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Previous experience often guides people's decision-making. How the corresponding consecutive outcomes in the gain-loss frame modulate feedback evaluation in dynamic situations remains unclear. In this study, we used event-related potentials (ERPs) with a Balloon Analogue Risk Task (BART) to investigate the effect of the consistency with previous feedback on current choices under the gain-loss frame and the neural mechanism by coding ERP signals evoked by consecutive outcomes among adults (N = 42). Results indicated that the framing effect on feedback-related negativity (FRN) amplitudes following current feedback in decision-making was insensitive to prior feedback. In contrast, the P300 amplitudes following two inconsistent consecutive rounds of feedback were greater than that following two consistent consecutive rounds of feedback in the gain frame, while this effect was absent in the loss frame, revealing a more significant valance-framing effect. These findings demonstrate that two inconsistent rounds of feedback enhance the framing effect, and suggest that the framing effect is sensitive to prior feedback in a late cognitive appraisal stage in decision-making under uncertainty, rather than in an early feedback processing stage. The present study provides novel insights into how consecutive outcomes in the gain-loss frame modulate feedback evaluation in dynamic situations.

Formulations from nanotechnology platform promote therapeutic drug delivery and offer various advantages such as biocompatibility, non-inflammatory effects, high therapeutic output, biodegradability, non-toxicity, and biocompatibility in comparison with free drug delivery. Due to inherent shortcomings of conventional drug delivery to cancerous tissues, alternative nanotechnological-based approaches have been developed for such ailments. Ovarian cancer is the leading gynecological cancer with higher mortality rates due to its reoccurrence and late diagnosis. In recent years, the field of medical nanotechnology has witnessed significant progress in addressing existing problems and improving the diagnosis and therapy of various diseases including cancer. Nevertheless, the literature and current reviews on nanotechnology are mainly focused on its applications in other cancers or diseases. In this review, we focused on the nanoscale drug delivery systems for ovarian cancer targeted therapy and diagnosis, and different nanocarriers systems including dendrimers, nanoparticles, liposomes, nanocapsules, and nanomicelles for ovarian cancer have been discussed. In comparison to non-functionalized counterparts of nanoformulations, the therapeutic potential and preferential targeting of ovarian cancer through ligand functionalized nanoformulations' development has been reviewed. Furthermore, numerous biomarkers such as prostatic, mucin 1, CA-125, apoptosis repeat baculoviral inhibitor-5, human epididymis protein-4, and e-cadherin have been identified and elucidated in this review for the assessment of ovarian cancer. Nanomaterial biosensor-based tumor markers and their various types for ovarian cancer diagnosis are explained in this article. In association, different nanocarrier approaches for the ovarian cancer therapy have also been underpinned. To ensure ovarian cancer control and efficient detection, there is an urgent need for faster and less costly medical tools in the arena of oncology.

Depressed patients suffered from severe psychological distress even after the first COVID-19 outbreak was initially controlled. The longitudinal changes and associations among stress and other psychological problems during this period remained unknown. In this study we investigated stress symptoms and the longitudinal impact of stress symptoms on other psychological symptoms in depressed patients after the first COVID-19 outbreak was initially controlled.A total of 5241 depressed patients at the outpatients of 56 hospitals across mainland China were recruited from May 18 to June 18, 2020. Five months later, 2113 of them responded again. Demographic characteristics were collected and psychological symptoms were evaluated at baseline and the follow-up. The longitudinal associations between stress symptoms at baseline and the changes of other psychological problems were assessed using Poisson regression.The prevalence of stress symptoms, depressive symptoms, anxiety symptoms and insomnia symptoms declined over time. Having stress symptoms at baseline was positively associated with the new occurrences of depressive symptoms, anxiety symptoms and insomnia symptoms (range, adjusted RRs 1.69-1.81).The sampling method and the high dropout rate are the major limitations. Additionally, the mental conditions of the participants were not obtained, which may lead to unavoidable bias.The prevalence of stress symptoms declined over time after the first COVID-19 outbreak was initially controlled. We found that having stress symptoms at baseline was a predictor for the new occurrences of depressive symptoms, anxiety symptoms and insomnia symptoms.

Can models based on artificial intelligence predict embryonic ploidy status or implantation potential of euploid transferred embryos? Can the addition of clinical features into time-lapse monitoring (TLM) parameters as input data improve their predictive performance?A single academic fertility centre, retrospective cohort study. A total of 773 high-grade euploid and aneuploid blastocysts from 212 patients undergoing preimplantation genetic testing (PGT) between July 2016 and July 2021 were studied for ploidy prediction. Among them, 170 euploid embryos were single-transferred and included for implantation analysis. Five machine learning models and two types of deep learning networks were used to develop the predictive algorithms. The predictive performance was measured using the area under the receiver operating characteristic curve (AUC), in addition to accuracy, precision, recall and F1 score.The most predictive model for ploidy prediction had an AUC, accuracy, precision, recall and F1 score of 0.70, 0.64, 0.64, 0.50 and 0.56, respectively. The DNN-LSTM model showed the best predictive performance with an AUC of 0.78, accuracy of 0.77, precision of 0.79, recall of 0.86 and F1 score of 0.83. The predictive power was improved after the addition of clinical features for the algorithms in ploidy prediction and implantation prediction.Our findings emphasize that clinical features can largely improve embryo prediction performance, and their combination with TLM parameters is robust to predict high-grade euploid blastocysts. The models for ploidy prediction, however, were not highly predictive, suggesting they cannot replace preimplantation genetic testing currently.

To investigate the relationship between systemic inflammatory response and short-term mortality in patients with non-cirrhotic chronic severe hepatitis (CSH) by using several indicators of inflammation including neutrophil-to-lymphocyte ratio (NLR), neutrophil (NEU), white blood cell (WBC), platelet-to lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR).Data were collected from two prospectively enrolled CATCH-LIFE noncirrhotic cohorts. Cox regression analysis was used to investigate the association between systemic inflammatory biomarkers and 90-day liver transplant (LT)-free mortality. A generalized additive model (GAM) was used to illustrate the quantitative curve relationship between NLR and 90-day LT-free mortality. Kaplan-Meier method was used to estimate the 90-year LT-free survival.The prevalence of CSH was 20.5% (226/1103). The 28-day and 90-day LT-free mortality rates were 17.7% and 26.1%, respectively, for patients with non-cirrhotic CSH. Patients with no infection accounted for 75.0% of all CSH patients, and NLR was independently associated with 90-day LT-free mortality. NLR of 2.9 might be related to disease deterioration in CSH patients without infection.NLR may be an independent risk factor for 90-day LT-free mortality in patients with non-cirrhotic chronic liver disease. A NLR of 2.9 as the cut-off value can be used to predict disease aggravation in CSH patients without infection.

