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In order to investigate the effects of temperature on the growth performance, biochemical indexes and genes expression in juvenile hybrid sturgeon (Acipenser baerii♀ × Acipenser schrenckii♂), five temperature treatment groups (18 °C, 21 °C, 24 °C, 27 °C, 30 °C) were set in this study. After 25 days of domestication, the specific growth rate (SGR) and relative weight gain rate of juvenile sturgeon increased at first and then decreased with the increase in temperature in the range of 18–30 °C and reached the highest value at 21 °C. A quadratic equation was used to fit the regression equation of SGR and temperature (T). The result showed that the temperature of the maximum SGR is 23.45 °C. Moreover, the expression level of the growth hormone (gh) and the content of blood glucose (GLU) increased significantly at 21 °C, while the expression level of the growth hormone receptor (ghr) in the liver decreased significantly. When the temperature exceeded 27 °C, the thyroid hormone levels were significantly affected, and the levels of total antioxidants (T-AOC) and reduced glutathione (GSH) were significantly higher than those in the control group. In addition, with the increase in temperature, the expression levels of hsp70 and hsp90 in the liver increased significantly, while the expression level of the luteinizing hormone (lh) in the brain decreased significantly. To summarize, the effect of temperature on the growth and development of juvenile sturgeon mainly occurs through the effects of glucose metabolism, thyroid hormone level, total antioxidant capacity and growth-related genes. Therefore, in a temperature range between 21 and 24 °C, juvenile sturgeon can obtain the maximum growth rate and survival rate.

Motivation DNA methylation is a key epigenetic factor regulating gene expression. While promoter methylation has been well studied, recent publications have revealed that functionally important methylation also occurs in intergenic and distal regions, and varies across genes and tissue types. Given the growing importance of inter-platform integrative genomic analyses, there is an urgent need to develop methods to discover and characterize gene-level relationships between methylation and expression. Results We introduce a novel sequential penalized regression approach to identify methylation-expression quantitative trait loci (methyl-eQTLs), a term that we have coined to represent, for each gene and tissue type, a sparse set of CpG loci best explaining gene expression and accompanying weights indicating direction and strength of association. Using TCGA and MD Anderson colorectal cohorts to build and validate our models, we demonstrate our strategy better explains expression variability than current commonly used gene-level methylation summaries. The methyl-eQTLs identified by our approach can be used to construct gene-level methylation summaries that are maximally correlated with gene expression for use in integrative models, and produce a tissue-specific summary of which genes appear to be strongly regulated by methylation. Our results introduce an important resource to the biomedical community for integrative genomics analyses involving DNA methylation. Availability and implementation We produce an R Shiny app (https://rstudio-prd-c1.pmacs.upenn.edu/methyl-eQTL/) that interactively presents methyl-eQTL results for colorectal, breast and pancreatic cancer. The source R code for this work is provided in the Supplementary Material. Supplementary information Supplementary data are available at Bioinformatics online.

Unsupervised clustering and deconvolution analysis identifies three intrinsic subtypes of Metastatic Castration-Resistant Prostate Cancer (M-CRPC): AR pathway-positive Prostate Cancer (ARPC), Neuro Endocrine Prostate Cancer (NEPC), and a novel subtype endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of large patient datasets and in vitro studies support the notion that MSPC originates from ARPC as a consequence of therapy-induced lineage plasticity. Intriguingly, AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP-SMAD pathway, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. MSPC cell lines and prostate adenocarcinoma cells reprogrammed in vitro to MSPC exhibit a marked dependency on HER2/3 signaling. Moreover, combinations of the panHER inhibitor neratinib with enzalutamide or the mTORC1 inhibitor MLN0128 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. Collectively, these results identify a novel subtype of M-CRPC, trace its origin to therapy induced lineage plasticity, and reveal its dependency on HER2/3 signaling.

Continuously alternating loads and environmental temperature fluctuations can easily cause material aging and fatigue defects in some in-service infrastructures. In order to improve the load-bearing capacities of these infrastructures and prevent unexpected accidents, a flexible continuous detection system that can evaluate the health of these structural systems is needed. The detection system should have the advantages of integrated miniaturization, low cost, high stability and sensitivity, suitability for engineering applications, etc. A full-optical strain sensor based on tunable laser demodulation is designed in this paper. It uses a home-made control mainboard to monitor a 2425-T3 aluminum alloy during tensile and fatigue tests. The tensile test results indicate that the FBG sensor response correlates well with the strain measured using a strain gauge. Therefore, the load and strain can be both monitored via the FBG sensor response. The fatigue test results demonstrate that the FBG sensor presented is superior to the strain gauge and has better sensitivity and stability for vibration monitoring in complex environments. In this letter, we make full use of the FBG’s advantages including its small size and light weight to implement an integrated, miniaturized FBG sensor design with significant structural health monitoring applications.

Glomerular podocyte damage is considered to be one of the main mechanisms leading to Diabetic nephropathy (DN). However, the relevant mechanism of podocyte injury is not yet clear. This study aimed to investigate the effect of peroxiredoxin 6 (Prdx6) on the pathogenesis of podocyte injury induced by high glucose (HG). The mouse glomerular podocyte MPC5 was stimulated with 30 nM glucose, and the Prdx6 overexpression vector or specificity protein 1 (Sp1) overexpression vector was transfected into MPC5 cells before the high glucose stimulation. As results, HG treatment significantly reduced the expression of Prdx6 and Sp1 in MPC5 cells. Prdx6 overexpression increased cell viability, while inhibited podocyte death, inflammation and podocyte destruction in HG-induced MPC5 cells. Prdx6 overexpression inhibited HG-induced ROS and MDA production, while restored SOD and GSH activity in MPC5 cells. Prdx6 overexpression also eliminated ferroptosis caused by HG, which was reflected in the suppression of iron accumulation and the increase in SLC7A11 and GPX4 expression. The improvement effect of Prdx6 on HG-induced podocyte damage could be eliminated by erastin. Moreover, Sp1 could bind to the three Sp1 response elements in the Prdx6 promoter, thereby directly regulating the transcriptional activation of Prdx6 in podocytes. Silencing Sp1 could eliminate the effect of Prdx6 on HG-induced podocyte damage. Further, Prdx6 overexpression attenuated renal injuries in streptozotocin-induced DN mice. Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis, which may provide new insights for the study of the mechanism of DN.

A short route manufacturing process of retaining rings was put forward, which was composed of hollow ingots manufacturing by Electro-Slag Re-melting (ESR), hot ring rolling and cold expanding strengthening. And microstructure mechanisms, deformation characteristics, and process parameters during both of hot ring rolling and cold hydraulic expanding strengthening were investigated. The results show that the multi-pass flow stresses decreased with increase of interval time. During multi-pass compression, grain refined at lower temperature of 1050 °C by static recrystallization, then grain refined at higher temperature of 1150 °C by both of dynamic and static recrystallization. Based on the influence of the contact arc length ratio on strain penetration in the wall deformation zone, the driving roller radius of 500 mm and the pressure roller radius of 130 mm were determined for the ring rolling process ofφ712 mm/308 mm × 902 mm thick-wall hollow ingot. The optimum rotate velocity of the driving roller should be 0.8 rad/s. And the feeding velocity of the pressure roller should to be 1 mm/s for matching. During cold deformation, planar slip and twinning predominated at small and large deformation, respectively, to increase strength. For the hydraulic expanding process of ϕ937/672 × 1034 mm hollow forging, the optimum matching of 60° punch angle and 5 mm contact seal height can be adopted for obtaining well-shaped strengthening forgings.

