Upregulation of TLR5 indicates a favorable prognosis in prostate cancer.

BACKGROUND: Toll-like receptors (TLRs) are the key sensors of innate immunity for triggering immune responses against infections. TLRs are well known to be expressed and activated in innate immune cells, such as macrophage and dendritic cells, but we and others have found that some TLRs are also functional in epithelial cells. However, the role of an epithelial TLR in prostate cancer remains elusive. METHODS: TLR5 expression in messenger RNA and protein level in prostate cancer was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The activation of TLR5 signaling in epithelial cells was detected upon nuclear factor-κB activation by luciferase assay and western blot analysis, and proinflammatory cytokine activation by RT-qPCR. Distinguishing between the TLR5 and NLRC4 pathways, both recognizing flagellin, is determined by small interfering RNA and proinflammatory cytokine activation. The role of TLR5 in prostate cancer was analyzed by IHC and bioinformatics using a general and single-cell database. RESULTS: In the present study, we show that TLR5, among other TLRs, is exceedingly expressed in human prostate cancer cells. This cancer epithelial cell TLR5 functions to activate the TLR5 signaling pathway in human prostate cancer cells, as it does with innate immune cell TLR5. The bacterial protein flagellin induces a robust immune response in prostate cancer cells in a TLR5-dependent but NLRC4-independent manner. TLR5 is highly expressed in prostate cancer patient specimens, and high TLR5 expression in prostate cancer patients indicates a favorable prognosis. CONCLUSIONS: TLR5, as an innate immunity receptor, is a functional TLR in human prostate cancer epithelial cells. TLR5 plays an important role in prostate cancer development and is a new potential prognosis biomarker. TLR5 may represent a novel immunotherapy target against prostate cancer.

The uncertainty of copy number variants: pregnancy decisions and clinical follow-up.

BACKGROUND: Next-generation sequencing for copy number variants is often used as a follow-up investigation of unusual fetal ultrasound results and is capable of detecting copy number variations with a resolution of ∼0.1 Mb. In a prenatal setting, observation and subsequent management of pregnancies with a fetal variant of uncertain significance remains problematic for counseling. OBJECTIVE: This study aimed to follow the decision-making processes in pregnancies with a fetal variant of uncertain significance and prospectively assess copy number variation interpretations and implications under the newer 2020 American College of Medical Genetics and Genomics guidelines. STUDY DESIGN: In a single prenatal unit, prospective chromosome testing using copy number variation sequencing for 8030 fetuses with unexpected noninvasive findings identified 139 pregnancies with a copy number variation classified as a variant of uncertain significance according to the 2015 American College of Medical Genetics and Genomics guidelines current at the time. Parent-of-origin testing was subsequently performed to determine if the copy number variation was inherited or de novo. All couples were offered specialized genetic counseling to assist in pregnancy management decisions. For the continued pregnancies that reached term, newborns were clinically assessed for evidence of any disease at 0 to 10 months and/or at 2 to 4 years of age. RESULTS: Of the 139 variants of uncertain significance found, most (78%) were inherited with no evidence of disease in the carrier parent. On the basis of primary ultrasound findings combined with results from noninvasive prenatal screening tests, most inherited variant of uncertain significance pregnancies were continued, whereas most pregnancies involving de novo variants of uncertain significance were terminated. From clinical follow-up of the 113 live births, only 5 showed any evidence of a phenotype that was not apparently related to the original variant of uncertain significance. Prospective reanalysis of the 139 variants of uncertain significance using recent 2020 American College of Medical Genetics and Genomics guidelines changed the status of 24 variants of uncertain significance, with 15 reclassified as benign and 9 as pathogenic. However, the 5 children born with an inherited variant of uncertain significance reclassified as pathogenic showed no evidence of a disease phenotype on clinical follow-up. CONCLUSION: The severity of fetal ultrasound findings combined with results from parent-of-origin testing were the key drivers in pregnancy management decisions for patients. According to birth outcomes from continued pregnancies, most variants of uncertain significance proved to be apparently benign in nature and potentially of low risk of adverse disease outcome. There was a discordance rate of 17% for variant of uncertain significance scoring between the 2015 and 2020 American College of Medical Genetics and Genomics guidelines for defining a variant of uncertain significance, suggesting that difficulties remain for predicting true pathogenicity. Nonetheless, with increasing knowledge of population copy number variation polymorphisms, and a more complete assessment for alternative genetic causes, patients having prenatal assessments should feel less anxious when a fetal variant of uncertain significance is identified.

