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Cell-cell fusion studies provide an experimental platform for evaluating disease progression and investigating cell infection. However, to realize sensitive and quantitative detection on cell-cell fusion is still a challenge. Herein, we report a facile molecular beacon (MB)-based method for precise detection on cell-cell fusion. By transfection of the spike protein (S protein) and enhanced green fluorescent protein (EGFP) in HEK 293 cells, the virus-mimicking fusogenic effector cells 293-S-EGFP cells were constructed to interact with target cells. Before mixing the effector cells with the target cells, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in 293-S-EGFP cells was silenced, and the MB for GAPDH mRNA detection was delivered into the GAPDH silenced 293-S-EGFP cells. Once cell-cell fusion occurred, MB migrated from the GAPDH silenced effector cells to the target cells and hybridized with GAPDH mRNA in the target cells to induce fluorescence emission. The cell-cell fusion can be easily visualized and quantitated by fluorescence microscopy and flow cytometry. The fluorescence intensity is strongly dependent on the number of fused target cells. This MB-based method can easily identify the differences in the cell fusions for various target cells with different angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) expression levels, resulting in dramatically different fluorescence intensities in fused target cells. Our study provides a convenient and efficient quantitative detection approach to study cell-cell fusion.

RationalePulmonary fibrosis is a devastating lung disease with few therapeutic options. Chitinase 1 (CHIT1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through regulation of Transforming Growth Factor (TGF)-β signaling and effector function. Therefore, CHIT1 is a potential therapeutic target of pulmonary fibrosis.ObjectivesThis study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis.MethodsExtensive screening of small molecule libraries identified the aminoglycoside antibiotic Kasugamycin as a potent CHIT1 inhibitor.Measurements and Main ResultsElevated levels of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In vivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, Kasugamycin showed impressive anti-fibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that Kasugamycin inhibits fibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation. Null mutation of transforming growth factor beta associated protein 1 (TGFBRAP1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of Kasugamycin in in vivo lungs and in vitro fibroblasts responses. Kasugamycin inhibits physical association between CHIT1 and TGFBRAP1, suggesting that antifibrotic effect of Kasugamycin is mediated through regulation of TGFBRAP1, at least in part.ConclusionsThese studies demonstrate that Kasugamycin is a novel CHIT1 inhibitor with strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

To investigate the clinical efficacy and safety of high intensity focused ultrasound (HIFU) combined with ultrasound-guided suction curettage in patients with type I/II/III cesarean scar pregnancy (CSP).A total of 153 patients with CSP were enrolled and classified according to the type of CSP. All of them were treated by HIFU combined with ultrasound-guided suction curettage. When active uterine bleeding was observed after curettage, a Foley balloon was used for hemostasis by compression. Baseline characteristics, technical parameters of HIFU, intraoperative blood loss in suction curettage, the time for serum β-HCG to return to normal levels, reproductive outcomes, and adverse effects were recorded and analyzed.152 patients completed one session of HIFU combined with suction curettage except one patient transferred to surgery. Total energy used for ablation and the time for serum β-HCG return to normal level in type II and III were significantly higher than type I (HIFU combined with ultrasound-guided suction curettage is a safe and effective treatment option for patients with type I/II/III CSP and desire for fertility. Patients with type III CSP were more dependent on Foley catheter balloon compression therapy than the other two types after HIFU combined with curettage.

Background: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer’s disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. Objective: We aimed to explore the cause and mechanism of impaired glucose uptake in AD. Methods: N2a/WT and N2a/APP695swe cells were cultured in vitro, and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. Results: GLUT1 expression was significantly decreased (p = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p > 0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p = 0.0006, p = 0.0008, p = 0.0009, p = 0.0001, p = 0.0013), while Aβ levels were significantly decreased (p = 0.0058, p = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p = 0.0008), and Aβ levels were increased (p = 0.0009, p = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p = 0.0002, p = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p = 0.0212, p = 0.0006). Conclusion: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells.

Wearable strain sensors have huge potential for applications in healthcare, human-machine interfacing, and augmented reality systems. However, the nonlinear response of the resistance signal to strain has caused considerable difficulty and complexity in data processing and signal transformation, thus impeding their practical applications severely. Herein, we propose a simple way to achieve linear and reproducible resistive signals responding to strain in a relatively wide strain range for flexible strain sensors, which is achieved via the fabrication of Janus and heteromodulus elastomeric fiber mats with micropatterns using microimprinting second processing technology. In detail, both isotropic and anisotropic fiber mats can turn into Janus fiber mats with periodical and heteromodulus micropatterns via controlling the fiber fusion and the diffusion of local macromolecular chains of thermoplastic elastomers. The Janus heterogeneous microstructure allows for stress redistribution upon stretching, thus leading to lower strain hysteresis and improved linearity of resistive signal. Moreover, tunable sensing performance can be achieved by tailoring the size of the micropatterns on the fiber mat surface and the fiber anisotropy. The Janus mat strain sensors with high signal linearity and good reproducibility have a very low strain detection limit, enabling potential applications in human-machine interfacing and intelligent control fields if combined with a wireless communication module.

As an emerging minimally invasive technology, endoscopic ultrasound (EUS) has been reported to treat pelvic abscess instead of surgical or image-guided percutaneous drainage (PCD) under certain conditions. The aim of this study was to assess the efficacy and safety of EUS-guided drainage for patients with pelvic abscesses. We conducted a comprehensive literature search on PubMed, Embase, Cochrane Library, and Web of Science databases (inception–March 2022). The main outcomes were technical success, clinical success, and complications. Comprehensive meta-analysis software was used to calculate the pooled event rate. Twelve studies containing 272 patients were included. These pelvic abscesses most frequently developed after abdominal and pelvic surgery (n = 180, 66.2%), inflammatory bowel disease (n = 32, 11.8%), and other inflammatory conditions. Respectively, the pooled technical and clinical success rate was 100% and 88.7% [95% confidence interval (CI): 83.8–92.2%, I2 = 1.0%, p < 0.001]. After excluding an individual study, the pooled rate of complications changed from 11.5% (95% CI: 7.4–17.4%, I2 = 38.8%, p < 0.001) to 8.2% (95% CI: 5.0–13.3%, I2 = 0, p < 0.001). EUS-guided drainage of the pelvic abscess was feasible, effective, and safe. Further randomized-controlled studies with large-sample sizes were required in the future.

