Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment ...remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Morbidity and mortality from tuberculosis (TB) are high in Taiwan. We conducted a nationwide population‐based matched cohort study using data retrieved from the Taiwan's National Health Insurance ...Research Database to determine the impact of TB after liver transplantation (LT). During 2000–2011, we identified 3202 liver transplant recipients and selected subjects from the general population matched for age, sex, and comorbidities on the same index date of recognition of LT with a 1:10 ratio. The data were analyzed using Cox proportional hazards models. Compared to the matched cohort, liver transplant patients had a higher risk for TB (adjusted HR 2.25, 95% CI 1.65–3.05, p < 0.001), and those with TB showed higher mortality (HR 2.27, 95% CI 1.30–3.97, p = 0.004). Old age (HR 2.64, 95% CI 1.25–5.54, p = 0.011) and mammalian target of rapamycin inhibitors (mTORis) (HR 3.09, 95% CI 1.68–5.69, p < 0.001) were significant risk factors for TB in LT; mTORis were also associated with mortality after adjusting for confounders (HR 2.13, 95% CI 1.73–2.62, p < 0.001). Therefore, regular surveillance of TB and treatment of latent TB infection in high‐risk patients after LT are important, especially in TB‐endemic areas.
The authors demonstrate the high risk of tuberculosis in liver transplant recipients and define old age and mammalian target of rapamycin inhibitors as risk factors for tuberculosis after liver transplantation, which provides a practical guide to selecting high‐risk liver transplant patients for regular surveillance and treatment of tuberculosis.
Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI; OMIM #130900) is a genetic disorder exhibiting severe hardness defects and reduced fracture toughness of dental enamel. While the ...condition is nonsyndromic, it can be associated with other craniofacial anomalies, such as malocclusions and delayed or failed tooth eruption. Truncation mutations in FAM83H (OMIM *611927) are hitherto the sole cause of ADHCAI. With human genetic studies, Fam83h knockout and mutation–knock-in mouse models indicated that FAM83H does not serve a critical physiologic function during enamel formation and suggested a neomorphic mutation mechanism causing ADHCAI. The function of FAM83H remains obscure. FAM83H has been shown to interact with various isoforms of casein kinase 1 (CK1) and keratins and to mediate organization of keratin cytoskeletons and desmosomes. By considering FAM83H a scaffold protein to anchor CK1s, further molecular characterization of the protein could gain insight into its functions. In this study, we characterized 9 kindreds with ADHCAI and identified 3 novel FAM83H truncation mutations: p.His437*, p.Gln459*, and p.Glu610*. Some affected individuals exhibited hypoplastic phenotypes, in addition to the characteristic hypocalcification enamel defects, which have never been well documented. Failed eruption of canines or second molars in affected persons was observed in 4 of the families. The p.Glu610* mutation was located in a gap area (amino acids 470 to 625) within the zone of previously reported pathogenic variants (amino acids 287 to 694). In vitro pull-down studies with overexpressed FAM83H proteins in HEK293 cells demonstrated an interaction between FAM83H and SEC16A, a protein component of the COP II complex at endoplasmic reticulum exit sites. The interaction was mediated by the middle part (amino acids 287 to 657) of mouse FAM83H protein. Results of this study significantly extended the phenotypic and genotypic spectrums of FAM83H-associated ADHCAI and suggested a role for FAM83H in endoplasmic reticulum–to–Golgi vesicle trafficking and protein secretion (dbGaP phs001491.v1.p1).
Magnetopause transients, observing as brief entries into the magnetosheath by satellites, are commonly observed in the vicinity of the magnetopause and have been explained by several possible ...mechanisms. However, satellite observations alone are insufficient to determine the dynamics and context of transients. Throat auroras are characterized as north‐south aligned discrete auroral forms extending from the equatorward edge of the discrete auroral oval that are only observed near dayside convection throat region and have been suggested as the ionospheric signature of localized magnetopause indentations. Using coordinated observations from the Magnetospheric Multiscale Mission (MMS) and ground‐based all‐sky imagers, we show apparent one‐to‐one correspondences between transients observed by MMS near the subsolar magnetopause and throat auroras observed on the ground. The correspondence is valid not only for typical throat aurora with larger spatial scale but also for these with tiny scales. We even notice that the transient durations observed by satellite are approximately proportional to the width (east‐west extension) of the throat aurora. These results provide direct evidence that throat auroras are ground signatures for the magnetopause transients. With the aid of auroral observations, we suggest that these transients reflect localized magnetopause indentations but are not produced by motion of the entire magnetopause. We also found that most transients observed here are associated with earthward flow enhancements, which indicates that high‐speed jets in the magnetosheath could be a driver for producing these transients.
