Employing Constrained Nonnegative Matrix Factorization for Microstructure Segmentation.

Materials characterization using electron backscatter diffraction (EBSD) requires indexing the orientation of the measured region from Kikuchi patterns. The quality of Kikuchi patterns can degrade due to pattern overlaps arising from two or more orientations, in the presence of defects or grain boundaries. In this work, we employ constrained nonnegative matrix factorization to segment a microstructure with small grain misorientations, (<1∘), and predict the amount of pattern overlap. First, we implement the method on mixed simulated patterns-that replicates a pattern overlap scenario, and demonstrate the resolution limit of pattern mixing or factorization resolution using a weight metric. Subsequently, we segment a single-crystal dendritic microstructure and compare the results with high-resolution EBSD. By utilizing weight metrics across a low-angle grain boundary, we demonstrate how very small misorientations/low-angle grain boundaries can be resolved at a pixel level. Our approach constitutes a versatile and robust tool, complementing other fast indexing methods for microstructure characterization.

Cutibacterium acnes induces acne-like lesions in hairless mice models - A comparative study.

Acne vulgaris, a chronic inflammatory skin disease with a high prevalence worldwide, necessitates reliable preclinical models for both understanding its pathogenesis and evaluating potential anti-acne therapies. This study aims to establish a robust mouse model using intracutaneous injection of Cutibacterium acnes bacterial suspension. Three hairless mouse strains (SKH-hr1, SKH-hr2 brown, and SKH-hr2 + ApoE) were systematically compared to ascertain the stains most closely resembling acne in humans. Various assessments, including photo documentation, biophysical evaluation, blood analysis, and histopathology, were conducted. Despite all strains exhibiting acne-like lesions, SKH-hr1 mice emerged as the most suitable model, demonstrating the most satisfactory results across multiple criteria. This research underscores the significance of employing hairless mice strains as models in acne studies to enhance and facilitate the development of effective therapeutic interventions.

Capivasertib in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative advanced breast cancer.

PURPOSE: This review discusses the role and efficacy of Capivasertib in managing Hormone Receptor-Positive (HR+) breast cancer. SUMMARY: Breast cancer is the most prevalent type of cancer among women worldwide. This article is an in-depth analysis of advanced therapeutic options involving Capivasertib in treating HR+ Breast Cancer. It focuses on the mode of action, efficacy, clinical trials, and comparison with fulvestrant alone. This review also highlights the therapy's precision in targeting specific cancer cells. Its mechanism of action involves preventing cancer cells from growing and having a cytotoxic effect on them. It improves progression-free survival while maintaining the quality of life. The side effects can be easily managed by dose reduction or discontinuation of the drug. This article sheds light on the ongoing trials and FDA recognition. CONCLUSION: In conclusion, Capivasertib-fulvestrant therapy shows potential as an innovative therapeutic option for HR+ breast cancer but warrants additional research, especially in randomized control trials (RCT). It resulted in longer progression-free survival compared to fulvestrant alone. Its side effect profile is minimal.

The DNA double-strand break repair proteins γH2AX, RAD51, BRCA1, RPA70, KU80, and XRCC4 exhibit follicle-specific expression differences in the postnatal mouse ovaries from early to older ages.

