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To investigate the effects of salivary esterases on biostability of collagen treated by galloylated polyphenols.Human dentin was microtomed into 6-μm-thick films, which were demineralized and treated for 60 s using solutions containing 0.6% and 2% of one of the crosslinkers: tannic acid (TAC), epigallocatechin gallate (EGCG), epigallocatechin (EGC), and N-[3-dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS), and for 1 h using EDC/NHS. Half of the treated and untreated (control) films were subjected to human saliva incubation. Collagen biostability was assessed via exogenous protease biodegradation by weight loss and hydroxyproline release, and endogenous MMPs by in situ zymography. The degradation products of galloylated polyphenols (TAC and EGCG) by saliva were monitored using proton nuclear magnetic resonance (Collagen films treated with TAC and EGCG exhibited significantly improved biostability (p 0.05); however, the enhanced biostability was severely reduced after saliva incubation (p 0.001). For EDC/NHS treated collagen, saliva incubation showed negligible effect on the biostability.The galloyl group plays important role in collagen crosslinking, inducing higher biostability. However, galloylated polyphenols crosslinked on collagen are highly susceptible to metabolism of human saliva by salivary esterase, dramatically compromising the enhanced biostability.

The physiologic process of blood clot formation is well understood and occurs naturally in the setting of tissue injury to achieve hemostasis and begin the process of wound healing. While the investigation of blood clots as a biomaterial is still in the early stages, there has been some research with similar biomaterials made of the components of blood clots that support the innovative idea of using an autologous blood clot as a scaffold or delivery method for therapeutic agents. Here, we review the physiology of blood clots in wound healing and how using blood clots as a biomaterial and delivery system can potentially promote wound healing, provide targeted therapeutic agent delivery and use it as an innovative tool in regenerative medicine.Wounds and tissue injuries are unfortunately still common, and research is very active in trying to discover ways to augment the healing process. Various biomaterials have been developed and studied to analyze their therapeutic potential in promoting regeneration of different tissues in the human body. The formation of blood clots is a natural process that occurs in response to tissue injury, and there has been recent work to investigate the utility of blood clots as therapeutic adjuncts. The practicality of obtaining blood clots, along with the feasibility of integrating therapeutic agents into them, make blood clots an attractive tool in regenerative medicine to be explored. This review article synthesizes current research on blood clot biology, physiology and potential therapeutic utility.

Clinical pharmacists play a pivotal role in ensuring medication safety due to their detailed understanding of the medication-use process. This study aimed to propose the concept of pharmaceutical care pathway (PCP) in surgical care and design the work pattern and workflow in the healthcare systems of China.Data were collected from patients in the Department of Hepatobiliary Surgery of the First People's Hospital of Lianyungang in China between January 2019 and December 2019.The study was conducted using 346 patients in the control group and 363 in the intervention group. The control group was managed only by the clinical pathway (CP), while the intervention group was managed by the CP and PCP.Adverse drug reactions (ADRs), patient satisfaction, hospital expense, drug cost, length of stay, and prescription situations were documented.Using PCP, the rational use of drugs increased from 56% in the control group to 94.2% in the intervention group. Further, 124 (35.8%) ADRs in the control group and 44 (12.1%) ADRs in the intervention group were assessed using the Karch and -Lasagna scale. The mean hospital expense was 21,949.12 ± 2,311.25 yuan in the control group and 17,566.25 ± 1,082.56 yuan in the intervention group. The mean drug cost was 6,250.69 ± 589.35 yuan and 4,894.22 ± 356.14 yuan (1 US$ = 6.37 yuan). The mean length of stay was 12.23 ± 2.51 days and 8.35 ± 1.32 days in the control and intervention groups, respectively. Patient satisfaction increased significantly.PCP reduced the length of stay for patients and drug-related adverse events, increased the rational use of drugs, cost-effectiveness, patient satisfaction, and consequently, improved the quality of service in surgery medicine.

The balance of bone turnover mediated by osteoclastogenesis and osteogenesis implants that could suppress osteoclastogenesis and promote osteogenesis is an appropriate treatment strategy for osteoporosis patients. Titanium is one of the most applied materials in implants. In this study, titania nanotubes (Ti-NTs) were produced by anodization at 10, 40, and 60 V. We found that Ti-NTs were nontoxic to bone marrow mesenchymal stem cells (BMSCs). Ti-NTs suppressed osteoclast formation and function in a diameter dependent manner in vitro. Furthermore, Ti-NTs enhanced the activity of osteogenesis, expressions of osteogenesis-related marker genes were increased and β-Catenin pathway was active. Alkaline phosphatase (ALP) activity and matrix mineralization were also promoted in vitro. To explore the possible mechanisms, we performed a series of experiments to indicate the effects of Ti-NTs on cytoskeletal organization and integrin ανβ3 expression of osteoclasts and osteoblasts. The results demonstrated that 90-nm-diameter Ti-NTs could suppress the expression of integrin ανβ3 in osteoclast precursor cells. Interestingly, it revealed an opposite effect on BMSCs. Moreover, 90 nm-diameter Ti-NTs prevented ovariectomy (OVX)-induced bone loss. These findings indicated that Ti-NTs could inhibit osteoclastogenesis and enhance osteogenesis; it was mediated via regulation of integrin ανβ3─90 nm-diameter Ti-NT revealed a good biological ability especially suited for osteoporosis treatment.

Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear.This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aβ42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter 2.5 μm (PMAmbient 2-year averaged exposure of PMThese findings demonstrated a strong link between PM

Soot, mainly derived from incomplete combustion of fossil fuel and biomass, exists ubiquitously in different environmental matrixes. To study the detrimental effects of soot on climate, air quality, and human health, accurate quantification of soot is an important prerequisite. However, until now, quantification of soot in environmental media, especially in carbonaceous media, is still very challenging. Here, we report a matrix-free laser desorption/ionization mass spectrometry (LDI-MS) method for in situ imaging of soot particles in size-segregated aerosol samples collected on filter membranes. A series of round-shaped sample spots in filter membranes were selected and subjected to MS imaging analysis, enabling direct in situ quantification of soot without solvent extraction or separation. Especially, the MS imaging with serial sample spots can overcome the problems of sweet-spot in LDI-MS and inhomogeneous distribution of soot in the filter membrane, thus greatly improving the precision of quantification. The limit of detection of soot was 4 ng/m

Most cases of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) involve small tumors. Although a few guidelines recommend mastectomy, several patients prefer repeat BCS (re-BCS). This study aimed to compare re-BCS and mastectomy in terms of prognosis in patients with IBTR and to identify candidates for re-BCS.The data of patients with small IBTR between 1999 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database. The outcomes of interest were overall survival (OS) and breast cancer-specific survival (BCSS). Multivariable Cox proportional hazards regression models and propensity score matching were applied.Of the 3648 patients with IBTR, 2831 (77.6%) underwent mastectomy and 817 (22.4%) underwent re-BCS. The multivariate Cox model showed that re-BCS was associated with a worse OS (hazard ratio [HR], 1.342; 95% confidence interval [CI], 1.084-1.663) and BCSS (HR, 1.454; 95% CI, 1.004-2.105) compared with mastectomy. The omission of radiation after re-BCS was associated with worse survival overall and especially in patients with estrogen receptor (ER)-negative IBTR (HR, 1.384; 95% CI, 1.110-1.724; and HR, 1.577; 95% CI, 1.075-2.314, respectively). No statistically significant differences were observed in the OS and BCSS between re-BCS with radiation and mastectomy. Subgroup analysis indicated that the surgical approach was not an independent factor for survival in the ER-positive patients with IBTR.Re-BCS should be considered with caution in patients with small IBTR. However, a positive ER status can be an important factor for choosing re-BCS, and radiation therapy may improve oncological safety after re-BCS.Repeat breast-conserving surgery (re-BCS) was investigated to determine if it is safe for patients with small ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS). This population-based cohort study included 2831 patients with small IBTR. Re-BCS was associated with a worse overall survival and breast cancer-specific survival compared with mastectomy. Further analysis found that the IBTR estrogen receptor status was an important basis for choosing re-BCS, and radiation may improve oncological safety after re-BCS.