Abdominal wall endometriosis（AWE）is an unusual extra-pelvic endometriosis. Currently, multiple treatment modalities are available, but no clear guidelines exist for the management of large AWE.We present a 36-year-old female patient with a large AWE lesion who underwent cesarean section due to abnormal fetal position 8 years ago. The mass lesion of AWE located in rectus muscle fascia and rectus muscle with a size of 61 × 25 × 49mm.HIFU treatment was completed in one session. One day post-HIFU MRI showed the mass was completely ablated. After HIFU treatment, the cyclical abdominal pain disappeared. The mass lesion shrank during follow-up period and disappeared in 1 year after HIFU. No complication was observed after HIFU.Surgical resection of AWE remains the standard of care. In patients with large AWE lesion located in rectus muscle fascia and rectus muscle where the muscle and fascia must be excised, HIFU treatment should be considered to avoid mesh implantation.

Due to the high prevalence of breast cancer in the female, a metastasis from primary breast cancer is usually considered in the differential diagnosis of metastatic carcinoma in the female patient, even for those without a history of breast cancer, as some breast cancers are first diagnosed as metastases. Immunohistochemical analysis for breast cancer markers is the most common way to determine breast cancer origin besides clinical history and histology. In this review, we (1) summarize the commonly used and the newly identified breast cancer markers, including GCDFP-15, mammaglobin, GATA3, SOX10, and TRPS1; (2) point out the strengths and weaknesses of using these markers for breast cancers with luminal/epithelial or basal/myoepithelial differentiation; and (3) recommend diagnostic panels to differentiate breast carcinoma from carcinoma with similar morphology of other origins.

In light of the significant clinical benefits of novel HER2-targeting antibody-drug conjugates in advanced HER2-low expressing breast cancers in recent phases I and III clinical trials, particularly trastuzumab-deruxtecan (T-Dxd), the new "HER2-low" category in breast cancers (breast cancer with a HER2 IHC score of 1+, or 2+ without gene amplification) has gained increasing attention. In the past year, "HER2-low" breast cancers have been under active investigation by both oncologists and pathologists. In this current review, we update the recent cutting-edge research on HER2-low breast cancers, with a focus on the biology of HER2-low breast cancers, the issues on the identification of HER2-low breast cancers by immunohistochemistry in current practice of pathology, and the future directions in this emerging category in breast cancers.

Hypoxia often occurs in inflammatory tissues, such as tissues affected by periodontitis and apical periodontitis lesions. Mitochondrial biogenesis can be disrupted in hypoxia. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a core factor required for mitochondrial biogenesis. Cementoblasts are root surface lining cells that play an integral role in cementum formation. There is a dearth of research on the effect of hypoxia on cementoblasts and underlying mechanisms, particularly in relation to mitochondrial biogenesis during the hypoxic process. In this study, we found that the expression of hypoxia inducible factor-1α was elevated in apical periodontitis tissues in vivo. In contrast, periapical lesions exhibited a reduction of PGC-1α expression. For in vitro experiments, cobalt chloride (CoCl

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

Objective. To construct the graph theory model and grey correlation model of table tennis mixed doubles technology and tactics so as to provide a new research method for the analysis of table tennis mixed doubles technology and tactics. The method of graphic theory and video observation is used to study the top tactical indicators of the game, and the method of graphic theory and video observation is used to analyze the tactical data of men and women, which has a certain contribution to the world level of table tennis. The grey correlation analysis can be better applied to the technical and tactical analysis of table tennis mixed doubles. The analysis of the contribution rate of men and women in eight rounds shows that there is little difference in the net average score between male and female athletes, and female athletes are slightly higher than male athletes. The net average score of the serving round is much higher than that of the receiving round, which shows that the serving round has certain advantages for the server, and the winner is often better able to grasp the opportunity of the serving round and get higher scores. Male athletes should strengthen physical training and adapt to a higher level of confrontation.

The aim of this research was to establish a nomogram for early prediction of the severity of acute pancreatitis (AP).A total of 1860 AP patients from 2013 to 2020 were included in this study. According to the 2012 revised Atlanta classification, patients were divided into nonsevere AP group and severe AP (SAP) group. The baseline characteristics and first laboratory indicators after admission between the 2 groups were analyzed using univariate and multivariate logistic regression analysis in training set. R language was used for establishing a predictive nomogram and further verified in validation set.Univariate and multivariate logistic regression analysis in the training set showed red blood cell distribution width, d -dimer, apolipoprotein A1, and albumin were independent factors for SAP. A predictive nomogram was accordingly established based on the 4 indicators. Validation on this predictive nomogram showed high internal validation concordance index of 0.940 (95% confidence interval, 0.922-0.958) and high external validation concordance index of 0.943 (95% confidence interval, 0.920-0.966). The calibration curve, receiver operating characteristic curve, and decision curve analysis all showed that the nomogram had good predictive ability.This nomogram may be an effective clinical tool for predicting the first episode of SAP.

Clinical studies are important in informing evidence-based practice for patients with acute pancreatitis (AP). To determine whether registered studies adequately meet this need, we leveraged the ClinicalTrials.gov database to provide an overview of studies pertaining to AP.ClinicalTrials.gov was searched and the search term used was AP. Analysis was restricted to studies registered before January 12, 2021.Of 363,632 trials overall, 234 (0.06%) were eventually included for analysis. Interventional studies and observational studies comprised 67.5% and 32.5% of these studies respectively. Most studies were initiated 2007 or later. Endoscopic retrograde cholangiopancreatography was the single most frequent cause of AP specified in these studies (16.7%). Nearly 72% of these studies had a sample size greater than 50. With respect to study design, 87.3% of interventional studies were randomized, 53.5% were blinded. The top 3 countries with the largest number of registered studies were China (n = 59), followed by the United States (n = 53) and India (n = 12).Our results indicate that the research activity falls short of what is needed in terms of the burden of AP. The distribution of these AP-related studies by global regions indicates that there exists regional disparities.