PURPOSE: Ovarian aging is closely related to a decrease in follicular reserve and oocyte quality. The precise molecular mechanisms underlying these reductions have yet to be fully elucidated. Herein, we examine spatiotemporal distribution of key proteins responsible for DNA double-strand break (DSB) repair in ovaries from early to older ages. Functional studies have shown that the γH2AX, RAD51, BRCA1, and RPA70 proteins play indispensable roles in HR-based repair pathway, while the KU80 and XRCC4 proteins are essential for successfully operating cNHEJ pathway. METHODS: Female Balb/C mice were divided into five groups as follows: Prepuberty (3 weeks old; n = 6), puberty (7 weeks old; n = 7), postpuberty (18 weeks old; n = 7), early aged (52 weeks old; n = 7), and late aged (60 weeks old; n = 7). The expression of DSB repair proteins, cellular senescence (ß-GAL) and apoptosis (cCASP3) markers was evaluated in the ovaries using immunohistochemistry. RESULT: ß-GAL and cCASP3 levels progressively increased from prepuberty to aged groups (P < 0.05). Notably, γH2AX levels varied in preantral and antral follicles among the groups (P < 0.05). In aged groups, RAD51, BRCA1, KU80, and XRCC4 levels increased (P < 0.05), while RPA70 levels decreased (P < 0.05) compared to the other groups. CONCLUSIONS: The observed alterations were primarily attributed to altered expression in oocytes and granulosa cells of the follicles and other ovarian cells. As a result, the findings indicate that these DSB repair proteins may play a role in the repair processes and even other related cellular events in ovarian cells from early to older ages.

Investigating the involvement of the NLRP3/ASC/caspase-1 and NF-κb/MAPK pathways in the pathogenesis of gouty arthritis: Insights from irradiated and non-irradiated Trifolium alexandrium L. extracts and some metabolites.

ETHNOPHARMACOLOGICAL RELEVANCE: Trifolium alexandrinum L. (TA), has traditionally been used in folk medicine for its anti-inflammatory properties against hyperuricemia and gout. However, the specific mechanisms of action of TA have not been thoroughly studied. AIM OF THE WORK: This study aimed to evaluate the protective effects of irradiated (TR25) and non-irradiated (TR0) Trifolium alexandrinum L. aqueous extract (TAAE), along with two isolated compounds, caffeine (CAF) and saponin (SAP), in a rat model of acute gouty arthritis (GA). MATERIALS AND METHODS: The GA model was established by injecting a monosodium urate (MSU) suspension into the knee joint. Synovial tissue pathology was assessed, and levels of TNF-α, IL-6, IL-1ß, NF-κB, mTOR, AKT1, PI3K, NLRP3, and ASC were measured by ELISA. mRNA expression of ERK1, JNK, and p-38 MAPK was detected using qRT-PCR, and Caspase-1 protein expression was assessed by immunohistochemical analysis. Knee swelling, uric acid levels, liver and kidney function, and oxidative stress markers were also evaluated. RESULTS: TAAE analysis identified 170 compounds, with 73 successfully identified using LC-HR-MS/MS, including caffeine citrate and theasapogenol B glycoside as the main constituents. The studied materials demonstrated significant protective effects against GA. TR25 administration significantly mitigated knee joint circumference compared to other treatments. It demonstrated potential in alleviating hyperuricemia, renal and hepatic impairments induced by MSU crystals. TR25 also alleviated oxidative stress and reduced levels of IL1ß, IL-6, TNF-α, and NF-κB. Weak Caspase-1 immune-positive staining was observed in the TR25 group. TR25 decreased NLRP3 and ASC expression, reducing inflammatory cytokine levels in GA. It effectively inhibited the PI3K, AKT, and mTOR signaling pathways, promoting autophagy. Additionally, TR25 suppressed ERK1, JNK, and p-38 MAPK gene expression in synovial tissue. These effects were attributed to various components in TAAE, such as flavonoids, phenolic acids, tannins, alkaloids, and triterpenes. CONCLUSION: Importantly, irradiation (25 KGy) enhanced the antioxidant effects and phtchemical contents of TAAE. Additionally, TR0, TR25, CAF, and SAP exhibited promising protective effects against GA, suggesting their therapeutic potential for managing this condition. These effects were likely mediated through modulation of the NLRP3/ASC/Caspase-1 and ERK/JNK/p-38 MAPK signaling pathways, as well as regulation of the PI3K/AKT/mTOR pathway. Further research is warranted to fully elucidate the underlying mechanisms and optimize their clinical applications.

HER4 Affects Sensitivity to Tamoxifen and Abemaciclib in Luminal Breast Cancer Cells and Restricts Tumor Growth in MCF-7-Based Humanized Tumor Mice.