Diagnostic performance of angiography-derived fractional flow reserve analysis based on bifurcation fractal law for assessing hemodynamic significance of coronary stenosis.

OBJECTIVES: Blood flow into the side branch affects the calculation of coronary angiography-derived fractional flow reserve (FFR), called Angio-FFR. Neglecting or improperly compensating for the side branch flow may decrease the diagnostic accuracy of Angio-FFR. This study aims to evaluate the diagnostic accuracy of a novel Angio-FFR analysis that considers the side branch flow based on the bifurcation fractal law. METHODS: A one-dimensional reduced-order model based on the vessel segment was used to perform Angio-FFR analysis. The main epicardial coronary artery was divided into several segments according to the bifurcation nodes. Side branch flow was quantified using the bifurcation fractal law to correct the blood flow in each vessel segment. In order to verify the diagnostic performance of our Angio-FFR analysis, two other computational methods were taken as control groups: (i) FFR_s: FFR calculated by delineating the coronary artery tree to consider side branch flow, (ii) FFR_n: FFR calculated by just delineating the main epicardial coronary artery and neglecting the side branch flow. RESULTS: The analysis of 159 vessels from 119 patients showed that our Anio-FFR calculation method had comparable diagnostic accuracy to FFR_s and provided significantly higher diagnostic accuracy than that of FFR_n. In addition, using invasive FFR as a reference, the Pearson correlation coefficients of Angio-FFR and FFRs were 0.92 and 0.91, respectively, while that of FFR_n was only 0.85. CONCLUSIONS: Our Angio-FFR analysis has demonstrated good diagnostic performance in assessing the hemodynamic significance of coronary stenosis by using the bifurcation fractal law to compensate for side branch flow. CLINICAL RELEVANCE STATEMENT: Bifurcation fractal law can be used to compensate for side branch flow during the Angio-FFR calculation of the main epicardial vessel. Compensating for side branch flow can improve the ability of Angio-FFR to diagnose stenosis functional severity. KEY POINTS: • The bifurcation fractal law could accurately estimate the blood flow from the proximal main vessel into the main branch, thus compensating for the side branch flow. • Angiography-derived FFR based on the bifurcation fractal law is feasible to evaluate the target diseased coronary artery without delineating the side branch.

Cationic Effects on Photo- and X-ray Radioluminescence of K3RE(PO4)2:Ce3+/Pr3+ (RE = La, Gd, and Y) Phosphors toward X-ray Detection.

Cationic tuning for lanthanide (Ce3+/Pr3+)-activated inorganic phosphors with stable, efficient, and fast-decay 5d-4f emissions has emerged as an important strategy toward the continuing pursuit of superior scintillators. The in-depth understanding of the cationic effects on photo- and radioluminescence of lanthanides Ce3+ and Pr3+ centers is requisite for the rational cationic tuning. Here, we perform a systematic study on the structure and photo- and X-ray radioluminescence properties of K3RE(PO4)2:Ce3+/Pr3+ (RE = La, Gd, and Y) phosphors to elucidate the underlying cationic effects on their 4f-5d luminescence. By using the Rietveld refinements, low-temperature synchrotron-radiation vacuum ultraviolet-ultraviolet spectra, vibronic coupling analyses, and vacuum-referred binding energy schemes, the origins of lattice parameter evolutions, 5d excitation energies, 5d emission energies, and Stokes shifts as well as good emission thermal stabilities of K3RE(PO4)2:Ce3+ systems are revealed. In addition, the correlations of Pr3+ luminescence to Ce3+ in the same sites are also discussed. Finally, the X-ray excited luminescence manifests that the K3Gd(PO4)2:1%Ce3+ sample possesses a light yield of ∼10,217 photons/MeV, indicating its potentiality toward X-ray detection application. These results deepen the understanding of cationic effects on Ce3+ and Pr3+ 4f-5d luminescence and inspire the inorganic scintillator development.

