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The objective of our study was to explore the expression pattern of circular ribonucleic acid (RNA)_0,007,331 (circ_0,007,331) in breast cancer (BC) and its functional association with cellular paclitaxel (PTX) resistance and proliferation, migration, invasion and apoptosis.Real-time quantitative polymerase chain reaction was applied to measure RNA expression. The PTX resistance of BC cells was analyzed by cell counting kit-8 assay. Flow cytometry was applied to assess cell cycle progression and cell apoptosis. Transwell assays were utilized to analyze cell migration and invasion abilities. Protein expression was determined by Western blot assay. The target relationship between microRNA-200b-3p (miR-200b-3p) and circ_0,007,331 or Anillin (ANLN) was verified by dual-luciferase reporter assay and RNA-pull down assay. The in vivo role of circ_0,007,331 was analyzed using xenograft tumor model.Circ_0,007,331 expression was elevated in PTX-resistant BC cell lines relative to parental BC cell lines. Circ_0,007,331 contributed to the PTX resistance, proliferation, migration, invasion and suppressed the apoptosis of BC cells. Circ_0,007,331 interacted with miR-200b-3p in BC cells. Circ_0,007,331 silencing-mediated effects in BC cells were largely overturned by the knockdown of miR-200b-3p. ANLN was a target of miR-200b-3p in BC cells. Circ_0,007,331 silencing reduced ANLN expression partly through upregulating miR-200b-3p in BC cells. miR-200b-3p overexpression-induced effects in BC cells were largely counteracted by the accumulation of ANLN. Circ_0,007,331 silencing aggravated PTX-mediated inhibitory effect on tumor growth in vivo.Circ_0,007,331 contributed to the PTX resistance, proliferation and motility and inhibited the apoptosis of BC cells through mediating miR-200b-3p/ANLN signaling.

ImportanceMild thyroid-associated ophthalmopathy (TAO) negatively impacts quality of life, yet no clinical guidelines for its treatment are available. Existing evidence supports the use of doxycycline in treating mild TAO.ObjectiveTo evaluate the short-term (12 weeks) efficacy of doxycycline in treating mild TAO.Design, Setting, and ParticipantsIn this placebo-controlled multicenter randomized double-masked trial, 148 patients were assessed for eligibility. After exclusions (patients who were pregnant or lactating, had an allergy to tetracyclines, or had uncontrolled systematic diseases), 100 patients with mild TAO (orbital soft tissue affected mildly) at 5 centers in China were enrolled from July 2013 to December 2019 and monitored for 12 weeks.InterventionsParticipants were randomly assigned 1:1 to receive doxycycline (50 mg) or placebo once daily for 12 weeks.Main Outcomes and MeasuresThe primary outcome was the rate of improvement at 12 weeks compared with baseline assessed by a composite indicator of eyelid aperture (reduction ≥2 mm), proptosis (reduction ≥2 mm), ocular motility (increase ≥8°), and Graves ophthalmopathy-specific quality-of-life (GO-QOL) scale score (increase ≥6 points). Adverse events were recorded.ResultsA total of 50 participants were assigned to doxycycline and 50 to placebo. The mean (SD) age was 36.7 (9.1) years; 75 participants (75.0%) were female and 100 (100.0%) were Asian. Medication compliance was checked during participant interviews and by counting excess tablets. At week 12, the improvement rate was 38.0% (19 of 50) in the doxycycline group and 16.0% (8 of 50) in the placebo group (difference, 22.0%; 95% CI, 5.0-39.0; P = .01) in the intention-to-treat population. The per-protocol sensitivity analysis showed similar results (39.6% [19 of 48] vs 16.0% [8 of 50]; difference, 23.6%; 95% CI, 6.4-40.8; P = .009). No adverse events other than 1 case of mild gastric acid regurgitation was recorded in either group.Conclusions and RelevanceThe results of this study indicate that oral doxycycline, 50 mg daily, resulted in greater improvement of TAO-related symptoms at 12 weeks compared with placebo in patients with mild TAO. These findings support the consideration of doxycycline for mild TAO but should be tempered by recognizing the relatively short follow-up and the size of the cohort.Trial RegistrationClinicalTrials.gov Identifier: NCT02203682

Background: Little is known about the long-term risks of stroke and ischemic heart disease (IHD) in women who had a hysterectomy alone (HA) or with bilateral oophorectomy (HBO) for benign diseases, particularly in China where the burden of cardiovascular diseases (CVD) is high. We assessed mean levels of cardiovascular risk factors and relative risks of stroke and IHD in Chinese women who had a HA or HBO. Methods: A total of 302 510 women, aged 30 to 79 years were enrolled in the China Kadoorie Biobank from 2004 to 2008 and followed up for a mean of 9.8 years. The analysis involved premenopausal women without prior cardiovascular disease or cancer at enrollment. We calculated adjusted hazard ratios for incident cases of CVD and their pathological types (ischemic stroke, hemorrhagic stroke, and IHD) after HA and HBO. Analyses were stratified by age and region and adjusted for levels of education, household income, smoking status, alcohol consumption, physical activity, body mass index, systolic blood pressure, diabetes, self-reported health, and number of pregnancies. Results: Among 282 722 eligible women, 8478 had HA, and 1360 had HBO. Women who had HA had 9% higher risk of CVD after HA (hazard ratio, 1.09 [95% CI, 1.06–1.12]) and 19% higher risk of CVD after HBO (1.19 [95% CI, 1.12–1.26]) compared with women who did not. Both HA and HBO were associated with higher risks of ischemic stroke and IHD but not with hemorrhagic stroke. The relative risks of CVD associated with HA and HBO were more extreme at younger age of surgery. Conclusions: Women who had either HA or HBO have higher risks of ischemic stroke and IHD, and these risks should be evaluated when discussing these interventions. Additional screening for risk factors for CVD should be considered in women following HA and HBO operations, especially if such operations are performed at younger age.

Mounting evidence indicates the involvement of the innate immune system in Parkinson's disease (PD). Nevertheless, the implications of peripheral monocytes have not been fully elucidated. Although alpha-synuclein (α-synuclein) has been described as a pathological hallmark of PD, the proinflammatory effect of α-synuclein on monocytes is understudied. This study aimed to comprehensively characterize peripheral monocytes in PD patients and to investigate the proinflammatory magnitude of fibrillar α-synuclein.Using flow cytometry, we explored the distribution of monocytic subpopulations. We also investigated the actions of peripheral monocytes in response to lipopolysaccharides (LPS) and to fibrillar α-synuclein stimuli by measuring inflammatory molecule levels in post-culture supernatants.Classical monocytes were enriched, in parallel with lower proportions of intermediate and nonclassical monocytes in patients with PD than in controls. Lower levels of TNF-α and IL-6 were spontaneously produced by unstimulated monocytes in patients with PD. LPS and fibrillar α-synuclein stimuli induced high levels of TNF-α, IL-1β, IL-6, and sCD163 in the PD and control groups. Strikingly, the fold induction of TNF-α and IL-6 was lower in patients with PD than that in normal controls under the same stimulation.Our results revealed a strong dysregulation of peripheral monocytes in PD patients, including subpopulation shifts and impaired response to specific stimuli, and the proinflammatory effect of α-synuclein on monocytes. Further studies are needed to clarify the specific mechanisms by which these immunological abnormalities are present in PD to open the possibility of immunoregulatory therapy.