The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients.

Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Structural characterization and bioactivity profiling of the fungal peptaibiotic tolypin reveal protective effects against influenza viruses.

In a bioprospection for new antivirals, we tested nonribosomally biosynthesized polypeptide antibiotics in MDCK II cells for their actions on influenza A and B viruses (IAV/IBV). Only tolypin, a mixture of closely related 16-residue peptaibiotics from the fungus Tolypocladium inflatum IE 1897, showed promising activity. It was selected for further investigation and structural characterization by ultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HR-MS/MS) and ultrahigh performance liquid chromatography coupled to in-source collision-induced dissociation tandem mass spectrometry (UHPLC-isCID-HR-MS/MS), revealing 12 partially co-eluting individual peptides that were fully sequenced. Since tolypin-related efrapeptins are potent inhibitors of F1/Fo-ATPase, we screened tolypin for its toxicity against MDCK II cells and larvae of the greater wax moth Galleria mellonella. We found that a nontoxic concentration of tolypin (1 µg/mL) reduced the titer of two IBV strains by 4-5 log values, and that of an H3N2 strain by 1-2 log values, but the H1N1pdm strain was not affected. The higher concentrations of tolypin were cytostatic to MDCK II cells, shifted their metabolism from oxidative phosphorylation to glycolysis, and induced paralysis in G. mellonella, supporting the inhibition of F1/Fo-ATPase as the mode of action. Our results lay the foundations for future work to investigate the interplay between viral replication and cellular energy metabolism, as well as the development of drugs that target host factors.

Liposomal irinotecan (HR070803) in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors: a phase 1b dose-escalation and expansion study.

This phase 1b study aimed to evaluate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of HR070803, a novel nanoliposomal formulation of irinotecan, in combination with 5-fluorouracil and leucovorin in patients with pretreated advanced solid tumors. This study consisted of dose-escalation and expansion stages. Dose escalation was performed with a traditional 3 + 3 design; patients received intravenous infusion of HR070803 from 60 to 80 mg/m2, followed by leucovorin (200 mg/m2) and 5-fluorouracil (2000 mg/m2) every 2 weeks. In the expansion stage, patients received treatments at selected tolerable dose. Fifteen patients received treatments at 60 mg/m2 (n = 12) and 80 mg/m2 (n = 3). DLTs occurred in 2 patients at 80 mg/m2 (grade 2 neutropenia that resulted in a dose delay of ≥ 7 days, n = 1; grade 3 febrile neutropenia, n = 1). The MTD was determined to be 60 mg/m2. The most frequent HR070803related adverse events included anorexia, leukopenia, neutropenia, nausea, fatigue, and diarrhea. SN-38, the active metabolite of irinotecan, exhibited lower maximum plasma concentrations and a prolonged terminal half-life when irinotecan was administered via nanoliposome compared to conventional injection. Overall, 4 patients achieved a partial response (confirmed, n = 2), and 9 had stable disease. The MTD of HR070803 was 60 mg/m2 when infused with 5-fluorouracil and leucovorin. Nanoliposomal encapsulation modified the pharmacokinetics of irinotecan and SN-38. HR070803 with 5-fluorouracil and leucovorin demonstrated a manageable safety profile and promising antitumor efficacy in advanced solid tumors. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05086848. Retrospectively registered on Oct. 12, 2021.

Decrotonylation of cGAS K254 prompts homologous recombination repair by blocking its DNA binding and releasing PARP1.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, also exhibits nuclear genomic localization and is involved in DNA damage signaling. In this study, we investigated the impact of cGAS crotonylation on the regulation of the DNA damage response, particularly homologous recombination repair, following exposure to ionizing radiation (IR). Lysine 254 of cGAS is constitutively crotonylated by the CREB-binding protein; however, IR-induced DNA damage triggers SIRT3-mediated decrotonylation. Lysine 254 decrotonylation decreased the DNA-binding affinity of cGAS and inhibited its interaction with PARP1, promoting HR repair. Moreover, SIRT3 suppression led to HR repair inhibition and markedly sensitized cancer cells to IR and DNA-damaging chemicals, highlighting SIRT3 as a potential target for cancer therapy. Overall, this study revealed the crucial role of cGAS crotonylation in the DNA damage response. Furthermore, we propose that modulating cGAS and SIRT3 activities could be potential strategies for cancer therapy.