The compact casting-rolling technique is an advanced method to produce seamless ring parts. The technique has been paid much attention in recent years. To find out the textual evolution rule of materials in this compact process, hot ring rolling of 42CrMo casting blank was conducted at different mandrel feed rates. The macro-textures of the as-obtained products were studied by X-ray diffraction, and micro-textural associated grain orientations were examined by electron backscattered diffraction techniques. The dominant textures in hot-rolled rings were similar, with γ-fibre consisted of {111} and {111} orientations as the most intense components. The α-fibre and e-fibre textures in the entire thickness of hot-rolled rings did not show significant change as feed rate increased. Moreover, shear textures, including Copper-type {112} and Goss {110} components were presented in different regions of hot-rolled rings. The grain refinement was found closely related to grain orientation and micro-texture evolution in the entire thickness. The inhomogeneous distribution of grain size in the hot-rolled ring at a higher feed rate resulted in poor plasticity and toughness, which was caused by inhomogeneous γ-fibre orientations, especially in the center layer of the ring. Overall, these findings look promising for future studies dealing with compact hot ring rolling processes.

BACKGROUND: To explore the variations of the gross tumor volume (GTV) from different three-dimensional computed tomography (3DCT) scan modes and the consistency of internal target volume (ITV) between different 3DCT, cone-beam computed tomography (CBCT) and four-dimensional computed tomography (4DCT) scan, a study using a motion phantom simulating sinusoidal movement was conducted. METHODS: For three 3DCT scan modes: the GTV was contoured, and ITV(I) was generated on the basis of GTV with a 10-mm margin while ITV(II) and ITV(III) with a 0-mm margin on the motion direction. ITV(CBCT) and ITV(MIP) were contoured on the images of CBCT and maximum-intensity projection (MIP) reconstructed 4DCT images. The centroid position shifts of ITVs were analyzed. The volume consistency between ITV(I), ITV(II), ITV(III) and ITV(MIP) were evaluated by calculating the Dice similarity coefficient (Dsc) and the value of Δ Volume (ΔV). Furthermore, the 3DCT and CBCT images from 12 NSCLC patients were retrospectively collected, then the Dsc and ΔV were calculated. RESULTS: The mean ± standard deviation of centroid position of ITV(I), ITV(II) and ITV(III) were 2.3±4.7, 2.6±4.0, and 1.0±1.4 mm, respectively. The mean ± standard deviation of Dsc between ITV(I), ITV(II), ITV(III) and ITV(MIP) were 0.78±0.77, 0.86±0.1, and 0.94±0.05, respectively. The ΔV of ITV(I), ITV(II), ITV(III) were 29.67%, 17.22%, and 6.46%, respectively. The ITV from CBCT showed a deduction rate of 3.1–9.3% compared to 4DCT. For the patients, the mean Dsc andΔV between ITV(I) and ITV(CBCT) were 0.50 and 60.76%. CONCLUSIONS: The GTV acquired from 3DCT scan mode I possessed great deviation of centroid position and target volume. ITV on the basis of this GTV was significantly larger than ITV(MIP). A good similarity was showed between ITV(III) and ITV(MIP), 4DCT is still a golden standard for the ITV delineation, but in the absence of 4DCT, image from 3DCT scan mode III and KV-CBCT may be considered for ITV delineation with caution.

Cr and Al coating were respectively deposited on Zr-4 alloy by magnetron sputtering and high temperature oxidation (HTO) tests were conducted in air environment at 1200 °C for 3 h for Cr-coated and Al-coated specimens. The morphology and phase composition of the specimens were detected by SEM, EDS and XRD. The adhesion properties were characterized by scratch test. The XRD results revealed that the two coatings were crystalline with preferred orientation. The results of scratch testing showed that critical load of Cr coating was higher than that of Al coating. After HTO test, the Cr-coated specimen was intact without cracking and spalling off, only the outermost layer of Cr coating was oxidized to a Cr2O3 layer of about 4 μm thick with a residual Cr layer of about 4 μm thick, and the internal zirconium alloy was not oxidized. For Al-coated specimen, besides the complete oxidation of the Al coating, there were also about 500 μm Zr-4 alloy oxidized on each side, and there were a lot of voids and cracks in the specimen. The EDS results indicated that a thickness of about 5 μm Cr-Zr diffusion layer developed at the interface between Cr coating and Zr-4 alloy for the Cr-coated Zr-4 specimen. While, for the Al-coated Zr-4 specimen, Al diffused into the specimen to a depth of about 100 μm, and Zr diffused almost to the outermost layer. Moreover, Sn in the Zr-4 alloy is concentrated at the interface between the residual Zr-4 alloy and ZrO2 layer. The obtained results manifested that Cr coating shows better oxidation resistance than Al coating.

Purpose: Consensus molecular subtyping (CMS) of colorectal cancer has potential to reshape the colorectal cancer landscape. We developed and validated an assay that is applicable on formalin-fixed, paraffin-embedded (FFPE) samples of colorectal cancer and implemented the assay in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Experimental Design: We performed an in silico experiment to build an optimal CMS classifier using a training set of 1,329 samples from 12 studies and validation set of 1,329 samples from 14 studies. We constructed an assay on the basis of NanoString CodeSets for the top 472 genes, and performed analyses on paired flash-frozen (FF)/FFPE samples from 175 colorectal cancers to adapt the classifier to FFPE samples using a subset of genes found to be concordant between FF and FFPE, tested the classifier's reproducibility and repeatability, and validated in a CLIA-certified laboratory. We assessed prognostic significance of CMS in 345 patients pooled across three clinical trials. Results: The best classifier was weighted support vector machine with high accuracy across platforms and gene lists (>0.95), and the 472-gene model outperforming existing classifiers. We constructed subsets of 99 and 200 genes with high FF/FFPE concordance, and adapted FFPE-based classifier that had strong classification accuracy (>80%) relative to “gold standard” CMS. The classifier was reproducible to sample type and RNA quality, and demonstrated poor prognosis for CMS1–3 and good prognosis for CMS2 in metastatic colorectal cancer (P < 0.001). Conclusions: We developed and validated a colorectal cancer CMS assay that is ready for use in clinical trials, to assess prognosis in standard-of-care settings and explore as predictor of therapy response.

