Vitamin D regulates microbiome-dependent cancer immunity.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

MRI-Based Kinetic Heterogeneity Evaluation in the Accurate Access of Axillary Lymph Node Status in Breast Cancer Using a Hybrid CNN-RNN Model.

BACKGROUND: Accurate evaluation of the axillary lymph node (ALN) status is needed for determining the treatment protocol for breast cancer (BC). The value of magnetic resonance imaging (MRI)-based tumor heterogeneity in assessing ALN metastasis in BC is unclear. PURPOSE: To assess the value of deep learning (DL)-derived kinetic heterogeneity parameters based on BC dynamic contrast-enhanced (DCE)-MRI to infer the ALN status. STUDY TYPE: Retrospective. SUBJECTS: 1256/539/153/115 patients in the training cohort, internal validation cohort, and external validation cohorts I and II, respectively. FIELD STRENGTH/SEQUENCE: 1.5 T/3.0 T, non-contrast T1-weighted spin-echo sequence imaging (T1WI), DCE-T1WI, and diffusion-weighted imaging. ASSESSMENT: Clinical pathological and MRI semantic features were obtained by reviewing histopathology and MRI reports. The segmentation of the tumor lesion on the first phase of T1WI DCE-MRI images was applied to other phases after registration. A DL architecture termed convolutional recurrent neural network (ConvRNN) was developed to generate the KHimage (kinetic heterogeneity of DCE-MRI image) score that indicated the ALN status in patients with BC. The model was trained and optimized on training and internal validation cohorts, tested on two external validation cohorts. We compared ConvRNN model with other 10 models and the subgroup analyses of tumor size, magnetic field strength, and molecular subtype were also evaluated. STATISTICAL TESTS: Chi-squared, Fisher's exact, Student's t, Mann-Whitney U tests, and receiver operating characteristics (ROC) analysis were performed. P < 0.05 was considered significant. RESULTS: The ConvRNN model achieved area under the curve (AUC) of 0.802 in the internal validation cohort and 0.785-0.806 in the external validation cohorts. The ConvRNN model could well evaluate the ALN status of the four molecular subtypes (AUC = 0.685-0.868). The patients with larger tumor sizes (>5 cm) were more susceptible to ALN metastasis with KHimage scores of 0.527-0.827. DATA CONCLUSION: A ConvRNN model outperformed traditional models for determining the ALN status in patients with BC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Blocking Superantigen-Mediated Diseases: Challenges and Future Trends.

Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vß and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases.

Boosting the Catalase-Like Activity of SAzymes via Facile Tuning of the Distances between Neighboring Atoms in Single-Iron Sites.

A nanozyme with neighboring single-iron sites (Fe2 -SAzyme) was introduced as a bioinspired catalase mimic, featuring excellent activity under varied conditions, twice as high as that of random Fe1 -SAzyme and ultrahigh H2 O2 affinity as that of bioenzymes. Surprisingly, the interatomic spacing tuning between adjacent iron sites also suppressed the competitive peroxidase pathway, remarkably increasing the catalase/peroxidase selectivity up to ~6 times compared to Fe1 -SAzyme. This dramatically switched the catalytic activity of Fe-SAzymes from generating (i.e. Fe1 -SAzymes, preferably mimicking peroxidase) to scavenging ROS (i.e. Fe2 -SAzymes, dominantly mimicking catalase). Theoretical and experimental investigations suggested that the pairwise single-iron sites may serve as a robust molecular tweezer to efficiently trap and decompose H2 O2 into O2 , via cooperative hydrogen-bonding induced end-bridge adsorption. The versatile mechano-assisted in situ MOF capsulation strategy enabled facile access to neighboring M2 -SAzyme (M=Fe, Ir, Pt), even up to a 1000 grams scale, but with no obvious scale-up effect for both structures and performances.

[Production and antigenicity analysis of a recombinant insulinoma associated protein-2 in HEK293 cells].