To investigate the outcomes of open reduction and internal fixation combined with medial buttress plate (MBP) and allograft bone-assisted cannulated screw (CS) fixation for patients with unstable femoral neck fracture with comminuted posteromedial cortex.In a retrospective study of patients operated on for unstable femoral neck fractures with comminuted posteromedial cortex from March 2016 to August 2020, the clinical and radiographic outcomes of 48 patients treated with CS + MBP were compared with the outcomes of 54 patients treated with CS only. All patients in the CS + MBP group were fixed by three CS and MBP (one-third tubular plates or reconstructive plates) with bone allografts. The surgery-related outcomes and complications were evaluated, including operative time, blood loss, union time, femoral head necrosis, femoral neck shortening, and other complications after the operation. The Harris score was evaluated at 12 months after the operation.All patients were followed up for 12-40 months. The average age of patients in the CS-only group (54 cases, 22 females) and CS + MBP group (48 cases, 20 females) was 48.46 ± 7.26 and 48.73 ± 6.38 years, respectively. More intraoperative blood loss was observed in the CS + MBP group than that of patients in CS-only group (153.45 ± 64.27 vs 21.86 ± 18.19 ml, t = 4.058, P = 0.015). The average operative time for patients in the CS + MBP group (75.35 ± 27.67 min) was almost double than that of patients in the CS-only group (36.87 ± 15.39 min) (t = 2.455, P 0.001). The Garden alignment index of patients treated by CS + MBP from type I to type IV was 79%, 19%, 2%, and 0%, respectively. On the contrary, they were 31%, 43%, 24% and 2% for those in the CS-only group, respectively. The average healing times for the CS-only and CS + MBP groups were 4.34 ± 1.46 and 3.65 ± 1.85 months (t = 1.650, P = 0.102), respectively. Femoral neck shortening was better in the CS + MBP group (1.40 ± 1.73 mm, 9/19) than that in the CS-only group (4.33 ± 3.32 mm, 24/44). Significantly higher hip function was found in the CS + MBP group (85.60 ± 4.36 vs 82.47 ± 6.33, t = 1.899, P = 0.06). There was no statistical difference between femoral head necrosis (4% vs 11%, χFor unstable femoral neck fractures with comminuted posteromedial cortex, additional MBP combined with bone allografts showed better reduction quality and neck length control than CS fixation only, with longer operative time and more blood loss.

Zenker's peroral endoscopic myotomy (Z-POEM) has revolutionized the therapeutic strategy for Zenker's diverticulum (ZD) with promising results. We conducted this meta-analysis to estimate the safety and efficacy of Z-POEM for ZD and compare the feasibility and effectiveness of Z-POEM with that of flexible endoscopic septotomy (FES).A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, and Cochrane Library databases to query for studies that assessed the safety and efficacy of Z-POEM for ZD. All articles published from inception to July 31, 2021 were included. The primary outcomes were the overall technical success rate, clinical success rate, incidence of adverse events, and clinical recurrence rate.Eleven studies involving 357 patients undergone Z-POEM were included. Overall, the quality of included studies was above average, with five studies rated as high quality and six ranked as moderate quality. The overall pooled technical success rate for Z-POEM was 96.3% (95% confidence interval [CI] 93.6-97.9%; IZ-POEM could be an effective and safe therapeutic modality for ZD, and even has a slightly higher clinical success rate than FES. However, comparative studies with long-term follow-up will be needed to further confirm our finding.

A body shape index (ABSI) has been proven to be related to a population's CVD incidence. However, the application of this indicator has produced different results.This study aimed to evaluate the applicability of the ABSI in predicting the incidence of CVD in rural Xinjiang, China, and compare it with waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body mass index (BMI).5375 people aged 18 years or older were included in the study. We used the Cox proportional hazard model to evaluate the relationship between WC, WHR, WHtR, BMI, and ABSI and the incidence of CVD, the area under the curve (AUC) to evaluate the predictive power of each anthropometric index for the incidence of CVD, and restricted cubic splines are used to analyse the trend relationship between anthropometric indicators and the incidence of CVD.After multivariate adjustment, standardised WC, WHR, WHtR, BMI, and ABSI all positively correlated with the incidence of CVD. WC had the highest HR (95% CI) value, 1.64 (1.51-1.78), and AUC (95% CI) value, 0.7743 (0.7537-0.7949). ABSI had the lowest HR (95% CI) value, 1.21(1.10-1.32), and AUC (95% CI) value, 0.7419 (0.7208-0.7630). In the sex-specific sensitivity analysis, the predictive ability of traditional anthropometric indicators for the incidence of CVD is higher than that of ABSI.In the rural areas of Xinjiang, the traditional anthropometric indicators of WC had better ability to predict the incidence of CVD than ABSI.

Animal-derived biological products, such as fetal bovine serum (FBS) and trypsin, are important supplements for scientific, pharmaceutical, and medical use. Although preventive guidelines and tests are implemented to reduce potential viral contamination in these biologicals, they do not target unusual or emerging viruses, leading to safety concerns. Using unbiased metagenomics, we investigated the presence of viruses in recently collected commercial FBS and trypsin samples from different geographic regions. In total, we detected viral sequences belonging to动物源性的生物制品，如胎牛血清（FBS）和胰蛋白酶（Trypsin），是科学、制药和医疗等领域的重要添加成分。尽管采取了预防性的指南和措施来减少这些生物制品中潜在的病毒污染，但是这些措施并未针对罕见的或新发的病毒，因此可能会导致潜在的安全问题。我们使用无偏的宏基因组方法，对来自不同区域的商业FBS和Trypsin样本中携带的病毒进行了分析。我们检测到了

In this paper, two cationic probes 1a and 1b and a neutral dye 1c were successfully designed and synthesized according to the Knoevenagel condensation reaction, which combines the good optical properties of hemocyanine and the biocompatibility of nitrogen-containing heterocyclic rings based on a quinoxaline skeleton. Probes 1a and 1b showed an OFF-ON fluorescence response to nucleic acids with excellent selectivity. Specifically, the fluorescence intensity of probe 1a was enhanced by 18 and 133 times, respectively, along with the increase of DNA or RNA concentrations (0-600 μg mL