Aims: The present study investigated the combined clinical significance of fibrinogen and neutrophil–lymphocyte ratio (F-NLR) in predicting postoperative recurrence of giant cell tumor of bone. Methods: A total of 113 participants were included in this retrospective study to examine the effects of inflammatory factors on postoperative tumor recurrence. Results: The high-score F-NLR group was significantly associated with larger tumor size (p = 0.001), advanced tumor stage (p = 0.018), wide resection (p = 0.004) and greater local recurrence (p = 0.014). Univariate and multivariate survival analyses revealed that F-NLR (p = 0.035) remained an independent factor influencing tumor recurrence rates. Conclusions: This study reveals that the F-NLR score is a promising blood biomarker for predicting giant cell tumor recurrence.

Objectives To determine if dynamic CT can differentiate local progression from radioactive seed-induced peritumoral reaction (RSIPR) after brachytherapy with iodine-125 radioactive seeds (BIRS) for advanced hepatic malignancies. Methods Enhanced CT images of seed-implanted lesions between 2006 and 2018 were retrospectively evaluated. Hounsfield units of peritumoral parenchyma were measured and assessed quantitatively. The classification, conversion, consequences, and serological indicators during follow-up were recorded and quantified. Statistical differences were analyzed using a Pearson χ2 test. Results RSIPR was observed in 201 of 290 (69.3%) lesions (161 patients; median age, 55 years; range, 26–79 years), while local progression occurred in 53 lesions. The low density of local progression was much lower than that of RSIPR (p < 0.001), and the former did not exhibit iso-/high density in the portal or equilibrium phase. Ring-like enhancement in progressive lesions was also quite different from RSIPR. Local progression rate was lower for lesions with RSIPR than for those without RSIPR (14.9% vs 25.8%; p = 0.03), and their doses were different (397.2 Gy vs 120.3 Gy, p < 0.001). Conclusions Radioactive seed-induced peritumoral reaction has characteristic manifestations on CT images, which is associated with a higher dose of lesions and lower local progression rate. Notably, the enhancement pattern of local progression was distinct from RSIPR and was clearly distinguishable on dynamic-enhanced CT. Key Points • Radioactive seed-induced peritumoral reaction after brachytherapy with125I seeds for liver malignancies has characteristic manifestations on CT images, which is associated with a higher dose of lesions (397.2 Gy vs 120.3 Gy, p < 0.001), as a focal radiation injury. • Lesions with RSIPR were less likely to develop local progression, while those without RSIPR had a higher rate of local progression (14.9% vs 25.8%; p = 0.03). • The enhancement pattern of local progression after brachytherapy was distinct from radioactive seed-induced peritumoral reaction and was clearly distinguishable on dynamic-enhanced CT.

Alzheimer's disease (AD) is a high incidence neurodegenerative disease. Emerging evidence suggests that circular RNAs (circRNAs) play an important modulator in the pathogenesis of AD. The aim of this paper was to reconnoiter the effects of circular RNA_0003611 (circ_0003611) on Aβ-triggered neuronal injury in AD. In this work, the abundance of circ_0003611 was augmented in AD patients and SH-SY5Y and SK-N-SH cells treated with Aβ. Aβ-mediated cell proliferation, apoptosis, inflammatory response, oxidative stress, and glycolysis were abolished through circ_0003611 silencing. Circ_0003611 worked as a miR-383-5p sponge, and the protective role of circ_0003611 absence on Aβ-triggered neuronal injury was overturned by releasing miR-383-5p. Meanwhile, miR-383-5p directly targeted KIF1B, and miR-383-5p upregulation might relieve Aβ-triggered neuronal injury by reducing KIF1B expression. Mechanical analysis discovered that circ_0003611 served as a sponge of miR-383-5p to impact KIF1B expression. These findings indicated that circ_0003611 improved Aβ-triggered neuronal injury in AD through targeting the miR-383-5p/KIF1B axis, which might deliver innovative therapy targeting for AD.

This research was aimed at analyzing the diagnosis of severe sepsis complicated with acute kidney injury (AKI) by ultrasonic image information based on the artificial intelligence pulse-coupled neural network (PCNN) algorithm and at improving the diagnostic accuracy and efficiency of clinical severe sepsis complicated with AKI. In this research, 50 patients with sepsis complicated with AKI were collected as the observation group and 50 patients with sepsis as the control group. All patients underwent ultrasound examination. The clinical data of the two groups were collected, and the scores of acute physiology and chronic health assessment (APACHE II) and sequential organ failure assessment (SOFA) were compared. The ultrasonic image information enhancement algorithm based on artificial intelligence PCNN is constructed and simulated and is compared with the maximum between-class variance (OSTU) algorithm and the maximum entropy algorithm. The results showed that the PCNN algorithm was superior to the OSTU algorithm and maximum entropy algorithm in the segmentation results of severe sepsis combined with AKI in terms of regional consistency (UM), regional contrast (CM), and shape measure (SM). The acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores in the observation group were substantially higher than those in the control group ( P < 0.05 ). The interlobular artery resistance index (RI) in the observation group was substantially higher than that in the control group ( P < 0.05 ). Moreover, the mean transit time (mTT) in the observation group was significantly higher than that in the control group ( 4.85 ± 1.27 vs. 3.42 ± 1.04 ), and the perfusion index (PI) was significantly lower than that in the control group ( 134.46 ± 17.29 vs. 168.37 ± 19.28 ), with statistical significance ( P < 0.05 ). In summary, it can substantially increase ultrasonic image information based on the artificial intelligence PCNN algorithm. The RI, mTT, and PI of the renal interlobular artery level in ultrasound images can be used as indexes for the diagnosis of severe sepsis complicated with AKI.