Over the years, with the widespread use of computer technology and the dramatic increase in electronic medical data, data-driven approaches to medical data analysis have emerged. However, the analysis of medical data remains challenging due to the mixed nature of the data, the incompleteness of many records, and the high level of noise. This paper proposes an improved neural network DBN-LSTM that combines a deep belief network (DBN) with a long short-term memory (LSTM) network. The subset of feature attributes processed by CFS-EGA is used for training, and the optimal selection test of the number of hidden layers is performed on the upper DBN in the process of training DBN-LSTM. At the same time, the validation set is combined to determine the hyperparameters of the LSTM. Construct the DNN, CNN, and long short-term memory (LSTM) network for comparative analysis with DBN-LSTM. Use the classification method to compare the average of the final results of the two experiments. The results show that the prediction accuracy of DBN-LSTM for cardiovascular and cerebrovascular diseases reaches 95.61%, which is higher than the three traditional neural networks.

During bone tissue regeneration, neovascularization is critical, and the formation of a blood supply network is crucial for bone growth stimulation and remodeling. Previous studies suggest that bioelectric signals facilitate the process of angiogenesis. Owing to their biomimetic electroactivity, piezoelectric membranes have garnered substantial interest in the field of guided bone regeneration. Nevertheless, the knowledge of their influence due to varying surface potentials on the progression of angiogenesis remains ambiguous. Therefore, we proposed the preparation of an electroactive material, P(VDF-TrFE), and investigated its effects on the activity and angiogenic functions of human umbilical vein endothelial cells (HUVECs). The HUVECs were directly cultured on P(VDF-TrFE) membranes with different surface potentials. Subsequently, cell viability, proliferation, migration, tube formation, and expressions of related factors were assessed through appropriate assays. Our results revealed that the negative surface potential groups exerted differential effects on the modulation of angiogenesis in vitro. The P(VDF-TrFE) membranes with negative surface potential exhibited the greatest effect on cellular behaviors, including proliferation, migration, tube formation, and promotion of angiogenesis by releasing key factors such as VEGF-A and CD31. Overall, these results indicated that the surface potential of piezoelectric P(VDF-TrFE) membranes could exert differential effects on angiogenesis in vitro. We present a novel approach for designing bioactive materials for guided bone regeneration.

Objectives. This in vitro study is aimed at assessing the oral all-ceramic materials energy transmission and temperature changes after Er:YAG laser irradiation of monolithic zirconia all-ceramic materials with varying optical properties. Materials and Methods. Two monolithic zirconia materials, Zenostar T and X-CERA TT (monolithic Zirconia), were studied. Specimens were divided into four groups, with a thickness of 1.0, 1.5, 2.0, and 2.5 mm, respectively. The chemical elemental composition of the two materials was determined using X-ray spectroscopy and Fourier transform infrared spectroscopy. The light transmittance of specimens with different thicknesses was measured using a spectrophotometer at three wavelength ranges: 200–380, 380–780, and 780–2500 nm. Irradiation with Er:YAG laser was performed, and the resultant temperature changes were measured using a thermocouple thermometer. Results. Compositional analysis indicated that Si content in X-CERA TT was higher than that in Zenostar T. The light transmittance of both materials decreased as specimen thickness increased. Er:YAG laser irradiation led to temperature increase at both Zenostar T (26.4°C–81.7°C) and X-CERA TT (23.9°C–53.5°C) specimens. Both optical transmittance and temperature changes after Er:YAG laser irradiation were consistent with exponential distribution against different thickness levels. Conclusion. Er:YAG laser penetration energy and resultant temperature changes were mainly determined by the thickness and composition of the examined monolithic zirconia materials.

Brief therapy for insomnia (BTI) is a short-term cognitive behavioral therapy for insomnia. At present, there is no study combining BTI with digital technology. However, in the context of the outbreak of coronavirus disease 2019 (COVID-19), patients with acute insomnia may need an online treatment which can quickly improve insomnia symptoms. Our team built a digital BTI (dBTI) platform based on the WeChat mini program. This research provides a framework design and a course design of dBTI, and evaluates the system via recruiting participants suffering from acute insomnia in pandemic. What's more, it explores patients' adherence, the efficiency of the system and their relationship. As the result demonstrates, 68% of participants have completed more than half of the course with medium to high adherence. Gender, pre-sleep arousal scale (PSAS) somatic score and insomnia severity index (ISI) score have affected participants' adherence, and higher adherence has led to better improvement in the severity of insomnia and somatic pre-sleep arousal. It is proved that the platform we built is effective, which not only offers an entry point for the study of how to set up a dBTI platform, but also provides theoretical basis for its clinical application.

There is emerging evidence that α1-blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1-blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1-blockers as add-on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1-blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1-blockers have to be used under several considerations. Among the currently available agents, only long-acting α1-blockers, such as doxazosin gastrointestinal therapeutic system 4-8 mg daily and terazosin 2-4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1-blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1-blocker with a diuretic.

This network meta-analysis aimed to compare the efficacy and safety of fluoroquinolone (FQ) monotherapy, β-lactam (BL) monotherapy and β-lactam/macrolide (BL-M) combination therapy in hospitalized patients with community-acquired pneumonia (CAP).Pubmed, Embase and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing FQ monotherapy, BL monotherapy and BL-M combination therapy up to July 2021. The outcomes of interest included all-cause mortality, clinical success, microbiological success and drug-related adverse events. The summary relative risks (RRs) were estimated using pairwise and Bayesian network meta-analysis.A total of 12 RCTs involving 5009 patients were included. In pairwise meta-analysis, no significant differences were found among FQ monotherapy, BL monotherapy and BL-M dual therapy for all-cause mortality, clinical success or microbiological success. FQ monotherapy was associated with fewer adverse events compared with BL-M therapy (RR 0.80, 95% confidence interval [CI] 0.66-0.98). The network meta-analysis showed that there was no significant difference observed among FQ monotherapy, BL monotherapy and BL-M dual therapy regarding all the outcomes.FQ monotherapy, BL monotherapy and BL-M combination therapy demonstrated similar efficacy and safety for hospitalized patients with CAP in this network meta-analysis. Due to the limitations of quality and quantity of the included studies, it is difficult to make a definitive recommendation before more large-scale and high-quality RCTs are conducted.

Traditional fermented foods and beverages (TFFB) are an important dietary component consumed in large quantities worldwide. Currently, much attention has been focused on the health benefits of TFFB. Melanoidins, a class of bioactive substance produced in the final stage of the Maillard reaction, not only have a significant impact on sensory properties of TFFB but also contribute to the health effects. Melanoidins formed in the fermentation system with a long reaction time at low temperature could be different from those obtained from high-temperature, short-duration roasted systems due to the multiple formative stages and involvement of microorganisms and enzymes. In this paper, the current state of knowledge regarding the formation, distribution, extraction and purification, physicochemical properties, structure characteristics, and biological activities of TFFB melanoidins are comprehensively reviewed, with predominant focus on TFFB that are typically brown like douchi, miso, cheonggukjang, soy sauce, huangjiu (Chinese rice wine), beer, vinegar, and sweet wine. The current challenges and prospective recommendations for the research of melanoidins in fermented systems are also presented. In future, people should pay more attention to the basic research on TFFB melanoidins, especially purification methods and formation mechanisms, further substantiation of health properties of TFFB melanoidins in vivo, and development of specific melanoidins to fulfill technological, productive, or health needs of consumers.