Insulinoma-associated protein-2 (IA-2) is a transmembrane glycoprotein belonging to the tyrosine phosphatase-like protein family as well as an important autoantigen in the diagnosis of type 1 diabetes. IA-2 products have been marketed in Europe and the United States. At present, commercially available IA-2 antigens are either the recombinant IA-2ic domain or the IA-2 naturally extracted from bovine islets. However, the recombinant IA-2 antigen displays weak positive in clinic practice, which often results in occasional detection failures, thus cannot completely replace the naturally extracted IA-2 antigen. In this study, an HEK293 expression system was used to explore the production of recombinant IA-2. An IA-2 transmembrane fragment (IA-2 TMF) located at amino acid position 449-979, also known as the natural membrane protein form of IA-2, was produced in HEK293 through transfection, and both the expression conditions and dissolution conditions of the membrane protein were also optimized. The purified membrane protein yield was 0.78 mg/L cell culture. Subsequently, the antigen activity of IA-2 TMF was compared with RSR rhIA-2 through enzyme linked immunosorbent assay. The serum of 77 type 1 diabetes patients and 32 healthy volunteers were detected. Receiver operating characteristic curve (ROC) curve was used to characterize the sensitivity and specificity of the test results. The results showed that the sensitivity of IA-2 TMF was 71.4% (55/77), while the sensitivity of RSR rhIA-2 was 63.6% (49/77), and the specificity of both antigens were all 100%. There was no significant difference in specificity between the two antigens, but the sensitivity of IA-2 TMF was appreciably better than that of the imported gold standard RSR rhIA-2 antigen. In conclusion, the recombinant IA-2 TMF produced in HEK293 cells can be used as a raw material to develop in vitro diagnostic reagents for type 1 diabetes.

Allyl-isothiocyanate against colorectal cancer via the mutual dependent regulation of p21 and Nrf2.

Allyl-isothiocyanate (AITC) is a common Isothiocyanates (ITC) and its chemo-preventive and anti-tumor effects are believed to be related to the activation of NF-E2 p45-related Factor 2 (Nrf2). However, its anti-tumor effects on colorectal cancer (CRC) are not well elucidated. Here, we investigated the therapeutic in vitro and/or in vivo effects and mechanisms of action (MOA) for AITC on CRC cell line HCT116 (human) and MC38 (mouse). AITC treatment in a low concentration range (1 mg/kg in vivo) significantly inhibited the tumor cell growth and increased the expression of p21 and Nrf2. The AITC-mediated induction of p21 was dependent on Nrf2 but independent on p53 in vitro and in vivo at low dose. In contrast, the high dose of AITC (5 mg/kg in vivo) failed to increase substantial levels of p21/MdmX, and impaired the total antioxidant capacity of tumors and subsequent anti-tumor effect in vivo. These results suggest that an optimal dose of AITC is important and required for the proper Nrf2 activation and its anti-CRC effects and thus, providing insights into the potential applications of AITC for the prevention and treatment of CRC.

Monocyte/macrophage mediates the impact of depression on Crohn's disease.