Polarity and viscosity, as important microenvironment parameters, play an essential role in cell metabolism. Therefore, 9-acridine carboxaldehyde reacted with cyano compounds to obtain polarity-sensitive probes 1a-b and viscosity-sensitive probes 1c-d. Among them, with the increase in solvent polarity, the maximum emission wavelength of acridine-dicyanoisophorone-based probe 1a red-shifted from 553 nm to 594 nm, the fluorescence quantum yield increased from 0.5% to 35.6%, and the fluorescence intensity enhanced 38 fold. The acridine-cyanofuranone based probe 1b also has a polarity response similar to 1a. Nevertheless, when the solution viscosity increased from 0.89 cP (100% water) to 856 cP (1% water), the fluorescence intensity of the acridine-tricyanodihydrofuran based probe 1c at 430 nm enhanced 5.6 times. The acridine-cyanobenzothiazole based probe 1d also had a viscosity response similar to 1c. In addition, probes 1a-b were used for further HeLa cell imaging experiments due to their good photostability and the results suggested that probe 1a could locate lipid droplets and probes 1b-c could stain lysosomes. Moreover, probes 1a-b could dynamically monitor the changes in intracellular polarity.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma. We report one case of primary kidney SEF occurring in a 38-year-old man. Microscopically, epithelioid neoplastic cells are mainly arranged in cords and nests embedded in the dense sclerosing stroma. Diffuse immunohistochemical staining for MUC4 in neoplastic cells and the presence of the EWSR1 gene split by fluorescence in situ hybridization (FISH) analysis confirmed the histological diagnosis. Primary kidney SEF is extremely rare, the differential diagnosis strategy broadly includes a series of tumors with epithelioid morphology and sclerosing matrix, mainly including sclerosing variants of clear cell sarcoma of the kidney (CCSK), renal synovial sarcoma (SS), renal solitary fibrous tumor (SFT), metanephric stromal tumor (MST), sclerosing perivascular epithelioid cell tumor (PEComa), and carcinomas, and immunohistochemical expression of MUC4 and evidence of the EWSR1 gene split are helpful in making a definite diagnosis.

Background Recent studies have revealed that circular RNA participates in endometrial carcinoma (EC) progression. Here we investigated the role of circRNA zinc finger protein 124 (circZNF124) in EC genesis and underlying mechanism. Methods The expression levels of circZNF124, microRNA‐199b‐5p (miR‐199b‐5p) and solute carrier family 7 member 5 (SLC7A5) were detected by quantitative real‐time polymerase chain reaction. The expression of SLC7A5 and other indicated marker proteins was determined by western blot analysis. For functional assay, cell proliferation, leucine uptake and metastasis were investigated by total cell number, cell counting kit‐8, cell colony formation, leucine uptake or transwell assay. The interaction between miR‐199b‐5p and circZNF124 or SLC7A5 was predicted by starbase online database, and identified by mechanism assays. The impact of circZNF124 absence on tumor growth in vivo was revealed by xenograft mouse model assay. Immunohistochemistry assay was implemented to detect the positive expression rate of nuclear proliferation marker (Ki67). Results CircZNF124 and SLC7A5 expression were significantly increased, while miR‐199b‐5p was decreased in EC tissues and cells compared with normal endometrial tissues or cells. CircZNF124 expression was closely associated with EC severity and lymph node metastasis. Additionally, circZNF124 depletion repressed cell proliferation, leucine uptake, migration and invasion in both HEC1A and Ishikawa cells. CircZNF124 regulated SLC7A5 expression by binding to miR‐199b‐5p. MiR‐199b‐5p inhibitors or SLC7A5 overexpression attenuated circZNF124 silencing‐mediated EC malignant progression. Furthermore, SLC7A5 absence inhibited tumor growth in vivo. Conclusion CircZNF124 depletion inhibited EC cell malignancy by miR‐199b‐5p/SLC7A5 pathway, which demonstrated that circZNF124 had the potential as a therapeutic target for EC., CircZNF124 expression was related to severity of EC and lymph node metastasis. CircZNF124 silencing inhibited EC tumorigenesis by hindering leucine uptake through miR‐199b‐5p/SLC7A5 axis. This study demonstrates that circZNF124 can be employed as a diagnosis biomarker and circZNF124 inhibitors may be used as an anticancer drug for EC.

Inducing mitochondrial malfunction is an appealing strategy to overcome tumor multidrug resistance (MDR). Reported here a versatile mitochondrial-damaging molecule, vitamin E succinate (VES), is creatively utilized to assist MDR reversal of doxorubicin hydrochloride (DOX·HCl) via a nanovesicle platform self-assembled from amphiphilic polyphosphazenes containing pH-sensitive 1H-benzo-[d]imidazol-2-yl) methanamine (BIMA) groups. Driven by multiple non-covalent interactions, VES is fully introduced into the hydrophobic membrane of DOX·HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust anti-leakage property toward DOX·HCl under normal physiological conditions. More importantly, upon release within acidic tumor cells, VES can target mitochondria and result in various dysfunctions including excessive generation of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) loss, and inhibited adenosine triphosphate (ATP) synthesis, which contribute to cell apoptosis and insufficient energy supply for drug efflux pumps. Consequently, the killing-effect of DOX·HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX·HCl to VES. Further in vivo antitumor investigation on nude mice bearing xenograft drug-resistant human chronic myelogenous leukemia K562/ADR tumors verifies the extremely enhanced anti-tumor efficacy of the dual drug-loaded nanovesicle with the tumor inhibition rate (TIR) of 82.38%. Collectively, this study provides a s safe, facile and promising strategy for both precise drug delivery and MDR eradication to improve cancer therapy.

BackgroundThe genomic landscape of breast malignant phyllodes tumors (PTs) is not well defined, especially pregnancy-related malignant PTs. To clarify this topic, whole-exome next-generation sequencing (NGS) was performed on tumor samples and paired normal breast tissues from two pregnancy-related malignant PTs, followed by a functional analysis of the genetic alterations.MethodsDNA from malignant PT samples and matched normal breast tissues of both patients were subjected to molecular profiling. NGS of the whole-exome was performed in a commercial molecular pathology laboratory. Predictive tools were used to estimate genetic variation in somatic and germline genes.ResultsIn total, 29 somatic genomic alterations and 18 germline alterations were found in both patients. In Patient 1, 12 aberrations were identified in the tumor tissue, and 9 alterations were identified in matched normal breast tissue. One pathogenic variant in tumor suppressor genes (TP53) was detected in patient 1. In Patient 2, 18 and 10 variants were found in the tumor and matched normal breast tissue, respectively. In Patient 2, pathogenic alterations were identified in two tumor suppressor genes (PTENandTP53).PTENandTP53may be potential drug targets. The functional predictive tools showed that genes of unknown significance for PTs, includingFCHO1in Patient 1, andLRP12andPKMin Patient 2, were pathogenic. Several genes, includingFCHO1,LRP12andPKM, were shown for the first time to be altered in malignant PTs. A potentially pathogenic germline variant inPRF1, was detected in Patient 1.ConclusionOur study first demonstrated somatic and germline gene alterations in two malignant PTs during pregnancy and lactation. These two PTs shared major genetic events, includingTP53mutation, which commonly occurs in malignant PTs; additionally, we identified two potential genes for targeted therapy,TP53andPTEN. One germline mutation inPRF1was also detected. These results provide clues regarding tumor pathogenesis and precision therapy development.

