography sensitivity profiles in realistic head models among infants ranging from 2 weeks to 24 months with narrow age bins, children (4 and 12 years) and adults (20 to 24 years). The sensitivity profiles changed systematically with the source-detector separation distance. The peak of the sensitivity function in the head was largest at the smallest separation distance and decreased as separation distance increased. The fluence value dissipated more quickly with sampling depth at the shorter source-detector separations than the longer separation distances. There were age-related differences in the shape and variance of sensitivity profiles across a wide range of source-detector separation distances. Our findings have important implications in the design of sensor placement and diffuse optical tomography image reconstruction in (functional) near-infrared light spectroscopy research. Age-appropriate realistic head models should be used to provide anatomical guidance for standalone near-infrared light spectroscopy data in infants.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The N170 ERP component has been widely identified as a face‐sensitive neural marker. Despite extensive investigations conducted to examine the neural sources of N170, there are two issues in prior ...literature: (a) few studies used individualized anatomy as head model for the cortical source analysis of the N170, and (b) the relationship between the N170 and face‐selective regions from fMRI studies is unclear. Here, we addressed these questions by presenting pictures of faces and houses to the same group of healthy adults and recording structural MRI, fMRI, and high‐density ERPs in separate sessions. Source analysis based on the participant's anatomy showed that the middle and posterior fusiform gyri were the primary neural sources for the face‐sensitive aspects of the N170. Source analysis based on regions of interest from the fMRI revealed that the fMRI‐defined fusiform face area was the major contributor to the N170. The current study suggests that the fusiform gyrus is a major neural contributor to the N170 ERP component and provides further insights about the spatiotemporal characteristics of face processing.
The N170 is a face‐sensitive ERP component. We recorded structural MRI, fMRI, and high‐density ERPs to presentations of pictures of faces and houses. We used individualized head models to localize the source of the N170 and explored the relationship between the N170 and face‐selective regions from participants’ fMRI data. The middle and posterior fusiform gyri as well as the fMRI‐defined fusiform face area were the neural sources of the N170 for faces. The current study confirms the cortical source of the N170 ERP component and suggests the timing sequence of the fusiform face area found in fMRI studies.
Top-down modulation in the infant brain Emberson, Lauren L.; Richards, John E.; Aslin, Richard N.
Proceedings of the National Academy of Sciences - PNAS,
08/2015, Letnik:
112, Številka:
31
Journal Article
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Recent theoretical work emphasizes the role of expectation in neural processing, shifting the focus from feed-forward cortical hierarchies to models that include extensive feedback (e.g., predictive ...coding). Empirical support for expectation-related feedback is compelling but restricted to adult humans and nonhuman animals. Given the considerable differences in neural organization, connectivity, and efficiency between infant and adult brains, it is a crucial yet open question whether expectation-related feedback is an inherent property of the cortex (i.e., operational early in development) or whether expectation-related feedback develops with extensive experience and neural maturation. To determine whether infants’ expectations about future sensory input modulate their sensory cortices without the confounds of stimulus novelty or repetition suppression, we used a cross-modal (audiovisual) omission paradigm and used functional near-infrared spectroscopy (fNIRS) to record hemodynamic responses in the infant cortex. We show that the occipital cortex of 6-month-old infants exhibits the signature of expectation-based feedback. Crucially, we found that this region does not respond to auditory stimuli if they are not predictive of a visual event. Overall, these findings suggest that the young infant’s brain is already capable of some rudimentary form of expectation-based feedback.
White matter (WM) changes occur throughout the lifespan at a different rate for each developmental period. We aggregated 10879 structural MRIs and 6186 diffusion-weighted MRIs from participants ...between 2 weeks to 100 years of age. Age-related changes in gray matter and WM partial volumes and microstructural WM properties, both brain-wide and on 29 reconstructed tracts, were investigated as a function of biological sex and hemisphere, when appropriate. We investigated the curve fit that would best explain age-related differences by fitting linear, cubic, quadratic, and exponential models to macro and microstructural WM properties. Following the first steep increase in WM volume during infancy and childhood, the rate of development slows down in adulthood and decreases with aging. Similarly, microstructural properties of WM, particularly fractional anisotropy (FA) and mean diffusivity (MD), follow independent rates of change across the lifespan. The overall increase in FA and decrease in MD are modulated by demographic factors, such as the participant's age, and show different hemispheric asymmetries in some association tracts reconstructed via probabilistic tractography. All changes in WM macro and microstructure seem to follow nonlinear trajectories, which also differ based on the considered metric. Exponential changes occurred for the WM volume and FA and MD values in the first five years of life. Collectively, these results provide novel insight into how changes in different metrics of WM occur when a lifespan approach is considered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNA-155 (miR-155) is frequently upregulated in various types of human cancer; however, its role in cancer angiogenesis remains unknown. Here, we demonstrate the role of miR-155 in angiogenesis ...through targeting von Hippel-Lindau (VHL) tumour suppressor in breast cancer. Ectopic expression of miR-155 induced whereas knockdown of miR-155 inhibited human umbilical vein endothelial cell network formation, proliferation, invasion and migration. Furthermore, mammary fat pad xenotransplantation of ectopically expressed miR-155 resulted in extensive angiogenesis, proliferation, tumour necrosis and recruitment of pro-inflammatory cells such as tumour-associated macrophages. Expression of VHL abrogated these miR-155 effects. Moreover, miR-155 expression inversely correlates with VHL expression level and is associated with late-stage, lymph node metastasis and poor prognosis, as well as triple-negative tumour in breast cancer. These findings indicate that miR-155 has a pivotal role in tumour angiogenesis by downregulation of VHL, and provide a basis for miR-155-expressing tumours to embody an aggressive malignant phenotype, and therefore miR-155 is an important therapeutic target in breast cancer.
Background Data used for evaluating quality of medical care need to be of high reliability to ensure valid quality assessment and benchmarking. The American College of Surgeons National Surgical ...Quality Improvement Program (ACS NSQIP) has continually emphasized the collection of highly reliable clinical data through its program infrastructure. Study Design We provide a detailed description of the various mechanisms used in ACS NSQIP to assure collection of high quality data, including training of data collectors (surgical clinical reviewers) and ongoing audits of data reliability. For the 2005 through 2008 calendar years, inter-rater reliability was calculated overall and for individual variables using percentages of agreement between the data collector and the auditor. Variables with > 5% disagreement are flagged for educational efforts to improve accurate collection. Cohen's kappa was estimated for selected variables from the 2007 audit year. Results Inter-rater reliability audits show that overall disagreement rates on variables have fallen from 3.15% in 2005 (the first year of public enrollment in ACS NSQIP) to 1.56% in 2008. In addition, disagreement levels for individual variables have continually improved, with 26 individual variables demonstrating > 5% disagreement in 2005, to only 2 such variables in 2008. Estimated kappa values suggest substantial or almost perfect agreement for most variables. Conclusions The ACS NSQIP has implemented training and audit procedures for its hospital participants that are highly effective in collecting robust data. Audit results show that data have been reliable since the program's inception and that reliability has improved every year.
Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source ...of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM
Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM
Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.
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