BACKGROUND: Depression increases the risk of Crohn's disease (CD) and worsens its prognosis. Monocytes/macrophages, immune modulate cells, play vital roles in both depression and CD. OBJECTIVES: We investigated whether monocyte/macrophage could mediate the impact of depression on CD through induction of CD4 + T lymphocyte differentiation and epithelial barrier dysfunction, in addition to the alteration of their own phagocytic ability and cytokines production. METHODS: Circulating monocytes and intestinal macrophages were isolated from eligible CD patients, divided into depressed and non-depressed groups. Phagocytosis was determined using flow cytometry while in vitro cytokine production was quantified using Luminex assay and qPCR. CD4 + T cells were cocultured with monocytes, then Type 1 Helper T Lymphocytes Th1/Type 2 Helper T Lymphocytes (Th2) /Type 17 Helper T Lymphocytes (Th17)/Treg subsets were analyzed using flow cytometry and qPCR. Caco-2 monolayers simulating epithelial barrier were cocultured with macrophages, and integrity and proliferation were evaluated. Tight junction protein expression was detected using immunofluorescence and western blot. RESULTS: Decreased monocyte/macrophage phagocytosis and enhanced production of pro-inflammatory cytokines including Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and Interleukin-1ß (IL-1ß) were revealed in the depressed versus non-depressed CD groups. Higher proportions of Th1 and Th17 cells with a lower proportion of Treg cell were observed after cocultured with monocytes from the depressed versus non-depressed CD patients. So were the expressions of their corresponding transcription factors T-bet, Retinoic Acid Related Orphan Nuclear Receptor gamma T (RORγt) and Forkhead box protein P3 (FoxP3). Caco-2 cells cocultured with macrophages from depressed CD displayed lower Transepithelial electric resistance (TEER), reduced proliferation activity, and decreased tight junction protein expressions compared with their counterpart cocultured with macrophages from non-depressed CD. CONCLUSIONS: Monocyte/macrophage may underlie the impact of depression upon CD via decreased phagocytosis, increased pro-inflammatory cytokine production, inducing CD4 + T cell differentiation toward Th1/Th17 cells rather than Treg cell, and impairing macrophage-enhanced epithelial barrier.

Efficacy and Safety of Plasma Exchange Combined with Hemoperfusion in the Treatment of Organophosphorus Poisoning: A Meta-Analysis.

INTRODUCTION: The aim of the study was to systematically evaluate the efficacy and safety of plasma exchange combined with hemoperfusion in the treatment of organophosphorus poisoning. METHODS: PubMed, Embase, the Cochrane Library, China National Knowledge Internet, Wanfang database, and Weipu database were searched for articles about this subject. Literature screening and selection were conducted in strict accordance with the inclusion and exclusion criteria. RESULTS: 14 randomized controlled trials with 1,034 participants were included in this meta-analysis study, including 518 cases in plasma exchange combined with hemoperfusion group (the combination treatment group) and 516 cases in hemoperfusion group (the control group). Compared with the control group, the combination treatment group was associated with a higher effective rate (relative risk [RR] = 1.20, 95% confidence interval [CI] [1.11, 1.30], p < 0.00001) and lower fatality rate (RR = 0.28, 95% CI [0.15, 0.52], p< 0.0001); reduced TNF-α (standardized mean difference [SMD] = -1.95, 95% CI [-2.42, -1.48], p < 0.00001), IL-6 (SMD = -1.94, 95% CI [-3.08, -0.80], p = 0.0009), and C-reactive protein (CRP) (SMD = -1.94, 95% CI [-2.86, -1.03], p < 0.0001); shorten coma time (SMD = -1.99, 95% CI [-2.75, -1.24], p < 0.00001), recovery time of cholinesterase activity (SMD = -1.71, 95% CI [-1.90, -1.53], p < 0.00001), and hospital stay (SMD = -1.29, 95% CI [-1.59, -0.98], p < 0.00001). The incidence of complications in the combination treatment group such as liver and kidney damage (RR = 0.30, 95% CI [0.18, 0.50], p < 0.00001), pulmonary infection (RR = 0.29, 95% CI [0.18, 0.47], p < 0.00001), and intermediate syndrome (RR = 0.32, 95% CI [0.21, 0.49], p < 0.00001) was lower than that in the control group. CONCLUSIONS: The current evidence suggests that the combination of plasma exchange with hemoperfusion therapy can reduce the mortality of patients with organophosphorus poisoning, shorten the recovery time of cholinesterase activity and the time of coma, reduce the average length of hospital stay, and reduce the levels of IL-6, TNF-α, and CRP, but high-quality randomized double-blind controlled trials are still required to confirm the current findings in the future.

Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases.