In order to further curb the damage to the ecological environment from the perspective of legal synergistic supervision, a synergistic analysis method between the ecological protection environmental law and the ecological Civil Code is proposed. Coordinated supervision, with the new Civil Code as the research background, from the perspective of interpretation, explores the solution to the problem of “ecological environmental damage” in the newly promulgated Civil Code for behavior that damages the ecological environment. The research results believe that, from the perspective of rights, environmental rights should be regarded as the concentrated expression of rights in the sense of private law in the ecological environment law. Article 1234 of the Tort Liability Section stipulates that “the state-specified agency or the law-specified organization” as the representative of environmental public interests proposes damage. The request resolves the legitimacy of relevant agencies and organizations as civil subjects to represent environmental public interests. Finally, it clearly stipulates the responsibility for ecological restoration, expands the way of undertaking tort liability caused by environmental damage, and solves the problem that it was limited to “restoration” in the past and could not be actually performed.

Intervertebral disc (IVD) degeneration (IVDD) is the most common spinal disorder, which can lead to the symptoms of neck pain or low back pain. In healthy mature IVD tissues, extracellular matrix (ECM) complex possesses favorable biochemical and biomechanical properties, withstanding compression and torsion forces. IVD cells and ECM associate with each other to form a coordinated functional system. IVD cells are the main producers of ECM components, while ECM could modulate the viability and phenotype of IVD cells via direct interactions or indirect regulations. However, with the process of IVDD and ageing, ECM of IVD undergoes content loss and structure degeneration. Moreover, the accumulation of catabolic products may further deteriorate the IVD microenvironment. A better understanding of the physiology and the pathology of ECM within the IVD provides new insight into potential IVD regeneration strategies. Natural ECM components, functional motifs, or mimetic peptides are widely used in IVD repair by not only restoring structural support but also regulating cell fate and tissue microenvironment. Herein, we reviewed recent advances in the involvement of ECM in IVD health and disease, with an emphasis on ECM composition and organization, cell-matrix interactions, pathological ECM degradation, and promising matrix-based biomaterials for IVD regeneration.

Corona virus disease 2019 (COVID-19) has spread around the world since its outbreak, and there is no ascertained effective drug up to now. Lianhua Qingwen (LHQW) has been widely used in China and overseas Chinese, which had some advantages in the treatment of COVID-19.To evaluate the efficacy and safety of LHQW for COVID-19 by conducting a systematic review with meta-analysis.A comprehensive literature search was conducted in 12 electronic databases from their establishment to October 30, 2021. Note Express 3.2.0 was used for screening of trials, and the data was independently extracted in duplicate by 2 researchers. The risk of bias of randomized controlled trials (RCTs) and retrospective studies were assessed by using the Cochrane collaboration tool and Newcastle Ottawa Scale, respectively, followed by data analysis using RevMan 5.3. The RCTs or retrospective studies to treat COVID-19 using LHQW were included. The intervention measures in the experimental group were LHQW alone or combined with chemical drugs (LCWC), and that in the control group were chemical drugs (CDs). Outcome measures included computed tomography (CT) recovery rate, disappearance rates of primary (fever, cough, fatigue), respiratory, gastrointestinal and other symptoms, exacerbation rate and adverse reaction. Subgroup analysis was conducted according to whether LHQW was combined with CDs and the different treatment methods in the control group.Nine trials with 1,152 participants with COVID-19 were included. The CT recovery rates of LHQW and LCWC were 1.36 and 1.32 times of CDs, respectively (P0.05). Compared with CDs, LCWC remarkably increased the disappearance rates of fever, cough, fatigue, expectoration, shortness of breath, and muscle soreness (P0.05). LHQW also obviously decreased the exacerbation rate, which was 0.45 times of CDs alone (P0.05). There was no obvious difference between LCWC and CDs in adverse reaction (P0.05).LHQW was more suitable for treating COVID-19 patients with obvious expectoration, shortness of breath and muscle soreness. LHQW had advantages in treating COVID-19 with no obvious exacerbation. (PROSPERO No. CRD42021235937).

To clarify the technical pearls of cavernous sinus molding technique with hemostatic agent injection during endoscopic endonasal pituitary surgery.All patients pretreated with cavernous sinus hemostatic agent injection molding technique for hemostasis in endoscopic endonasal surgery for pituitary adenoma resection between November 2017 and June 2021 were included. A small incision was made in the cavernous sinus wall before intracavernous manipulation. The hemostatic agent was injected with gentle pressure. It spread along the venous channels and established partial molding of the cavernous sinus. Intraoperative bleeding, surgical field score, and complications were evaluated.Thirty-eight patients with pituitary adenoma requiring cavernous sinus manipulation were pretreated with this technique. Technically, the tailored thin blunt metal tube with its 1 cm head end bended up 45° were the best instrument to accomplish injection. Multi-spot injections were preferred to control different compartments of the cavernous sinus, which both had a better effect in bleeding control and helped to reduce the influence of trigemino-cardiac reflex. Postoperative complications, including temporal lobe edema, hemorrhage, and exophthalmos were not observed.Pretreating cavernous sinus with hemostatic agent injection molding technique during endoscopic endonasal pituitary surgery is a practical, effective and safe method for intracavernous bleeding control.

This study aimed to establish a non-invasive model based on the virtual portal pressure gradient (vPPG) to predict the first variceal hemorrhage (VH) in patients with cirrhosis.This single-center study prospectively enrolled cirrhotic patients as the training and validation cohorts during different time periods. The PPG-detection software (PPGS 1.0) was used to perform vPPG calculation, which involves 2 steps including three-dimensional (3D) reconstruction of portal vein tree and subsequent application of computational fluid dynamics. All patients were given standard primary prophylaxis against VH and followed up for 2 years. Data from the training cohort were assessed using univariate and multivariate Cox regression and Kaplan-Meier analyses, by which a nomogram with its dynamic form was developed to estimate the probability of VH.In the training cohort (n = 128), 37 (28.9%) experienced VH during 2-year follow-up. Four variables including vPPG ≥ 10.5 mmHg (p 0.001), PLT 56 × 10The vPPG-based nomogram could be used for risk stratification of the first VH in patients with cirrhosis.

CGG/GGC repeat expansion in FMR1 and NOTCH2NLC is reportedly associated with movement disorders; therefore, we hypothesized that the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1, which was previously identified in myopathy, might also be associated with movement-disorder phenotypes. Here, we investigated whether CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 presents in a cohort of patients with movement disorders.We screened for the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 in 1,346 movement-disorder patients and 1,451 matched healthy controls.No patients or controls harbored expanded CGG repeats in LRP12 or NUTM2B-AS1, whereas 16 patients harbored40 CGG repeats in GIPC1, with 11 of these patients harboring60 CGG repeats. One control individual harbored an expanded GIPC1 allele (83 CGG units), suggesting that approximately 1% of patients affected by movement disorders in our population might harbor GIPC1 CGG repeat expansion, with this likely extremely rare in healthy controls (0.001). The clinical phenotypes of the GIPC1 CGG repeat-positive patients strongly resembled those in patients displaying NOTCH2NLC GGC repeat-positive movement disorders. Additionally, the GIPC1 CGG repeat-positive patients presented white-matter hyperintensities but without typical NOTCH2NLC-related high-intensity signals in the corticomedullary junction. Furthermore, 44% of the GIPC1 CGG repeat-positive patients showed a cognitive deficit, and skin biopsies in 2 patients revealed deposition of intranuclear inclusions.The CGG repeat expansion in GIPC1 might be associated with movement-disorder phenotypes and lead to diseases related to intranuclear inclusions. ANN NEUROL 2022;91:704-715.