Carthamus tinctorius is proved potent in treating ischemic stroke. Flavonoids, such as safflower yellow, hydroxysafflor yellow A(HSYA), nicotiflorin, safflower yellow B, and kaempferol-3-O-rutinoside, are the main substance basis of C. tinctorius in the treatment of ischemic stroke, and HSYA is the research hotspot. Current studies have shown that C. tinctorius can prevent and treat ischemic stroke by reducing inflammation, oxidative stress, and endoplasmic reticulum stress, inhibiting neuronal apoptosis and platelet aggregation, as well as increasing blood flow. C. tinctorius can regulate the pathways including nuclear factor(NF)-κB, mitogen-activated protein kinase(MAPK), signal transducer and activator of transcription protein 3(STAT3), and NF-κB/NLR family pyrin domain containing 3(NLRP3), and inhibit the activation of cyclooxygenase-2(COX-2)/prostaglandin D2/D prostanoid receptor pathway to alleviate the inflammatory development during ischemic stroke. Additionally, C. tinctorius can relieve oxidative stress injury by inhibiting oxidation and nitrification, regulating free radicals, and mediating nitric oxide(NO)/inducible nitric oxide synthase(iNOS) signals. Furthermore, mediating the activation of Janus kinase 2(JAK2)/STAT3/suppressor of cytokine signaling 3(SOCS3) signaling pathway and phosphoinositide 3-kinase(PI3 K)/protein kinase B(Akt)/glycogen synthase kinase-3β(GSK3β) signaling pathway and regulating the release of matrix metalloproteinase(MMP) inhibitor/MMP are main ways that C. tinctorius inhibits neuronal apoptosis. In addition, C. tinctorius exerts the therapeutic effect on ischemic stroke by regulating autophagy and endoplasmic reticulum stress. The present study reviewed the molecular mechanisms of C. tinctorius in the treatment of ischemic stroke to provide references for the clinical application of C. tinctorius.

Fluorescent lamp manufacturing workers have been extensively exposed to mercury (Hg). Our aim was to assess their health risks using several approved occupational health risk assessment methods, and to find out which method was more suitable for identification of occupational health risks. Work locations, and air and urine samples were collected from 530 exposed workers in Zhejiang, China. Based on the calculated exposure doses, health risks and risk ratios (RRs) as health risk indices, were evaluated using: Environmental Protection Agency (EPA), Australian, Romanian, Singaporean, International Council on Mining and Metals (ICMM), and Control of Substances Hazardous to Health (COSHH) methods. Among the workers, 86.0% had higher Hg levels than the Chinese occupational exposure limits of 0.02 mg/m3, and 16.7% urine samples were higher than the biological exposure limits of 35.0 μg/g·creatinine. Among workers at the injection, etc. locations, their average RRs, evaluated by the EPA, COSHH and Singaporean methods were 0.97, 0.76, and 0.60, respectively, and were significantly higher than the ICMM (0.39), Australian (0.30) and Romanian (0.29) methods. The RRs from the Singaporean method showed significant correlations with the urinary Hg levels (P < 0.01). In conclusion, the Singaporean method was more appropriate than the others for health risk evaluation because the excessive risks were significantly associated with urinary Hg levels among the workers.

Mesenchymal stem cells (MSCs) are known for their multilineage differentiation potential with immune-modulatory properties. The molecular underpinnings of differentiation remain largely undefined. In this study, we investigated the cellular and molecular features of chemically induced osteogenesis from MSC isolated from human adipose tissue (human adipose MSCs, hAMSCs) using single-cell RNA-sequencing (scRNA-seq). We found that a near complete differentiation of osteogenic clusters from hAMSCs under a directional induction. Both groups of cells are heterogeneous, and some of the hAMSCs cells are intrinsically prepared for osteogenesis, while variant OS clusters seems in cooperation with a due division of the general function. We identified a set of genes related to cell stress response highly expressed during the differentiation. We also characterized a series of transitional transcriptional waves throughout the process from hAMSCs to osteoblast and specified the unique gene networks and epigenetic status as key markers of osteogenesis.

The development of radioresistance by nasopharyngeal carcinoma (NPC) cells almost always results in tumor recurrence and metastasis, making clinical treatment of the disease difficult. In this study, the mechanism of radioresistance in NPC cells was investigated. First, a gene array and quantitative reverse-transcription-PCR assays were used to screen for genes exhibiting significantly altered expression in the DNA damage signaling pathway. Based on those results, GADD45G was further studied in the context of radioresistance. A GADD45G-knockout NPC cell line (CNE-2R-KO) was constructed using CRISPR-Cas9 technology and used for a comparison of differences in radioresistance with other radiosensitive and radioresistant NPC cells, as evaluated using colony formation assays. Cell cycle changes were observed using flow cytometry. Cell proliferation and migration were measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and wound healing assays, respectively. The sequencing results revealed the successful construction of the CNE-2R-KO cell line, the radiosensitivity of which was higher than that of its parent radioresistant cell line owing to the GADD45G knockout. This was likely related to the increase in the number of cells in the G1 phase and decrease in those in the S1 phase as well as the increased cell proliferation rate and decreased migratory ability. GADD45G is associated with radioresistance in NPC cells and likely has a role in the occurrence and metastasis of NPC.