Laparoscopic left-sided hepatectomy (LLH) and additional biliary tract exploration are effective methods to treat left-sided hepatolithiasis (LSH) combined with extrahepatic bile duct stones. Although biliary tract exploration through common bile duct (CBD) incision has been widely accepted, the safety and effectiveness of the left hepatic duct (LHD) orifice approach after LLH is still in debate.One hundred and forty-four patients with LSH who underwent LLH and biliary tract exploration in our institution from April 2014 to September 2021 were enrolled in the retrospectively study. They were divided into 3 groups: LHD group (n=67), CBD/T-tube group (n=58), and CBD/PC group (n=19). Patients' demographic characteristics, intraoperative, and postoperative outcomes were retrospectively analyzed.LHD group exhibited a shorter operative time (202.8±42.2 vs. 232.7±47.5 min, P =0.000), time to first bowel movement (2.3±0.5 vs. 2.9±0.7 d, P =0.000) and postoperative hospital stay (7.5±2.1 vs. 9.8±5.2 d, P =0.001) compared with the CBD/T-tube group. The lithotomy time in the LHD group was significantly longer than that in the CBD/T-tube group (33.6±7.3 vs. 29.0±6.3 min, P =0.000) and CBD/PC group (33.6±7.3 vs. 28.7±3.7, P =0.006). Intraoperative blood loss, blood transfusion rate, initial stone clearance rate, and stone recurrence rate all had no significant differences between the 3 groups (all P0.05). LHD group showed less rate of electrolyte imbalance than that of the CBD/T-tube group (3.0% vs. 19.0%, P =0.004) but it was equivalent to the CBD/PC group ( P0.05). The type of biliary tract exploration (odds ratio: 5.43, 95% confidence interval: 0.04-0.95, P =0.032) as independent predictors of electrolyte imbalance. No reoperation and mortality occurred in the 3 groups. The conversion rate was comparable among 3 groups (1.5% vs. 1.7% vs. 0, all P0.05). No significant difference in stone recurrence rate was seen (1.5% vs. 3.4% vs. 0, all P0.05).Biliary tract exploration through LHD orifice after LLH is a safe and effective treatment for selected patients with LSH, with an advantage over the T-tube drainage in the field of operative time, the incidence of electrolyte imbalance, recovery of gastrointestinal function, and postoperative hospital stay.

Women with labial hypertrophy may opt for labiaplasty. The aim of the study was to analyze the complications, long-term follow-up of clinical outcomes and satisfaction in this population over the past 10 years.All women who underwent labiaplasty with or without clitoral hood reduction at our center between January 2008 and August 2020 were retrospectively identified. Retrospective study was conducted, recording follow-up outcomes, motivations, techniques, postoperative complications, reasons requiring reoperation, and surgical satisfaction concerned different clinical characteristics. A concrete analysis of each specific outcome and a detailed knowledge of these procedures were performed.A total of 52.41% reported functional impairment, 20.25% cited aesthetics complains, and 27.34% were motivated by both the previously mentioned reasons. Women undergoing surgical correction sometimes mixed with various psychological aspects. A total of 91.06% reported that they were moderately (6.04%) or extremely (85.02%) satisfied with the outcomes after surgery, and 37 (8.94%) reported dissatisfied. Revision surgery was needed in a small number of patients (n = 7 of 414 patients, 1.69%) because of undesirable appearance. The most common complication in our patients was asymmetry (6.28%). Women requested labiaplasty in the last 2 reasons or procedures or without psychological distress were more likely feel satisfied with the results (satisfaction rate90%). There was a significant difference in satisfaction among the 3 concerns as well as between the 2 kinds of psychological conditions ( P0.05). Satisfaction of patients with aesthetic complains compared with the other 2 worries was significantly lower ( P0.05). There was no significant difference among the 3 procedures in this comparison group ( P0.05). In addition, satisfaction in labiaplasty with or without clitoral hoodoplasty, neither of which was statistically different ( P0.05). Patients aged 30 to 39 years reported the lowest satisfaction in comparison with the other age groups.Labiaplasty of the labia minora is the most commonly performed genital cosmetic surgery procedure. This study on 414 patients demonstrated that it is associated with a high degree of patient satisfaction and low morbidity and provided evidence of safety and effectiveness preliminary, indicating that the procedure may be regarded as safe.

To evaluate a novel method and computed tomography angiography (CTA) for locating anterolateral thigh flap (ALTF) perforators to design individualized ALTFs to reconstruct maxillofacial soft tissue defects.This study comprised a group of 36 patients (CTA group) with malignant oral and maxillofacial tumors who underwent CTA and who received individualized ALTFs and a group of 28 patients (control group) with the same condition but without preoperative CTA examination and with nonindividualized ALTFs. ALTFs in the CTA group were designed and harvested using the locating device and CTA, whereas ALTFs in the control group were designed and harvested according to each surgeon's experience.Fifty perforators were located and 36 ALTFs harvested in the CTA group. In the control group, 34 perforators were located and 28 ALTFs harvested. Less time was required to locate the perforators in the CTA group. Moreover, the CTA group had a higher flap survival rate and better patient satisfaction regarding the postoperative aesthetics and phonetic and swallowing functions.The results suggest that CTA and the locating device can be used to accurately locate ALTF perforators and that this method aids in the design and harvesting of individualized ALTFs to achieve good functional and aesthetic outcomes.

Background Rumex japonicus Houtt (R. japonicus) is used mainly to treat various skin diseases in Southeast Asia. However, there are few studies on its quality evaluation methods and antifungal activity. Objective To establish the quality control criteria for the effective parts from R. japonicus against psoriasis. Methods High-performance liquid chromatography (HPLC) was established for its fingerprint, and the similarity evaluation, cluster analysis (CA) and principal component analysis (PCA) were used to reveal the differences of those fingerprints among the tested R. japonicus. Network pharmacology analyzed the relationship between the components and psoriasis, revealing the potential targets of R. japonicus. Oxford cup anti-C. albicans experiment was used to verify the antifungal activity of R. japonicus. Results HPLC was developed for the R. japonicus fingerprint by optimizing for 10 batches of quinquennial R. japonicus from different habitats; the 18 common peaks were identified with 10 characteristic peaks such as rutin, quercetin, aloe-emodin, nepodin, emodin, musizin-8-O-β-D-glucoside, chrysophanol, emodin-8-O-β-D-glucopyranoside, chrysophanol-8-O-β-D-glucopyranoside, and aloin, respectively. The network pharmacology-based analysis showed a high correlation between R. japonicus and psoriasis, revealing the potential targets of R. japonicus. The oxford cup anti-Candida albicans experiment displayed a significant activity response to emodin-8-O-β-D-glucopyranoside and the ethyl acetate fraction of R. japonicus acidic aqueous extract. Conclusions A new and optimized HPLC method was created, and the research provides an experimental basis for the development of effective drugs related to C. albicans. Highlights The fingerprint of R. japonicus was organically combined with network pharmacology to further clarify its criteria for quality control.

Inflammatory bowel disease (IBD) is a chronic autoimmune disorder stemming from unrestrained immune activation and subsequent destruction of colon tissue. Genetic susceptibility, microbiota remodeling, and environmental cues are involved in IBD pathogenesis. Up to now, there are limited treatment options for IBD, so better therapies for IBD are eagerly needed. The therapeutic effects of naturally occurring compounds have been extensively investigated, among which quercetin becomes an attractive candidate owing to its unique biochemical properties. To facilitate the clinical translation of quercetin, we aimed to get a comprehensive understanding of the cellular and molecular mechanisms underlying the anti-IBD role of quercetin. We summarized that quercetin exerts the anti-IBD effect through consolidating the intestinal mucosal barrier, enhancing the diversity of colonic microbiota, restoring local immune homeostasis, and restraining the oxidative stress response. We also delineated the effect of quercetin on gut microbiome and discussed the potential side effects of quercetin administration. Besides, quercetin could serve as a prodrug, and the bioavailability of quercetin is improved through chemical modifications or the utilization of effective drug delivery systems. Altogether, these lines of evidence hint the feasibility of quercetin as a candidate compound for IBD treatment.