To examine the range of the area under the concentration-time curve (AUC) calculated using plasma 5-FU concentration at steady-state plasma concentration-time of 5-fluorouracil (5-FU) and correlation between 5-FU metabolites (5,6-dihydro-5-fluorouracil, 5-FUH74 patients with advanced CRC receiving 5-FU-based chemotherapy from Aug. 2017 to Nov. 2020 in Harbin Medical University Cancer Hospital were involved in this study, the dosage of 5-FU being determined according to the patient's body surface area (BSA). Using an ultra-high performance liquid chromatography-tandem mass spectrum (UPLC-MS/MS) to determine the 5-FU steady-state plasma concentration (CThe AUC of 5-FU was not normally distributed and ranged from 3.13 to 41.12mgh/L, with an average value of 14.81 ± 8.62 mg·h /L, and the AUC values had obvious inter-individual differences up to 13 times. 5-FUHThere are obvious individual differences in AUC values in CRC patients receiving different dosages of 5-FU based on BSA. The ideal AUC range of 5-FU is 18.23-29.17 mg·h/L. There was a significant correlation between 5-FUH

Purpose To compare the image quality, examination time, and total energy release of a standardized pediatric brain tumor magnetic resonance imaging (MRI) protocol performed with and without compressed sensitivity encoding (C-SENSE). Recently introduced as an acceleration technique in MRI, we hypothesized that C‑SENSE would improve image quality, reduce the examination time and radiofrequency-induced energy release compared with conventional examination in a pediatric brain tumor protocol. Methods This retrospective study included 22 patients aged 2.33–18.83 years with different brain tumor types who had previously undergone conventional MRI examination and underwent follow-up C‑SENSE examination. Both examinations were conducted with a 3.0-Tesla device and included pre-contrast and post-contrast T1-weighted turbo-field-echo, T2-weighted turbo-spin-echo, and fluid-attenuated inversion recovery sequences. Image quality was assessed in four anatomical regions of interest (tumor area, cerebral cortex, basal ganglia, and posterior fossa) using a 5-point scale. Reader preference between the standard and C‑SENSE images was evaluated. The total examination duration and energy deposit were compared based on scanner log file analysis. Results Relative to standard examinations, C‑SENSE examinations were characterized by shorter total examination times (26.1 ± 3.93 vs. 22.18 ± 2.31 min; P = 0.001), reduced total energy deposit (206.0 ± 19.7 vs. 92.3 ± 18.2 J/kg; P P Conclusion C‑SENSE contributes to the improvement of image quality, reduction of scan times and radiofrequency-induced energy release relative to the standard protocol in pediatric brain tumor MRI.

Background TOAST subtype classification is important for diagnosis and research of ischemic stroke. Limited by experience of neurologist and time-consuming manual adjudication, it is a big challenge to finish TOAST classification effectively. We propose a novel active deep learning architecture to classify TOAST. Methods To simulate the diagnosis process of neurologists, we drop the valueless features by XGB algorithm and rank the remaining ones. Utilizing active learning framework, we propose a novel causal CNN, in which it combines with a mixed active selection criterion to optimize the uncertainty of samples adaptively. Meanwhile, KL-focal loss derived from the enhancement of Focal loss by KL regularization is introduced to accelerate the iterative fine-tuning of the model. Results To evaluate the proposed method, we construct a dataset which consists of totally 2310 patients. In a series of sequential experiments, we verify the effectiveness of each contribution by different evaluation metrics. Experimental results show that the proposed method achieves competitive results on each evaluation metric. In this task, the improvement of AUC is the most obvious, reaching 77.4. Conclusions We construct a backbone causal CNN to simulate the neurologist process of that could enhance the internal interpretability. The research on clinical data also indicates the potential application value of this model in stroke medicine. Future work we would consider various data types and more comprehensive patient types to achieve fully automated subtype classification.

The aim of this study was to evaluate the efficacy and safety of antiulcer oral mucosal protectant-RADoralex® in the prevention and treatment of radiation-induced oral mucosal reactions elicited during intensity-modulated radiation therapy (IMRT). for locally advanced nasopharyngeal carcinoma (NPC). A total of 90 patients with locally advanced NPC who developed post-treatment grade 1 oral mucositis were selected for this study. They were randomly assigned to the experimental group (n = 44) treated by mouth rinsing with the RADoralex® during radiochemotherapy and the control group (n = 43) treated by mouth rinsing with sodium bicarbonate solution, and the patients’ oral mucosal conditions, quality of life, weight change and oral pain levels were analyzed. The incidence of Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 2 and grade 3 oral mucositis were significantly lower in the experimental group than in the control group. Compared to the control group, the time to progression, and the time from the end of treatment to oral mucosa healing in the experimental group was significantly shorter. The experimental group lost 8.66 ± 3.543% of their body weight during treatment period, while the control group lost 12.53 ± 4.284% (p

Stroke continues to be the most common cause of death in China. It has great significance for mortality prediction for stroke patients, especially in terms of analyzing the complex interactions between non-negligible factors. In this paper, we present a gated spatio-temporal correlation network (GSTCNet) to predict the one-year post-stroke mortality. Based on the four categories of risk factors: vascular event, chronic disease, medical usage and surgery, we designed a gated correlation graph convolution kernel to capture spatial features and enhance the spatial correlation between feature categories. Bi-LSTM represents the temporal features of five timestamps. The novel gated correlation attention mechanism is then connected to the Bi-LSTM to realize the comprehensive mining of spatio-temporal correlations. Using the data on 2275 patients obtained from the neurology department of a local hospital, we constructed a series of sequential experiments. The experimental results show that the proposed model achieves competitive results on each evaluation metric, reaching an AUC of 89.17%, a precision of 97.75%, a recall of 95.33% and an F1-score of 95.19%. The interpretability analysis of the feature categories and timestamps also verified the potential application value of the model for stroke.

Purpose of review: There is increasing interest in the links between exposure to air pollution and a range of health outcomes. The association with mental health however is much less established. This article reviews developments in the field over the past 12 months, highlighting the evidence for causation, associations between multiple air pollutants and mental health outcomes, and assesses the challenges of researching this topic. Recent findings: Increasingly rigorous methods are being applied to the investigation of a broader range of mental health outcomes. These methods include basic science, neuroimaging, and observational studies representing diverse geographical locations. Cohort studies with linked high resolution air pollutant exposure data are common, facilitating advanced analytic methods. To date meta-analyses have demonstrated small and significant positive associations between long-term exposure to fine particulate matter and depressive symptoms and cognitive decline. Methodological complexities in measuring exposure and outcome pose ongoing difficulties for the field. Summary: Literature on this topic has recently seen an appreciable expansion. Work that better estimates daily exposure, controls for complex confounders, and is driven by hypotheses founded in candidate causal mechanisms would help clarify associations, and inform targeted interventions and policy makers.

lncRNA is a transcript that is more than 200 bp in length. Currently, evidence has shown that lncRNA is of great significance in cell activity, involved in epigenetics, gene transcription, chromatin regulation, etc. The existence of an intestinal mucosal mechanical barrier hinders the invasion of pathogenic bacteria and toxins, maintaining the stability of the intestinal environment. Serious destruction or dysfunction of the mechanical barrier often leads to intestinal diseases. This review first summarizes the ability of lncRNAs to regulate the intestinal mucosal mechanical barrier. We then discussed how lncRNAs participate in various intestinal diseases by regulating the intestinal mucosal mechanical barrier. Finally, we envision its potential as a new marker for diagnosing and treating intestinal inflammatory diseases.