Background. Lung cancer is the cancer with the highest morbidity and mortality. Lung adenocarcinoma (LUAD) is a subtype of lung cancer. The aim of this study is to explore the functions of miR-579 and CRABP2 in lung adenocarcinoma. Methods. Cell counting kit-8 (CCK-8) and colony formation assays were applied to calculate cell proliferative abilities. Transwell assay was utilized to measure cell invasive ability. Results. MiR-579 is low expressed in LUAD tissues and cell lines. MiR-579 inhibits cell viability and invasion of lung adenocarcinoma. Knockdown of CRABP2 inhibits cell proliferation and invasion of Calu-3 cells. MiR-579 suppresses cell proliferation and invasion by regulating CRABP2 in Calu-3 cells. Conclusion. Our study reveals that miR-579 acts as a tumor suppressor in LUAD and miR-579 can target and regulate the expression of CRABP2 to mediate cell proliferation and invasion. This study indicates that miR-579 has a potential to be a candidate biomarker for the treatment of LUAD.

To assess safety and long-term outcome of stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) of epileptic foci in eloquent motor areas.We retrospectively reviewed medical charts and surgical features of 15 patients with drug-resistant focal epilepsy in eloquent motor areas treated between 2017 and 2021. All patients underwent SEEG-guided RFTC as the first option. General characteristics, SEEG findings, morbidity, and seizure outcome after RFTC were analyzed to extract the potential value of SEEG-guided RFTC for epileptic foci in eloquent motor areas.There were 12 male and 3 female patients. Mean age at RFTC was 25 ± 8.5 years (range, 14-48 years), and mean duration of epilepsy before SEEG was 9.5 ± 7.0 years (range, 2-26 years). Mean follow-up period was 22.1 months (range, 8-41 months). Magnetic resonance imaging findings were negative in 2 cases, suspected focal cortical dysplasia in 10 cases, central region band heterotopias in 2 cases, and malformations of cortical development in 1 case. RFTC sites included primary precentral area (M1) (7, 46.7%), paracentral lobule (4, 26.7%), supplemental motor area (2, 13.3%), and premotor area (2, 13.3%). Of 15 patients, 12 (80%) experienced a ≥75% decrease in seizure frequency, of whom 9 (60%) experienced a long-term seizure-free period (10-29 months, mean 21.3 months). Three (20%) patients did not benefit from RFTC. Nine patients had neurological deficits immediately after RFTC (transient in 8 patients [3 days to 3 weeks] and prolonged in 1 patient).SEEG-guided RFTC for epileptic foci in eloquent motor areas seems to be a safe and effective procedure. It could be the first option for drug-resistant epilepsy that is not amenable to surgical resection, especially for extremally focused epileptic foci in the cortex close to or inside the central region. Larger series and prospective studies are necessary to validate our conclusions.

To compare short-term follow-up outcomes after primary arthroscopy in femoroacetabular impingement syndrome (FAIS) patients with untreated central acetabular osteophytes (CAO) to a control group without CAO.A retrospective analysis was performed using data from FAIS patients who had primary arthroscopy between 2017 and 2018. The presence of CAO was confirmed arthroscopically, and there were 2 groups created. The CAO group was 1:1 propensity-score matched to a control group (without CAO) based on age, gender, body mass index (BMI), Tӧnnis grade, symptom duration before surgery, and follow-up time. Patient-reported outcomes (PROs), such as the Hip Outcome Score-Activities of Daily Living (HOS-ADL), International Hip Outcome Tool 12-component form (iHOT-12)，modified Harris Hip Score (mHHS), and visual analog scale (VAS) scores were used to evaluate the level of function included. The minimal clinically important difference (MCID) and patient acceptable symptomatic state (PASS) were also calculated to determine meaningful outcome improvement. Radiographic measures, performed procedures, complications, and revision surgery were also compared and analyzed for both groups. P values less than .05 were considered statistically significant.A total of 46 hips with CAO and 46 hips without CAO were propensity matched. At the minimum final follow-up of 2 years, the CAO group had significantly lower HOS-ADL (78.8 vs 85.5; P = .008), iHOT-12 (74.8 vs 79.3; P = .019), and mHHS (78.9 vs 87.2; P = .002) scores, as compared to the CAO group. Furthermore, patients in the CAO group were significantly less likely to achieve the MCID and PASS for the mHHS score (78.3% vs 93.5%; P = .036, 58.7% vs 78.2%; P = .043, respectively). There was no change in the rate of complications (4.3% vs 0%) and revision hip arthroscopy (4.3% vs 2.2%) between the two groups at the final follow-up.This study demonstrated that surgically treated FAIS patients with CAO might experience worse short-term, patient-reported outcomes, as compared with propensity-matched patients without CAO.III, case-control study.

Finger tapping test is crucial for diagnosing Parkinson's Disease (PD), but manual visual evaluations can result in score discrepancy due to clinicians' subjectivity. Moreover, applying wearable sensors requires making physical contact and may hinder PD patient's raw movement patterns. Accordingly, a novel computer-vision approach is proposed using depth camera and spatial-temporal 3D hand pose estimation to capture and evaluate PD patients' 3D hand movement. Within this approach, a temporal encoding module is leveraged to extend A2J's deep learning framework to counter the pose jittering problem, and a pose refinement process is utilized to alleviate dependency on massive data. Additionally, the first vision-based 3D PD hand dataset of 112 hand samples from 48 PD patients and 11 control subjects is constructed, fully annotated by qualified physicians under clinical settings. Testing on this real-world data, this new model achieves 81.2% classification accuracy, even surpassing that of individual clinicians in comparison, fully demonstrating this proposition's effectiveness. The demo video can be accessed at https://github.com/ZhilinGuo/ST-A2J.

Recently, the definition of primary plasma cell leukemia (pPCL) has been revised as the presence of circulating plasma cells (CPCs) ≥5% in peripheral blood smear. Consequently, the clinical features and prognosis of this aggressive disease can be truly identified by the larger patient cohort. Herein, we identified 158 new-defined pPCL patients among 2,266 MM patients (7.0%), and such prevalence doubled the previous estimate. Our study firstly provided solid support for the application of the new definition. We also found that cytopenias and adverse prognostic biomarkers were more common in new-defined pPCL compared with MM (

Background: Pulmonary arterial hypertension is an incurable disease, in which the extracellular CaSR (calcium sensing receptor) is mechanistically important. This study was aimed to genetically link the CaSR gene and function to the disease severity. Methods: Sanger sequencing, Sugen/hypoxia pulmonary arterial hypertension rat model, CaSR mutated rat, transcriptional reporter assay and measurement of CaSR activity were used. Results: Sanger sequencing identified a significant association between the variant rs1042636(A>G), located in CaSR exon 7, and idiopathic pulmonary arterial hypertension (IPAH) formation in patients. The frequency of 2968G homozygotes was higher in patients with IPAH compared with healthy individuals (23.6% versus 17.5%; P =0.001, OR=1.864), and the minor alleles of rs6776158, rs1048213, and rs9883099, located in CaSR promoter, raised the IPAH odds ratio to 2.173. Patients with IPAH carrying heterozygotes or homozygotes genotype of rs1042636 showed markedly higher pulmonary artery pressure and reduced survival compared with individuals carrying the wild-type allele. The minor alleles of rs6776158, rs1048213, and rs9883099 increased CaSR expression in reporter assay. In Sugen/hypoxia pulmonary arterial hypertension rats, the point mutation replicating rs1042636 found in IPAH exacerbated pulmonary arterial hypertension severity by promoting the overexpression and the enhanced activity of CaSR. Conclusions: Our functional genomic analysis thus indicates that the CaSR minor alleles of rs1042636, rs6776158, rs1048213, and rs9883099 contribute to the development and severity of IPAH. These findings may benefit clinical prognosis and treatment for IPAH.