Post-translational modifications regulate numerous biochemical reactions and functions through covalent attachment to proteins. Phosphorylation, acetylation and ubiquitination account for over 90% of all reported post-translational modifications. As one of the tyrosine protein kinases, spleen tyrosine kinase (SYK) plays crucial roles in many pathophysiological processes and affects the pathogenesis and progression of various diseases. SYK is expressed in tissues outside the hematopoietic system, especially the heart, and is involved in the progression of various cardio-cerebrovascular diseases, such as atherosclerosis, heart failure, diabetic cardiomyopathy, stroke and others. Knowledge on the role of SYK in the progress of cardio-cerebrovascular diseases is accumulating, and many related mechanisms have been discovered and validated. This review summarizes the role of SYK in the progression of various cardio-cerebrovascular diseases, and aims to provide a theoretical basis for future experimental and clinical research targeting SYK as a therapeutic option for these diseases.

Autocrine activation of MAPK signaling mediates intrinsic tolerance to androgen deprivation in LY6D prostate cancer cells.

The emergence of castration-resistant prostate cancer remains an area of unmet clinical need. We recently identified a subpopulation of normal prostate progenitor cells, characterized by an intrinsic resistance to androgen deprivation and expression of LY6D. We here demonstrate that conditional deletion of PTEN in the murine prostate epithelium causes an expansion of transformed LY6D+ progenitor cells without impairing stem cell properties. Transcriptomic analyses of LY6D+ luminal cells identified an autocrine positive feedback loop, based on the secretion of amphiregulin (AREG)-mediated activation of mitogen-activated protein kinase (MAPK) signaling, increasing cellular fitness and organoid formation. Pharmacological interference with this pathway overcomes the castration-resistant properties of LY6D+ cells with a suppression of organoid formation and loss of LY6D+ cells in vivo. Notably, LY6D+ tumor cells are enriched in high-grade and androgen-resistant prostate cancer, providing clinical evidence for their contribution to advanced disease. Our data indicate that early interference with MAPK inhibitors can prevent progression of castration-resistant prostate cancer.

Total Hip Arthroplasty in Patients with Crowe III/IV Developmental Dysplasia of the Hip: Acetabular Morphology and Reconstruction Techniques.

The severe anatomic deformities render acetabular reconstruction as one of the greatest challenges in total hip arthroplasty (THA) for patients with Crowe III/IV developmental dysplasia of the hip (DDH). Thorough understanding of acetabular morphology and bone defect is the basis of acetabular reconstruction techniques. Researchers have proposed either true acetabulum position reconstruction or high hip center (HHC) position reconstruction. The former can obtain the optimal hip biomechanics, including bulk femoral head autograft, acetabular medial wall displacement osteotomy, and acetabular component medialization, while the latter is relatively easy for hip reduction, as it can avoid neurovascular lesions and obtain more bone coverage; however, it cannot achieve good hip biomechanics. Both techniques have their own advantages and disadvantages. Although there is no consensus on which approach is better, most researchers suggest the true acetabulum position reconstruction. Based on the various acetabular deformities in DDH patients, evaluation of acetabular morphology, bone defect, and bone stock using the 3D image and acetabular component simulation techniques, as well as the soft tissue tension around the hip joint, individualized acetabular reconstruction plans can be formulated and appropriate techniques can be selected to acquire desired clinical outcomes.

The association between liver fibrosis scores and chronic kidney disease.

Purpose: This study aimed to clarify the relationship between liver fibrosis scores (Fibrosis-4, BARD score, and BAAT score) and chronic kidney disease (CKD). Methods: We collected a range of data from 11,503 subjects (5,326 men and 6,177 women) from the rural regions of Northeastern China. Three liver fibrosis scores (LFSs) including fibrosis-4 (FIB-4), BARD score, and BAAT score were adopted. A logistic regression analysis was used to calculate odds ratios and the 95% confidence interval. A subgroup analysis showed the association between LFSs and CKD under different stratifications. Restricted cubic spline could further explore whether there is a linear relationship between LFSs and CKD. Finally, we used C-statistics, Net Reclassification Index (NRI), and Integrated Discrimination Improvement (IDI) to assess the effect of each LFS on CKD. Results: Through the baseline characteristics, we observed that LFSs were higher in the CKD population than in non-CKD. The proportion of participants with CKD also increased with LFSs. In a multivariate logistic regression analysis, the ORs of CKD were 6.71 (4.45-10.13) in FIB-4, 1.88 (1.29-2.75) in the BAAT score, and 1.72 (1.28-2.31) in the BARD score by comparing the high level with the low level in each LFSs. Moreover, after adding LFSs to the original risk prediction model, which consisted of age, sex, drinking, smoking, diabetes, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and mean waist circumference, we found the new models have higher C-statistics. Furthermore, NRI and IDI both indicate LFSs had a positive effect on the model. Conclusions: Our study showed that LFSs are associated with CKD among middle-aged populations in rural areas of northeastern China.