Background The present study aimed to compare and evaluate the efficacy of antidepressants in remission of esophageal reflux symptoms. Methods A comprehensive literature review was performed including sources published on MEDLINE, EMBASE, the Cochrane Central Registry of Controlled Trials (Cochrane), Web of Science, China National Knowledge Infrastructure Database (CNKI), Chinese VIP Information Databases (VIP), Chinese Biology Medicine disc (CBM), and Wan-Fang databases for randomized controlled trials, published up to and including March 31, 2020. We analyzed relevant randomized, placebo-controlled trials reporting the effect of antidepressant therapy in relieving esophageal reflux symptoms ADDIS 1.16.8 was used to perform the network meta-analysis. Furthermore, we performed a split analysis to test inconsistency, and rank probability was complemented for comparison among antidepressants. Results A total of 10 randomized controlled trials (RCTs) examining the effects of antidepressants, selective 5-HT reabsorption inhibitor (SSRI), 5-HT 1A receptor agonist (5-HT1AA), tricyclic antidepressants (TCAs), and the complex of flupentixol-melitracen (FM) were included. Flupentixol-melitracen and SSRIs exhibited a significantly higher rate of remission than placebo. However, there was no statistically significant difference among different antidepressants compared. Rank probability showed that FM exhibited the highest probability of rank 1 compared with other antidepressants and placebo. Conclusion This network meta-analysis of RCTs supported the use of FM and SSRIs as a potentially effective regimen for symptom remission of gastroesophageal reflux. Furthermore, according to our analysis, FM represents the most efficient antidepressant with highest probability of symptom remission.

Background Eukaryotic ribosomes are widely presumed to scan mRNA for the AUG codon to initiate translation in a strictly 5′–3′ movement (i.e., strictly unidirectional scanning model), so that ribosomes initiate translation exclusively at the 5′ proximal AUG codon (i.e., the first-AUG rule). Results We generate 13,437 yeast variants, each with an ATG triplet placed downstream (dATGs) of the annotated ATG (aATG) codon of a green fluorescent protein. We find that out-of-frame dATGs can inhibit translation at the aATG, but with diminishing strength over increasing distance between aATG and dATG, undetectable beyond ~17 nt. This phenomenon is best explained by a Brownian ratchet mechanism of ribosome scanning, in which the ribosome uses small-amplitude 5′–3′ and 3′–5′ oscillations with a net 5′–3′ movement to scan the AUG codon, thereby leading to competition for translation initiation between aAUG and a proximal dAUG. This scanning model further predicts that the inhibitory effect induced by an out-of-frame upstream AUG triplet (uAUG) will diminish as uAUG approaches aAUG, which is indeed observed among the 15,586 uATG variants generated in this study. Computational simulations suggest that each triplet is scanned back and forth approximately ten times until the ribosome eventually migrates to downstream regions. Moreover, this scanning process could constrain the evolution of sequences downstream of the aATG to minimize proximal out-of-frame dATG triplets in yeast and humans. Conclusions Collectively, our findings uncover the basic process by which eukaryotic ribosomes scan for initiation codons, and how this process could shape eukaryotic genome evolution.

There is a strong link between fecal microbiota and the development of type 1 diabetes. As an emerging therapeutic modality, fecal microbiota transplantation has been shown to be safe and effective in the treatment of many intestinal and extraintestinal diseases. Various studies have found that fecal microbiota transplantation can treat diseases by correcting patients’ immune disorders. Besides, many studies have found that fecal microbiota transplantation can improve glycemic control and insulin resistance in diabetic patients. Therefore, this paper reviews the mechanism of action of fecal microbiota transplantation on autoimmune-mediated T1DM and the current research progress, feasibility, and issues that need to be addressed in the future development of fecal microbiota transplantation in the treatment of autoimmune-mediated T1DM.

Background Cardiovascular magnetic resonance (CMR) offers comprehensive right ventricular (RV) evaluation in pulmonary arterial hypertension (PAH). Emerging four-dimensional (4D) flow CMR allows visualization and quantification of intracardiac flow components and calculation of phasic blood kinetic energy (KE) parameters but it is unknown whether these parameters are associated with cardiopulmonary exercise test (CPET)-assessed exercise capacity, which is a surrogate measure of survival in PAH. We compared 4D flow CMR parameters in PAH with healthy controls, and investigated the association of these parameters with RV remodelling, RV functional and CPET outcomes. Methods PAH patients and healthy controls from two centers were prospectively enrolled to undergo on-site cine and 4D flow CMR, and CPET within one week. RV remodelling index was calculated as the ratio of RV to left ventricular (LV) end-diastolic volumes (EDV). Phasic (peak systolic, average systolic, and peak E-wave) LV and RV blood flow KE indexed to EDV (KEIEDV) and ventricular LV and RV flow components (direct flow, retained inflow, delayed ejection flow, and residual volume) were calculated. Oxygen uptake (VO2), carbon dioxide production (VCO2) and minute ventilation (VE) were measured and recorded. Results 45 PAH patients (46 ± 11 years; 7 M) and 51 healthy subjects (46 ± 14 years; 17 M) with no significant differences in age and gender were analyzed. Compared with healthy controls, PAH had significantly lower median RV direct flow, RV delayed ejection flow, RV peak E-wave KEIEDV, peak VO2, and percentage (%) predicted peak VO2, while significantly higher median RV residual volume and VE/VCO2 slope. RV direct flow and RV residual volume were significantly associated with RV remodelling, function, peak VO2, % predicted peak VO2 and VE/VCO2 slope (all P Conclusion In this 4D flow CMR and CPET study, RV direct flow provided incremental value over RVEF for discriminating adverse RV remodelling, impaired exercise capacity, and PAH with intermediate and high risk based on risk score. These data suggest that CMR with 4D flow CMR can provide comprehensive assessment of PAH severity, and may be used to monitor disease progression and therapeutic response. Trial registration number: https://www.clinicaltrials.gov. Unique identifier: NCT03217240.