In order to explore the ability of vaginal ultrasound combined with bleeding pattern to predict factors related to abnormal uterine bleeding (AUB), a total of 205 patients with abnormal uterine bleeding were selected as experimental subjects. According to the corresponding diagnostic criteria, patients were divided into the endometrial polyp group (56 cases), endometrial hyperplasia and canceration group (84 cases), and normal cycle endometrial group (65 cases). The efficiency of the method was determined by comparing the prediction efficiency of the single/joint model. The results showed that there were statistically significant differences in the body mass index, dysmenorrhea, endometrial thickness, diabetes, hypertension, and polycystic ovary syndrome among the three groups, P < 0.05 . The sensitivity, specificity, positive predictive value, negative predictive value, and Youden index of endometrial polyp diagnosis were 86.89%, 88.12%, 83.54%, 90.11%, and 0.74, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and JordAn index in diagnosing endometrial hyperplasia and canceration were 96.71%, 98.40%, 96.54%, 98.24%, and 0.96, respectively. In summary, the body mass index, dysmenorrhea, endometrial thickness, diabetes, hypertension, and polycystic ovary syndrome were related factors, and the combination of vaginal ultrasound and bleeding pattern had a stronger predictive power for abnormal uterine bleeding.

Keloids are benign fibroproliferative diseases with abnormally proliferated bulges beyond the edge of the skin lesions, and they are characterized by uncontrolled fibroblast proliferation and excessive extracellular matrix deposition in the dermis. However, the definite mechanisms that increase fibroblast proliferation and collagen deposition in keloids remain unclear. Thrombospondin 1 (TSP1) has been suggested to play an important role in wound healing and fibrotic disorders, but its role in keloids is unknown. In this study, we aimed to clarify the specific role of TSP1 in keloids and explore the potential mechanism. Our results demonstrated that TSP1 was highly expressed in keloid lesions compared to normal skin. Knockdown of TSP1 in keloid fibroblasts decreased cell proliferation and collagen I deposition. Exogenous TSP1 treatment increased cell proliferation and collagen I deposition in normal fibroblasts. We further investigated the underlying mechanism and found that TSP1 promoted fibroblast proliferation and extracellular matrix deposition by upregulating the IL6/JAK2/STAT3 pathway. Moreover, we verified that TSP1 expression was positively correlated with IL6/STAT3 signalling activity in keloids. Taken together, our findings indicate that TSP1 promotes keloid development via the IL6/JAK2/STAT3 signalling pathway and blocking TSP1 may represent a potential strategy for keloid therapy.

Background: Tendon-bone interface (TBI) healing is a clinical dilemma that is closely relevant to new bone formation and remodeling at the repair site. Previous studies showed that metformin is an osteogenic inducer for stem cells in vitro and capable of stimulating bone regeneration in vivo. Hypothesis: Metformin would be effective for promoting TBI healing by enhancing new bone formation and remodeling. Study Design: Controlled laboratory study. Methods: Canine bone marrow stem cells (BMSCs) were cultured with various concentrations of metformin (0, 10, 50, 100, 200 μM). The effect of metformin on the osteogenic differentiation of canine BMSCs was evaluated via alizarin red staining and osteogenic gene expression. Eighteen mature beagles were included in a bilateral Achilles tendon–calcaneus (ATC) interface injury model. The right interface was reattached via surgical repair only, while the left was surgically reattached after implanting a fibrin glue containing metformin. At postoperative week 4 or 8, the healing quality of the wounded ATC interfaces was evaluated. Results: In vitro experiments determined that metformin was an osteogenic inducer for canine BMSCs. In vivo experiments showed that the metformin-treated ATC interfaces were repaired with significantly greater failure load and stiffness than was the no-metformin control site ( P < .05 for all). Micro–computed tomography analysis showed that the metformin-treated specimens presented significantly higher bone volume/total volume and trabecular thickness than did the no-metformin control specimens ( P < .05 for all), as confirmed via hematoxylin and eosin staining. Immunohistochemical staining showed that significantly more osteocalcin-positive cells were located at the newly formed bones treated with metformin than at the no-metformin control site at week 4 ( P < .05). Masson trichrome staining showed that significantly more oriented collagen fibers anchored into the newly formed bone of the metformin-treated site than the no-metformin control site ( P < .05). Conclusion: Metformin induced the osteogenesis of canine BMSCs in vitro, and local administration of metformin provided an improvement of bone microarchitecture at the calcaneus as well as an increase in the tensile properties of the repaired ATC interfaces in canines. Clinical Relevance: Findings of the study indicate that local administration of metformin may be an effective strategy for TBI healing in clinic.