Insights into the toxicological effects of nanomaterials on atherosclerosis: mechanisms involved and influence factors.

Atherosclerosis is one of the most common types of cardiovascular disease and is driven by lipid accumulation and chronic inflammation in the arteries, which leads to stenosis and thrombosis. Researchers have been working to design multifunctional nanomedicines with the ability to target, diagnose, and treat atherosclerosis, but recent studies have also identified that nanomaterials can cause atherosclerosis. Therefore, this review aims to outline the molecular mechanisms and physicochemical properties of nanomaterials that promote atherosclerosis. By analyzing the toxicological effects of nanomaterials on cells involved in the pathogenesis of atherosclerosis such as vascular endothelial cells, vascular smooth muscle cells and immune cells, we aim to provide new perspectives for the prevention and treatment of atherosclerosis, and raise awareness of nanotoxicology to advance the clinical translation and sustainable development of nanomaterials.

Associations of serum carotenoids with visceral adiposity index and lipid accumulation product: a cross-sectional study based on NHANES 2001-2006.

BACKGROUND: Visceral adiposity index (VAI) and lipid accumulation product (LAP) are comprehensive indicators to evaluate visceral fat and determine the metabolic health of individuals. Carotenoids are a group of naturally occurring antioxidants associated with several diseases. The purpose of this investigation was to explore the association between serum carotenoid concentration and VAI or LAP. METHODS: The data were obtained from the National Health and Nutrition Examination Survey between 2001 and 2006. The levels of serum carotenoids were evaluated using high-performance liquid chromatography. Multivariate linear regression models were employed to investigate the relationship between levels of serum carotenoids and VAI or LAP. The potential non-linear relationship was determined using threshold effect analysis and fitted smoothing curves. Stratification analysis was performed to investigate the potential modifying factors. RESULTS: In total, 5,084 participants were included in this population-based investigation. In the multivariate linear regressions, compared to the lowest quartiles of serum carotenoids, the highest quartiles were significantly associated with VAI, and the effect size (ß) and 95% CI was - 0.98 (- 1.34, - 0.62) for α-carotene, - 1.39 (- 1.77, - 1.00) for ß-carotene, - 0.79 (- 1.18, - 0.41) for ß-cryptoxanthin, - 0.68 (- 0.96, - 0.39) for lutein/zeaxanthin, and - 0.88 (- 1.50, - 0.27) for trans-lycopene. Using piece-wise linear regression models, non-linear relationships were found between ß-carotene and trans-lycopene and VAI with an inflection point of 2.44 (log2-transformed, ug/dL) and 3.80 (log2-transformed, ug/dL), respectively. The results indicated that α-carotene, ß-cryptoxanthin, and lutein/zeaxanthin were linearly associated with VAI. An inverse association was also found between serum carotenoids and LAP after complete adjustments. CONCLUSION: This study revealed that several serum carotenoids were associated with VAI or LAP among the general American population. Further large prospective investigations are warranted to support this finding.

A fast and accurate brain extraction method for CT head images.

BACKGROUND: Brain extraction is an essential prerequisite for the automated diagnosis of intracranial lesions and determines, to a certain extent, the accuracy of subsequent lesion recognition, location, and segmentation. Segmentation using a fully convolutional neural network (FCN) yields high accuracy but a relatively slow extraction speed. METHODS: This paper proposes an integrated algorithm, FABEM, to address the above issues. This method first uses threshold segmentation, closed operation, convolutional neural network (CNN), and image filling to generate a specific mask. Then, it detects the number of connected regions of the mask. If the number of connected regions equals 1, the extraction is done by directly multiplying with the original image. Otherwise, the mask was further segmented using the region growth method for original images with single-region brain distribution. Conversely, for images with multi-region brain distribution, Deeplabv3 + is used to adjust the mask. Finally, the mask is multiplied with the original image to complete the extraction. RESULTS: The algorithm and 5 FCN models were tested on 24 datasets containing different lesions, and the algorithm's performance showed MPA = 0.9968, MIoU = 0.9936, and MBF = 0.9963, comparable to the Deeplabv3+. Still, its extraction speed is much faster than the Deeplabv3+. It can complete the brain extraction of a head CT image in about 0.43 s, about 3.8 times that of the Deeplabv3+. CONCLUSION: Thus, this method can achieve accurate brain extraction from head CT images faster, creating a good basis for subsequent brain volume measurement and feature extraction of intracranial lesions.