To assess the variations of soil quality among land use types and with altitude in the rocky mountain area of northern Hebei Province is critical for preventing further human-induced degradation of land and vegetation, and for formulating a strategic plan on vegetation restoration after the Beijing Winter Olympics. Taking为防止北方土石山区的土地和植被在人类活动下进一步退化,为冬奥会赛后制定战略性植被恢复计划,以白桦天然林、落叶松人工林、天然灌草地和弃耕农地为研究对象,基于土壤容重、孔隙度和土壤养分含量等13种土壤理化指标,对冀北土石山区不同土地利用类型土壤质量进行综合评价。结果表明: 冀北土石山区不同土地利用类型土壤质量呈现出白桦天然林天然灌草地落叶松人工林弃耕农地。白桦天然林的土壤质量显著高于其他3种土地利用类型,其土壤全氮(3.24±1.42 g·kg

Disruption of intestinal homeostasis is an important event in the development of inflammatory bowel disease (IBD), and genistein (GEN) is a candidate medicine to prevent IBD. However, the clinical application of GEN is restricted owing to its low oral bioavailability. Herein, a reactive oxygen species (ROS)-responsive nanomaterial (defined as GEN-NP2) containing superoxidase dismutase-mimetic temporally conjugated β-cyclodextrin and 4-(hydroxymethyl)phenylboronic acid pinacol ester-modified GEN was prepared. GEN-NP2 effectively delivered GEN to the inflammation site and protected GEN from rapid metabolism and elimination in the gastrointestinal tract. In response to high ROS levels, GEN was site-specifically released and accumulated at inflammatory sites. Mechanistically, GEN-NP2 effectively increased the expression of estrogen receptor β (ERβ), simultaneously reduced the expression of proinflammatory mediators (apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase1-p20), attenuated the infiltration of inflammatory cells, promoted autophagy of intestinal epithelial cells, inhibited the secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), modulated the gut microbiota, and ultimately alleviated colitis. In addition, the oral administration of these nanoparticles showed excellent safety, thereby providing confidence in the further development of precise treatments for IBD.

Primary biliary cholangitis (PBC) is an autoimmune disease. CD8 + T cell (CTLs) cytotoxicity played a crucial rule in of PBC with unclear detailed pathogenesis. The role of the programmed death-1 (PD-1) pathway in CD8 + T cell cytotoxicity in patients with PBC was determined. We recruited 69 patients with PBC and 57 healthy controls (HCs). PD-1 pathway in peripheral CD8 + T cells and related cytokines were detected, and gene expression levels were detected. Immunofluorescence staining of PD-1/PD-L1 was performed on liver tissue. PD-1 ± CTLs were cocultured with human intrahepatic biliary epithelial cells (HiBECs) to measure CTL cytotoxicity, proliferation and cytokine levels and HiBEC apoptosis. The upstream signaling pathway of PD-1 was detected. PBC patients exhibited Tbet gene upregulation and PD-1 downregulation in CTLs, with PD-1 expression reduced in CTLs and PD-L1 reduced in the liver portal region relative to HCs. Higher plasma IL-10, interferon-γ and transforming growth factor-β concentrations were observed in the PBC group than the HC group. In CTL and HiBEC coculture experiment, compared with PD-1- CTLs, PD-1 + CTLs exhibited weaker cytotoxicity, less proliferation and lower cytokine production. When the system was blocked by anti-PD-1 antibodies, these effects were antagonized. PD-1 expression in CD8 + T cells decreased, and PD-1 pathway-related cytokines changed in patients with PBC. PD-1/PD-L1 pathway silencing increased CD8 + T cell proliferation, related cytokine production and CTL cytotoxic effects on HiBECs in coculture experiment. The PD-1/PD-L1 pathway might represent an important pathway in the immunological mechanism underlying PBC.

Objective Unidentified mechanisms largely restrict the viability of effective therapies in pharmacoresistant epilepsy. Our previous study revealed that hyperactivity of the subiculum is crucial for the genesis of pharmacoresistance in temporal lobe epilepsy (TLE), but the underlying molecular mechanism is not clear. Methods Here, we examined the role of subicular caspase-1, a key neural pro-inflammatory enzyme, in pharmacoresistant TLE. Results We found that the expression of activated caspase-1 in the subiculum, but not the CA1, was upregulated in pharmacoresistant amygdaloid-kindled rats. Early overexpression of caspase-1 in the subiculum was sufficient to induce pharmacoresistant TLE in rats, whereas genetic ablation of caspase-1 interfered with the genesis of pharmacoresistant TLE in both kindled rats and kainic acid-treated mice. The pro-pharmacoresistance effect of subicular caspase-1 was mediated by its downstream inflammasome-dependent interleukin-1β. Further electrophysiological results showed that inhibiting caspase-1 decreased the excitability of subicular pyramidal neurons through influencing the excitation/inhibition balance of presynaptic input. Importantly, a small molecular caspase-1 inhibitor CZL80 attenuated seizures in pharmacoresistant TLE models, and decreased the neuronal excitability in the brain slices obtained from patients with pharmacoresistant TLE. Interpretation These results support the subicular caspase-1-interleukin-1β inflammatory pathway as a novel alternative mechanism hypothesis for pharmacoresistant TLE, and present caspase-1 as a potential target. ANN NEUROL 2021;90:377-390.

Aim Exosomes has been shown to be involved in the regulation of cancer progression. However, the role of exosome miR-134-5p in breast cancer (BC) progression is unclear. Methods Exosomes were extracted from BC cells (MCF-7 and MDA-MB-231) using differential centrifugation and were observed by transmission electron microscope (TEM). The protein levels of exosome markers, apoptosis markers, Rho GTPase activating protein 1 (ARHGAP1, an important oncogene in BC) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) markers were detected by western blot (WB) assay. Quantitative real-time PCR was used to measure the expression levels of miR-134-5p and ARHGAP1. Cell cycle and apoptosis, colony number, viability, migration, and invasion were determined by flow cytometry, colony formation assay, MTT assay, and transwell assay, respectively. The interaction between miR-134-5p and ARHGAP1 was confirmed using a dual-luciferase reporter assay. Xenograft models were constructed to verify the role of exosome miR-134-5p in BC tumor growth in vivo. Results MiR-134-5p was lowly expressed in BC cells and in the exosomes of BC cells. Overexpressed exosome miR-134-5p suppressed the proliferation, migration, invasion, and promoted the apoptosis of BC cells. ARHGAP1 was a target of miR-134-5p, and its silencing could inhibit BC progression. In addition, ARHGAP1 overexpression could reverse the negative regulation of miR-134-5p on BC progression. MiR-134-5p could target ARHGAP1 to inhibit the activity of PI3K/AKT pathway. Exosome miR-134-5p overexpression could suppress BC tumor growth via targeting ARHGAP1 in vivo. Conclusion Exosome miR-134-5p restrained BC progression through regulating ARHGAP1/PI3K/AKT signaling pathway, suggesting that miR-134-5p might be a therapeutic target for BC.

HCC undergoes active metabolic reprogramming. Reactive oxygen species (ROS) are excessively generated in cancer cells and are neutralized by NADPH. Malic enzymes (MEs) are the less studied NADPH producers in cancer. We found that ME1 but not ME3 was regulated by the typical oxidative stress response pathway mediated by kelch-like ECH associated protein 1 (KEAP1)/ nuclear factor erythroid 2-related factor (NRF2). Surprisingly, ME3 was constitutively induced by super-enhancers. Disruption of any ME regulatory pathways decelerated HCC progression and sensitized HCC to Sorafenib. Therapeutically, simultaneous blockade of NRF2 and super-enhancer complex completely impeded HCC growth. Here we show that super-enhancer allows cancer cells to counteract the intrinsically high level of ROS through constitutively activating ME3 expression. When HCC cells encounter further episodes of ROS insult, NRF2 allows cancer cells to adapt by transcriptionally activating ME1. In conclusion: Our study reveals the complementary regulatory mechanisms which control MEs and provide cancer cells multiple layers of defence against oxidative stress. Targeting both regulatory mechanisms represents a potential therapeutic approach for HCC treatment.