Oviposition strategies in Pieridae butterflies and the role of an egg-killing plant trait therein.

Most herbivorous insects are host-plant specialists that evolved detoxification mechanisms to overcome their host plant's toxins. In the evolutionary arms-races between Pieridae butterflies and Brassicaceae plants, some plant species have evolved another defence against the pierids: egg-killing. Underneath the eggs, leaves develop a so-called hypersensitive response (HR)-like cell death. Whether some butterflies have evolved oviposition strategies to counter-adapt against egg-killing remains to be studied. In this study, we assessed the oviposition site location of Pieridae butterflies on their natural host plants. We described the plant tissue on which we located the eggs of the most common Pieridae in the Netherlands: Gonepteryx rhamni, Anthocharis cardamines, Pieris rapae, P. napi, P. brassicae and P. mannii. Additionally, we assessed expression of HR-like cell death in response to the deposited butterfly eggs. We found that both A. cardamines and G. rhamni mainly oviposited on the floral stem and the branch, respectively, and oviposited on host plants from lineages not expected to kill pierid eggs. Accordingly, no HR-like cell death was seen. All Pieris eggs found were located on leaves of their host, the only tissue found to express HR-like cell death. Furthermore, each Pieris species was found to at least occasionally oviposit on Brassica nigra. This was the only plant species in this survey that expressed HR-like cell death in response to the eggs of P. rapae, P. napi and P. brassicae. Our observations demonstrate that HR-like cell death remains an effective defence strategy against these Pieris species and as such did not find evidence for the hypothesized counterstrategies. Surveying certain key species and disentangling the micro-evolution of oviposition strategies within a species would allow us to further investigate potential counter-adaptations that evolved against HR-like cell death. This study provides the basis for further investigation of potential counter-adaptations to egg-killing defences.

Effects of Nasal Packing on Patients' Post-operative Vital Signs.

Background Since bilateral nasal packing entails nasal and airway obstruction, this practice consequently leads to oral breathing. The resulting hypoxemia may then negatively impact vital signs, including blood pressure (BP), blood oxygen saturation (SpO2), and heart rate (HR). These systemic effects have a detrimental effect on patients. Objective The objective of this study is to observe the effects of bilateral nasal packing on patients' post-operative vital signs. Materials and methods This prospective study was conducted in the department of otolaryngology - head and neck surgery over a six-month period. The study included 83 post-operative patients with nasal surgery, in which bilateral merocele nasal packing was performed. The patients' pulse oximetry, systolic and diastolic BP, and HR were recorded four times the night before and after surgery. A statistical analysis was performed, and the mean values, standard deviation, and range were calculated. A paired sample t-test was also applied. The results are presented in figures and tables. Results The mean age of the participants was 27.65 ± 10.72 years, and 56 (67.5%) were male. Septoplasty was the most common surgery performed, with 63 participants having undergone this procedure (75.9%). When the pre-operative mean values of systolic and diastolic BP, SpO2, and HR were compared with the post-operative mean values, when a bilateral nasal pack was in place, a significant increase was found in all, with a p-value of <0.001 in each. Conclusion Bilateral nasal packing affects patients' vital signs by significantly increasing diastolic and systolic BP and decreasing SpO2. The HR is also significantly increased when packing is in place.

Bone and muscle differences in children and adolescents with type 1 diabetes: The mediating role of physical activity.