The value of 320-slice spiral computed tomography (CT) perfusion imaging in staging and long-term dynamic evaluation of breast cancer was explored. 120 breast cancer patients who underwent preoperative CT examination and were confirmed by surgery and pathology were selected. All patients underwent preoperative TNM staging of breast cancer, with 120 cases in each stage. According to the results of 320-slice spiral CT, the postoperative pathology and surgical methods were compared and analyzed. CT diagnosis of breast cancer showed that T1 sensitivity was 71% and accuracy was 61%, T2 sensitivity was 74% and accuracy was 64%, T3 sensitivity was 94% and the accuracy was 84%, and the T4 sensitivity was 100% and the accuracy was 91%. The sensitivity of N1 stage was 71%, and the accuracy was 61%; and the sensitivity of N2 ~ N3 stage was 81%, and the accuracy was 76%. There were 7 cases of M1 with distant metastasis, the sensitivity was 71%, and the accuracy was 71%. At T1 stage, blood flow (BF) was 39.2 ± 16.7 mL/min/100 g, blood volume (BV) was 2.66 ± 1.4 mL/100 g, mean transit time (MTT) was 8.16 ± 2.7 s, and permeability surface (PS) was 16.6 ± 9.7 mL/min/100 g. 320-slice spiral CT perfusion imaging technology provided a new diagnostic mode for everyone, which can quantitatively identify breast cancer with multiple parameters, which was of great significance for clinical auxiliary diagnosis.

The most frequent mode of progression in the majority of non-small cell lung cancer (NSCLC) patients treated with Epidermal growth factor - receptor tyrosine kinase inhibitors (EGFR-TKIs) is failure to respond to treatment at the primary lesion, suggesting that concurrent radiotherapy (CRT) to the primary lesion (CPRT) during first-line treatment with EGFR-TKI may be a novel therapeutic approach with a potential of additional benefit for metastatic NSCLC. Therefore, this study investigated the progression-free survival (PFS) and safety of CPRT during first-line icotinib treatment in NSCLC patients with EGFR mutations.EGFR-mutant NSCLC patients diagnosed with limited multiple metastases were treated with first-line icotinib. The decision to treat the primary lesions with radiation largely depended on the patient's preference. The study endpoints included PFS, toxicity, progression pattern, and acquisition of the T790M mutation.The median PFS in the CPRT and Non-CPRT groups was 13.6 and 10.6 months (hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.15-0.37, P 0.001). Subgroup analysis showed that the results were statistically significant with 14.7 and 11.5 months for the 19del mutation (HR 0.20, 95% CI 0.10-0.40, P 0.001) and 12.9 and 9.9 months for the L858R mutation (HR 0.25, 95% CI 0.13-0.48, P 0.001). There were no reports of interstitial pneumonia associated with treatment at grade 4 or above. Patients who received CPRT during first-line icotinib treatment had the potential to decrease the primary lesion progression (P 0.05) without increasing newly metastatic lesions (P 0.05). The proportion of acquired T790M mutations was 26.7% and 45.7% in both groups (P 0.05).This study suggests that CPRT is a viable option for patients with EGFR-sensitive mutations in NSCLC with limited multiple metastases during first-line icotinib treatment, which can significantly improve PFS with acceptable toxicities. Data on progression patterns and T790M mutations suggest the need to further investigate the benefits of radiation treatment from a molecular perspective.

Intestinal dysbiosis is one of the major causes of the occurrence of metabolic syndromes, such as obesity, diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases. Polysaccharide-based microbial therapeutic strategies have excellent potential in the treatment of metabolic syndromes, but the underlying regulatory mechanisms remain elusive. Identification of the internal regulatory mechanism of the gut microbiome and the interaction mechanisms involving bacteria and the host are essential to achieve precise control of the gut microbiome and obtain valuable clinical data. Polysaccharides cannot be directly digested; the behavior in the intestinal tract is considered a "bridge" between microbiota and host communication. To provide a relatively comprehensive reference for researchers in the field, we will discuss the polysaccharide extraction and purification processes and chemical and structural characteristics, focusing on the polysaccharides in gut microbiota through the immune system, gut-liver axis, gut-brain axis, energy axis interactions, and potential applications.

Despite significant advances in targeted and immune therapy for non-small cell lung cancer (NSCLC), effective therapies for wild-type epidermal growth factor receptor/anaplastic lymphoma kinase ( EGFR/ALKWT) with low expression of programmed death ligand-1 (PD-L1) NSCLC remain elusive. Numerous studies have shown that ferroptosis plays an essential role in antitumor activity. To identify the molecular regulation patterns associated with ferroptosis, 351 EGFR/ALKWT NSCLC samples with low-level PD-L1 were extracted from The Cancer Genome Atlas (TCGA) and clustered using the k-means clustering technique. The two clusters associated with ferroptosis showed significantly different prognoses. In total, 169 differential expression genes (DEGs) were identified. Cluster differential analysis revealed that Cluster 1 had a significantly poorer overall survival (OS) and was associated with more negative immune regulation. In addition, TCGA samples were randomly assigned in a 7:3 ratio to a training group or testing group. A signature of eight genes associated with ferroptosis was established in the training cohort using DEGs and validated in the test cohort and three independent cohorts (GSE72049, GSE41271, and GSE50081). The 5-year area under the curve (AUC) was 0.713, which was significantly higher than that of other predictors, including TNM stage and age. Furthermore, the risk score was associated with immune function, immune infiltration, and immunotherapy response, with high-risk patients having a worse prognosis, an immune-suppressing phenotype, and a poor response to immune checkpoint inhibitors. This study aims to contribute to our understanding of the biological role of ferroptosis in EGFR/ALKWT NSCLC with low-level PD-L1, laying the groundwork for the development of novel therapeutic strategies.

Dihydromethysticin, a natural component from Piper methysticum Forst, has been reported to display pharmacological effects in mental disorders and some malignant tumors. However, the metabolism of this component remained unknown. The goal of this work was conducted to discover the metabolic profiles of dihydromethysticin. The in vitro incubation was performed by incubating dihydromethysticin with rat, monkey, and human liver microsomes and hepatocytes. An analytical assay of ultra-high performance liquid chromatography combined with Orbitrap high-resolution mass spectrometry was utilized to detect and identify the metabolites. With high resolution mass spectrometric determination, the accurate mass, elemental composition, and product ions of the metabolites were determined, which enabled structural characterization to become easy. Under the present conditions, four phase-I metabolites, as well as six phase-II metabolites, were detected and their tentative structures were characterized by mass spectra. M4 was found as the most abundant metabolite both in liver microsomes and hepatocytes. Cytochrome P450 1A2, 2C9, and 3A4 contributed to the formation of this metabolite by using human recombinant P450 enzymes. M4 can be oxidized into reactive ortho-quinone intermediate followed by conjugating with glutathione. M4 was also subject to glucuronidation (M1 and M2) and methylation (M5). Demethylenation, oxidation, hydroxylation, glucuronidation, glutathionylation, and methylation were the primary metabolic pathways of dihydromethysticin. This study provides in vitro metabolism data of dihydromethysticin, which is indispensable for understanding the disposition of this compound.

Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood.Using osteoblast MR knockout (MRMR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients.

Objective To explore the relationship between high density lipoprotein (HDL) and lower extremities deep venous thrombosis (DVT) in patients undergoing hip arthroplasty. Methods A total of 348 patients undergoing hip arthroplasty in our hospital were enrolled, and divided into observation ( n = 154, 44.25%) and control ( n = 194, 55.75%) groups according to the occurrence of lower extremities DVT. The presence of DVT was assessed 1 day before surgery and routinely every 2 days after surgery. The factors of DVT were analyzed by single factor analysis, multivariate logistic regression analysis, and Pearson correlation. Results The age and body mass index in the observation group were significantly higher ( p = .045, p = .041, respectively), while HDL-C was significantly lower ( p = .032) than the control group. Increase age, high BMI, low apolipoprotein-A1 level and low HDL-C level were risk factors for lower extremities DVT. The mean HDL-C in the observation and control groups was 0.91 ± 0.27 and 1.19 ± 0.37, respectively, the adjusted odds ratio was 1.050; 95% CI 1.010–1.092, p = .014. Conclusion Elderly patients with high BMI and low HDL-C level undergoing hip arthroplasty are at risk of lower extremities DVT, and should be paid attention to clinically.