Death receptor 4 (DR4) is a cell surface protein that is generally thought to mediate apoptosis upon binding to its ligand named TRAIL. However, its contribution to apoptosis resistance has also been reported. MET (or c-MET) gene amplification represents an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) against EGFR mutant non-small cell lung cancer (NSCLC). This study focuses on demonstrating the impact of MET inhibition on DR4 modulation in MET-amplified EGFR mutant NSCLC cell lines and the underlying mechanisms. Several MET inhibitors decreased DR4 levels in MET-amplified HCC827 cell lines resistant to EGFR-TKIs with no or limited effects on modulating DR5 levels, while increasing DR4 levels in HCC827 parental cells and other NSCLC cell lines. MET inhibitors did not affect DR4 stability, but decreased DR4 mRNA levels with suppression of AP-1-dependent DR4 promoter transactivation. Moreover, these inhibitors suppressed ERK and c-Jun phosphorylation accompanied with decreasing c-Jun levels. Hence, it is likely that MET inhibition downregulates DR4 expression in MET-amplified EGFR mutant NSCLC cells through suppressing AP-1-mediated DR4 transcription. Osimertinib combined with MET inhibition synergistically induces apoptosis in the MET-amplified EGFR mutant NSCLC cells accompanied with augmented DR4 reduction both in vitro and in vivo. Furthermore, MET inhibition combined with TRAIL enhanced killing of MET-amplified EGFR mutant HCC827/AR cells, but not HCC827 parental cells. These data collectively suggest that DR4 may possess an unrecognized anti-apoptotic function, contributing to apoptosis resistance under given conditions.

OBJECTIVE: To summarize the characteristics of the learning curve and the occurrence of postoperative adverse events during the development of unilateral biportal endoscopy (UBE) technique by comparing the clinical data of early and late patients treated with UBE technique. METHODS: All patients who underwent single-level UBE technique between April 1, 2020 and December 31, 2021 were selected as the research subjects. According to the surgical options, all patients were allocated into 3 groups: unilateral decompression and discectomy (UDD) group, unilateral laminotomy for bilateral decompression (ULBD) group, and lumbar intervertebral fusion (LIF) group. The first 60 cases from each group were extracted and ranked orderly. The endoscopic operation time, the times of fluoroscopy during non-internal fixation implantation, the postoperative hospital stay, the drainage volume, the decrease of hemoglobin, the decrease of hematocrit, and the adverse events were collected. In each group, the patients were allocated into early and late cases according to the operation sequence. The first 30 cases of each group were classified as early cases, and the last 30 cases as late cases. Statistical analysis was performed on the above observation indicators between the early and late cases, and a scatter plot of relevant data changes was drawn to observe the change trend. RESULTS: Compared with the early cases, the endoscopic operation time and the times of fluoroscopy during non-internal fixation implantation of late cases in each group were significantly lower (P0.05). CONCLUSION: In the early practice of UBE technique, there is a high incidence of complication, and the surgical trauma is relatively large, which is related to the lack of understanding of the UBE technique characteristics and insufficient surgical experience. With the proficiency of surgical techniques and accumulation of experience, the operation time and the incidence of postoperative adverse events were significantly reduced.

Cancer is a disease with high morbidity and mortality in the world. In the past, the main treatment methods for cancer patients were surgery, radiotherapy and chemotherapy. However, with early treatment, the recurrence rate of cancer is higher, and the drug resistance of cancer cells is faster. In recent years, with the discovery of immune escape mechanism of cancer cells, Immunotherapy, especially Immune Checkpoint Inhibitors (ICIs), has made a breakthrough in the treatment of solid tumors, significantly prolonging the overall survival time and disease-free progression in some solid tumors, and its clinical benefits are more prominent than those of traditional anti-tumor drugs, which has become the hope of cancer patients after the failure of multi-line therapy. More and more studies have shown that there is a correlation between cancer driving genes and the clinical benefits of ICIs treatment, and the therapeutic effects and adverse reactions of ICIs can be predicted by the status of driving genes. Therefore, screening potential biomarkers of people who may benefit from immunotherapy in order to maximize the therapeutic benefits is a top priority. This review systematically summarizes the cancer driving genes that may affect the clinical benefits of immune checkpoint inhibitors, and provides accurate scientific basis for clinical practice.

Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem cell properties that sustain cancers, which may be responsible for cancer metastasis or recurrence. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in the plasma membrane that mediate various intracellular signaling. The occurrence and progression of cancer are closely related to lipid rafts. Emerging evidence indicates that lipid raft levels are significantly enriched in CSCs compared to cancer cells and that most CSC markers such as CD24, CD44, and CD133 are located in lipid rafts. Furthermore, lipid rafts play an essential role in CSCs, specifically in CSC self-renewal, epithelial-mesenchymal transition, drug resistance, and CSC niche. Therefore, lipid rafts are critical regulatory platforms for CSCs and promising therapeutic targets for cancer therapy.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disorders in the world, and yet has no approved pharmacotherapy due to the etiology is complex. In the last ten years, increasing evidence have identified the environmental pollutants as risk factors for MAFLD. However, the underlying mechanism remains unclear. Our study found that bromoacetic acid (BAA, a typical kind of environmental toxin) increased triglycerides and total cholesterol levels as well as induced obvious hepatic steatosis and inflammation. The lipidomics showed that ferroptosis was implicated in the environmental toxin-linked MAFLD. Besides, the analysis of microbial metabolomics showed significant change of gut microbiome in BAA groups and the content of gut microbiota metabolite (glycochenodeoxycholate, GCDCA) increased sharply. In vitro study, we observed features of ferroptotic cells by transmission electron microscopy after BAA/GCDCA treatment. Besides, we demonstrated that BAA/GCDCA significantly increased iron contents, with upregulating transferrin receptor (TFR) and acyl-CoA synthetase long-chain family 4 (ACSL4) expression levels. By contrast, iron chelator or silencing TFR relieved BAA/GCDCA-induced lipid metabolism disorder and inflammation. What's more, the interaction between TFR and ACSL4 was also identified. Taken together, we found that, in response to environmental toxin, gut microbiota metabolite GCDCA activates TFR-ACSL4-mediated ferroptosis, which triggered subsequent lipid metabolism disorder and inflammation. Moreover, these findings firstly highlighted the functional relevance among ferroptosis, lipid metabolism and gut microbiota metabolite during environmental pollutant exposure, which shed light on the deep mechanism of environmental toxin-related MAFLD, providing potential targets for the prevention of MAFLD.