Children with type 1 diabetes (T1D) experience an increased risk of fracture, which may be related to altered bone development. We aimed to assess differences in bone, muscle and physical activity (PA), and explore if better muscle and PA measures would mitigate bone differences between children and adolescents with T1D and typically developing peers (TDP). We matched 56 children and adolescents with T1D (mean age 11.9 yrs) and 56 TDP (11.5 yrs) by sex and maturity from 171 participants with T1D and 66 TDP (6-17 yrs). We assessed the distal radius and tibia with high-resolution peripheral quantitative computed tomography (HR-pQCT), and the radius and tibia shaft bone and muscle with pQCT. We also measured muscle function from force-related measures in neuromuscular performance tests (push-up, grip test, countermovement and long jump). We compared PA based on questionnaire scores and accelerometers between groups. Bone, muscle, and neuromuscular performance measures were compared using MANOVA. We used mediation to explore the role of PA and muscle in bone differences. Children and adolescents with T1D had 6-10 % lower trabecular density, bone volume fraction, thickness and number at both distal radius and tibia, and 11 % higher trabecular separation at the distal radius than TDP. They also had 3-16 % higher cortical and tissue mineral density, and cortical thickness at the distal radius, 5-7 % higher cortical density and 1-3 % higher muscle density at both shaft sites compared to TDP. PA mediated the between-group difference in trabecular number (indirect effect -0.04) at the distal radius. Children and adolescents with T1D had lower trabecular bone density and deficits in trabecular micro-architecture, but higher cortical bone density and thickness at the radius and tibia compared to TDP. They engaged in less PA but had comparable muscle measures to those of TDP. PA participation may assist in mitigating deficit in trabecular number observed in children and adolescents with T1D.

Hierarchically design MoS2/CdNi@RGO ultra-thin hybrid sheet for Photocatalytic degradation of organic contaminants fingerprinting in environmental matrices.

The aim of this study was to synthesize effective and economical MoS2/CdNi@rGO photocatalysts and investigate their performance in the degradation of organic pollutants in synthetic effluent. The objective was to assess the characterization results of the synthesized photocatalysts using XRD, SEM/EDS, TEM/HR-TEM, Raman spectrum, and BET isotherm analysis tools. These analyses revealed the good adhesion of MoS2 with rGO and provided insights into the structure and properties of the materials. The results showed that the MoS2/CdNi@rGO photocatalysts exhibited remarkable degradation efficiency for organic pollutants such as Rhodamine-B, erichrome black, and malachite green. The outcomes of the study demonstrated that the MoS2/CdNi@rGO catalyst had the greatest rate constant for Rhodamine-B (RhB) decomposition. which would have been approximately 33 times higher than that of pure RGO (0.0121 min-1). The MoS2/CdNi@rGO photocatalysts also showed excellent recyclability and persistence across five recycle assays, indicating their potential for practical applications in wastewater treatment. The photocatalyst was moderately active, stable up to its fifth usage and stability of the photocatalyst before and after the photocatalytic reaction was also been studied using XRD and SEM. Further research in this area could lead to the development of advanced photocatalytic technologies for environmental remediation.

MRI-confirmed cochlear artery infarct clinically diagnosed in a patient with sickle cell disease: a case report.

PURPOSE: To corroborate the vascular etiology of sudden sensorineural hearing loss (SNHL) utilizing magnetic resonance imaging (MRI). PATIENT: A 24-year-old male with a history of sickle cell disease experienced sudden SNHL and right horizontal nystagmus, without accompanying vertigo. INTERVENTION: Audiometric evaluation revealed left-sided SNHL, predominantly affecting high frequencies. Video head impulse testing demonstrated isolated dysfunction of the left posterior semicircular canal. An urgent brain MRI identified a recent punctiform ischemic stroke in the frontal region. A subsequent MRI, conducted with a 4-hour delay and post-contrast enhancement, highlighted a hyperintense signal within the left cochlear region and the left posterior semicircular canal. CONCLUSION: The investigative results substantiate an infarction in the territory of the cochlear artery, precipitated by a vaso-occlusive event, thereby reinforcing the vascular hypothesis of cochleovestibular artery syndrome. This case underscores the congruence between clinical observations and delayed post-contrast MRI findings.