Acute Oral Toxicity and Genotoxicity Test and Evaluation of Cinnamomum camphora Seed Kernel Oil.

Cinnamomum camphora seed kernel oil (CCSKO) is one of the important natural medium chain triglycerides (MCT) resources, with more than 95.00% of medium chain fatty acids found in the world, and has various physiological effects. However, CCSKO has not been generally recognized as a safe oil or new food resource yet. The acute oral toxicity test and a standard battery of genotoxicity tests (mammalian erythrocyte micronucleus test, Ames test, and in vitro mammalian cell TK gene mutation test) of CCSKO as a new edible plant oil were used in the study. The results of the acute oral toxicity test showed that CCSKO was preliminary non-toxic, with an LD50 value higher than 21.5 g/kg body weight. In the mammalian erythrocyte micronucleus test, there was no concentration-response relationship between the dose of CCSKO and micronucleus value in polychromatic erythrocytes compared to the negative control group. No genotoxicity was observed in the Ames test in the presence or absence of S9 at 5000 µg/mL. In vitro mammalian cell TK gene mutation test showed that CCSKO did not induce in vitro mammalian cell TK gene mutation in the presence or absence of S9 at 5000 µg/mL. These results indicated that CCSKO is a non-toxic natural medium-chain oil.

LncRNA SPINT1-AS1/miR-433-3p/E2F3 positive feedback loop promotes the KRAS-mutant colorectal cancer cell proliferation, migration and invasion.

Colorectal cancer (CRC) features high prevalence and mortality. Long non-coding RNAs (lncRNAs) exert nonnegligible roles in human cancer development. Nevertheless, the functions of most lncRNAs still remain unexplored. We currently focused on detecting the influence of SPINT1 antisense RNA 1 (SPINT1-AS1) on CRC development and investigating into the potential regulatory mechanism. RT-qPCR analysis first confirmed that SPINT1-AS1 exhibited high expression in KRAS-mutant (KRASMUT) CRC cells. Through series of functional experiments, we observed that knockdown of SPINT1-AS1 weakened KRASMUT CRC cell proliferation, migration and invasion. Afterwards, the implementation of mechanism assays help to verify that SPINT1-AS1 sequestered microRNA-433-3p (miR-433-3p) to regulate the expression of E2F transcription factor 3 (E2F3). Besides, E2F3 was validated to activate the transcription of SPINT1-AS1 in turn. Rescue experiments confirmed the functional influence of SPINT1-AS1/miR-433-3p/E2F3 on CRC cells. In summary, the molecular axis of SPINT1-AS1/miR-433-3p/E2F3 forms a positive loop which might become a potential biomarker in CRC.

Impact of liver fibrosis score on the incidence of stroke: A cohort study.