Activating mutations of the KRAS gene are one of the major genomic alterations associated with tumorigenesis of non-small cell lung cancer (NSCLC). Thus far, treatment of KRAS-mutant NSCLC remains an unmet medical need. We determined the in vivo treatment responses of 13 KRAS mutant and 14 KRAS wild type NSCLC patient-derived xenografts (PDXs) to agents that target known NSCLC vulnerabilities: the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, and the BCL-X(L)/BCL-2 inhibitor navitoclax. The results showed that the tumor regression rate after single agent therapy with KRT-232, trametinib and navitoclax was 11%, 10% and 0%, respectively. Combination therapies of trametinib plus KRT-232 and trametinib plus navitoclax led to improved partial response rates over single-agent activity in a subset of PDX models. Tumor regression was observed in 23% and 50% of PDXs after treatment with trametinib plus KRT-232 and trametinib plus navitoclax, respectively. The disease control rates in KRAS-mutant PDXs tested were 90%-100% after treatment with trametinib plus KRT-232 or plus navitoclax. A correlation analysis of treatment responses and genomic and proteomic biomarkers revealed that sensitivity to KRT-232 was significantly associated with TP53 wild-type or STK11 mutant genotypes (P

Objective: Observe the clinical characteristics of children with SLE, namely, to observe the symptoms and laboratory examinations, such as blood routine, blood lipid, immunoglobulin, complement, autoantibodies, serum 25 (OH) D and other indicators, and to explore the clinical characteristics, the difference and the significance of vitamin D supplements between male and female SLE patients in children respectively. Methods: We enrolled 64 cases of SLE patients in children who were admitted into the department of pediatrics and rheumatology of the third affiliated hospital of sun yat-sen university in guangzhou from May 1, 2011 to February 1, 2019, They were analyzed retrospectively, adopting ?² test for statistical analysis. Results: 64 cases of SLE in children, which included 10 cases of male and 54 cases of female. Clinical manifestations: facial skin rash in 48 patients (75%), fever in 38 cases (59.4%), arthritis in 28 cases (43.8%), oral ulcer in 18 cases (28.1%), serositis in13 cases (20.3%), and the sun allergy in 9 cases (14.1%), the damage of central nervous system in 7 cases (10.9%) . Laboratory examination: 30 cases of leukopenia (46.9%), anemia in 30 cases (46.9%), thrombocytopenia in 12 cases (18.8%), hematuria in 18 cases (28.1%), proteinuria in 33 cases (51.2%), 6 patients with renal impairment (9.4%), antinuclear antibody positive in 63 cases (98.4%), anti-double-stranded DNA (dsDNA) antibody positive in 48 cases (75%), anti SSA antibody positive in 44 cases (68.7%), SSB antibody positive in 33 cases (51.6%), Sm antibody positive in 40 cases (62.5%), nucleosome antibody positive in 28 cases (43.8%) .Among these children, male SLE patients were higher than female children with SLE in the damage of kidney, Sm antibodies and resisting nucleosome antibody positive rates (?²= 4.451, 8.336, 6.803, P

The process of smelting, pouring, and solidification for steel determines the inevitable existence of all kinds of macroscopic and microscopic void defects in the ingot. These voids need to be eliminated by a proper plastic forming process. However, the mechanism of void closure is not well understood at present. In particular, the investigation on the evolution law of void closure under complex stress state is not deep enough. Based on the representative volume element model, numerical simulations and theoretical analysis, the effects of the spherical stress tensor and the deviatoric stress tensor on the evolution of void are expounded. It is found that the relative size of the three principal values of the deviatoric stress tensor determines the shape change of the void during plastic deformation. Besides, the change of the relative value of the principal values of the deviatoric stress tensor has little effect on the maximum compressive strain required for void closure. Moreover, the smaller the principal value of the spherical stress tensor is, the smaller the strain required for void closure is.

International audience; This work deals with epipole estimation related to egocentric camera localization in surveillance and security applications. Matching visual features in the images provides some evidences for various solutions, so that epipole localization can be addressed as a fusion task with a large number of sources including outlier ones. In order to deal with source imprecision and uncertainty, we rely on the belief function theory and a 2D framework suited for our application. In this framework, we address the challenges introduced by a large number of sources with a strategy based on clustering and intra-cluster fusion. The proposed method exhibits more robustness in terms of accuracy and precision when compared on real data with the standard algorithms which provide single solution. Since we provide a Basic Belief Assignment as a result, our strategy is particularly adapted for the prospective combination with additional sources of information. Index Terms-Egocentric camera localization, epipole uncertainty , large number of sources, belief function theory 2D

The inner nuclear membrane (INM) selectively accumulates proteins that are essential for nuclear functions; however, overaccumulation of INM proteins results in a range of rare genetic disorders. So far, little is known about how defective, mislocalized, or abnormally accumulated membrane proteins are actively removed from the INM, especially in plants and animals. Here, via analysis of a proximity-labeling proteomic profile of INM-associated proteins in Arabidopsis, we identify critical components for an INM protein degradation pathway. We show that this pathway relies on the CDC48 complex for INM protein extraction and 26S proteasome for subsequent protein degradation. Moreover, we show that CDC48 at the INM may be regulated by a subgroup of PUX proteins, which determine the substrate specificity or affect the ATPase activity of CDC48. These PUX proteins specifically associate with the nucleoskeleton underneath the INM and physically interact with CDC48 proteins to negatively regulate INM protein degradation in plants., Maintaining protein integrity at the inner nuclear membrane (INM) is critical for eukaryotic cellular function. Here, using proximity-labeling proteomics, Huang et al. profile the INM in Arabidopsis and identify the CDC48 complex and PUX proteins as components of an INM protein degradation pathway.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.

Radon exposure is the most frequent cause of lung cancer in non-smokers. The high linear energy transfer alpha-particles from radon decay cause the accumulation of multiple genetic changes and lead to cancer development. Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis. However, the mechanisms underlying chronic radon exposure-induced EMT attributed to carcinogenesis are not understood. This study aimed to explore the EMT and potential molecular mechanisms induced by repeated radon exposure. The EMT model of 16HBE and BEAS-2B cells was established with radon exposure (20000 Bq/m3, 20 min each time every 3 days). We found repeated radon exposure facilitated epithelial cell migration, proliferation, reduced cell adhesion and ability to undergo EMT through a decrease in epithelial markers and an increase in mesenchymal markers. Radon regulated the expression of matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 2 (TIMP2) to disrupt the balance of MMP2/TIMP2. In vivo, BALB/c mice were exposed to 105 Bq/m3 radon gas for cumulative doses of 60 and 120 Working Level Months (WLM). Radon inhalation caused lung damage and fibrosis in mice, which was aggravated with the increase of exposure dose. EMT-like transformation also occurred in lung tissues of radon-exposure mice. Moreover, radon radiation increased p-PI3K, p-AKT and p-mTOR in cells and mice. Radon reduced the GSK-3β level and elevated the active β-catenin in 16HBE cells. The m-TOR and AKT inhibitors attenuated radon exposure-induced EMT by regulation related biomarkers. These data demonstrated that radon exposure induced EMT through the PI3K/AKT/mTOR pathway in epithelial cells and lung tissue.