The objectives of this study were (1) to prepare Armillariella tabescens mycelia polysaccharides (PAT) with remarkably growth inhibitory effect on typical food-borne pathogenic bacteria using a green and efficient polyamide method and (2) to explore the antibacterial mechanism of PAT for use as a natural antibacterial agent. The sugar and uronic acid contents of PAT were 93.41% and 12.24%, respectively. PAT could inhibit the growth of Escherichia coli, Proteus vulgaris, Bacillus subtilis, and Staphylococcus aureus cells, with minimum inhibitory concentrations of 0.5, 1.0, 4.0, and 4.0 mg/mL, respectively. Ultra-high-resolution field emission scanning electron microscopy and high-resolution transmission electron microscopy analysis revealed cell wall and membrane rupture of E. coli treated with PAT. Further, 0.5-4.0 mg/mL PAT was found to significantly (P 0.01) and concentration-dependently increase the conductivity of the broth, exudation of the intracellular protein, and alkaline phosphatase and β-galactosidase activities. Confocal laser scanning microscopy revealed morphological changes in E. coli DNA after PAT treatment and intracellular reactive oxygen species accumulation; flow cytometry revealed E. coli cell apoptosis. Our findings provide a theoretical basis and technical support for the development of PAT as a natural antibacterial product.

With the rapid development of artificial intelligence (AI) technologies, and the large amount of pharmacovigilance-related data stored in an electronic manner, data-driven automatic methods need to be urgently applied to all aspects of pharmacovigilance to assist healthcare professionals. However, the quantity and quality of data directly affect the performance of AI, and there are particular challenges to implementing AI in limited-resource settings. Analyzing challenges and solutions for AI-based pharmacovigilance in resource-limited settings can improve pharmacovigilance frameworks and capabilities in these settings. In this review, we summarize the challenges into four categories: establishing a database for an AI-based pharmacovigilance system, lack of human resources, weak AI technology and insufficient government support. This study also discusses possible solutions and future perspectives on AI-based pharmacovigilance in resource-limited settings.

This study aimed to assess the clinical characteristics affecting outcomes after immune checkpoint inhibitors (ICI) therapies in non-small cell lung cancer (NSCLC) patients, and the underlying mechanism in tumor immune micro-environment (TIME).A total of 144 patients treated with ICI-based strategies were retrospectively analyzed. Expression of 10 immune antibodies in tumor tissues from other 60 untreated NSCLC patients were sequentially tested using multiplexed immunofluorescence (mIF) staining method. Correlation of clinical characteristics with ICI treatment outcomes and TIME characteristics were analyzed.Multivariate logistic and cox regression indicated that BoM negatively affected disease control rate (OR = 0.32, 95%CI: 0.13-0.82, P = 0.018), progression free survival (HR = 3.44, 95% CI:1.97-6.00, P 0.001) and overall survival (HR = 3.24, 95% CI:1.62-6.50, P = 0.001), irrespective of programmed death-ligand 1 (PD-L1) expression. BoM patients were with significantly lower PD-L1, and this heterogeneity of TIME was then confirmed in the mIF staining, where 36 (61.0%) patients were clustered into immune-subtype A, with low expression of all the detected immune markers, similar to "cold" tumors, and 23 (39.0%) in cluster B with likely "hot" tumors. More patients in immune-subtype A were non-smokers (63.9% vs. 39.1% P = 0.063), with BoM (66.7% vs. 21.7%, P = 0.001), in stage IV(88.9% vs. 65.2%, P = 0.045), and with adenocarcinoma (91.7% vs. 69.6%, P = 0.037). Multivariate logistic regression indicated that BoM was independently associated with the "cold" immune characteristics (OR = 0.19, 95% CI:0.04-0.84, P = 0.028). Combination therapy with chemotherapy /antiangiogenesis or use of bisphosphonate during ICI treatment significantly improved clinical outcomes in BoM patients.BoM displays adverse impact on clinical outcomes after ICI treatments in NSCLC patients. The "cold" characteristics of TIME may be the underlying mechanism for the attenuated efficacy of ICIs in bone metastatic NSCLC patients.

Background Catheter-directed thrombolysis (CDT) is one of the main treatment methods for acute deep venous thrombosis (DVT), which has the characteristics of long treatment time and large dosage of thrombolytic drugs. In the absence of good monitoring methods, problems such as low thrombolytic efficiency and high risk of bleeding are easy to occur. Objective To evaluate the value of D-dimer (D-D) and fibrinogen (FIB) testing as a thrombolysis-monitoring method during CDT for acute DVT. Methods Twenty patients with acute DVT were divided into group A and group B. During CDT, the D-D and FIB testing every 8 h were used in group A, and the venography and FIB testing every 24 h in group B. The thrombolysis rate, thrombolysis time, urokinase dosage, and X-ray radiation dose were compared. Results The thrombolysis rate in group A was significantly higher than that in group B ( p < 0.05), but the number of venography and radiation dose were significantly lower than those in group B ( p < 0.05). Conclusion D-D and FIB testing can improve the thrombolysis rate, reduce the risk of bleeding, and decrease the number of angiograms and X-ray radiation dose during CDT.

The loss of inner ear hair cells leads to irreversible acoustic injury in mammals, and regeneration of inner ear hair cells to restore hearing loss is challenging.

Purpose Study reported that C-reactive protein (CRP) would peak at 48 h after the initiation of an acute inflammatory response. We proposed that the ratio of CRP level on postoperative day 3 to day 2 (POD3/2 CRP) can be used to early predict major postoperative complications (PCs) for patients who underwent laparoscopic radical gastrectomy. Methods Patients were randomized into training cohort and validation cohort at a ratio of 7:3. PCs greater than grade II or more, according to Clavien-Dindo classification, were defined as major PCs. Three predictive models for major PCs based on CRP level were constructed, including POD3/2 CRP, the CRP level on POD3 (POD3 CRP), and the ratio of CRP level on POD3 to POD1 (POD3/1 CRP). The performances of three prediction models were assessed by AUC. Univariate and multivariate logistic regression analyses were performed to identify risk factors of major PCs. Results 344 patients were included. Major PCs were observed in 57 patients (16.6%). In the training cohort, POD3/2 CRP provided the best diagnostic accuracy with an AUC of 0.929 at an optimal cut-off value of 1.08, and the sensitivity and specificity were 0.902 and 0.880, respectively. In the validation cohort, the corresponding AUC was 0.917. BMI ≥ 25 kg/m2 and POD3/2 CRP > 1 were identified as risk factors for major PCs. Conclusion POD3/2 CRP is a reliable marker to predict major PCs after laparoscopic radical gastrectomy. If CRP is higher on POD3 than on POD2, major PCs are highly likely.