A Blockchain-Based Authentication and Authorization Scheme for Distributed Mobile Cloud Computing Services.

Authentication and authorization constitute the essential security component, access control, for preventing unauthorized access to cloud services in mobile cloud computing (MCC) environments. Traditional centralized access control models relying on third party trust face a critical challenge due to a high trust cost and single point of failure. Blockchain can achieve the distributed trust for access control designs in a mutual untrustworthy scenario, but it also leads to expensive storage overhead. Considering the above issues, this work constructed an authentication and authorization scheme based on blockchain that can provide a dynamic update of access permissions by utilizing the smart contract. Compared with the conventional authentication scheme, the proposed scheme integrates an extra authorization function without additional computation and communication costs in the authentication phase. To improve the storage efficiency and system scalability, only one transaction is required to be stored in blockchain to record a user's access privileges on different service providers (SPs). In addition, mobile users in the proposed scheme are able to register with an arbitrary SP once and then utilize the same credential to access different SPs with different access levels. The security analysis indicates that the proposed scheme is secure under the random oracle model. The performance analysis clearly shows that the proposed scheme possesses superior computation and communication efficiencies and requires a low blockchain storage capacity for accomplishing user registration and updates.

Global dispersal and diversification in ground beetles of the subfamily Carabinae.

The origin and diversification process of lineages of organisms that are currently widely distributed among continents is an interesting subject for exploring the evolutionary history of global species diversity. Ground beetles of the subfamily Carabinae are flightless except for one lineage, but nevertheless occur on all continents except Antarctica. Here, we used sequence data from ultraconserved elements to reconstruct the phylogeny, divergence time, biogeographical history, ancestral state of hind wings and changes in the speciation rate of Carabinae. Our results show that Carabinae originated in the Americas and diversified into four tribes during the period from the late Jurassic to the late Cretaceous, with two in South America (Celoglossini) and Australasia (Pamborini) and two in Laurasia (Cychrini and Carabini). The ancestral Carabinae were inferred to be winged; three of four tribes (Cychrini, Ceglossini and Pamborini) have completely lost their hind wings and flight capability. The remaining tribe, Carabini, diverged into the subtribes Carabina (wingless) and Calosomina (winged) in the Oligocene. Carabina originated in Europe, spread over Eurasia and diversified into approximately 1000 species, accounting for around 60% of all Carabinae species. Calosomina that were flight-capable dispersed from North America or Eurasia to South America, Australia, and Africa, and then flightless lineages evolved on oceanic islands and continental highlands. The speciation rate increased in the Cychrini and Carabini clades in Eurasia. Within Carabini, the speciation rate was higher for wingless than winged states. Our study showed that the global distribution of Carabinae resulted from ancient dispersal before the breakup of Gondwana and more recent dispersal through flight around the world. These patterns consequently illustrate the causal relationships of geographical history, evolution of flightlessness, and the global distribution and species diversity of Carabinae.

Noninvasive photoacoustic computed tomography/ultrasound imaging to identify high-risk atherosclerotic plaques.