The survival of motor neuron (SMN) genes, SMN1 and SMN2, are two highly homologous genes related to spinal muscular atrophy (SMA). Different patterns of alternative splicing have been observed in the SMN genes. In this study, the long-read sequencing technique for distinguishing SMN1 and SMN2 without any assembly were developed and applied to reveal multiple alternative splicing patterns and to comprehensively identify transcript variants of the SMN genes. In total, 36 types of transcript variants were identified, with an equal number of variants generated from both SMN1 and SMN2. Of these, 18 were novel SMN transcripts that have never been reported. The structures of SMN transcripts were revealed to be much more complicated and diverse than previously discovered. These novel transcripts were derived from diverse splicing events, including skipping of one or more exons, intron retention, and exon shortening or addition. SMN1 mainly produces FL-SMN1, SMN1Δ7, SMN1Δ5 and SMN1Δ3. The distribution of SMN2 transcripts was significantly different from those of SMN1, with the majority transcripts to be SMN2Δ7, followed by FL-SMN2, SMN2Δ3,5 and SMN2Δ5,7. Targeted long-read sequencing approach could accurately distinguish sequences of SMN1 from those of SMN2. Our study comprehensively addressed naturally occurring SMN1 and SMN2 transcript variants and splicing patterns in peripheral blood mononuclear cells (PBMCs). The novel transcripts identified in our study expanded knowledge of the diversity of transcript variants generated from the SMN genes and showed a much more comprehensive profile of the SMN splicing spectrum. Results in our study will provide valuable information for the study of low expression level of SMN proteins and SMA pathogenesis based on transcript levels.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge, and effective tracking requires rapid return of results. Surveillance of variants is typically performed by whole genome sequencing (WGS), which can be financially prohibitive and requires specialized equipment and bioinformatic expertise. Genotyping approaches are rapid methods for monitoring SARS-CoV-2 variants but require continuous adaptation. Fragment analysis may represent an approach for improved SARS-CoV-2 variant detection. Methods A multiplex fragment analysis approach (CoVarScan) was validated using PCR targeting variants by size and fluorescent color. Eight SARS-CoV-2 mutational hot spots in variants of concern (VOCs) were targeted. Three primer pairs (recurrently deleted region [RDR] 1, RDR2, and RDR3–4) flank RDRs in the S-gene. Three allele-specific primers target recurrent spike receptor binding domain mutants. Lastly, 2 primer pairs target recurrent deletions or insertions in ORF1A and ORF8. Fragments were resolved and analyzed by capillary electrophoresis (ABI 3730XL), and mutational signatures were compared to WGS results. Results We validated CoVarScan using 3544 clinical respiratory specimens. The assay exhibited 96% sensitivity and 99% specificity compared to WGS. The limit of detection for the core targets (RDR1, RDR2, and ORF1A) was 5 copies/reaction. Variants were identified in 95% of samples with cycle threshold (CT) Conclusions Multiplex fragment analysis is adaptable and rapid and has similar accuracy to WGS to classify SARS-CoV-2 variants.

Glioma originated from excessively proliferative and highly invaded glial cells is a common intracranial malignant tumor with poor prognosis. Resistance to temozolomide (TMZ) is a clinical challenge in glioma treatment due to the fact that chemoresistance remains a main obstacle in the improvement of drug efficacy. Salvianolic acid A (Sal A), originated from traditional Chinese herbal medicine

The article summarizes the control strategy by discussing the risk factors of nosocomial infections in the nephrology department. A survey of hospitalized patients from January 2020 to December 2020 showed that there are six types of bacteria that can cause infections. The age of the patient, the risk of invasive surgery, the low use of antibiotics, and age are all independent factors that affect the risk of nosocomial infections in the patient. The more antibiotics used, the better the infection prevention effect. Among the many risk factors for patient infection, bacterial infection is the main risk factor. Klebsiella pneumoniae infection rate was the highest, 33.98%; Staphylococcus aureus infection rate was the lowest, 6.80%. Therefore, the nephrology department should focus on strengthening the prevention of Klebsiella pneumoniae infection, and implement early prevention and management interventions for various risk factors.

Ustekinumab has been approved for the treatment of patients with plaque psoriasis (PSO), psoriatic arthritis (PSA), Crohn's disease (CD), and ulcerative colitis (UC). This study was performed to investigate whether the pharmacokinetics of ustekinumab differ across different disease populations.An integrated population pharmacokinetic analysis was conducted to characterize ustekinumab pharmacokinetics across four disease indications (i.e., PSO, PSA, CD, and UC) and healthy subjects.The pooled ustekinumab pharmacokinetic data consisted of 46,970 serum concentrations from 3,217 subjects (n = 356 for PSO, 696 for PSA, 1196 for CD, 823 for UC, and 24 for healthy subjects) in 7 clinical trials following subcutaneous or intravenous ustekinumab administrations. The pharmacokinetics of ustekinumab were adequately described by a two-compartment linear model with first-order absorption and elimination. Ustekinumab clearance (CL) and volume of distribution parameters increased nonlinearly with body weight, and the CL was higher in subjects with lower serum albumin, non-Caucasians, and positive antibodies to ustekinumab. Although CL in subjects with PSO and PSA appeared to be slightly different (- 12.7% and + 8.87%, respectively) from CL in other populations (including CD, UC, and healthy subjects), the model-derived post-hoc pharmacokinetic parameters were generally comparable across the 4 disease populations. Simulations also suggested overall comparable ustekinumab exposure (i.e., trough concentration and AUC) at steady state across the disease populations following the same subcutaneous dose regimen.Ustekinumab pharmacokinetics are generally comparable across all approved inflammatory-mediated indications and healthy subjects after accounting for the body weight-related pharmacokinetic difference.

Objectives To explore efficacy, risk factors, safety, and persistence of teriflunomide in relapsing–remitting multiple sclerosis (RRMS) cohort. Methods This prospective, observational cohort study included 217 consecutive teriflunomide treated RRMS patients, 192 of which with at least 3-month persistence on teriflunomide were included in effectiveness and risk factor analyses. Multivariate Cox proportional regression analysis was performed to identify factors associated with failure of no evidence of disease activity (NEDA) 3. Results At baseline 82% patients were treatment naïve while 18.0% interferon-β1b treated patients had stopped treatments for more than 1 year. After treatment, 79.0% patients achieved NEDA 3 at 12-month, mean annualized relapse rate (ARR) reduced significantly (0.79 ± 0.80 vs 0.16 ± 0.70; P P > 0.05). Male sex (hazard ratio [HR] 1.856; 95% confidence interval [CI] 1.118–3.082, P P P Conclusions Our results support efficacy and tolerability of teriflunomide for treatment-naïve RRMS patients in real-world practice. Female patients, patients with less relapses and less disability before treatment are most likely to benefit from teriflunomide treatment.

Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.

It is known that long intergenic non-protein coding RNA 00707 (LINC00707) promotes lipopolysaccharide (LPS)-injury and microRNA-199-3p (miR-199-3p) regulates chondrocyte proliferation and apoptosis. Both processes participate in osteoarthritis (OA). We predicted that LINC00707 and miR-199-3p may interact with each other. Therefore, LINC00707 and miR-199-3p may interact with each other to participate in OA. In this study, the expression of LINC00707 and miR-199-3p in both OA and normal articular cartilage tissues was analyzed using RT-qPCR. The subcellular location of LINC00707 and its direct interaction with miR-199-3p were explored by nuclear fractionation assay, RNA pull-down assay and Luciferase reporter assay, respectively. The role of LINC00707 and miR-199-3p in regulating the expression of each other was analyzed using an overexpression assay, followed by RT-qPCR. The role of LINC00707 and miR-199-3p in regulating OA chondrocyte proliferation and apoptosis was analyzed by BrdU assay and cell apoptosis assay, respectively. OA tissues exhibited increased expression of LINC00707 and decreased expression of miR-199-3p. LINC00707 directly interacted with miR-199-3p in cytoplasm. However, LINC00707 and miR-199-3p overexpression failed to affect each other's expression. LPS treatment increased LINC00707 expression and decreased miR-199-3p expression in OA chondrocyte. LINC00707 overexpression increased the apoptosis of OA chondrocytes induced by LPS and suppressed the proliferation of OA chondrocytes. Moreover, LINC00707 suppressed the role of miR-199-3p in enhancing cell proliferation and suppressing cell apoptosis. In conclusion, LINC00707 can be detected in cytoplasm and it may sponge miR-199-3p to regulate chondrocyte proliferation and apoptosis in OA.

Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.

Emodin (EMO) is an active ingredient of Chinese traditional medicine with the potential to reportedly treat ulcerative colitis (UC). However, the solubility of EMO in water is poor coupled with low oral bioavailability, whilst existing conventional oral preparations of the drug lack targeting ability. Thus, this work sought to design and fabricate a mannose modified colon targeted micelle drug delivery system comprising quantum dots (QDs) and EMO to obtain Eu-CS-Man-Ps-P(HEMA-DMAM)/EMO-QDs, which exhibited stable physicochemical properties, smaller average sized droplets (226.22 ± 1.83 nm), better polydispersity (PDI = 0.060 ± 0.005), negative ζ-potential (-19.19 ± 0.89 mV) and high efficiency of encapsulation (95.14 ± 0.23%). We observed Eu-CS-Man-Ps-P(HEMA-DMAM)/EMO-QDs to be an effective approach for the improvement of EMO solubility in an aqueous medium with an increased oral bioavailability (3.23 times higher than native drug) of the drug. Besides, the micelle could increase the retention and release of EMO in colonic ulcers through multi-stage targeting, improve oral bioavailability, regulate the expression of inflammatory factors and repair damaged tissues, which helped us to achieve the design goal of integrated diagnosis and treatment of UC. Conclusively, the therapeutic effect of EMO was enhanced through an integrated micelle, which exhibited good prospects in improving solubility and oral biological availability.

PURPOSE: To determine the application value of next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidies (PGT-A). METHODS: We conducted a retrospective case–control study on a cohort of frozen-thawed embryo transfer (FET) cycles following preimplantation genetic testing for monogenic disorders (PGT-M) between 2014 and 2017. Cycles that produced live births or early miscarriages were divided into live birth group (n = 76) or miscarriage group (n = 19), respectively. The NGS-based aneuploidy screening was performed on the multiple displacement amplification (MDA) products of the embryonic trophectoderm biopsy samples that were cryopreserved following PGT-M. RESULTS: In the live birth group, 75% (57/76) embryos were euploid and 14.5% (11/76) were aneuploid. The remaining 10.5% (8/76) embryos were NGS-classified mosaic with the high- (≥ 50%) and low-level (

Acalabrutinib received approval for the treatment of adult patients with mantle cell lymphoma who received at least 1 prior therapy and adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study investigated the impact of hepatic impairment (HI) on acalabrutinib pharmacokinetics (PK) and safety at a single 50-mg dose in fasted subjects. This study was divided into 2 parts: study 1, an open-label, parallel-group study in Child-Pugh class A or B subjects and healthy subjects; and study 2, an open-label, parallel-group study in Child-Pugh class C subjects and healthy subjects. Baseline characteristics and safety profiles were similar across groups. Acalabrutinib exposure (area under the plasma concentration-time curve) increased slightly (1.90- and 1.48-fold) in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment compared with healthy subjects. In severe hepatic impairment (Child-Pugh class C), acalabrutinib exposure (area under the plasma concentration-time curve and maximum plasma concentration) increased ≈5.0- and 3.6-fold, respectively. Results were consistent across total and unbound exposures. Severe hepatic impairment did not impact total/unbound metabolite (ACP-5862) exposures; the metabolite-to-parent ratio decreased to 0.6 to 0.8 (vs 3.1-3.6 in healthy subjects). In summary, single oral dose of 50-mg acalabrutinib was safe and well tolerated in subjects with mild, moderate, and severe hepatic impairment and in healthy control subjects. In subjects with severe hepatic impairment, mean acalabrutinib exposure increased by up to 5-fold and should be avoided. Acalabrutinib does not require dose adjustment in patients with mild or moderate hepatic impairment.

Which of the two mainstream endometrial preparation regimens, assisted natural cycle (NC) or hormone replacement treatment cycle (HRT), help frozen-thawed embryo transfer (FET) cycles after preimplantation genetic testing (PGT) achieve better clinical outcomes?This retrospective analysis included 3400 vitrified-warmed single blastocyst transfer cycles after PGT from January 2011 to November 2020, and involved 2332 patients with regular menstrual cycles. The decision to proceed with an assisted NC (n = 827) or HRT (n = 2573) before FET was reached based on a combination of patient preference and physician guidance. Clinical pregnancy rate, live birth rate, early miscarriage rate and obstetric outcomes were compared.No significant difference was observed between the assisted NC and HRT groups in terms of clinical pregnancy rate (51.6% versus 50.7%, P = 0.634), live birth rate (44.0% versus 43.4%, P = 0.746) or early miscarriage rate (12.6% versus 12.0%, P = 0.707). Multivariate analysis indicated that the endometrial preparation protocol was not an independent factor for a clinical pregnancy or live birth. In the HRT group, the Caesarean section rate (64.7% versus 51.9%, P 0.001) and pregnancy complication rate (20.2% versus 13.8%, P = 0.003) were significantly higher. The two groups were not statistically different with respect to gestational age, early preterm birth rate, fetal weight or fetal birth defect rate.For patients undergoing a PGT-FET cycle involving a single blastocyst transfer, using assisted NC and HRT for the endometrial preparation could lead to comparable rates of clinical pregnancy and live birth. Additionally, NC is safer than HRT in terms of avoiding pregnancy complications and adverse obstetric outcomes.

Tracheobronchomalacia and complete tracheal rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea’s cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/β-catenin target genes, including targets of WNT signaling: Notum and Axin2. In vitro, recombinant (r)BMP4 rescued the expression of Notum in Bmp4-deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4-deficient tracheas identified genes essential for chondrogenesis and muscle development coregulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/β-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.

Background Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune‐related adverse events (irAEs) remain poorly understood, especially in a real‐world setting. Methods A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD‐L1) monotherapy, anticytotoxic T‐lymphocyte antigen‐4 monotherapy, or combination therapy. Results In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28–87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3–5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0–1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD‐L1 expression (≥1%) and who received first‐line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p, This was a multicenter observational study of real‐world treatment status immune checkpoint inhibitors (ICIs) and incidence of immune‐related adverse events (irAEs). A total of 512 (26.9%) of 1905 patients developed 671 any grade irAEs and 110 (5.8%) patients developed 120 grades 3–5 irAEs. Positive programmed cell death‐ligand 1 expression, first‐line ICI treatment and sustained disease control were observed more in patients with irAEs.