Plain Language Summary
We present observational evidence that some of the magnetopause transient observed near subsolar point by satellite reflect magnetopause indentations and can be well displayed by auroral observation on the ground.
Key Points
One‐to‐one correspondences between magnetopause transients observed by MMS and throat auroras observed on the ground are identified
Auroral observation indicates that the transients reflect localized indentations, but not back‐and‐forth motions, of the magnetopause
The transients observed here are associated with earthward flow enhancements
Structured diffuse auroras are often observed near magnetic local noon (MLN), but their generation mechanisms are poorly understood. We have found that two types of structured diffuse auroras with ...obviously different dynamical properties often coexist near MLN. One type usually drifts from low to high latitude with higher speed and shows pulsation. The other type is always adjacent to the discrete aurora oval and drifts together with nearby discrete aurora with much lower speed. Using coordinated observations from MMS and ground all‐sky imagers, we found that the two types of diffuse auroras are well correlated with number density increase of O+ (from the ionosphere) and of He2+ (from magnetosheath) ions, respectively. These observations indicate that mangetosheath particles penetrated into the magnetosphere also can play an important role for producing the dayside diffuse aurora. In addition, for the first time, electron cyclotron harmonic waves are observed associated with dayside diffuse aurora.
Key Points
Two types of structured diffuse auroras observed near magnetic local noon with obviously different dynamical properties are identified
Types 1 and 2 are associated with number density increase of O+ from the magnetosphere and of He2+ from the magnetosheath, respectively
For the first time, ECH waves, but no whistler mode chorus waves, were observed associated with dayside diffuse auroras
Regulation of Dental Enamel Shape and Hardness Simmer, J.P.; Papagerakis, P.; Smith, C.E. ...
Journal of Dental Research,
10/2010, Letnik:
89, Številka:
10
Book Review, Journal Article
Recenzirano
Odprti dostop
Epithelial-mesenchymal interactions guide tooth development through its early stages and establish the morphology of the dentin surface upon which enamel will be deposited. Starting with the onset of ...amelogenesis beneath the future cusp tips, the shape of the enamel layer covering the crown is determined by five growth parameters: the (1) appositional growth rate, (2) duration of appositional growth (at the cusp tip), (3) ameloblast extension rate, (4) duration of ameloblast extension, and (5) spreading rate of appositional termination. Appositional growth occurs at a mineralization front along the ameloblast distal membrane in which amorphous calcium phosphate (ACP) ribbons form and lengthen. The ACP ribbons convert into hydroxyapatite crystallites as the ribbons elongate. Appositional growth involves a secretory cycle that is reflected in a series of incremental lines. A potentially important function of enamel proteins is to ensure alignment of successive mineral increments on the tips of enamel ribbons deposited in the previous cycle, causing the crystallites to lengthen with each cycle. Enamel hardens in a maturation process that involves mineral deposition onto the sides of existing crystallites until they interlock with adjacent crystallites. Neutralization of acidity generated by hydroxyapatite formation is a key part of the mechanism. Here we review the growth parameters that determine the shape of the enamel crown as well as the mechanisms of enamel appositional growth and maturation.
Solid tumors often exhibit simultaneously inflammatory and hypoxic microenvironments. The 'signal transducer and activator of transcription-3' (STAT3)-mediated inflammatory response and the ...hypoxia-inducible factor (HIF)-mediated hypoxia response have been independently shown to promote tumorigenesis through the activation of HIF or STAT3 target genes and to be indicative of a poor prognosis in a variety of tumors. We report here for the first time that STAT3 is involved in the HIF1, but not HIF2-mediated hypoxic transcriptional response. We show that inhibiting STAT3 activity in MDA-MB-231 and RCC4 cells by a STAT3 inhibitor or STAT3 small interfering RNA significantly reduces the levels of HIF1, but not HIF2 target genes in spite of normal levels of hypoxia-inducible transcription factor 1α (HIF1α) and HIF2α protein. Mechanistically, STAT3 activates HIF1 target genes by binding to HIF1 target gene promoters, interacting with HIF1α protein and recruiting coactivators CREB binding protein (CBP) and p300, and RNA polymerase II (Pol II) to form enhanceosome complexes that contain HIF1α, STAT3, CBP, p300 and RNA Pol II on HIF1 target gene promoters. Functionally, the effect of STAT3 knockdown on proliferation, motility and clonogenic survival of tumor cells in vitro is phenocopied by HIF1α knockdown in hypoxic cells, whereas STAT3 knockdown in normoxic cells also reduces cell proliferation, motility and clonogenic survival. This indicates that STAT3 works with HIF1 to activate HIF1 target genes and to drive HIF1-depedent tumorigenesis under hypoxic conditions, but also has HIF-independent activity in normoxic and hypoxic cells. Identifying the role of STAT3 in the hypoxia response provides further data supporting the effectiveness of STAT3 inhibitors in solid tumor treatment owing to their usefulness in inhibiting both the STAT3 and HIF1 pro-tumorigenic signaling pathways in some cancer types.