PURPOSE: Noninvasive detection of high-risk plaques is still challenging. In this study, we aimed to noninvasively assess αvß3-integrin expression using a customed photoacoustic (PA) computed tomography (PACT)/ultrasound (US) system in atherosclerotic lesions of varying degrees of severity and to explore its potential value for detecting high-risk plaques. METHODS: We constructed αvß3-integrin-targeted ultrasmall gold nanorods (AuNRs) with cyclo Arg-Gly-Asp (cRGD) and tested their properties. Employing C57BL/6 J (wild-type, WT) mice and apolipoprotein E gene knockout (ApoE-/-) mice fed either a chow diet or a high-fat/high-cholesterol diet (HFHCD), we established varying degrees of lesion severity. In vivo PACT/US imaging was performed to assess αvß3-integrin expression in the 4 groups by cRGD-AuNRs. Further histopathologic examination was conducted to evaluate the plaque vulnerability indicators. RESULTS: The data showed that cRGD-AuNRs exhibited excellent photothermal conversion capacity, stability, targeting ability, and biocompatibility. The immunohistochemical results indicated that αvß3-integrin was upregulated with increasing aggravation of the lesions. In vivo PACT/US imaging showed good consistency with αvß3-integrin expression. Notably, ApoE-/- mice fed a HFHCD showed an abrupt PA intensity increase compared with the other groups. The histopathologic examination verified that the atherosclerotic plaques of ApoE-/- mice fed the HFHCD developed unstable phenotypes. Correlation analysis showed that PA intensity was mainly related to inflammation and angiogenesis among all of the indicators. CONCLUSION: Our data indicated that αvß3-integrin is an effective indicator of plaque instability, and noninvasive PACT/US molecular imaging assessment of αvß3-integrin holds promise in detecting high-risk plaques.

Site Occupancies, Electron-Vibration Interaction and Energy Transfer of CaMgSi2 O6 : Eu2+ , Mn2+ Phosphors for Potential Temperature-Sensing and Anti-counterfeiting Applications.

Eu2+ -, Mn2+ - and Eu2+ -Mn2+ -doped CaMgSi2 O6 phosphors have been prepared by a high-temperature solid-state reaction. Systematic investigation of the concentration- and temperature-dependent luminescence of Mn2+ showed that Mn2+ ions occupy two distinct sites in CaMgSi2 O6 . Electron-vibration interaction (EVI) analyses of Mn2+ ions revealed Huang-Rhys factors of 4.73 and 2.82 as well as effective phonon energies of 313 and 383 cm-1 for the two sites. Eu2+ -Mn2+ energy transfer is also discussed, and its efficiency is estimated by lifetime and luminescence spectra. The different thermal quenching behaviours of Eu2+ and Mn2+ , the distinct emission colours of Eu2+ (blue, band peak at ∼451 nm) and Mn2+ (yellow-red range, band peaks at ∼583 and 693 nm) endow the co-doped samples with potential applications in luminescence thermometry and temperature-/excitation wavelength-responsive dual anti-counterfeiting.

Experimental and Theoretical Studies of the Site Occupancy and Luminescence of Ce3+ in LiSr4(BO3)3 for Potential X-ray Detecting Applications.

Ce3+-doped LiSr4(BO3)3 phosphors have been prepared by a high-temperature solid-state reaction method, and structural refinement of the host compound has been performed. The excitation and emission spectra in the vacuum ultraviolet-ultraviolet-visible range at cryogenic temperatures reveal that Ce3+ ions preferentially occupy eight-coordinated Sr2+ sites in LiSr4(BO3)3. Such experimental attribution is well corroborated by the calculated 4f-5d transition energies and defect formation energies of Ce3+ ions at two distinct Sr2+ sites in the first-principles framework. In addition, the doping concentration-dependent luminescence and the temperature-dependent luminescence are systematically investigated by luminescence intensity and lifetime measurements, respectively. This shows that concentration quenching does not occur in the investigated doping range, but inhomogeneous broadening exists in the concentrated samples. With the estimated thermal quenching activation energy, the discussions on the thermal quenching mechanisms suggest that the thermal-ionization process of the 5d electron is a dominant channel for thermal quenching of Ce3+ luminescence, despite the fact that thermally activated concentration quenching cannot be excluded for the highly doped samples. Finally, the X-ray excited luminescence measurement demonstrates the promising applications of the phosphors in X-ray detection.

Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis.