Although great progress has occurred in breast cancer (BC) treatment, including chemotherapy, chemoradiotherapy, and surgical resection, the rate of patients' survival is still unsatisfactory. Multiple genes and factors have proven to contribute to BC's occurrence. Thus, it's urgent to explore the molecular mechanisms in the development and progression of BC and find possible targets for therapy.The study intended to assess the mechanisms of miR-518a-5p's effect on BC by targeting the zinc finger E-box-binding homeobox 2 (ZEB2) gene.The research team designed a laboratory study and retrospective analysis.The study took place in the Department of Breast Surgery at the Xingtai People's Hospital in Xingtai, Hebei, China.The study measured the miR-518a-5p expression in BC tissues and normal tissues using a real-time quantitative reverse transcription (qRT)-polymerase chain reaction (PCR) test. The research team purchased the BC cells MDA-MB-231 and MCF-7 and measured the effects of the miR-518a-5p on BC cell activity as well as epithelial-mesenchymal transition (EMT) ability, using cell scratch tests and Transwell assays. The team assessed the ZEB2 protein expression and verified the targeting relationship using a Dual-Luciferase Reporter assay.The miR-518a-5p expressed was low in the BC tissues and cell lines compared with adjacent normal tissues (P.05). Overexpressing the miR-518a-5p inhibited BC-cell migration and invasion (P.05). Moreover, the ZEB2 was the target gene for the miR-518a-5p. The Luciferase assay verified that the miR-518a-5p directly targeted the ZEB2 in BC cells (P.05). The Transwell invasion assay, western blot analysis, and wound healing assay also showed that the miR-518a-5p inhibited BC cells by targeting ZEB2 (P.05).The miR-518a-5p suppressed BC migration, invasion, and process of EMT by regulating ZEB2. In the future, this method may be a new option for BC diagnosis and treatment. An in-depth understanding of the role of the miR-518a-5p in BC can help clinicians to understand the pathogenic mechanism of breast cancer more accurately.

Refereed/Peer-reviewed Reducing lead (Pb) exposure via oral ingestion of contaminated soils is highly relevant for child health. Elevating dietary micronutrient iron (Fe) intake can reduce Pb oral bioavailability while being beneficial for child nutritional health. However, the practical performance of various Fe compounds was not assessed. Here, based on mouse bioassays, ten Fe compounds applied to diets (100–800 mg Fe kg−1) reduced Pb oral relative bioavailability (RBA) in two soils variedly depending on Fe forms. EDTA-FeNa was most efficient, which reduced Pb-RBA in a soil from 79.5 ± 14.7 % to 23.1 ± 2.72 % (71 % lower) at 100 mg Fe kg−1 in diet, more effective than other 9 compounds at equivalent or higher doses (3.6–68 % lower). When EDTA-FeNa, ferrous gluconate, ferric citrate, and ferrous bisglycinate were supplemented, Fe-Pb co-precipitation was not observed in the intestinal tract. EDTA-FeNa, ferrous gluconate, ferric citrate, and ferrous sulfate suppressed duodenal divalent metal transporter 1 (DMT1)mRNA relative expression similarly (27–68 % lower). In comparison, among ten compounds, EDTA-FeNa elevated Fe concentrations in mouse liver, kidney, and blood (1.50–2.69-fold higher) most efficiently, suggesting the most efficient Fe absorption that competed with Pb. In addition, EDTA was unique from other organic ligands, ingestion of which caused 12.0-fold higher Pb urinary excretion, decreasing Pb concentrations in mouse liver, kidney, and blood by 68–88 %. The two processes (Fe-Pb absorption competition and Pb urinary excretion with EDTA) interacted synergistically, leading to the lowest Pb absorption with EDTA-FeNa. The results provide evidence of a better inhibition of Pb absorption by EDTA-FeNa, highlighting that EDTA-FeNa may be the most appropriate supplement for intervention on human Pb exposure. Future researches are needed to assess the effectiveness of EDTA-FeNa for intervention on human Pb exposure.

The relationship between fertility history and human health has long fascinated scholars; however, whether there is a link between number of children and cognitive function in older adults remains unclear. We investigated the associations between parity and the timing of first and last births with the cognitive function of older adults over 65.The mini-mental state examination (MMSE) was selected as a tool to measure cognitive function. We analyzed data on 5847 older adults in rural and urban communities in China from the 2018 Chinese Longitudinal Healthy Longevity Survey using ordinary least squares. To further explore the transmission mechanism, we also conducted a mediating effect analysis.We found a negative association between number of children and cognitive function in older adults. Compared with older adults with four children, the MMSE scores of older adults with more than five children decreased significantly, and the score of older adults with zero to three children increased. Further, a late age at first birth (≥35) and a late age at last birth (≥35) were negatively associated with cognitive function. We also found that the associations between parity and cognition might be partly explained by variations in health.Our analyses provided evidence from China to support the link between fertility history and cognitive function that has been observed in previous international studies: We suggest that high parity (≥5) is negatively associated with cognitive function.

Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against refractory differentiated thyroid cancer. The nanoscale metal organic frameworks (NMOFs) have shown great potential in cancer diagnostic and treatment due to their advantages in the aspect of structural diversities, high intrinsic biodegradability and drug-loading capacities. Here, we provide that intratumoral injection, in mouse of refractory differentiated thyroid cancer.In this work, we used the therapeutic 131I radioisotope modified Zr-MOF (Zr-MOF@131I) with aim to enable long-term relief of tumour therapy, which has successfully eliminated tumour at ralatively low radioactivity doses. Polyethylene glycol (PEG) was coated into Zr-MOF and, as a result, circulation time was significantly improved by intratumoral injection. These findings therefore suggest that nanoparticles could be used in vivo combined therapy. On injection, while it is a highly effective drug for radioisotope, Zr-MOF with attenuation ability could apply for a radio-sensitizer to enhance inner radiotherapy (RT). The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments. These could be further combined with systemic therapeutic responses for the inhibition of refractory differentiated thyroid cancer and the prevention of tumour recurrence in patients.

Abnormal ATPase H+ Transporting Accessory Protein 1 (ATP6AP1) expression may promote carcinogenesis. We investigated the association of ATP6AP1 with breast cancer (BC) and COVID-19. The Oncomine, Gene Expression Profiling Interactive Analysis, Human Protein Atlas and Kaplan-Meier plotter databases were used to evaluate the expression and prognostic value of ATP6AP1 in BC. ATP6AP1 was upregulated in BC tissues, and higher ATP6AP1 expression was associated with poorer outcomes. Data from the Tumor Immune Estimation Resource, Tumor-Immune System Interaction Database and Kaplan-Meier plotter indicated that ATP6AP1 expression correlated with immune infiltration, and that its prognostic effects in BC depended on tumor-infiltrating immune cell subtype levels. Multiple databases were used to evaluate the association of ATP6AP1 with clinicopathological factors, assess the mutation and methylation of ATP6AP1, and analyze gene co-expression and enrichment. The ATP6AP1 promoter was hypomethylated in BC tissues and differentially methylated between different disease stages and subtypes. Data from the Gene Expression Omnibus indicated that ATP6AP1 levels in certain cell types were reduced after SARS-CoV-2 infections. Ultimately, higher ATP6AP1 expression was associated with a poorer prognosis and with higher or lower infiltration of particular immune cells in BC. BC patients may be particularly susceptible to SARS-CoV-2 infections, which may alter their prognoses.

Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD‐1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death‐ligand 1 (PD‐L1) found on cancer cells. Blocking PD‐1/PD‐L1 binding improves T‐cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD‐1/PD‐L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti‐PD‐1/PD‐L1 treatment. Chemokine‐like factor (CKLF)–like MARVEL transmembrane domain–containing 6 (CMTM6) has been recently identified as a major regulator of PD‐L1. Another member in the CMTM family, CKLF‐like MARVEL transmembrane domain–containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD‐L1 in the context of liver cancer. Up‐regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD‐L1 expression, hence facilitating escape from T cell–mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD‐L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD‐L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T‐cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti‐PD‐L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti‐PD‐L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti‐PD‐L1 immunotherapy in patients with liver cancer., CMTM4 stabilizes PD‐L1 on liver cancer cells. CMTM4‐low ICC/HCC, which expresses lower PD‐L1, could be completely blocked by anti‐PD‐L1 mAb.