The relationship between microRNA (miRNA) and hosting long non-coding RNA (lncRNA) remains unclear. Here, the expression levels of microRNA-210 (miR-210) and hosting lncRNA MIR210HG are significantly increased and positively correlated in gastric cancer (GC). Gain- and loss-of-function studies demonstrate that miR-210 and MIR210HG synergistically promote the migration and invasion of GC cells in vitro. Furthermore, GC sublines simultaneously expressing miR-210 and MIR210HG display synergistic promotion of lung metastasis in vivo. Mechanistically, MIR210HG interacts with DExH-box helicase 9 (DHX9) to increase DHX9/c-Jun complex's occupancy on the promoter of matrix metallopeptidases (MMPs), and thus promotes migration and invasion of GC cells. Additionally, miR-210 directly suppresses the expression of dopamine receptor D5 (DRD5), serine/threonine kinase 24 (STK24) and MAX network transcriptional repressor (MNT), resulting in enhanced migration and invasion. Finally, MYC proto-oncogene (c-Myc) transactivates miR-210 and MIR210HG. Overexpression of miR-210 or/and MIR210HG can rescue the inhibitory effect on the migration and invasion by silencing c-Myc. Moreover, c-Myc inhibitor significantly decreases lung metastasis of GC in vivo. Collectively, our findings identify a novel mechanism, by which c-Myc-activated miR-210 and MIR210HG synergistically promote the metastasis of GC.

Introduction: Multiple studies have demonstrated that diffuse large B-cell lymphoma (DLBCL) can be divided into subgroups based on their biology. However, these biological subgroups overlap clinically. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for treating patients with DLBCL, predicting which patients will not benefit from such therapy is important so that alternative therapy or clinical trials can be considered. Most of the studies stratifying patients select biomarkers first, then explore how these biomarkers can stratify patients based on outcome. We explored the potential of using machine learning to first group patients with DLBCL based on survival, then isolating the biomarkers necessary for predicting these survival subgroups. Methods: RNA was extracted from tissue paraffin blocks from 379 R-CHOP treated patients with de novo DLBCL, and from 247 patients with extranodal DLBCL. A targeted hybrid capture RNA panel of 1408 genes was used for next generation sequencing (NGS). Sequencing was performed using an Illumina NextSeq 550 System platform. Ten million reads per sample in a single run were required, and the read length was 2 × 150 bp. An expression profile was generated from the sequencing coverage profile of each individual sample using Cufflinks. A machine learning system was developed to classify patients into four groups based on their overall survival. This machine learning approach based on Naïve Bayesian algorithm was also used to discover the relevant subset of genes with which to classify patients into each of the four survival groups. To eliminate the underflow problem commonly associated with the standard Naïve Bayesian classifiers, we applied Geometric Mean Naïve Bayesian (GMNB) as the classifier to predict the survival group for each patient. Results: Using machine learning, patients were first divided into two groups: short survival (S) and long survival (L). To refine this model, we used the same approach and divided the patients in each group into two subgroups, generating four groups: long survival in the long group (LL), short survival in the long group (LS), long survival in the short group (SL), and short survival in the short group (SS). The hazard ratio for this model was 0.174 (confidence interval: 0.120-0.251), and P-value Conclusions: Using a novel machine learning approach with the expression levels of 180 genes, we developed a model that can reliably stratify patients with DLBCL treated with R-CHOP into four survival subgroups. This model can be used to identify patients who may not respond well to R-CHOP to be considered for alternative therapy and clinical trials. Figure 1 Figure 1. Disclosures Hsi: AbbVie Inc, Eli Lilly: Research Funding. Ferreri: Ospedale San Raffaele srl: Patents & Royalties; BMS: Research Funding; Pfizer: Research Funding; Beigene: Research Funding; Hutchison Medipharma: Research Funding; Amgen: Research Funding; Genmab: Research Funding; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees. Piris: Millenium/Takeda, EUSA, Jansen, NanoString, Kyowa Kirin, Gilead and Celgene.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria.

To investigate the changes in posterior corneal elevations (PCEs) in the circular areas and local points after corneal collagen cross-linking (CXL) for the treatment of keratoconus.Method 1 divided the cornea into 0-2, 2-4, 4-6, and 6-8 mm regions centering on the apex. Method 2 obtained other 34 PCE values of local point that were identified on the nasal, supra-nasal, sub-nasal, superior, inferior, temporal, supra-temporal, and sub-temporal sides of the circle with diameters of 2, 4, 6, and 8 mm, and the apex and thinnest point.Method 1 showed a forward displacement of PCE at 1 month after CXL and then a backward displacement at 3 months. In Method 2, the points on the temporal side of 2 mm and 4 mm showed the same trend. The backward displacements of PCE on the temporal side of 2 mm at 6 months and on the temporal side of 4 mm at 12 months after CXL were both statistically different than those at 1 month after CXL (P 0.05). No significant forward displacement of PCE was found in all local points in different quadrants at 1 year after CXL.The PCEs in circular areas and characteristic points of different diameters in keratoconic eyes after CXL change with time. Local point assessment of the PCE is more clinically significant. In points selected in different quadrants of the cornea, the change in temporal points was more significant after CXL.

Aberrant angiogenesis is a hallmark of cancer and is critically associated with tumor progression. Perivascular cells are essential components of blood vessels, and the role of tumor perivascular cell-derived extracellular vesicles (TPC-EVs) in angiogenesis remains elusive. In the present study, using genetic mouse models and pharmacological inhibitors, we found that ablation of perivascular cells inhibited angiogenesis in allografted colorectal cancer tumors. Further studies demonstrated that TPC-EVs promoted the proliferation, migration, invasion, viability, and tube formation of HUVECs. They also facilitated vessel spouting in rat aortic rings and induced neovascularization in chick chorioallantoic membranes (CAMs). Silencing of Gas6 or blockade of the Axl pathway suppressed TPC-EV-induced angiogenesis in vitro and ex vivo. Moreover, inhibition of the Gas6/Axl signaling pathway impaired TPC-EV-mediated angiogenesis in vivo. Our findings present a deeper insight into the biological functions of TPCs and TPC-EVs in tumor angiogenesis and demonstrate that TPC-EV-derived Gas6 could be an attractive and innovative regulator of tumor angiogenesis.

Chemoresistance and metastasis are the major challenges for the current ovarian cancer treatment. Understanding the mechanisms of ovarian cancer progression and metastasis is critically important for developing novel therapies. The advances in extracellular vesicles (EVs) research in recent years have attracted extensive attention. EVs contain a variety of proteins, RNAs, DNAs, and metabolites. Accumulating evidence indicates that ovarian cancer cells secrete a large amount of EVs, playing an important role in tumor progression and recurrence. In the microenvironment of ovarian tumor, EVs participate in the information transmission between stromal cells and immune cells, promoting the immune escape of ovarian cancer cells and facilitating cancer metastasis. Here, we review the recent advances of EVs in chemoresistance, mechanisms of metastasis, and immune evasion of ovarian cancer. Furthermore, we also discuss the challenges of EV research and future application of EVs as promising biomarker sources in response to therapy and in therapy-delivery approaches for ovarian cancer patients.