BACKGROUND: Thrombotic events cannot be completely prevented by antithrombotics, implicating a therapeutic gap due to inflammation, a not yet sufficiently addressed mechanism. Neutrophil extracellular traps (NETs) are an essential interface between inflammation and thrombosis, but exactly how the NETotic process is initiated and maintained during arterial thrombosis remains incompletely understood. METHODS AND RESULTS: We found that the plasma concentrations of C5a were higher in patients with ST-elevation myocardial infarction (STEMI) than in patients with angina and higher in mice with left common carotid artery (LCCA) thrombosis induced by FeCl3 than in control mice. We observed that the thrombus area and weight were decreased and that NET formation in the thrombi was reduced in the group treated with the selective C5aR1 receptor inhibitor PMX53 compared with the NaCl group. In vitro, NETosis was observed when C5a was added to neutrophil cultures, and this effect was reversed by PMX53. In addition, our data showed that C5a increased the production of mitochondrial reactive oxygen species (ROS) and that the promotion of NET formation by C5a was mitochondrial ROS (Mito-ROS) dependent. Furthermore, we found that C5a induced the production of Mito-ROS by inhibiting mitochondrial STAT3 activity. CONCLUSIONS: By inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis.

Nomogram to predict rapid kidney function decline in population at risk of cardiovascular disease.

BACKGROUND: To develop a reliable model to predict rapid kidney function decline (RKFD) among population at risk of cardiovascular disease. METHODS: In this retrospective study, key monitoring residents including the elderly, and patients with hypertension or diabetes of China National Basic Public Health Service who underwent community annual physical examinations from January 2015 to December 2020 were included. Healthy records were extracted from regional chronic disease management platform. RKFD was defined as the reduction of estimated glomerular filtration rate (eGFR) ≥ 40% during follow-up period. The entire cohort were randomly assigned to a development cohort and a validation cohort in a 2:1 ratio. Cox regression analysis was used to identify the independent predictors. A nomogram was established based on the development cohort. The concordance index (C-index) and calibration plots were calculated. Decision curve analysis was applied to evaluate the clinical utility. RESULTS: A total of 8455 subjects were included. During the median follow-up period of 3.72 years, the incidence of RKFD was 11.96% (n = 1011), 11.98% (n = 676) and 11.92% (n = 335) in the entire cohort, development cohort and validation cohort, respectively. Age, eGFR, hemoglobin, systolic blood pressure, and diabetes were identified as predictors for RKFD. Good discriminating performance was observed in both the development (C-index, 0.73) and the validation (C-index, 0.71) cohorts, and the AUCs for predicting 5-years RKFD was 0.763 and 0.740 in the development and the validation cohort, respectively. Decision curve analysis further confirmed the clinical utility of the nomogram. CONCLUSIONS: Our nomogram based on five readily accessible variables (age, eGFR, hemoglobin, systolic blood pressure, and diabetes) is a useful tool to identify high risk patients for RKFD among population at risk of cardiovascular disease in primary care. Whereas, further external validations are needed before clinical generalization.

Cruxome: a powerful tool for annotating, interpreting and reporting genetic variants.

BACKGROUND: Next-generation sequencing (NGS) is an efficient tool used for identifying pathogenic variants that cause Mendelian disorders. However, the lack of bioinformatics training of researchers makes the interpretation of identified variants a challenge in terms of precision and efficiency. In addition, the non-standardized phenotypic description of human diseases also makes it difficult to establish an integrated analysis pathway for variant annotation and interpretation. Solutions to these bottlenecks are urgently needed. RESULTS: We develop a tool named "Cruxome" to automatically annotate and interpret single nucleotide variants (SNVs) and small insertions and deletions (InDels). Our approach greatly simplifies the current burdensome task of clinical geneticists and scientists to identify the causative pathogenic variants and build personal knowledge reference bases. The integrated architecture of Cruxome offers key advantages such as an interactive and user-friendly interface and the assimilation of electronic health records of the patient. By combining a natural language processing algorithm, Cruxome can efficiently process the clinical description of diseases to HPO standardized vocabularies. By using machine learning, in silico predictive algorithms, integrated multiple databases and supplementary tools, Cruxome can automatically process SNVs and InDels variants (trio-family or proband-only cases) and clinical diagnosis records, then annotate, score, identify and interpret pathogenic variants to finally generate a standardized clinical report following American College of Medical Genetics and Genomics/ Association for Molecular Pathology (ACMG/AMP) guidelines. Cruxome also provides supplementary tools to examine and visualize the genes or variations in historical cases, which can help to better understand the genetic basis of the disease. CONCLUSIONS: Cruxome is an efficient tool for annotation and interpretation of variations and dramatically reduces the workload for clinical geneticists and researchers to interpret NGS results, simplifying their decision-making processes. We present an online version of Cruxome, which is freely available to academics and clinical researchers. The site is accessible at http://114.251.61.49:10024/cruxome/ .