Elevated serum lactate dehydrogenase (sLDH) is associated with poor clinical outcomes in patients with stage IV metastatic melanoma (MM). It is currently unknown if sLDH elevation correlates with distinct molecular, metabolic, or immune features of melanoma metastases. The identification of such features may identify rational therapeutic strategies for patients with elevated sLDH. Thus, we obtained sLDH levels for melanoma patients with metastases who had undergone molecular and/or immune profiling. Our analysis of multi‐omics data from independent cohorts of melanoma metastases showed that elevated sLDH was not significantly associated with differences in immune cell infiltrate, point mutations, DNA copy number variations, promoter methylation, RNA expression, or protein expression in melanoma metastases. The only significant association observed for elevated sLDH was with the number of metastatic sites of disease. Our data support that sLDH correlates with disease burden, but not specific molecular or immunological phenotypes, in metastatic melanoma., The association between elevated serum lactate dehydrogenase (sLDH) and poor prognosis in metastatic melanoma patients is well‐established but poorly understood. Our multi‐omics analysis of multiple cohorts of patients with melanoma metastases identified no significant intratumoral molecular, immunological, or metabolic associations with sLDH, supporting that sLDH serves at least partially as a surrogate of tumor burden but not of adverse tumor features.

Dragon’s blood that is extracted from Dracaena plants has been widely used as traditional medicine in various ancient cultures. The application of dragon’s blood has a cherished history in China, even though the original plants were not discovered for some period. Dracaena cochinchinensis and Dracaena cambodiana were successively discovered in southern China during the 1970s−1980s. In the last half of the century, Chinese scientists have extensively investigated the production of dragon’s blood from these two Dracaena species, whereas these results have not been previously systematically summarized, as in the present paper. Herein, we present the applied history in ancient China and artificially induced technologies for dragon’s blood development based on these two Dracaena species, in particular, using tissue cultures seedlings and tender plants of D. cambodiana. Big data research, including transcriptomic and genomic studies, has suggested that dragon’s blood might be a defense substance that is secreted by Dracaena plants in response to (a)biotic stimuli. This review represents an effort to highlight the progress and achievements from applied history as well as induction techniques that are used for the formation of dragon’s blood that have taken place in China. Such knowledge might aid in the global conservation of wild Dracaena species and contribute to understanding dragon blood formation mechanisms, eventually assisting in the efficient utilization of limited Dracaena plant resources for the sustainable production of dragon’s blood.

Objective: The present study aimed to analyze the mechanism by which long-term occupational exposure of workers to low-dose ionizing irradiation induces epithelial–mesenchymal transition (EMT) of the human bronchial epithelial cells using transcriptome profiling. Methods: RNA-seq transcriptomics was used to determine gene expression in blood samples from radiation-exposed workers followed by bioinformatics analysis. Normal bronchial epithelial cells (16HBE) were irradiated for different durations and subjected to immunofluorescence, Western blotting, scratch healing, and adhesion assays to detect the progression of EMT and its underlying molecular mechanisms. Results: Transcriptomics revealed that exposure to ionizing radiation led to changes in the expression of genes related to EMT, immune response, and migration. At increased cumulative doses, ionizing radiation-induced significant EMT, as evidenced by a gradual decrease in the expression of E-cadherin, increased vimentin, elevated migration ability, and decreased adhesion capability of 16HBE cells. The expression of fibronectin 1 (FN1) showed a gradual increase with the progression of EMT, and may be involved in EMT. Conclusion: Ionizing radiation induces EMT. FN1 may be involved in the progression of EMT and could serve as a potential biomarker for this process.

In this paper, we introduce the application of three fixed point theorem by discussing the existence of three positive solutions for a class of Caputo fractional difference equation boundary value problem. We establish the condition of the existence of three positive solutions for this problem.

Background To compare the application value of serum and urinary β2-microglobulin in immunoglobulin A nephropathy (IgAN). Methods Two hundred thirteen patients were hospitalized at the First Affiliated Hospital of Bengbu Medical College in China because of physical abnormalities and diagnosed with IgAN by means of renal biopsy between January 2010 and December 2018. β2-MG levels in serum and urine were detected through immunoturbidimetric methods. The renal histopathology was quantified according to Katafuchi semi-quantitative standards and Lee's grading. Results One hundred twenty-four patients were male and 89 cases were female, for a 1.39:1 male to female ratio. The average age was 38.25 ± 12.48 years old when patients received their first renal biopsy. The levels of serum β2-MG and urine β2-MG increased gradually with the aggravation of tubulointerstitial lesions. Results of correlation analysis showed that serum β2-MG had higher application value. Serum β2-MG levels were positively correlated with SCr and tubulointerstitial lesions (r = 0.840, 0.652, p = 0.000), negatively correlated with CG-eGFR (r = -0.680, p = 0.000). The results of multivariate logistic regression analysis showed that serum β2-MG was a marker of independent risk factor for the score of tubulointerstitial lesions ≥ 3 (OR = 6.649, p = 0.000). ROC analysis showed better diagnostic performance for serum β2-MG, with the optimal cutoffs in predicting tubulointerstitial score ≥ 1, score ≥ 4 and score ≥ 7 of 1.905 mg/L, 2.13 mg/L, and 4.49 mg/L, respectively. Conclusions Serum β2-MG is valuable in evaluating renal function and pathological lesions in IgAN patients and has significant predictive value in evaluating tubulointerstitial lesions. Serum β2-MG may be used as a non-invasive diagnostic indicator for predicting renal function and tubulointerstitial lesions in IgAN.

Deep eutectic solvents (DESs) have garnered substantial interest from the scientific community in recent years due to their widely recognized potential as green alternatives to conventional solvents. On the other hand, to improve bioavailability of drugs and determination of trace level drugs are still challenging. In this context, numerous DESs have been evaluated as enhancers of drug solubility and preconcentration solvents for trace level pharmaceuticals in a variety of samples. In this review, the related studies reported between 2016 and 2021 have been systematically summarized and critically reviewed. Additionally, the mechanisms by which DESs promote drug solubility are demonstrated and explored in detail. Finally, the prospects and problems of using DESs as drug solubility enhancers and trace level drug extractants are reviewed and proposed thoroughly.

Solid solution treatment on Cu-1.0Cr-0.1Zr alloy was performed at different temperatures and holding times to study the impact on solid solution behavior. At low temperatures, the results show that solid solutions do not form in the Cr-rich phase, but they start to form when temperatures rise above 900 °C. The dissolution rate first increases and then decreases, as temperatures approach higher values. At 950 °C, substantial solid solution forms, and as the holding time extends, the dissolution rate gradually decreases until the formation of solid solution completed. The pinning of dislocations by the Cr-rich phase leads to fine grain generation in the structure to further enhance the strength and lower the conductivity. Formation of solid solution completes when held at 950 °C for 120 min. The strength is 63.7 HB and conductivity is 34.5% IACS. Solid solution increases strength and resistivity by 43.91% and 63.59%, respectively.