We report a measurement of electron antineutrino oscillation from the Daya Bay Reactor Neutrino Experiment with nearly 4 million reactor νover ¯_{e} inverse β decay candidates observed over 1958 days ...of data collection. The installation of a flash analog-to-digital converter readout system and a special calibration campaign using different source enclosures reduce uncertainties in the absolute energy calibration to less than 0.5% for visible energies larger than 2 MeV. The uncertainty in the cosmogenic ^{9}Li and ^{8}He background is reduced from 45% to 30% in the near detectors. A detailed investigation of the spent nuclear fuel history improves its uncertainty from 100% to 30%. Analysis of the relative νover ¯_{e} rates and energy spectra among detectors yields sin^{2}2θ_{13}=0.0856±0.0029 and Δm_{32}^{2}=(2.471_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the normal hierarchy, and Δm_{32}^{2}=-(2.575_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the inverted hierarchy.
We present measurements as part of the Southern Oxidant and Aerosol Study (SOAS) during which atmospheric aerosol particles were comprehensively characterized. We present results utilizing a Filter ...Inlet for Gases and AEROsol coupled to a chemical ionization mass spectrometer (CIMS). We focus on the volatility and composition of isoprene derived organic aerosol tracers and of the bulk organic aerosol. By utilizing the online volatility and molecular composition information provided by the FIGAERO–CIMS, we show that the vast majority of commonly reported molecular tracers of isoprene epoxydiol (IEPOX) derived secondary organic aerosol (SOA) is derived from thermal decomposition of accretion products or other low volatility organics having effective saturation vapor concentrations <10–3 μg m–3. In addition, while accounting for up to 30% of total submicrometer organic aerosol mass, the IEPOX-derived SOA has a higher volatility than the remaining bulk. That IEPOX-SOA, and more generally bulk organic aerosol in the Southeastern U.S. is comprised of effectively nonvolatile material has important implications for modeling SOA derived from isoprene, and for mechanistic interpretations of molecular tracer measurements. Our results show that partitioning theory performs well for 2-methyltetrols, once accretion product decomposition is taken into account. No significant partitioning delays due to aerosol phase or viscosity are observed, and no partitioning to particle-phase water or other unexplained mechanisms are needed to explain our results.
Summary
Background
The risk factors for gastrointestinal bleeding (GIB) in clopidogrel users have not been identified.
Aim
To clarify whether clopidogrel use is a risk factor for upper GIB (UGIB) and ...lower GIB (LGIB) and identify the risk factors in clopidogrel users.
Methods
Using the National Health Insurance Research Database of Taiwan, 3238 clopidogrel users and 12 952 age‐, sex‐, and enrolment time‐matched controls in a 1:4 ratio were extracted for comparison from a cohort dataset of 1 000 000 randomly sampled subjects. Cox proportional hazard regression models were used to identify the independent risk factors for UGIB and LGIB in all enrollees and clopidogrel users after adjustments for age, gender, comorbidity i.e., coronary artery disease, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease (CKD), cirrhosis, uncomplicated peptic ulcer disease, and peptic ulcer bleeding (PUB), and medications e.g., nonsteroidal anti‐inflammatory drugs (NSAIDs), cyclooxygenase‐2 inhibitors, aspirin, steroids, selective serotonin reuptake inhibitors (SSRIs), warfarin and alendronate.
Results
Cox proportional hazard regression analysis showed that use of clopidogrel increased the risk of UGIB hazard ratio (HR): 3.66; 95% confidence interval (CI): 2.96–4.51 and LGIB HR: 3.52, 95% CI: 2.74–4.52. Age, CKD, PUB history, use of aspirin and NSAIDs were independent risk factors for UGIB in the clopidogrel users. Age, CKD, PUB history, use of aspirin and SSRIs were independent risk factors for LGIB.
Conclusions
In clopidogrel users, age, CKD, PUB history, use of aspirin and NSAIDs are independent risk factors for UGIB; age, CKD, PUB history, use of aspirin and SSRIs are independent risk factors for LGIB.
PDF