The potential of expanded noninvasive prenatal screening for detection of microdeletion and microduplication syndromes.

OBJECTIVES: To evaluate the clinical potential of a higher resolution noninvasive prenatal screening (NIPS-Plus) test for detection of microdeletion/microduplication syndromes (MMS) in addition to common aneuploidies. METHODS: In a multicenter prospective study, 37,002 pregnant women with unremarkable first-trimester ultrasound scans had a NIPS-Plus test. Ultrasound screen positive women were not included in this study. RESULTS: Of 36,970 ultrasound negative women there were 291 NIPS-Plus screen positive results indicating 237 aneuploidies and 54 MMS. Following amniocentesis, 171 (72%) were confirmed as genuine, comprising 3 T13s, 10 T18s, 61 T21s, 70 SCAs and 27 MMS. The PPV for MMS with unremarkable ultrasound findings was 50%. Routine clinical examination of children born from NIPS-Plus negative pregnancies revealed no obvious signs of chromosome disease syndromes at one year of age. CONCLUSIONS: NIPS-Plus has the potential for clinical utility not only for routine aneuploid screening but also for MMS that do not show overt signs during early pregnancy ultrasound screening. We suggest that ultrasound with NIPS-Plus in combination with appropriate counselling could be considered as a comprehensive first-tier prenatal screening approach for all pregnant women.

The independent risks and specific biomarker of breast cancer-related ischemic stroke.

AIM: This retrospective study was designed to investigate the independent risks and specific biomarker for breast cancer-related ischemic stroke (BCRS). METHODS: Clinical features and laboratory findings were compared between BCRS group and breast cancer group without stroke, and further multivariate analyses were performed to predict independent risks factors for BCRS patients. A receiver operator characteristic (ROC) curve analysis was configured to estimate the diagnostic efficacy of each independent risk and the product of these risks and to obtain the optimal cut-off value of diagnosis, which was termed the BCRS Index. RESULTS: BCRS patients had elevated plasma D-dimer and CA153 levels and platelet-to-lymphocyte ratio (PLR), as well as more patients received endocrine therapy (all p ＜ 0.05). Moreover, multivariate analysis revealed that D-dimer levels (odds ratio [OR]: 1.002; 95% confidence interval [CI]: 1.001-1.003; p = 0.000), CA153 levels (OR: 1.005; 95% CI: 1.001-1.008; p = 0.007), PLR (OR: 1.010; 95% CI: 1.004-1.015; p = 0.001), and endocrine therapy (OR: 1.268; 95% CI: 1.087-1.479; p = 0.003) were identified as independent risks of BCRS. Furthermore, ROC analysis displayed that the product of risks had the best diagnostic efficacy, of which the area under the curve was 0.846 ± 0.28. The optimum cut-off point was 2.37 × 106/mL, which was termed the BCRS Index with higher diagnostic accuracy and validity. CONCLUSIONS: Endocrine therapy, as well as elevated plasma D-dimer and CA153 levels and PLR values may be independent risks for BCRS. Furthermore, BCRS Index should be served as a novel specific biomarker for BCRS, which is useful to distinguish BCRS for clinicians.