Background HIV counseling and testing (HCT) is provided free of charge on college campuses, but very few studies have examined whether HCT uptake is equitably distributed. This cross-sectional study aimed to compare the relative importance of various determinants of HCT uptake among undergraduates in mainland China so as to assess and subsequently to suggest ways to eliminate inequities in its use, guided by the Andersen’s behavioral model. Methods A total of 10,665 eligible undergraduates were conveniently selected to complete an online survey. Hierarchical logistic regression analyses were performed to identify the factors associated with HCT utilization. Results Only 7.7% of undergraduates had utilized HCT services. HCT uptake was inequitably distributed, since it was mainly determined by predisposing and enabling factors rather than by need factors. Further analysis indicated that HCT uptake was significantly related to two need factors, one enabling factor and six predisposing factors. Those with a higher need [i.e., perceiving themselves to be at higher risk of acquiring HIV infection (AOR = 2.76, 95% CI:2.02–3.78) and engaging in condomless sex (AOR = 1.29, 95% CI:1.00–1.67)] and those with more resources [i.e., being knowledgeable of local AIDS service organization (AOR = 1.59, 95% CI:1.37–1.85)] were more likely to utilize HCT services. Compared to non-heterosexual men, non-heterosexual women (AOR = 0.51, 95% CI:0.37–0.72), heterosexual men (AOR = 0.44, 95% CI:0.33–0.57) and women (AOR = 0.31, 95%CI: 0.24–0.41) were less likely to utilize HCT service. Furthermore, those with more knowledge (AOR = 0.80, 95% CI:0.69–0.94) and taking a positive attitude towards HCT services [i.e, expressing their willingness to utilize HCT services (AOR = 0.68, 95% CI:0.56–0.81) and having recognized the necessity to provide HTC services in the local university (AOR = 0.46, 95% CI:0.36–0.57)] were less likely to utilize HCT services. However, medical students (AOR = 1.34, 95% CI: 1.15–1.56) and non-freshmen (AOR = 1.22, 95% CI:1.03–1.45) were more likely to utilize HCT services. Conclusions To increase HCT uptake and simultaneously reduce the remaining inequities, a comprehensive intervention should be continued to target non-heterosexual men and non- freshmen and those with a higher need for HCT services, conduct health education, improve the availability and accessibility of HIV testing services.

quot;Xiang thinkingquot; is the main thinking mode in traditional Chinese medicine(TCM) with both philosophical and scientific connotations, and has an important influence on the emergence and development of TCM. This study systematically expounded the philosophical connotation and characteristics ofquot;Xiang thinkingquot;, and its application in the construction of TCM theory, clinical syndrome differentiation and treatment, the formation of medicinal properties, and interpretation of efficacy of Chinese medicine.quot;Xiang thinkingquot; in TCM develops and changes continuously with practical application, and its historical evolution can be summarized into three stages, i.e.,quot;Ying Xiang(corresponding to Xiang)quot;quot;Fa Xiang(following Xiang)quot;, andquot;Bian Xiang(differentiating Xiang)quot;. The understanding of Xiang is based on the means and methods of human observation of things and the backgrounds of the philosophy, science, and development. The result of comparison depends on the depth and breadth of Xiang. In the real world, Xiang is showing new construction characteristics with multiple dimensions and levels. Therefore, this study proposed the thinking ofquot;Bian Xiangquot;, which is expected to provide a thinking approach that can realize the transformation fromquot;Xiang thinkingquot; to scientific research for the exploration and innovative research on life origin in the field of contemporary and TCM.

Endothelial inflammation is a crucial event in the initiation of atherosclerosis. Here, we identify Ataxin-10 protein as a novel negative modulator of endothelial activation by suppressing IRF-1 transcription activity. The protein level of Ataxin-10 is relatively higher in human vascular endothelial cells, which can be significantly suppressed by TNF-α in both HUVECs and HLMECs. Overexpression of Ataxin-10 markedly inhibited the mRNA expressions of VCAM-1 and several cytokines including MCP-1, CXCL-1, CCL-5, and TNF-α; thus, it can also suppress monocyte adhesion to endothelial cells. Accordingly, Ataxin-10 silencing promoted endothelial inflammation. However, Ataxin-10 did not affect the MAPK/NF-κB signaling pathway stimulated by TNF-α in HUVECs. Using the yeast two-hybrid assay, we found that Ataxin-10 can directly bind to interferon regulatory factor-1 (IRF-1). Upon TNF-α stimulation, Ataxin-10 promoted the cytoplasmic localization of IRF-1, which inhibited the transcription of VCAM-1. Moreover, knockdown of IRF-1 can eliminate the effect of Ataxin-10 on the expression of VCAM-1 in HUVECs induced by TNF-α. Taken together, these results indicate that Ataxin-10 inhibits endothelial cell activation and may serve as a promising therapeutic target for some vascular inflammatory-related diseases such as atherosclerosis.

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4–11 cells at low picomolar concentrations (IC(50) = 3 pM; BRD4 DC(50) = 0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.

Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms “acute lung injury,” “ubiquitin ligases,” “tripartite motif protein,” “inflammation,” and “ubiquitination” using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.

Epigenetics play a fundamental role in induced pluripotent stem cell (iPSC) technology due to their effect on iPSC's reprogramming efficiency and their subsequent role in iPSC differentiation toward a specific lineage. Epigenetics can skew the differentiation course of iPSCs toward a specific lineage based on the epigenetic memory of the source cells, or even lead to acquisition of new cell phenotypes, due to its aberrations during reprogramming. This viewpoint discusses key features of the epigenetic process during iPSC reprogramming/differentiation and outlines important epigenetic factors that need to be considered for successful generation and differentiation of iPSCs for downstream applications.

Background Pituitary carcinomas (PCs), defined as distant metastases of pituitary neoplasms, are very rare malignancies. Because the clinical presentation of PCs is variable, early diagnosis and management remain challenging. PCs are always refractory to comprehensive treatments, and patients with PCs have extremely poor prognoses. Case presentation We describe one case of a prolactin-secreting pituitary adenoma (PA) refractory to conventional therapy that evolved into a PC with intraspinal metastasis. A 34-year-old female was diagnosed with an invasive prolactin-secreting PA in 2009 and was unresponsive to medical treatment with bromocriptine. The tumor was gross totally removed via transsphenoidal surgery (TSS). However, the patient experienced multiple tumor recurrences or regrowth despite comprehensive treatments, including medical therapy, two gamma knife radiosurgeries (GKSs), and four frontal craniotomies. In 2016, she was found to have an intradural extramedullary mass at the level of the fourth lumbar vertebra. The intraspinal lesion was completely resected and was confirmed as a metastatic PC based on histomorphology and immunohistochemical staining. The literature on the diagnosis, molecular pathogenesis, treatment, and prognosis of patients with prolactin-secreting PCs was reviewed. Conclusion PCs are very rare neoplasms with variable clinical features and poor prognosis. Most PCs usually arise from aggressive PAs refractory to conventional therapy. There is no reliable marker to identify aggressive PAs with a risk for progression to PCs; thus, it is difficult to diagnose these PCs early until the presence of metastatic lesions. It is still very challenging to manage patients with PCs due to a lack of standardized protocols for diagnosis and treatment. Establishing molecular biomarkers and the pathobiology of PCs could help in the early identification of aggressive PAs most likely to evolve into PCs.