Whether amino acids act on cellular insulin signaling remains unclear, given that increased circulating amino acid levels are associated with the onset of type 2 diabetes (T2D). Here, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or phenylalanine-producing aspartame or overexpressing human phenylalanyl-tRNA synthetase (hFARS) develop insulin resistance and T2D symptoms. Mechanistically, FARS phenylalanylate lysine 1057/1079 of IRβ (F-K1057/1079), inactivating IRβ and preventing insulin from promoting glucose uptake by cells. SIRT1 reverse F-K1057/1079 and counteract the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels in white blood cells from T2D patients are positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitizes insulin signaling and relieves T2D symptoms in hFARS-transgenic and db/db mice. These findings shed light on the activation of insulin signaling and T2D progression through inhibition of phenylalanylation.

Aim: To investigate the relationship between expression of C-MYC protein and clinicopathologic characteristics in angioimmunoblastic T-cell lymphoma (AITL), then discuss the prognosis. Methods: Patient samples were collected and made into tissue microarray for the same experimental condition. Pathomorphological features and immunohistochemistry of specific markers were used to determine the diagnosis of AITL. Epstein-Barr virus (EBV) infection was detected by EBV-encoded small RNA by in situ molecular hybridizations. B cells atypical hyperplasia was explored by the immunohistochemistry and gene rearrangement, C-MYC protein was expressed by the immunohistochemical staining and C-MYC gene abnormalities were detected by fluorescence in situ hybridization (FISH). 44 AITL patients were divided into two groups and the relation among C-MYC protein, EBV infection and B cells hyperplasia was observed. We followed up the overall survival rate (OS) and progression-free survival (PFS), and analyzed C-MYC protein, and the relationship between the prognosis of survival. Results: Among 44 AITL patients, 29 cases (65.9%) were C-MYC protein-positive, and 32 (32/44, 72.3%) were EBV-positive. The expression rate of C-MYC protein in the high-risk group ranked by international prognostic index (IPI) and stage III–IV were higher than that in the low-risk group and stage I–II (P0.05). C-MYC gene rearrangement was not found in any samples, while the multi-copies of the C-MYC gene were found in only one case. As followed, 5-year OS was significantly low, and there was no significant difference in OS between the C-MYC protein-positive and negative groups. PFS in the positive group was significantly lower than that of the negative group. The difference in response to treatment between the two groups was statistically significant (P

Background Recurrent retinal detachment (Re-RD) usually affects the prognosis of surgery for rhegmatogenous retinal detachment (RRD). Previous clinical studies of Re-RD were not specific. This study aimed to analyze the clinical characteristics of Re-RD in post-vitrectomy eyes with RRD and surgical outcomes after revitrectomy without combining it with retinectomy or scleral buckling. Methods This is a retrospective case series analyzed the ocular characteristics of 20 recurrent and contralateral eyes, evaluated the significance of the associations between variables before reoperation and the final best-corrected visual acuity (BCVA), and calculated the outcome of revitrectomy. Results Patients with phakic eyes, those undergoing only one surgery, and those with more than one break had better final BCVA. The final BCVA was negatively correlated with the axial length and positively correlated with the preoperative BCVA. Among the 12 eyes with no break detected before surgery, 11 (92%) were found to have a small crevice-like break beside the pigment scar of a large number of original laser spots. The single-operation complete retinal reattachment rate was 75%, the complete retinal reattachment rate was 80%, and the final incomplete retinal reattachment rate was 90%. The BCVA improved from 1.2 ± 0.6LogMAR (0.06 ± 0.25) before surgery to 0.8 ± 0.7LogMAR (0.15 ± 0.2) at the last follow-up. The BCVA of 16 patients with complete retinal reattachment improved from 1.0 ± 0.5LogMAR (0.1 ± 0.3) to 0.6 ± 0.4LogMAR (0.25 ± 0.4). In the contralateral eyes, 15% already had vision-damaging disease, and the incidence of eyesight-threating lesions was 5.9% during follow-up. Conclusions Revitrectomy without retinectomy or scleral buckling can effectively treat Re-RD in post-vitrectomy eyes. In Re-RD patients with no definite retinal break detected preoperatively, the retinal hole usually shows small crevice-like changes alongside a large number of original laser pigment scars.

Due to the hugely important roles of neurotransmitter acetylcholine (ACh) and amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), the development of multi-target directed ligands (MTDLs) focused on cholinesterase (ChE) and Aβ becomes one of the most attractive strategies for combating AD. To date, numerous preclinical studies toward multifunctional conjugates bearing ChE inhibition and anti-Aβ aggregation have been reported. Noteworthily, most of the reported multifunctional cholinesterase inhibitors are carbamate-based compounds due to the initial properties of carbamate moiety. However, because their easy hydrolysis in vivo and the instability of the compound-enzyme conjugate, the mechanism of action of these compounds is rare. Thus, non-carbamate compounds are of great need for developing novel cholinesterase inhibitors. Besides, given that Aβ accumulation begins to occur 10-15 years before AD onset, modulating Aβ is ineffective only in inhibiting its aggregation but not eliminate the already accumulated Aβ if treatment is started when the patient has been diagnosed as AD. Considering the limitation of current Aβ accumulation modulators in ameliorating cognitive deficits and ineffectiveness of ChE inhibitors in blocking disease progression, the development of a practically valuable strategy with multiple pharmaceutical properties including ChE inhibition and Aβ modulation for treating AD is indispensable. In this review, we focus on summarizing the scaffold characteristics of reported non-carbamate cholinesterase inhibitors with Aβ modulation since 2020, and understanding the ingenious multifunctional drug design ideas to accelerate the pace of obtaining more efficient anti-AD drugs in the future.

Background Chronic inflammatory disorders in atrial fibrillation (AF) contribute to the onset of ischemic stroke. Systemic immune inflammation index (SIII) and system inflammation response index (SIRI) are the two novel and convenient measurements that are positively associated with body inflammation. However, little is known regarding the association between SIII/SIRI with the presence of AF among the patients with ischemic stroke. Methods A total of 526 ischemic stroke patients (173 with AF and 353 without AF) were consecutively enrolled in our study from January 2017 to June 2019. SIII and SIRI were measured in both groups. Logistic regression analysis was used to analyse the potential association between SIII/SIRI and the presence of AF. Finally, the correlation between hospitalization expenses, changes in the National Institutes of Health Stroke Scale (NIHSS) scores and SIII/SIRI values were measured. Results In patients with ischemic stroke, SIII and SIRI values were significantly higher in AF patients than in non-AF patients (all p p = 0.047; log-transformed SIRI: OR: 6.197, 95% CI = 2.196–17.484, p = 0.001). Finally, a positive correlation between hospitalization expenses, changes in the NIHSS scores and SIII/SIRI were found, which were more significant in patients with AF (all p Conclusions Our study suggests SIII and SIRI are convenient and effective measurements for predicting the presence of AF in patients with ischemic stroke. Moreover, they were correlated with increased financial burden and poor short-term prognosis in AF patients presenting with ischemic stroke.