The objective of this research was to study the physiological performance of young novice male drivers after they were administered different doses of alcohol. The physiological performance...

Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5′ fusion partner genes have been reported, treatment of ALK-rearranged cancers is decided without regard to which 5′ partner is present. There is little data addressing how the 5′ partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKI). On the basis of the hypothesis that the 5′ partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated. Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC50s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5–10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 5′ fusion partner plays an important biological role that affects sensitivity to ALK TKIs. Implications: This study shows that the 5′ ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies. Mol Cancer Res; 16(11); 1724–36. ©2018 AACR.

Despite a therapeutic paradigm shift into targeted-driven medicinal approaches, resistance to therapy remains a hallmark of lung cancer, driven by biological and molecular diversity. Using genomic and expression data from advanced non-small cell lung cancer (NSCLC) patients enrolled in the BATTLE-2 clinical trial, we identified RICTOR alterations in a subset of lung adenocarcinomas and found RICTOR expression to carry worse overall survival. RICTOR-altered cohort was significantly enriched in KRAS/MAPK axis mutations, suggesting a co-oncogenic driver role in these molecular settings. Using NSCLC cell lines, we showed that, distinctly in KRAS mutant backgrounds, RICTOR blockade impairs malignant properties and generates a compensatory enhanced activation of the MAPK pathway, exposing a unique therapeutic vulnerability. In vitro and in vivo concomitant pharmacologic inhibition of mTORC1/2 and MEK1/2 resulted in synergistic responses of anti-tumor effects. Our study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations.

Hot deformation behavior of as-cast antibacterial austenitic stainless steel containing 3.60% copper was investigated in a temperature range of 900-1150 °C and strain rate range of 0.01-20 s−1. At strain rates higher than 1 s −1, the flow stress curves were corrected considering adiabatic heating. Kinetic analysis indicated that the hot deformation activation energy of steel was 376.02 kJ mol−1. The microstructural evolution under different temperatures was observed by optical microscopy. The nucleation sites for recrystallization and different orientations and twin ratios under different strain rates were analyzed by electron backscatter diffraction. The results showed that hot deformation was dominated by continuous dynamic recrystallization in the high-temperature and high-strain-rate region (1050-1150 °C, 1-20 s−1). On increasing the temperature and strain rate, the degree of recrystallization and twinning increased simultaneously. These phenomena promoted one another. Thus, the volume fraction of the recrystallized and twinned grains increased with the addition of Cu.

In this paper, we study the minimal wave speed of a competitive system. By constructing upper and lower solutions, we confirm the existence of travelling wave solution at the critical wave speed. T...

Background: Bone is the most common site of metastasis of breast cancer, and bone metastasis is associated with a high rate of skeletal-related events, all of which contribute to decreased quality of life and poor outcomes. Biological mechanisms of metastasis to bone may be unique, and identification of distinct signaling pathways and somatic mutations may provide biological insight into or rational targets for treatment of and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone only versus non-bone as first metastatic site. Methods: Tumor samples were collected from 389 patients who had metastasis and untreated primary breast cancer. In each sample, 46 or 50 cancer-related genes were selectively amplified and analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. We used Fisher's exact test to identify somatic mutations associated with bone-only first metastasis and logistic regression models to identify differences in clinicopathologic characteristics, survival, and somatic mutations between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only (“other-only first metastasis”). Results: Among the 389 patients, the first metastasis was located in bone only in 72 patients (18.5%), non-bone sites only in 223 patients (57.3%), and both in 94 patients (24.2%). Of the cancer-related genes analyzed, the most commonly mutated were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and low nuclear grade (grade 1 or 2) (all 3 comparisons, p Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer. Citation Format: Kono M, Fujii T, Matsuda N, Harano K, Chen H, Wathoo C, Aron JY, Tripathy D, Meric-Bernstam F, Ueno NT. Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-04.

This paper deals with uniqueness of solutions for integral boundary value problem {8

Understanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations.Archival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model.A total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P 0.001 for both).Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments.

A class of boundary value problems of Caputo fractional q-difference equation is introduced. Green’s function and its properties for this problem are deduced. By applying these properties and the Leggett-Williams fixed-point theorem, existence criteria of three positive solutions are obtained. At last, some examples are given to illustrate the validity of our main results.

Introduction: The ATR (ataxia-telangiectasia and Rad3 related protein) kinase inhibitor BAY 1895344 is currently in clinical development for the treatment of advanced solid tumors and has demonstrated promising antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein. There is further need to identify robust predictive biomarkers to optimize patient selection for ATR inhibitors. For that purpose, we tested the antitumor activity of BAY 1895344 in patient-derived xenograft (PDX) models that are characterized by a variety of DDR alterations. Methods: PDX models were characterized by genomic sequencing and ATM loss by immunohistochemistry (IHC). PDX models with deleterious ATM, BRCA1 or BRCA2 mutations or loss derived from a variety of histologies were tested. BAY1895344 treatment was tested with two monotherapy regimens 20 mg/kg and 40 mg/kg PO BID both 3 days on/4 days off. For in vivo studies, the percent tumor volume change per time point was calculated as a relative level of tumor growth change from baseline: , where is the tumor volume at time and is the tumor volume at baseline. T/C ratio was defined as the ratio of tumor volume change in treated vs control group. An event in each animal was defined as a doubling of tumor volume from initial tumor volume. Event free survival was analyzed by Kaplan-Meier survival analysis. Results: Seventeen PDX models from sixteen patients were treated with BAY 1895344. The PDX models spanned multiple tumor types: breast, colon, pancreas, and cholangiocarcinoma. BAY 1895344 has shown potent and dose-dependent antitumor activity. Strongest activity was observed with BAY 1895344 at 40 mg/kg PO BID applied for 3 days on and 4 days off treatment, achieving a regression or T/C ratio Citation Format: Christian X. Cruz Pico, Dali Li, Christopher D. Lanier, Kurt Evans, Maria G. Raso, Timothy DiPeri, Yasmeen Rizvi, Min Jin Ha, Huiqin Chen, Ming Zhao, Argun Akcakanat, Xiaofeng Zheng, Gokce Toruner, Erkan Yuca, Stephen Scott, Antje M. Wengner, Timothy A. Yap, Funda Meric-Bernstam. Anti-tumor activity of ATR inhibitor BAY 1895344 in patient-derived xenograft (PDX) models with DNA damage response (DDR) pathway alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P058.

The purpose of this study was to investigate the periodic seasonal changes in endocrine activity and gonadal development of female rainbow trout (Oncorhynchus mykiss) in a high-altitude cold-water environment. The fish were sampled monthly from January to November and the levels of plasma hormones (estradiol (E2), cortisol and thyroid hormones (THS)) and vitellogenin (VTG) were measured by ELISA. Moreover, the transcriptions of sex-related genes in the ovary, brain, and liver were detected by qRT-PCR. The results showed a seasonal fluctuation of plasma hormones and VTG together with the development of the ovary, which reached a peak from August to October. Similarly, the transcription of hypothalamic gonadotropin-releasing hormone-2 (cgnrh-2), hypothalamic gonadotropin-releasing hormone receptors (gnrhr) and follicle-stimulating hormone (fsh) in the brain varied from January to September, but the highest level was detected in September to November. In addition, the transcription of sex-related genes located in the ovary and liver increased significantly during August to October, accompanied by a continuous increase in the gonadosomatic index (GSI) and a decrease in the hepatosomatic index (HSI). Therefore, plasma hormones and sex-related genes regulate the development and maturation of O. mykiss oocytes with the change in seasons and peaked in November. The results of this study provide a reference for improving the efficiency of the artificial reproduction of O. mykiss.