Efficacy, safety and mechanism of Simiaoyongan decoction in the treatment of carotid atherosclerotic plaque: a randomized, double-blind, placebo-controlled clinical trial protocol.

INTRODUCTION: Chronic inflammation is the major pathological feature of Atherosclerosis(As). Inflammation may accelerate plaque to develop, which is a key factor resulting in the thinning of the fibrous cap and the vulnerable rupture of plaque. Presently, clinical treatments are still lacking. It is necessary to find a safe and effective treatment for As inflammation. Simiaoyongan Decoction (SMYA) has potential anti-inflammatory and plaque protection effects. This protocol aims to evaluate the efficacy, safety, and mechanism of SMYA for patients with carotid atherosclerotic plaque. METHODS/DESIGN: The assessment of SMYA clinical trial is designed as a randomized, double-blind, placebo-controlled study. The sample size is 86 cases in total, with 43 participants in the intervention group and the control group respectively. The intervention group takes SMYA, while the control group takes SMYA placebo. The medication lasts for 14 days every 10 weeks, with a total of 50 weeks. We will use carotid artery high resolution magnetic resonance imaging (HR-MRI) to measure plaque. The plaque minimum fiber cap thickness (PMFCT) is adopted as the primary outcome. The secondary outcomes include plaque fiber cap volume, volume percentage of fiber cap, lipid-rich necrotic core (LRNC) volume, volume percentage of LRNC, internal bleeding volume of plaque, internal bleeding volume percentage of plaque, plaque calcification volume, volume percentage of plaque calcification, lumen stenosis rate, average and a maximum of vessel wall thickness, vessel wall volume, total vessel wall load, carotid atherosclerosis score, hs-CRP, IL-1ß and IL-6, the level of lipid profiles and blood glucose, blood pressure, and body weight. DISCUSSION: We anticipate that patients with As plaque will be improved from SMYA by inhibiting inflammation to enhance plaque stability. This study analyzes plaque by using HR-MRI to evaluate the clinical efficacy and safety of SMYA. Moreover, we conduct transcriptome analysis, proteomic analysis, and metagenomic analysis of blood and stool of participants to study the mechanism of SMYA against As plaque. This is the first prospective TCM trial to observe and treat As plaque by inhibiting inflammatory reaction directly. If successful, the finding will be valuable in the treatment of As plaque and drug development, especially in the "statin era". TRIAL REGISTRATION NUMBER: This trial is registered on Chinese Clinical Trials.gov with number ChiCTR2000039062 on October 15, 2020 ( http://www.chictr.org.cn ).

CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer.

PURPOSE: CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown. METHODS: The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data. RESULTS: Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/ß-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts. CONCLUSION: CD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.

The comparison of white-to-white via triple person-times caliper measuring and machine-measuring in V4c implantable collamer lens implantation.

This study aimed to compare the differences and characteristics of white-to-white (WTW) values obtained before V4c implantation using triple person-times caliper, IOL-Master 700, Pentacam HR, and UBM, and to assess their correlation with vaulting. A total of 930 myopia patients (1842 eyes) who were interested in undergoing ICL surgery were assessed before the procedure using various instruments. The WTW measurements were obtained using a triple person-times caliper, Pentacam HR, and IOL-Master 700, whereas the angle-to-angle (ATA) measurements were obtained using UBM. The size of the ICL was subsequently calculated using triple person-times caliper measurements. The vault of the ICL was assessed using Pentacam HR three months after the surgery. The WTW was determined to be 11.30 ± 0.29 mm, 11.43 ± 0.29 mm, and11.86 ± 0.38 mm, respectively, using the triple person-times caliper, Pentacam HR, and IOL-Master 700. The measurement of ATA was 11.57 ± 0.51 mm, as done by UBM. The ICL vault was measured to be 400.97 ± 198.46 µm when examined with Pentacam HR three monthsafter the procedure. The linear regression analyses of ICL size and WTW of triple person-times caliper, ICL vault and WTW were (R = 0.703, p < 0.001; R = 0.0969, p < 0.001) respectively. The highest correlation was found between IOL-Master and Pentacam HR (r = 0.766, p = 0.000). The lowest correlation was found between UBM and Pentacam HR (r = 0.358, p = 0.002). Bland-Altman analysis showed that the 95% limits of agreement (LoA) were the triple person-times caliper and Pentacam HR (- 0.573, 0.298) and the triple person-times caliper and UBM (- 1.15, - 0.605). This indicated a strong agreement between the triple person-times caliper and Pentacam HR and a lack of agreement between the triple person-times caliper and UBM. Triple person-times caliper measurements offer excellent maneuverability, practicality, and reliable outcomes for determining ICL vaults. Measurements obtained using the triple-person caliper were less differece than those obtained using the Pentacam HR.