The amino sugar N-acetyl-d-glucosamine (GlcNAc) is the key constituent of cell wall components and plays an important role in pathogenesis in a wide range of fungi. However, catabolism of GlcNAc has not been studied in basidiomycete fungi. In this study, we identified and characterized a gene cluster essential for GlcNAc utilization in Cryptococcus deneoformans, an environmental human fungal pathogen. The C. deneoformans genome contains a GlcNAc transporter (Ngt1), a GlcNAc kinase (Hxk3), a GlcNAc-6-phosphate deacetylase (Dac1), and a glucosamine-6-phosphate deaminase (Nag1). Their expression levels were highly induced in cultures containing GlcNAc as the sole carbon source, and the corresponding mutants showed severe growth defects in the presence of GlcNAc. Functional and biochemical analyses revealed that HXK3 encodes a novel GlcNAc kinase. Site-directed mutations of conserved residues of Hxk3 indicated that ATP binding and GlcNAc binding are essential for GlcNAc kinase activities. Taken together, the results from this study provide crucial insights into basidiomycete GlcNAc catabolism. IMPORTANCE N-Acetylglucosamine (GlcNAc) is recognized as not only the building block of chitin but also an important signaling molecule in fungi. The catabolic pathway of GlcNAc also plays an important role in vital biological processes in fungi. However, the utilization pathway of GlcNAc in the phylum Basidiomycota, which contains more than 41,000 species, remains unknown. Cryptococcus deneoformans is a representative basidiomycetous pathogen that causes life-threatening meningitis. In this study, we characterized a gene cluster essential for GlcNAc utilization in C. deneoformans and identified a novel GlcNAc kinase. The results of this study provide important insights into basidiomycete GlcNAc catabolism and offer a starting point for revealing its role in pathogenesis.

The unipolar/bipolar pacing mode of pacemaker is related to its circuit impedance, which affects the battery life. In this study, the

To investigate the safety and efficacy of femtosecond laser-assisted penetrating keratoplasty (FLAK) versus conventional penetrating keratoplasty (CPK). A literature search of PubMed, Cochrane, Embase, Web of Science, and Clinicaltrials.gov was conducted for comparative studies published from January 2007 to October 2019. Studies that involved both FLAK and CPK groups and reported on the relevant efficacy and/or safety parameters were included. The Newcastle–Ottawa quality assessment scale was used to analyse the methodological quality of these studies. Further, weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated. From the screened articles, a total of 1991 eyes from nine comparative studies were included. FLAK was not statistically superior for twelve-month postoperative best corrected visual acuity (WMD = − 0.06; 95% CI [− 0.16, 0.04]; P = 0.22), corneal astigmatism (WMD = − 0.81; 95% CI [− 1.63, 0.01]; P = 0.05) or six-month postoperative uncorrected visual acuity (WMD = − 0.11; 95% CI [− 0.27, 0.06]; P = 0.21). There were no significant differences in corneal graft rejection rate and the graft failure between FLAK and CPK at twelve months postoperative. However, best-corrected visual acuity (BCVA) and corneal astigmatism corrected with FLAK were better than those with CPK six months postoperative after elimination of data heterogeneity. Visual outcomes improvement in FLAK was better than that in CPK at six months postoperative, but not twelve months postoperative. This review recommends selecting a technique based on patients’ work demands and economic burdens.

Human epidermal growth factor receptor 2 (HER2) positive (+) classical type invasive lobular carcinoma (cILC) of the breast is extremely rare and its clinicopathologic features have not been well characterized. We compared features of HER2(+) and HER2 negative (−) cILCs. A total of 29 cases were identified from the clinical database at our institution from 2011-2019, 9 were HER2(+) cILC tumors and 20 were HER2(−) cILC tumors. The results reveal that HER2(+) cILC group had significantly increased Ki-67 expression and reduced estrogen receptor (ER) expression compared to HER2(−) cILC group (both p &lt, 0.05). In addition, HER2(+) cILCs tended to be diagnosed at a younger age and more common in the left breast, and appeared to have a higher frequency of nodal or distant metastases. These clinicopathologic features suggest HER2(+) cILC tumors may have more aggressive behavior than their HER2(-) counterpart although both groups of tumors showed similar morphologic features. Future directions of the study: (1) To conduct a multi-institutional study with a larger case series of HER2(+) cILC to further characterize its clinicopathologic features, (2) to compare molecular profiles by next generation sequencing (NGS) assay between HER2(+) cILC and HER2(−) cILC cases to better understand tumor biology of this rare subset of HER2(+) breast cancer, and (3) to compare molecular characteristics of HER2(+) cILC and HER2(+) high grade breast cancer in conjunction with status of tumor response to anti-HER2 therapy to provide insight to management of this special type of low grade breast cancer to avoid unnecessary treatment and related toxicity

Peroral endoscopic myotomy (POEM) has emerged as a rescue treatment for recurrent or persistent achalasia after failed initial management. Therefore, we aimed to investigate the efficacy and safety of POEM in achalasia patients with failed previous intervention. We searched the MEDLINE, Embase, Cochrane, and PubMed databases using the queries “achalasia,” “peroral endoscopic myotomy,” and related terms in March 2019. Data on technical and clinical success, adverse events, Eckardt score and lower esophageal sphincter (LES) pressure were collected. The pooled event rates, mean differences (MDs) and risk ratios (RR) were calculated. A total of 15 studies with 2,276 achalasia patients were included. Overall, the pooled technical success, clinical success and adverse events rate of rescue POEM were 98.0% (95% confidence interval [CI], 96.6% to 98.8%), 90.8% (95% CI, 88.8% to 92.4%) and 10.3% (95% CI, 6.6% to 15.8%), respectively. Seven studies compared the clinical outcomes of POEM between previous failed treatment and the treatment naive patients. The RR for technical success, clinical success, and adverse events were 1.00 (95% CI, 0.98 to 1.01), 0.98 (95% CI, 0.92 to 1.04), and 1.17 (95% CI, 0.78 to 1.76), respectively. Overall, there was significant reduction in the pre- and post-Eckardt score (MD, 5.77; p