Background Next-generation sequencing (NGS) based on liquid biopsy has been an emerging technology to identify tumor-specific genetic aberrations in adult lymphoma. However, there were few studies on the genomic profiling of plasma circulating tumor-derived DNA (ctDNA) in pediatric mature B-NHL. Methods Paraffin-embedded tissue (FFPE) and plasma samples from the newly diagnosed patients were collected and sequenced by 475 genes panel before, during and post of treatment. Clinical stage system, risk stratification and treatment of pediatric mature B-NHL followed a the modified BFM-95 protocol. Results A total of 53 pediatric mature B-NHLs were enrolled，including 35 Burkitt lymphoma, 18 diffused large B cell lymphoma/high-grade B cell lymphoma (DLBCL/HGBCL). We collected 38 tissue and 124 plasma samples for somatic mutation testing. The number of somatic mutations and the TOP 5 genes detected in the 38 tissues and 31 baseline plasma samples, were 416 vs 496, and MYC(71%), DDX3X(45%)，ID3 (42%), TP53(40%), SMARCA4(29%) (Fig1. A)vs MYC(52%), DDX3X(45%)，ID3(42%), TP53(36%), GNA13(23%) (Fig1. B), respectively. The median allele frequency of mutations in plasma was 3%(ranged from 0.2% to 96.6%) and MYC, DDX3X, ID3, TP53, SMARCA4,ARID1A shows higher max somatic allele frequency (MSAF), indicated that was the early events in tumor genesis. The sensitivity of plasma ctDNA to detecting tissue mutations was 63.4% in the 19 matched samples (11 samples from BL and 8 samples from DLBCL/HGBCL) and the sensitivity in BL and DLBCL/HGBCL were 64.1% and 62%, respectively. All genomic alteration types, including single nucleotide variants (SNVs), indels, and gene fusions were detected in similar proportions in each sample type and the gene mutation rate of every gene detected in paired tissue and ctDNA samples. Among the 37 mature B-NHL patients, 6 patients were collected plasma samples after resection of tumor, of which 4 patients was not detected the somatic gene mutations in plasma (Fig. 2). The abundance of ctDNA in patients with stage IV (N=10) was significantly higher than that of stage I-II (N=6) (P=0.0002) and stage III patients(N=15)(P With a median follow-up of 182 Days, 33 patients have completed anti-tumor treatment, 27 patients completed post-treatment PET-CT, and 20 patients have done ctDNA testing synchronously. PET-CT showed tumor residue in 4 patients, of which 2 patients showed no tumor residue in pathology and ctDNA, 1 patient showed tumor residue in pathology but not in ctDNA and with tumor progression 6 months after treatment, 1 patient unable to take biopsy showed no tumor residue in ctDNA and was no tumor reccourence with regular follow-up. At the last follow-up, 1 patient was disease progression, and all of the 53 patients survived. Conclusion Plasma ctDNA testing by NGS was practicable in pediatric mature B-NHL. The abundance of ctDNA is significantly related to tumor burden. CtDNA testing may be more sensitive than PET-CT for residual disease assessment. Nevertheless, sample size expansion is required to verify such conclusions. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Despite increasing utilization of patient-derived xenografts (PDXs) in early drug development, there are no agreed upon metrics for assessment of PDX growth inhibition for agents given alone or in combination. In the present study, we aim to investigate what metrics are being used in the literature, as well as among the National Cancer Institute PDX Development and Trial Centers Research Network (PDXNet) investigators. Methods: Relevant PDX literature was identified and retrieved using an information retrieval tool, RetriLite, to search for articles that met following criteria: 1) Published between 01/2018 through 12/2019; 2) Published in a journal with impact factor of 10 or above; 3) Search terms included: Cancer, PDX(s), patient derived xenograft(s), and patient-derived xenograft(s). Exclusion criteria included: 1) Brain tumors; 2) Immune-oncology/non-solid tumors; 3) Studies with no detailed information; 4) studies from PDXNet investigators. In addition, a questionnaire regarding PDX analysis practices was distributed to NCI PDXNet investigators and responses were analyzed. Results: Sixty-five studies with relevant information were included in this systematic literature review and 15 NCI PDXNet PIs from all six centers responded to the survey representing the general practice in the network. The most commonly used tumor growth assessment metric was comparisons in tumor volumes in different treatment arms, used by 33 (51%) of 65 PDX papers and 13 (87%) of 15 PDXNet investigators. Thirteen different growth metrics were reported in the PDX literature and ten different metrics were used by PDXNet investigators. PDXNet investigators were more likely to use growth metrics analogous to clinical endpoints compared to the PDX literature, including percent change of tumor volume (80% vs 17%), event-free survival (EFS: 40% vs 11%), and overall survival (33% vs 8%). PDXNet investigators were also more likely to assess objective response rate (ORR) compared to the PDX literature (60% vs 12%); several different cutoffs were used for defining response and progression. For combination therapy, most investigators and literature compared tumor volumes across treatment arms, with few looking at measures of synergy or dynamic effects and with variable utilization of other metrics such as OR and EFS. In PDX literature, of the 40 papers with combination therapies presented, at least one monotherapy control arm was missing in 7 (18%), and four (10%) only compared growth with the no treatment control arm. Conclusions: In summary, there is great variability in growth metrics used in the PDX community. To better use PDXs as preclinical models and increase the reproducibility of treatment effect on PDXs, a joint effort is needed to harmonize approaches in PDX growth assessment. Citation Format: Dali Li, Min Jin Ha, Yvonne A. Evrard, Huiqin Chen, Lisa M. McShane, Jeffrey Grover, Jing Wang, Bingliang Fang, Timothy DiPeri, Michael T. Lewis, Lawrence Rubinstein, Jack A. Roth, Jeffrey H. Chuang, James H. Doroshow, Jeffrey A. Moscow, Funda Meric-Bernstam. A systematic review of the tumor growth metrics of patient-derived xenograft (PDX) models in the literature and in NCI PDXNet centers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3009.