Air pollution is a critical risk factor for the prevalence of COVID-19. However, few studies have focused on whether air pollution affects the efficacy of the SARS-CoV-2 vaccine. To better guide the knowledge surrounding this vaccination, we conducted a cross-section study to identify the relationships between air pollutant exposure and plasma neutralizing antibody (NAb) titers of an inactivated SARS-CoV-2 vaccine (Vero cell, CoronaVac, SINOVΛC, China). We recruited 239 healthcare workers aged 21–50 years who worked at Suining Central Hospital. Of these, 207 were included in this study, depending on vaccination date. The data regarding air pollutants were collected to calculate individual daily exposure dose (DED). The geometric mean of all six pollutant DEDs was applied to estimate the combined toxic effects (DEDcomplex). Then, the participants were divided into two groups based on the mean value of DEDcomplex. The median plasma NAb titer was 12.81 AU/mL, with 85.99% vaccine efficacy in healthcare workers against SARS-CoV-2. In exposure group, observations included lower plasma NAb titers (median: 11.13 AU/mL vs. 14.56 AU/mL), more peripheral counts of white blood cells and monocytes (mean: 6.71 × 109/L vs. 6.29 × 109/L and 0.49 × 109/L vs. 0.40 × 109/L, respectively), and a higher peripheral monocyte ratio (7.38% vs. 6.50%) as compared to the reference group. In addition, elevated air pollutant DEDs were associated with decreased plasma NAb titers. To our knowledge, this study is the first to report the relationship between air pollutant exposure and plasma NAb titers of the SARS-CoV-2 vaccine. This suggests that long-term exposure to air pollutants may inhibit plasma NAb expression by inducing chronic inflammation. Therefore, to achieve early herd immunity and hopefully curb the COVID-19 epidemic, vaccinations should be administered promptly to those eligible, and environmental factors should be considered as well. Supplementary Information The online version contains supplementary material available at 10.1007/s11356-021-16786-y.

BackgroundTo reduce incision complications, minimally invasive operative approaches for treatment with acute Achilles tendon rupture have been developed, such as Mini-open repair and percutaneous repair. Which technique is the better surgical option? In the present study, we compared the two surgical procedures— modified Mini-open repair versus percutaneous repair—in the treatment of acute Achilles tendon rupture.MethodsFrom January 2016 to November 2018, 68 matched patients with acute Achilles tendon rupture were divided into treatment group (Mini-open with modified Ma-Griffith technique) and control group (the Ma–Griffith technique). The patients were then treated with different surgical techniques and followed up for no less than 24 months, and the functional outcome scores and complications were retrospectively evaluated.ResultsThe mean follow-up time in Mini-open repair group was 29.0±2.9 months, and that in control group was 27.9±2.9 months (P=0.147). The Mini-open repair group showed reliably higher American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score and Achilles tendon Total Rupture Score (ATRS) than the control group in functional assessment (95.0±3.8 vs. 92.3±5.3,P=0.000; 93.8±3.8 vs. 90.9±4.5,P=0.000). There was no cases of sural nerve injury in Mini-open repair group, whereas the percutaneous repair group had 5 cases of the same (P=0.027). No significant differences were found in the calf circumference (32.3±3.9 vs. 31.8±3.6) (P=0.564), range of motion of the ankle (51.3±4.8 vs. 50.5±4.2,P=0.362), or wound complications (34/0 vs. 34/0) (P=1.000) between the two groups at the end of the follow-up time. However, the percutaneous repair group had a shorter average operating time (23.1±5.2 min) than that of the Mini-open repair group (27.7±4.3 min) (P=0.000).ConclusionsAcute Achilles tendon ruptures may be treated successfully with a new Mini-open repair system or percutaneous repair technique. However, the Mini-open repair system may represent a superior surgical option, since it offers advantages in terms of direct visual control of the repair, AOFAS Ankle-Hindfoot Score, Achilles tendon Total Rupture Score and risk of sural nerve palsy.Study designCase-control studies, Level of evidence, 3.

Osteosarcoma is the most common primary bone cancer in children and young adults. Recent experimental evidence has indicated that Runx2/OPN axis play important roles in the metastasis of osteosarcoma cells. The present study aimed to explore their relationship and prognostic significance in surgically resected osteosarcoma. The expression of runt‐related transcription factor2(Runx2) and osteopontin (OPN) in clinical specimens from 105 osteosarcoma patients were detected by immunohistochemistry. The correlations between Runx2, OPN, and clinicopathologic data were analyzed by Chi-square (χ2) tests. The prognostic values were determined by univariate and multivariate survival analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics curves. The results showed there is a significant positive correlation between Runx2 and OPN expression at protein levels (P = 0.015). Runx2 and OPN were both independent predictors for overall survival and metastasis-free survival. When Runx2 and OPN were taken into consideration together, the predictive range was extended and the sensitivity was improved, and more significant and better biomarkers for osteosarcoma metastasis and survival. These results suggest that a combined Runx2/OPN expression could be a valuable independent predictor of tumor metastasis and survival in osteosarcoma patients.

Association between fine particulate matter (PM2.5) and respiratory health has attracted great concern in China. Substantial epidemiological evidences confirm the correlational relationship between PM2.5 and respiratory disease in many Chinese cities. However, the causative impact of PM2.5 on respiratory disease remains uncertain and comparative analysis is limited. This study aims to explore and compare the correlational relationship as well as the causal connection between PM2.5 and upper respiratory tract infection (URTI) in two typical cities (Beijing, Shenzhen) with rather different ambient air environment conditions. The distributed lag nonlinear model (DLNM) was used to detect the correlational relationship between PM2.5 and URTI by revealing the lag effect pattern of PM2.5 on URTI. The convergent cross mapping (CCM) method was applied to explore the causal connection between PM2.5 and URTI. The results from DLNM indicate that an increase of 10 μg/m3 in PM2.5 concentration is associated with an increase of 1.86% (95% confidence interval: 0.74%-2.99%) in URTI at a lag of 13 days in Beijing, compared with 2.68% (95% confidence interval: 0.99-4.39%) at a lag of 1 day in Shenzhen. The causality detection with CCM quantitatively demonstrates the significant causative influence of PM2.5 on URTI in both two cities. Findings from the two methods consistently show that people living in low-concentration areas (Shenzhen) are less tolerant to PM2.5 exposure than those in high-concentration areas (Beijing). In general, our study highlights the adverse health effects of PM2.5 pollution on the general public in cities with various PM2.5 levels and emphasizes the needs for the government to provide appropriate solutions to control PM2.5 pollution, even in cities with low PM2.5 concentration.

To derive and validate a prediction score for cardiovascular disease (CVD) risk in hemodialysis patients in China. Three hundred and eighty-eight patients with regular hemodialysis for more than 3 months were recruited from January 1, 2015 to September 30, 2019 and followed up till May 31, 2020. We derived a prediction score using all participants as a training data set and validated using a bootstrap validation data set. Discriminatory ability of the prediction score was assessed by the area under the receiver operating characteristic curve (AUC). Of 388 patients without CVD at baseline, 132 developed first CVD events during an average follow-up of 3.27 (inter-quartile range = 3.08) years. Of 26 clinical parameters, age, hypertension, diabetes and abnormal white blood cell (WBC) count were identified as significant predictors and included in the prediction model. Compared to those without any of these risk factors, those with one, two, and three to four points showed increased risks of CVD, with the adjusted hazards ratio and 95% confidence interval (CI) being 3.29 (1.17–9.26), 7.42 (2.68–20.51) and 15.43 (5.44–43.75), respectively. The score showed satisfactory discriminatory ability in both training and validation data set (AUC = 0.7025, 95% CI 0.6520–0.7530, and 0.6876, 95% CI 0.6553–0.7200, respectively). We derived and validated a prediction score for CVD risk in hemodialysis patients in China. Given there is a rapid increase in the number of hemodialysis patients, this simple point score can be used to identify high-risk individuals in clinical practice for more precise and efficient personalized treatment.