Genetic profiling of primary and secondary tumors from patients with lung adenocarcinoma and bone metastases reveals targeted therapy options.

BACKGROUND: Patients newly diagnosed with lung adenocarcinoma with bone metastases (LABM) have poor survival rates after treatment with conventional therapies. To improve outcomes, we retrospectively investigated whether the application of a more comprehensive genetic test of tumor biopsies samples from LABM patients could provide the basis for treatment with more effective tyrosine kinase inhibitors (TKIs) regimens. METHODS: Fine needle biopsies were taken from the primary tumor (PT) and a secondary bone metastasis (BM) of 17 LABM patients before treatment. Simple genetic profiles for selecting therapies were initially obtained using an ARMS-PCR test for EGFR and ALK fusion mutations. More detailed genetic profiles of somatic exon SNVs and CNVs in 457 cancer-related genes were retrospectively derived using capture single molecule amplification and resequencing technology (capSMART). RESULTS: ARMS-PCR identified 14 EGFR positive, 3 EGFR negative and 1 ALK fusion positive patient. A therapy regimen incorporating TKIs Gefitinib and Crizotinib was offered to the EGFR and ALK fusion positive patients, respectively. With the exception of two patients, molecular profiling of matching PT and BM biopsies identified a highly shared somatic variant fingerprint, although the BMs exhibited additional genomic instability. In six of 13 EGFR positive patients and in all three EGFR negative patients, examination of the genetic profiles identified additional clinically significant mutations that are known or experimental drug targets for treatment of lung cancer. CONCLUSION: Our findings firstly suggest that treatment regimens based on comprehensive genetic assessment of newly diagnosed LABM patients should target both the PT and secondary BMs, including rogue clones with potential to form new BMs. Second, the additional information gained should allow clinicians to design and implement more personalized treatment regimens and potentially improve outcomes for LABM patients.

Site Occupancies, VUV-UV-vis Photoluminescence, and X-ray Radioluminescence of Eu2+-Doped RbBaPO4.

RbBaPO4:Eu2+ phosphors have been prepared by a high-temperature solid-state reaction method, and the structure was determined by Rietveld refinement based on powder X-ray diffraction (P-XRD) data. Their VUV-UV-vis photoluminescence properties are systematically investigated with three objectives: (1) based on low-temperature spectra, we clarify the site occupancies of Eu2+, and demonstrate that the doublet emission bands at ∼406 and ∼431 nm originate from Eu2+ in Ba2+ [Eu2+(I)] and Rb+ [Eu2+(II)] sites, respectively; (2) an electron-vibrational interaction (EVI) analysis is conducted to estimate the Huang-Rhys factors, the zero-phonon lines (ZPLs) and the Stokes shifts of Eu2+ in Rb+ and Ba2+ sites; (3) the studies on luminescence decay of Eu2+(I) reveal that dipole-dipole interaction is mainly responsible for the energy transfer from Eu2+(I) to Eu2+(II), and the energy migration between Eu2+(I) is weak. Finally, the X-ray excited luminescence (XEL) spectrum indicates that the light yield of the sample RbBa0.995Eu0.005PO4 is ∼17 700 ph/MeV, showing its potential application in X-ray detecting.

The stability of coordination polyhedrons and distribution of europium ions in Ca6BaP4O17.

In this work, the coordination polyhedron stabilities and distributions of europium ions in Ca6BaP4O17 (CBPO) luminescent materials are investigated. The density functional theory (DFT)-based first principles calculation results show that the PO4 tetrahedrons can tilt in the structure, which leads to the atomic distortion of O13 and O12 in CBPO and the Eu2+/Eu3+-doped systems. The energy scale of about ∼0.1 eV suggests that stabilities of coordination polyhedrons are easily influenced by dynamic factors. The atomic distortion and vacancy of work as charge compensations in CBPO:Eu3+, and three lattice sites of europium are extracted and summarized. The X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) confirm that Eu3+ can occupy the Ca1, Ca2 and Ba sites of CBPO. The combination of first principles calculation and X-ray absorption fine structure (XAFS) provides more information about microstructures of luminescent materials.