Osimertinib, the only third-generation EGFR-TKI approved for the treatment of T790M-mutant non-small cell lung cancer, shows robust clinical activity, yet patients inevitably develop secondary resistance. TUSC2, an immunogene therapy, has multifunctional activity, which a) directly blocks downstream signaling through inhibiting MAPK and mTOR, b) arrests growth and proliferation of cancer cells, c) induces direct tumor cell death, and d) activates both innate and adaptive immunity. An osimertinib resistant H1975-OsiR isogenic cell line was developed through continuous exposure to osimertinib, and an osimertinib resistant clone was selected which showed 100 fold higher resistance to osimertinib compared with its parental counterpart (H1975-parental). Xenograft tumors from both H1975-parental and H1975-OsiR cells were developed in NSG mice and were treated with osimertinib. H1975-OsiR tumors were significantly less sensitive than their parental counterparts. To maintain the resistance in H1975-OsiR, the cells were cultured in the presence of osimertinib, and the osimertinib pressure was maintained in vivo throughout the experiments. Synergistic antitumor activity of TUSC2+osimertinib was found in H1975-OsiR tumors where both TUSC2+osimertinib (5mg/kg) and TUSC2+osimertinib (10mg/kg) combinations showed a robust antitumor effect compared with single agent treatment groups. No synergistic effect was observed for H1975-parental tumors. RPPA analysis of residual tumors showed a distinct set of proteins including CD44, VEGFR-2, SHP2, Akt2, and YAP-pS127 overexpressed in H1975-OsiR vs H1975-parental. Among H1975-OsiR tumors, RPPA data showed that PDK1 protein was significantly altered in osimertinib treated groups as compared with controls. PDK1 was also found to be significantly upregulated in the TUSC2+osimertinib group when compared with either control, osimertinib alone, or TUSC2 alone treated H1975-OsiR tumors indicating that PDK1 may be associated with osimertinib resistance. PDK1 was not altered by TUSC2 alone treatment. PDK1 was not altered in any treatment groups in H1975-parental tumors. In order to validate the role of PDK1 in H1975-OsiR, we performed XTT assays of osimertinib and TUSC2+osimertinib combinations in the presence or absence of a PDK1 inhibitor (BX-795). Only the osimertinib and TUSC2+osimertinib groups showed significantly increased sensitivity to osimertinib in the presence of BX-795 as compared with the same treatment without the inhibitor. No PDK1 inhibitor effect was found in the TUSC2 treated group validating the specific role of PDK1 in osimertinib resistance. In conclusion, TUSC2 therapy in combination with osimertinib showed synergistic antitumor efficacy in EGFR mutant osimertinib resistant NSCLC tumors, and upregulation of PDK1 was associated with osimertinib resistance. Citation Format: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Lihui Gao, Meng Feng, Huiqin Chen, Min Jin Ha, Jack A. Roth. Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1105.

The aging precipitation behavior in Mn18Cr18N austenitic stainless steel was investigated at temperatures from 600 °C to 900 °C. During isothermal aging treatment, the primary precipitate was Cr2N with a = 0.478 nm and c = 0.444 nm, and it preferentially nucleates along initial grain boundaries and gradually grows towards the interior of grains in discontinuous cellular way. Meanwhile, a small amount of granular face-centred cubic M23C6 with a = 1.066 nm also were observed, which mainly form along grain boundaries. The effect of these precipitates on mechanical properties of the alloy was studied. It was found that precipitates result in degeneration of the matrix hardness. Meanwhile, the SEM morphologies of aged tensile sample show that the brittle fracture predominates during deformation, i.e. the fracture mode transforms from intergranular fracture to transgranular fracture with the increasing of aging time. Compared with the solution-treated sample, the strength of the aged tensile samples slightly decreases and plasticity remarkably deteriorates.

Hot deformation behavior and microstructure evolution of as-cast Mn18Cr18N austenitic stainless steel were investigated by isothermal compression experiments. The results indicate that the microstructure evolution of the as-cast Mn18Cr18N steel is sensitive to strain rates. Discontinuous dynamic recrystallization, characterized by nucleation and growth controlled by grain boundary migration, occurs at lower strain rates. However, higher strain rates result in higher adiabatic temperature rise, which could be contributed to dynamic recrystallization (DRX) nucleation and growth by acceleration boundary migration. In addition, at higher strain rates, a large number of deformation microbands in the interior of coarse columnar grains were observed, which would provide potential nucleation sites for DRX. Meanwhile, a great number of Σ3 twins were observed, which reveals that twinning accelerates the separation of subgrains from bulging grain boundaries, and the iterative processing among Σ3 twins and its variants promotes the transformation from specific CSL grain boundaries to random high-angle boundaries.

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy in which cells reside in bone marrow, lymph nodes, and peripheral blood, each of which provides a unique microenvironment. Although the levels of certain proteins are reported to induce, changes in the CLL cell proteome in the presence of bone marrow stromal cells have not been elucidated. Reverse-phase protein array analysis of CLL cells before and 24 h after stromal cell interaction revealed changed levels of proteins that regulate cell cycle, gene transcription, and protein translation. The most hit with respect to both the extent of change in expression level and statistical significance was caveolin-1, which was confirmed with immunoblotting. Caveolin-1 mRNA levels were also upregulated in CLL cells after stromal cell interaction. The induction of caveolin-1 levels was rapid and occurred as early as 1 h. Studies to determine the significance of upregulated caveolin-1 levels in CLL lymphocytes are warranted.

The compression and tensile consecutive deformation behavior and microstructure evolution of Mn18Cr18N steel were investigated by cyclic loading tests at room temperature and strain amplitude from 0.005 to 0.15. The results indicated that the cyclic loading stress-strain curves of the steel show plastic deformation characterized by almost the same working hardening rates without yield plateaus at various strain amplitudes. At the lower strain amplitudes from 0.005 to 0.01, the stress amplitudes and subsequent yield surface radius decreased with cycles, which suggest that stress softening occurs during cyclic loading. At the strain amplitudes from 0.02 to 0.15, the stress amplitudes and subsequent yield surface radius increased with cycles, which imply that stress hardening occurs during cyclic loading. With the increasing of strain amplitudes, the cyclic hardening coefficients monotonically increased, while the cyclic softening coefficients rapidly decreased. The maximum flow stress increased up to 1549.6 MPa after three cycles at the strain amplitude of 0.15, which increased by 395.4 MPa compared to the maximum uniaxial tensile flow stress. It was also demonstrated that the cyclic loading stress-strain behaviors (cyclic softening and hardening) depend on internal stress component rather than effective stress component. TEM observation shows that planar slip with parallel substructures along one direction at high number cycles evolved from various dislocation configurations at low number cycles occurs at the lower strain amplitude of 0.005; double planar slip with grid substructures along two directions at high number cycles evolved from parallel substructures along one direction at low number cycles occurs at the higher strain amplitude of 0.04. Internal stress could be released by dislocation rearrangement and activation of cross slips during cyclic loading process, which induce stress softening at lower strain amplitudes; while slipping and twining alone two intersectional directions caused stress hardening at higher strain amplitudes.