Background The diagnosis of pediatric pancreatitis has been increasing over the last 20 years. We aimed to compare the clinical characteristics for pediatric acute pancreatitis (AP) with adult AP, and investigate the risk factor for acute recurrent pancreatitis (ARP) in children. Method From June 2013 to June 2019, a total of 130 pediatric patients with AP at the inpatient database were enrolled. Univariate analysis and multivariate Cox regression analysis were performed to identify the risk factors for ARP in children. Result Major etiologic factors in 130 patients were biliary (31.5%), idiopathic (28.5%). The etiology of pancreatitis in children was markedly different from that in adults (p p = 0.018) and occurrence rate of pancreatic necrosis (p = 0.041), SIRS (p = 0.021), acute peripancreatic fluid collection (p = 0.014). Univariate and Multivariate Cox regression analysis showed that female (p = 0.020; OR 3.821; 95% CI 1.231–11.861), hypertriglyceridemia (p = 0.045; OR 3.111; 95% CI 1.024–9.447), pancreatic necrosis (p = 0.023; OR 5.768; 95% CI 1.278–26.034) were the independent risk factors of ARP. Hypertriglyceridemia AP had the highest risk of recurrence compared to other etiology (p = 0.035). Conclusion Biliary and idiopathic disease were the major etiologies of AP in children. Children have simpler conditions than adults. Female, hypertriglyceridemia, and pancreatic necrosis were associated with the onset of ARP.

Purpose The purpose of this study was to explore the efficacy, safety, and tolerability of a novel cyclosporine formulation for dry eye disease (DED). Methods This is an exploratory, multicenter, single-blind, randomized, positive-controlled Phase II clinical trial between cyclosporine ophthalmic gel (CyclAGel) and an open-label comparator (Restasis, positive control). A total of 240 eligible patients with moderate to severe DED were randomized to 4 study groups: CyclAGel 0.05%/once daily (QD) (n = 59), CyclAGel 0.05%/BID (n = 60), CyclAGel 0.1%/QD (n = 60), and Restasis 0.05%/BID (n = 61). After receiving BID dosing of hypromellose eye drops during a 2-week run-in period, patients were randomized to the respective treatment group and dosed QD or BID for 12 weeks. Efficacy was assessed based on a number of sign and symptom end points, including eye dryness score (visual analog scale), 6 other parameters of symptoms for dryness (burning/stinging, itching, foreign body sensation, discomfort, sensitivity to light, and pain), and corneal fluorescein staining. The Schirmer test was used to assess dry eye symptoms (visual analog scale severity) at visit 3 (week 2), visit 4 (week 6), and visit 5 (week 12). Findings CyclAGel showed a consistent improvement in eye dryness score and the 6 other parameters of symptoms for dryness, corneal fluorescein staining, breakup time, and Schirmer test scores compared with Restasis over the 12-week treatment period. However, there were no statistically significant differences between CyclAGel and Restasis after baseline corrections were made, and the results of the full analysis set remained consistent with those of the per-protocol set (P > 0.05). Moreover, each CyclAGel-treated group (0.05%/QD, 0.05%/BID, and 0.1%/QD) exerted better effects than the Restasis group, and CyclAGel 0.05%/QD showed the most significant improvement. The number of ocular-related treatment-emergent adverse events was low in all treatment groups, with no serious drug-related treatment-emergent adverse events. Implications CyclAGel showed excellent safety, tolerability, and comfort profiles at 2 concentrations and frequency in moderate to severe DED.

F-box proteins are essential components of the E3 ubiquitin ligases which are involved in the regulation of almost all life activities such as cell cycle, proliferation, and apoptosis, which have become an important research and drug target. However, there are few studies on F-box and leucine-rich repeat protein 16 (FBXL16) in endometrial carcinoma.Clinical samples were collected for determining the correlation between FBXL16 and endometrial carcinoma. Cells were screened and established with Ishikawa cells which proved the fundamental role of FBXL16 in regulating cell proliferation and cell cycle. The MPA-resistant endometrial carcinoma cell line Ishikawa/MPA was established. FBXL16, PP2AThe high expression of FBXL16 was positively correlated with MPA resistance and poor prognosis of endometrial cancer. MPA tolerance of endometrial cancer cells was inhibited by knockdown of FBXL16 in DNA content assessment, CCK-8, and colony formation. It was confirmed that FBXL16 inhibited the activity of substrate PP2AIn our experiments, FBXL16 binds PP2A to promote the dephosphorylation of Thr286 site of cyclin D1 via AKT1/GSK3

Background Diagnosis of rare diseases remains a challenge in China. We describe our experience with Birt-Hogg-Dubé syndrome (BHDS) encountered at a Rare Lung Disease Clinic recently established in China. Methods After the first patient with BHDS was recognized in 2017, a Rare Lung Disease Clinic with a multidisciplinary team of specialists was established. We retrospectively analyzed the data of consecutive patients with BHDS encountered from inception to December 2021. Results There were 1, 1, 15, 12 and 21 cases with BHDS diagnosed from year 2017 to 2021, respectively. All 50 patients (34 women) were of Han race with a mean age of 47.4 years. The common manifestations were pulmonary cysts (98%), pneumothorax (54%) and skin lesions (68%). Renal cancer was detected in two patients and renal angiomyolipoma in four other patients. The main presentations leading to diagnosis were pneumothorax (42%), family screening (36%), and lung cysts identified on radiologic imaging (20%). The average delay in diagnosis was 8.3 years, and 4.7 years in patients with only pulmonary cysts. The most frequent pathogenic variant was c.1285del/dup on exon 11 (23%) among 44 patients confirmed by genetic testing. Renal cancer has not been found on follow-up surveillance thus far. Conclusions Increasing number of patients with BHDS are being recognized in China, facilitated by establishment of a Rare Lung Disease Clinic. Pulmonary cysts and pneumothorax were commonly encountered features, but skin lesions appeared to be more prevalent in Chinese subjects than previously reported in other Asian countries.