Background Pretreatment and on‐treatment plasma cytokine levels in predicting clinical benefit in patients with advanced non‐small cell lung cancer (NSCLC) treated with anti‐programmed death‐1 (PD‐1)‐based chemotherapy is still a matter of debate. Methods We measured 12 kind of plasma cytokines in patients with stage III/IV NSCLC before and during treatment with anti‐PD‐1 based chemotherapy. Associations with best overall response, and survival including progression‐free survival (PFS) and overall survival (OS) were assessed using Chi‐square test and Kaplan–Meier plots with log‐rank test, respectively. Logistic regression and Cox regression were used to determine independent risk factors. Results Of a total of 60 patients, high‐level of pretreatment interleukin‐2 was associated with longer PFS (log rank p = 0.049), while high‐level of pretreatment interleukin‐8 was associated with shorter OS (log rank p = 0.006). Increased on‐treatment interleukin‐1β (IL‐1β) was associated with both better response (odds ratio [OR] 6.233, 95% confidential interval [CI]: 1.451–26.344, p = 0.013) and longer PFS (hazard ratio [HR] 0.305, 95% CI: 0.127–0.730, p = 0.008). On the contrary, increased on‐treatment interleukin‐6 (IL‐6) was associated with a worse response (OR 0.015, 95% CI: 0.001–0.400, p = 0.012), worse PFS (HR 2.639, 95% CI: 1.163–5.991, p = 0.020) and worse OS (HR 2.742, 95% CI: 1.063–7.074, p = 0.037). Increased interferon‐γ (IFN‐γ) was found to be associated with better PFS (HR 0.336, 95% CI: 0.153–0.745, p = 0.007). Conclusions In patients with advanced NSCLC who received chemoimmunotherapy, on‐treatment increased IL‐1β and IFN‐γ may serve as positive indicator of efficacy, while on‐treatment increased IL‐6 might play a predictive role of worse clinical outcome., We retrospectively measured 12 kind of plasma cytokines in patients with stage III/IV non‐small cell lung cancer before and during immune checkpoint inhibitor (ICI)‐based chemoimmunotherapy. Results showed that increased on‐treatment interleukin‐1β, interferon‐γ were related to longer progression‐free survival (PFS). Increased on‐treatment IL‐6 was related to shorter PFS. We suggest the indicative role played by circulating cytokines and efficacy of ICI‐based chemotherapy.

Heparins are natural and partially degraded polyelectrolytes that consist of sulfated polysaccharide backbones. However, as clinically used anticoagulants, heparins are associated with clinical bleeding risks and thus require rapid neutralization. Protamine sulfate is the only clinically approved antidote for unfractionated heparin (UFH), which not only may cause severe adverse reactions in patients, but also is only partially effective against low molecular weight heparins (LMWHs). We here present the facile synthesis of four porous multicationic dynamic covalent polymers (DCPs) from the condensation of tritopic aldehyde and acylhydrazine precursors. We show that, as new water-soluble polymeric antidotes, the new DCPs can effectively include both UFH and LMWHs and thus reverse their anticoagulating activity, which is confirmed by the activated partial thromboplastin time and thromboelastographic assays as well as mouse tail transection assay (bleeding model). The neutralization activities of two of the DCPs were found to be overall superior to that of protamine and have wider concentration windows and good biocompatibility. This pore-inclusion neutralization strategy paves the way for the development of water-soluble polymers as universal heparin binding agents.

Background Epithelial-to-mesenchymal transition (EMT) is a pivotal cellular phenomenon involved in tumour metastasis and progression. In gastric cancer (GC), EMT is the main reason for recurrence and metastasis in postoperative patients. Acacetin exhibits various biological activities. However, the inhibitory effect of acacetin on EMT in GC is still unknown. Herein, we explored the possible mechanism of acacetin on EMT in GC in vitro and in vivo. Methods In vitro, MKN45 and MGC803 cells were treated with acacetin, after which cell viability was detected by CCK-8 assays, cell migration and invasion were detected by using Transwell and wound healing assays, and protein expression was analysed by western blots and immunofluorescence staining. In vivo, a peritoneal metastasis model of MKN45 GC cells was used to investigate the effects of acacetin. Results Acacetin inhibited the proliferation, invasion and migration of MKN45 and MGC803 human GC cells by regulating the expression of EMT-related proteins. In TGF-β1-induced EMT models, acacetin reversed the morphological changes from epithelial to mesenchymal cells, and invasion and migration were limited by regulating EMT. In addition, acacetin suppressed the activation of PI3K/Akt signalling and decreased the phosphorylation levels of TGF-β1-treated GC cells. The in vivo experiments demonstrated that acacetin delayed the development of peritoneal metastasis of GC in nude mice. Liver metastasis was restricted by altering the expression of EMT-related proteins. Conclusion Our study showed that the invasion, metastasis and TGF-β1-induced EMT of GC are inhibited by acacetin, and the mechanism may involve the suppression of the PI3K/Akt/Snail signalling pathway. Therefore, acacetin is a potential therapeutic reagent for the treatment of GC patients with recurrence and metastasis.

Key Points The clonal architecture of MM at relapse was identified using QM-FISH at the single-cell level.The prognostic values of different clonal evolution patterns were explored in large-scale clinical analysis., Visual Abstract, Single-cell analysis is of significant importance in delineating the exact phylogeny of the subclonal population and in discovering subtle diversification. So far, studies of intratumor heterogeneity and clonal evolution in multiple myeloma (MM) were largely focused on the bulk tumor population level. We performed quantitative multigene fluorescence in situ hybridization (QM-FISH) in 129 longitudinal samples of 57 MM patients. All the patients had newly diagnosed and relapsed paired samples. An expanded cohort of 188 MM patients underwent conventional FISH (cFISH) to validate the cytogenetic evolution in bulk tumor level. Forty-three of 57 patients (75.4%) harbored 3 or 4 cytogenetic clones at diagnosis. We delineated the phylogeny of the subclonal tumor population and derived the evolutionary architecture in each patient. Patients with clonal stabilization had a significantly improved overall survival (OS) than those with other evolutionary patterns (median OS, 71.2 months vs 39.7 months vs 35.2 months vs 25.5 months, for stable, differential, branching, and linear patterns, respectively; P = .001). A high degree of consistency and complementarity across QM-FISH and cFISH was observed in the evaluation of cytogenetic evolution patterns in MM. Survival after relapse was greater influenced by the presence of high-risk aberrations at relapse (hazard ratio = 2.07) rather than present at diagnosis (hazard ratio = 1.55). This study shows that QM-FISH is a valuable tool to elucidate the clonal architecture at the single-cell level. Clonal evolution pattern is of prognostic significance, highlighting the need for repeated cytogenetic evaluation in relapsed MM.