Determinants of Orthostatic Hypotension in Type 2 Diabetes: Is Cardiac Autonomic Neuropathy the Main Factor?

OBJECTIVES: To evaluate the determinants of orthostatic hypotension (OH) in type 2 diabetes (T2D) and the usefulness of Δheart rate (HR)/Δsystolic blood pressure (SBP), index of cardiac baroreflex function, in identifying neurogenic OH. METHODS: In 208 participants with T2D, we diagnosed early cardiovascular autonomic neuropathy (CAN) and confirmed CAN according to 1 and 2 HR-based cardiovascular reflex tests (HR-CARTs). Through OH test we defined OH as SBP falls of ≥20 and ≥30 mm Hg with supine SBPs of <140 and ≥140 mm Hg, respectively. In participants with OH, we used the lying-to-standing and OH test and its diagnostic accuracy for neurogenic OH (as OH plus confirmed HR-CAN). RESULTS: OH was present in 25 participants and associated with lower HR-CART scores, higher glycosylated hemoglobin level, the presence of CAN, retinopathy, and peripheral vascular disease, the absence of hypertension, and physical activity (all, P < .05) but not with interfering drugs and ß-blockers. In a multiple logistic regression, HR-CAN was the main determinant of OH (odds ratio, 4.74) with physical activity and hypertension (odds ratios, 0.16 and 0.23; R2 = 0.22). ΔHR/ΔSBP had a good diagnostic accuracy for neurogenic OH (area under the receiver operating characteristic curve, 0.816 ± 0.087) and, at the cutoff of 0.5 bpm/mm Hg, a sensitivity of 100% and specificity of 63.2%. CONCLUSION: CAN remains the primary determinant of OH in T2D but does not explain all its variance. The index ΔHR/ΔSBP may represent a useful clinical tool to identify neurogenic OH.

Epstein-Barr virus deubiquitinating enzyme BPLF1 is involved in EBV carcinogenesis by affecting cellular genomic stability.

Increased mutational burden and EBV load have been revealed from normal tissues to Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs). BPLF1, encoded by EBV, is a lytic cycle protein with deubiquitinating activity has been found to participate in disrupting repair of DNA damage. We first confirmed that BPLF1 gene in gastric cancer (GC) significantly increased the DNA double strand breaks (DSBs). Ubiquitination mass spectrometry identified histones as BPLF1 interactors and potential substrates, and co-immunoprecipitation and in vitro experiments verified that BPLF1 regulates H2Bub by targeting Rad6. Over-expressing Rad6 restored H2Bub but partially reduced γ-H2AX, suggesting that other downstream DNA repair processes were affected. mRNA expression of BRCA2 were significantly down-regulated by next-generation sequencing after over-expression of BPLF1, and over-expression of p65 facilitated the repair of DSBs. We demonstrated BPLF1 may lead to the accumulation of DSBs by two pathways, reducing H2B ubiquitination (H2Bub) and blocking homologous recombination which may provide new ideas for the treatment of gastric cancer.