PURPOSE: The purpose was to explore the value of liver fibrosis scores (fibrosis-4, BAAT score and BARD score) for incidence risk of stroke in a cohort study. METHODS: A total of 9088 participants without stroke history enrolled the follow-up. Three liver fibrosis scores (LFSs) including FIB-4, BARD score and BAAT score were adopted. The end point was stroke. Cox regression analysis was used to calculate hazard ratios and 95% confidence interval. Kaplan-Meier curve was used to show the probability of stoke in different levels of LFSs. Subgroup analysis showed the association between LFSs and stroke under different stratification. Restricted cubic spline could further explore whether there is a linear relationship between LFSs and stroke. Finally, we used C-statistics, Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) to assess the discriminatory power of each LFS for stroke. RESULTS: During a median follow-up time of 4.66 years, 272 participants had a stroke. Through the baseline characteristics, we observed that the stroke incidence population tends to be male and older. It was shown by Kaplan-Meier that three LFSs were associated with stroke and high levels of LFSs significantly increase the probability of stroke. In the univariate Cox regression analysis, the HR of stroke risk was 6.04 (4.14-8.18) in FIB-4, 2.10 (1.45-3.04) in BAAT score and 1.81 (1.38-2.38) in BARD score by comparing the high level with the low level at each LFSs. The adjusted HRs for three LFSs were 2.05 (1.33-3.15) in FIB-4, 1.61 (1.10-2.35) in BAAT score and 1.54 (1.17-2.04) in BARD score by comparing the high group with low group. We found that multivariable-adjusted HRs of three LFSs still increased for stroke when stratified by various factors in subgroup analysis. Moreover, after adding LFSs to original risk prediction model which consist of age, sex, drinking, smoking, hypertension, diabetes, low-density lipoprotein cholesterol, total cholesterol and triglycerides, we found that new models have higher C-statistics of stroke. Furthermore, we calculated Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) to show the ability of LFSs to predict stroke. CONCLUSIONS: Our study showed that three LFSs were associated with stroke amongst middle-aged populations in rural areas of Northeast China. Furthermore, it suggests that LFSs can be used as a risk stratification tool to predict stroke.

Rapid Optical Biosensing of SARS-CoV-2 Spike Proteins in Artificial Samples.

Tests for SARS-CoV-2 are crucial for the mass surveillance of the incidence of infection. The long waiting time for classic nucleic acid test results highlights the importance of developing alternative rapid biosensing methods. Herein, we propose a fiber-optic biolayer interferometry-based biosensor (FO-BLI) to detect SARS-CoV-2 spike proteins, extracellular domain (ECD), and receptor-binding domain (RBD) in artificial samples in 13 min. The FO-BLI biosensor utilized an antibody pair to capture and detect the spike proteins. The secondary antibody conjugated with horseradish peroxidase (HRP) reacted with the enzyme substrate for signal amplification. Two types of substrates, 3,3'-diaminobenzidine (DAB) and an advanced 3-Amino-9-ethylcarbazole (i.e., AMEC), were applied to evaluate their capabilities in enhancing signals and reaching high sensitivity. After careful comparison, the AMEC-based FO-BLI biosensor showed better assay performance, which detected ECD at a concentration of 32-720 pM and RBD of 12.5-400 pM in artificial saliva and serum, respectively. The limit of detection (LoD) for SARS-CoV-2 ECD and RBD was defined to be 36 pM and 12.5 pM, respectively. Morphology of the metal precipitates generated by the AMEC-HRP reaction in the fiber tips was observed using field emission scanning electron microscopy (SEM). Collectively, the developed FO-BLI biosensor has the potential to rapidly detect SARS-CoV-2 antigens and provide guidance for "sample-collect and result-out on-site" mode.

Efficacy and Safety of Fuzheng Yiqi Kang-Ai Decoction Combined with External Irradiation in the Treatment of Undifferentiated Thyroid Carcinoma and Its Influence on Antiangiogenesis.