Diabetic wound infection is a common disease that has significantly reduced people's quality of life. Although tremendous achievements have been made in clinical treatment, the crucial challenge in diabetic infected wound management stems from the detrimental diabetic wound environment and the emergence of bacterial resistance after long-term medication, which result in a reduced efficacy, an increased dosage of medication, and severe side effects. To tackle these issues, it is of great significance to develop an innovative treatment strategy for diabetic wound infection therapy. Currently, the exploitation of nanobiomaterial-based therapeutic systems for diabetic infected wounds is booming, and therapeutic systems with a stimuli-responsive performance have received extensive attention. These therapeutic systems are able to accelerate diabetic infected wound healing due to the on-demand release of therapeutic agents in diabetic infected wounds in response to stimulating factors. Based on the characteristics of diabetic infected wounds, many endogenous stimuli-responsive (

Background Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with a short replication time and a rapid growth rate. Prognostic factors for SCLC in clinical practice are scarce. Retrospective analysis of 8‐year extensive‐stage SCLC data from the Department Respiratory and Intensive Care Unit, Peking Union Medical College Hospital (Beijing, China) was performed to develop a risk prediction model that can facilitate the identification of extensive‐stage SCLC with differing prognosis in clinical practice. Methods A retrospective analysis of data from patients with extensive‐stage SCLC at a single‐center from January 2013 to January 2021, including age, sex, ECOG physical score, immunohistochemistry (CgA, Syn, CD56, TTF1, and Ki67), staging, treatment regimen, laboratory examinations, and survival period, was performed. Clinical variables with potential prognostic significance were screened by univariate Cox analysis. Next, multifactor Cox risk prediction regression analysis was performed to establish an extensive‐stage SCLC risk prognostic model. Survival curves and ROC curves for high and low risk groups were plotted according to risk scores. Nomogram and calibration curves were developed to assess the accuracy of the risk prediction model. Results This study included 300 patients who were diagnosed with extensive‐stage SCLC at our center from January 2013 to January 2021. The most common first presentation was respiratory symptoms, especially cough (162, 54%). The most common extra‐thoracic metastatic organs were bone (36.3%), liver (24.7%), brain (15.7%), and adrenal glands (15.7%). A total of 99% of patients received first‐line systemic therapy, with 86.3% of patients treated with platinum‐etoposide and 10.7% of patients treated with immune checkpoint inhibitor combined with platinum‐etoposide backbone. First‐line progression‐free survival was up to 198 days, and the median OS was 439 days. After Cox regression screening and backward stepwise selection, “time from initial therapy to relapse or progression (PFS1), liver metastases, adrenal metastases, M stage and first‐line treatment pattern” were retained to establish a prognostic model with an AUC value of 0.763. The prognostic model was shown as a nomogram with good agreement between predicted and observed outcomes. Conclusions The first‐line treatment of SCLC patients admitted to our hospital in the past 8 years was relatively standardized, and the progression‐free survival and OS were slightly longer than those reported in the literature. We developed a prognostic risk score model for extensive‐stage SCLC to calculate individual survival in clinical practice.

The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3β (STAT3β), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3β contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3β was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3β blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3β and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3β sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3β in ESCC therapy.

With wide application of Zinc oxide (ZnO) nanoparticles, their biological toxicity has received more and more attention in recent years. In this research, two ZnO dispersions with different particle sizes, small size Zinc oxide (S-ZnO) and big size Zinc oxide (B-ZnO), were prepared using polycarboxylic acid as dispersant. We found that the S-ZnO nanoparticles showed stronger toxicity on Human Pulmonary Alveolar Epithelial Cells (HPAEpiC) under same concentration. Only 9 ppm S-ZnO could decrease HPAEpiC viability to about 50%, which means that, a small amount of well-dispersed ZnO nanoparticles in industrial production process may cause serious damage to the human body through oral inhalation. Focusing on mechanism for cytotoxicity, ZnO nanoparticles promoted generation and accumulation of Reactive Oxygen Species (ROS) in mitochondria via inhibiting Superoxide Dismutase (SOD) enzyme activity and reducing Glutathione (GSH) content. ROS in turn opened the mitochondrial Ca2+ pathway and lowered the Mitochondrial Membrane Potentials (MMP), leading to cell death. To simulate the lung environment in vitro, mixed dipalmitoyl phosphatidylcholine (DPPC) and ZnO nanoparticles (1:1) were incubated for 72 hours and then cytotoxicity was evaluated on HPAEpiC. Results showed that the cell viability was significantly increased, which proved that the DPPC effectively inhibited the toxicity of ZnO nanoparticles.

Conventionally, Rho guanine nucleotide exchange factors (GEFs) are known activators of Rho guanosine triphosphatases (GTPases) that promote tumorigenesis. However, the role of Rho GEFs in non-small cell lung cancer (NSCLC) remains largely unknown. Through the screening of 81 Rho GEFs for their expression profiles and correlations with survival, four of them were identified with strong significance for predicting the prognosis of NSCLC patients. The four Rho GEFs, namely ABR, PREX1, DOCK2 and DOCK4, were downregulated in NSCLC tissues compared to normal tissues. The downregulation of ABR, PREX1, DOCK2 and DOCK4, which can be attributfed to promoter methylation, is correlated with poor prognosis. The underexpression of the four key Rho GEFs might be related to the upregulation of MYC signaling and DNA repair pathways, leading to carcinogenesis and poor prognosis. Moreover, overexpression of ABR was shown to have a tumor-suppressive effect in PC9 and H1703 cells. In conclusion, the data reveal the unprecedented role of ABR as tumor suppressor in NSCLC. The previously unnoticed functions of Rho GEFs in NSCLC will inspire researchers to investigate the distinct roles of Rho GEFs in cancers, in order to provide critical strategies in clinical practice.

Tongfu traditional Chinese medicine (TCM) preparation is a common alternative therapy for clinical treatment of patients with septic gastrointestinal dysfunction. In recent years, a number of randomized controlled trials (RCTs) have been conducted to verify the effectiveness of Tongfu TCM preparation in the treatment of sepsis gastrointestinal dysfunction, but all of them have been small sample studies, and the research conclusions have been controversial. Here, this study conducted a meta-analysis on the clinical efficacy of the treatment of septic gastrointestinal dysfunction with TCM preparation, to produce a more objective and comprehensive systematic review to guide clinical application.To evaluate the efficacy and safety of Tongfu traditional Chinese medicine (TCM) preparation in the treatment of patients with septic gastrointestinal dysfunction.Randomized controlled trials (RCTs) of Tongfu TCM preparation in the treatment of septic gastrointestinal dysfunction published before February 2021 were searched for in the Chinese databases China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedical Literature Disk (CBMdisc), and Chongqing VIP (CQVIP), and English databases PubMed, Web of Science, EBSCO, and The Cochrane Library. Meta-analysis was performed using RevMan 5.3 software, and funnel plots were drawn to evaluate the bias of literatures.A total of 22 RCTs involving 1,558 patients were included. There were 772 patients in the control group and 786 in the trial group. Meta-analysis results showed that: gastrointestinal dysfunction score [mean difference (MD) =-0.50, 95% confidence interval (CI): -0.61 to -0.38], Acute Physiology and Chronic Health Evaluation II (APACHE II) score (MD =-3.30, 95% CI: -3.73 to -2.86), and mortality (MD =0.34, 95% CI: 0.25-0.47) in the experimental group were significantly lower than those in the control group, and the difference was statistically significant (P0.001). The funnel plot results showed that there was little possibility of publication bias.Tongfu TCM preparation can effectively improve the gastrointestinal function of patients with sepsis gastrointestinal dysfunction, prevent the deterioration of the disease, and reduce the mortality; however, more evidence is required to substantiate these findings.