Hot deformation behavior of as-cast Mn18Cr18N austenitic stainless steel was studied in the temperature range of 950-1200 °C and strain rate range of 0.001-1 s-1 using isothermal hot compression tests. The true stress-strain curves of the steel were characterized by hardening and subsequent softening and varied with temperatures and strain rates. The hot deformation activation energy of the steel was calculated to be 657.4 kJ/mol, which was higher than that of the corresponding wrought steel due to its as-cast coarse columnar grains and heterogeneous structure. Hot processing maps were developed at different plastic strains, which exhibited two domains with peak power dissipation efficiencies at 1150 °C/0.001 s-1 and 1200 °C/1 s-1, respectively. The corresponding microstructures were analyzed by optical microscopy (OM), scanning electron microscopy (SEM), and electron backscatter diffraction (EBSD). It has been confirmed that dynamic recrystallization (DRX) controlled by dislocation slipping and climbing mechanism occurs in the temperature and strain rate range of 1050-1200 °C and 0.001-0.01 s-1; And DRX controlled by twinning mechanism occurs in the temperature and strain rate range of 1100-1200 °C, 0.1-1 s-1. These two DRX domains can serve as the hot working windows of the as-cast steel at lower strain rates and at higher strain rates, respectively. The processing maps at different strains also exhibit that the instability region decreases with increasing strain. The corresponding microstructures and the less tensile ductility in the instability region imply that the flow instability is attributed to flow localization accelerated by a few layers of very fine recrystallized grains along the original grain boundaries.

// Xiaofeng Li 1 , Huiqin Chen 1 , Yun Cai 1 , Pingping Zhang 1 and Zhuanggui Chen 1 1 Department of Pediatrics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China Correspondence to: Zhuanggui Chen, email: zhangsuqin3313@163.com Keywords: autoimmune hepatitis, STAT4, PTPN22, single nucleotide polymorphism, interaction Received: February 09, 2017 Accepted: April 12, 2017 Published: April 27, 2017 ABSTRACT Aims: To investigate the impact of signal transducer and activator of transcription 4 (STAT4) and the protein tyrosine phosphatase N22 (PTPN22) gene single nucleotide polymorphisms (SNPs), gene–gene interactions and haplotype on type-1 Autoimmune Hepatitis (AIH) risk. Results: Logistic regression analysis showed that type 1 AIH was significantly higher in carriers of T allele of rs7574865 than those with GG genotype ( P - value less than 0.001), higher in carriers of C allele of rs7582694 than those with GG genotype ( P - value < 0.001), and lower in carriers of T allele of rs2476601 than those with CC genotype ( P - value < 0.001). GMDR model indicated a significant two-locus model ( p = 0.0100) involving rs7582694 and rs2476601. Participants with GC or CC of rs7582694 and CC of rs2476601 genotype have the highest type 1 AIH risk ( P - value < 0.001), after covariates adjustment. Haplotype containing the rs7582694-C and rs7574865-T alleles were associated with a statistically increased type 1 AIH risk ( P < 0.001). Materials and Methods: Logistic regression was performed to investigate association between SNPs within STAT4 and PTPN22 gene and susceptibility to type 1 AIH. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combinations among the 4 SNPs. Conclusions: We conclude that rs7574865 and rs7582694 in STAT4 gene minor alleles, interaction between rs7582694 and rs2476601, and haplotype containing the rs7582694-C and rs7574865-T alleles are associated with increased type 1 AIH risk, but rs2476601 in PTPN22 gene minor allele is associated with decreased type 1 AIH risk.

Orf virus has been utilized as a safe and efficient viral vector against not only diverse infectious diseases, but also against tumors. However, the nature of the genes triggered by the vector in human cells is poorly characterized. Using RNA sequencing technology, we compared specific changes in the transcriptomic profiles in human foreskin fibroblast cells following infection by the orf virus. The results indicated that orf virus upregulates or downregulates expression of a variety of genes, including genes involved in antiviral immune response, apoptosis, cell cycle and a series of signaling pathways, such as the IFN and p53-signaling pathways. The orf virus stimulates or inhibits immune gene expression such as chemokines, chemokine receptors, cytokines, cytokine receptors, and molecules involved in antigen uptake and processing after infection. Expression of pro-apoptotic genes increased at 8 hours post-infection. The p53 signaling pathway was activated to induce apoptosis at the same time. However, the cell cycle program was promoted after infection, which may be due to the immunomodulatory genes of the orf virus. This presents the first description of transcription profile changes in human foreskin fibroblast cells after orf virus infection and provides an in-depth analysis of the interaction between the host and orf virus. These data offer new insights into the understanding of the mechanisms of infection by orf virus and identify potential targets for future studies.

Hot deformation behavior and microstructure evolution of as-cast Mn18Cr18N austenitic stainless steel were studied by uniaxial compression experiments at temperatures from 1123 K to 1473 K under strain rates of 0.001–1 s−1 up to the true strain of 0.69. The true stress-strain curves, characterized by hardening and subsequent softening, varied with temperatures and strain rates. By multiple linear regressions of the flow stress-strain data, the hyperbolic sine constitutive equation for the steel was developed and the hot deformation activation energy is calculated to be 672 KJ mol−1, which implies that the recrystallization is sluggish during hot deformation. Furthermore, two dynamic recrystallization mechanisms, dislocation and twinning, were demonstrated. At higher temperatures and lower strain rates, the dynamic recrystallization was controlled by dislocation slip and climbing. The fully recrystallized grains, composed of sub-grains and various dislocation configurations, can be obtained at 1473 K and 0.001 s−1 up to the true strain of 0.69. However, the dynamic recrystallization was controlled by twinning at higher strain rates and lower temperatures. Most of recrystallized grains are composed of twins, micro-twins and dislocation cells in twins. It suggests that twinning plays an important role during nucleation and progress of DXR by inducing separation of bulged grain boundaries and accelerating the expansion of migratory boundaries. The uniformly refined recrystallized grains with a large number of Σ3 twins were obtained at 1373 K and 1 s−1 up to the true strain of 0.69.

Two new polyimide based porous covalent organic frameworks (PI-COF 201 and PI-COF 202) were synthesized in high yields by directly heating mixtures of melamine and pyromellitic dianhydride and naphthalenetetracarboxylic dianhydride in a N2 atmosphere, respectively. Their structures and properties were characterized using elemental analysis, Fourier transform infrared spectra, X-ray photoelectron spectroscopy, X-ray powder diffraction, N2 adsorption–desorption and scanning electron microscopy and their fluorescence properties were studied in detail. These two COFs emitted strong fluorescence in appropriate solvents that originated from the π* → n transition caused by the high electro-delocalization and inherently rigid structure of the COF materials. The strong quenching effects of Fe3+ on the fluorescence of the COFs allowed selective chemosensing for Fe3+.

Covalent organic frameworks (COFs) are a new class of porous organic materials, which are prepared with organic building units via strong covalent bonds. Their well-defined crystalline porous structures together with special functionalities have endowed COF materials with important potential in wide applications, such as gas storage, adsorption, optoelectricity, catalysis and chemical sensing. Particularly, the fluorescence properties and the sensing applications of COF materials have attracted wide attention of analysts. This critical review presents the important development in the design, synthesis and analytical application of fluorescent COF materials as well as the investigation of luminescence characteristics.