Objective: To explore the efficacy and safety of Fuzheng Yiqi Kang-ai (FZYQKA for short) decoction with external irradiation in the treatment of undifferentiated thyroid carcinoma (UTC) and its influence on antiangiogenesis. Methods. In this retrospective study, the clinical data of 120 patients with UTC admitted to Zibo Central Hospital (February 2019-February 2020) were retrospectively analyzed, and the patients were equally divided into the experimental group (EG) and the control group (CG) according to the order of admission. All patients received external irradiation, and the EG received FZYQKA decoction additionally. FZYQKA decoction was taken orally 1 dose daily in 3 times with a total of 100 ml, for a total of 2 months. Short-term efficacy, incidence of acute radiotoxic responses, levels of matrix metalloproteinases (MMPs), indexes of immune function, and level of vascular endothelial growth factor (VEGF) were compared between both groups. Results: Compared with the CG, the disease control rate of the EG was obviously higher (73.3% vs. 40.0%, P < 0.001). The acute radiotoxic responses of the two groups were mainly grade I-II oral mucositis, radiodermatitis, pharyngitis, esophagitis, and myelosuppression, and only three patients (5.0%) had grade III-IV toxic reactions. Compared with the CG, the incidence of grade I-II oral mucositis, radiodermatitis, pharyngitis, and esophagitis in the EG was obviously lower (P < 0.05). After treatment, compared with the CG, levels of MMPs and VEGF of the EG were obviously lower (P < 0.001). After treatment, compared with the CG, indexes of immune function of the EG were obviously higher (P < 0.001). Conclusion: For patients with UTC, FZYQKA decoction combined with external irradiation can exert the antiangiogenesis effect, reduce levels of MMPs, and optimize the short-term efficacy. The safe treatment method has mild toxic and side effects, which should be popularized in practice.

Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol.

Apoptosis is regulated by interactions between the BH3-only and multi-domain Bcl-2 family proteins. These interactions are integrated on the outer mitochondrial membrane (OMM) where they set the threshold for apoptosis, known as mitochondrial priming. However, how mitochondrial priming is controlled at the level of single cells remains unclear. Retrotranslocation of Bcl-XL has been proposed as one mechanism, removing pro-apoptotic Bcl-2 proteins from the OMM, thus reducing priming. Contrary to this view, we now show that Bcl-XL retrotranslocation is inhibited by binding to its BH3-only partners, resulting in accumulation of these protein complexes on mitochondria. We find that Bcl-XL retrotranslocation dynamics are tightly coupled to mitochondrial priming. Quantifying these dynamics indicates the heterogeneity in priming between cells within a population and predicts how they subsequently respond to a pro-apoptotic signal.

DNA Polymerase Gamma Recovers Mitochondrial Function and Inhibits Vascular Calcification by Interacted with p53.

DNA polymerase gamma (PolG) is the major polymerase of mitochondrial DNA (mtDNA) and essential for stabilizing mitochondrial function. Vascular calcification (VC) is common senescence related degenerative pathology phenomenon in the end-stage of multiple chronic diseases. Mitochondrial dysfunction was often observed in calcified vessels, but the function and mechanism of PolG in the calcification process was still unknown. The present study found PolGD257A/D257A mice presented more severe calcification of aortas than wild type (WT) mice with vitamin D3 (Vit D3) treatment, and this phenomenon was also confirmed in vitro. Mechanistically, PolG could enhance the recruitment and interaction of p53 in calcification condition to recover mitochondrial function and eventually to resist calcification. Meanwhile, we found the mutant PolG (D257A) failed to achieve the same rescue effects, suggesting the 3'-5' exonuclease activity guarantee the enhanced interaction of p53 and PolG in response to calcification stimulation. Thus, we believed that it was PolG, not mutant PolG, could maintain mitochondrial function and attenuate calcification in vitro and in vivo. And PolG could be a novel potential therapeutic target against calcification, providing a novel insight to clinical treatment.

Protein powder derived nitrogen-doped carbon supported atomically dispersed iron sites for selective oxidation of ethylbenzene.

Atomically dispersed Fe species embedded in the nitrogen-containing carbon supports (Fe1/NC) are successfully synthesized using a ball milling approach, with commercial protein powder as the nitrogen source. The catalyst exhibits outstanding performance in the oxidation of aromatic compounds containing saturated C-H bonds into corresponding ketones under ambient conditions, which is superior to those of a nanoparticle catalyst (Fen/NC) and a metal-free catalyst (NC).