Context Understanding phenotypic connection between type II diabetes (T2D) mellitus and amyotrophic lateral sclerosis (ALS) can offer valuable sight into shared disease etiology and have important implication in drug repositioning and therapeutic intervention. Objective This work aims to disentangle the nature of the inverse relationship between T2D mellitus and ALS. Methods Depending on summary statistics of T2D (n = 898 130) and ALS (n = 80 610), we estimated the genetic correlation between them and prioritized pleiotropic genes through a multiple-tissue expression quantitative trait loci–weighted integrative analysis and the conjunction conditional false discovery rate (ccFDR) method. We implemented mendelian randomization (MR) analyses to evaluate the causal relationship between the 2 diseases. A mediation analysis was performed to assess the mediating role of T2D in the pathway from T2D-related glycemic/anthropometric traits to ALS. Results We found supportive evidence of a common genetic foundation between T2D and ALS (rg = –0.223, P = .004) and identified 8 pleiotropic genes (ccFDR Conclusion We provide new evidence supporting the observed inverse link between T2D and ALS, and revealed that a shared genetic component and causal association commonly drove such a relationship. We also demonstrate the mediating role of T2D standing in the pathway from T2D-related glycemic/anthropometric traits to ALS.

Genome-wide association studies (GWASs) have successfully identified a large amount of single-nucleotide polymorphisms associated with many complex phenotypes in diverse populations. However, a comprehensive understanding of the genetic correlation of associated loci of phenotypes across populations remains lacking and the extent to which associations discovered in one population can be generalized to other populations or can be utilized for trans-ethnic genetic prediction is also unclear. By leveraging summary statistics, we proposed MAGIC to evaluate the trans-ethnic marginal genetic correlation (rm) of per-allele effect sizes for associated SNPs (P

We compared chromosomal mosaicism, detected by next-generation sequencing (NGS), during preimplantation genetic testing (PGT) with that detected by single-nucleotide polymorphism (SNP) array-based PGT to assess the pregnancy outcomes associated with both platforms in a retrospective cohort study of patients undergoing in vitro fertilization in a single university-based assisted reproduction center. In total, 6427 blastocysts biopsied from 1513 patients who underwent 2833 oocyte retrievals from January 2017 to February 2019 were identified. The incidence of mosaicism was significantly higher in the NGS-based PGT group than in the SNP array-based PGT group. Furthermore, some aneuploid specimens were affected by mosaicism. The total mosaicism detection rate with NGS-based PGT (23.3%) was significantly higher than that with SNP array-based PGT (7.7%). Mosaicism rates were similar when stratified by maternal age or PGT type. The SNP array cohort showed a significantly higher spontaneous abortion rate than the NGS cohort (10.07% versus 6.33%; P = 0.0403). The ongoing pregnancy/live birth rate was higher in the NGS cohort (44.1%) than in the SNP array cohort (42.28%). Our results confirm that NGS-based PGT can detect mosaicism more frequently than SNP array-based PGT in trophectoderm specimens. Therefore, clinical application of NGS for PGT may improve pregnancy outcomes compared with that of SNP array-based PGT. More detailed blastocyst detection and classification is necessary to prioritize embryo transfers.

Background and aims Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery and transplantation, especially in non-alcoholic steatohepatitis (NASH). The mechanism of NASH susceptibility to I/R injury has not been fully clarified. We investigated the role of liver-produced histidine-rich glycoprotein (HRG) in NASH I/R injury. Approach and results A NASH mouse model was established using C57Bl/6j mice fed a methionine- and choline-deficient diet (MCD) for 6 weeks. The MCD and standard diet (SD) groups were exposed to 60 min of partial hepatic ischemia with reperfusion. We further evaluated the impact of HRG in this context using HRG knockdown (KD) mice. I/R injury increased HRG expression in the SD group but not in the MCD group after I/R. HRG expression was inversely correlated with neutrophil infiltration and neutrophil extracellular traps (NETs) formation. HRG KD mice showed severe liver injury with neutrophil infiltration and NETs formation. Pre-treatment with supplementary HRG protected against I/R with inhibition of neutrophil infiltration and NETs formation. In vitro, hepatocytes showed that the expression of HRG was upregulated under hypoxia/re-oxygenation conditions, but not in response to oleic acid treated hepatocytes. The decrease in HRG expression in fatty hepatocytes was accompanied by decreased Farnesoid X receptor (FXR) and Hypoxia-inducible factor-2α (HIF-2α) expression. Conclusions HRG is a hepatoprotective factor during hepatic I/R injury by decreasing neutrophil infiltration and NETs formation. The decrease in HRG is a cause of susceptibility to I/R injury in steatotic livers. Therefore, HRG is a new therapeutic target for minimizing liver damage in NASH patients.

Objective The aim of this study was to establish a preoperative prediction method for sparsely granulated (SG) growth hormone (GH) secreting pituitary adenoma, an aggressive tumor subtype with high recurrence risk, in acromegaly patients. Methods Eighty-three patients with GH-secreting pituitary adenomas were included in this study. GH measurements, cytokeratin immunostaining and electron microscopy were performed to detect granulation patterns. Preoperative factors, including general, radiological and endocrinological features and acute octreotide suppression test outcomes, were compared between SG and densely granulated (DG) groups. The predictive capabilities of these features were analyzed using a receiver operating characteristic (ROC) curve, and the most predictive features were combined to establish a grading scale. Results Thirty-nine of the 83 patients had SG GH-secreting pituitary adenomas; 44 had DG tumors. SG tumors tended to occur in younger patients and have larger diameters and volumes, higher Knosp grades, lower GH indexes and normalized insulin-like growth factor-1 (IGF-1) levels, and a lower ∆GH% after octreotide treatment. The tumor size, Knosp grade, GH index and ∆GH% after octreotide treatment had good predictive performance, with area under the curve (AUC) values ranging from 0.70 to 0.80. Combining four parameters, including diameter, Knosp grade, GH index and ∆GH% after octreotide treatment, we established a grading scale for predicting SG GH-secreting pituitary adenomas with an AUC of 0.84 and relatively high sensitivity and specificity. Conclusions We propose a predictive method for distinguishing SG and DG GH-secreting pituitary adenomas preoperatively. This method will help physicians identify candidates for presurgical medical treatment and neurosurgeons determine radical surgical strategies for high-risk tumors.

OBJECTIVES This study aimed to compare the effect of atorvastatin 60 (AT60) mg to that of rosuvastatin 10 (RT10) mg on the morphological changes in lipid-rich plaques (LRPs) and plaque volume, using serial optical coherence tomography (OCT) and intravascular ultrasound imaging (IVUS). BACKGROUND Intensive lipid lowering therapy by statin provides more clinical benefit compared to that of moderate lipid lowering therapy. METHODS Fifty patients who underwent OCT and IVUS at baseline, 6, and 12 months were grouped by statin therapy into the AT60 mg (n = 27) and RT10 mg (n = 23) groups. The relationships between absolute and percentage changes in biomarkers and fibrous cap thickness (FCT) during follow-up were investigated using a simple regression analysis. RESULTS At 6 months, the mean low-density lipoprotein cholesterol level reduced from 113.5 to 65.5 mg/dl (AT60 mg group) and 100.2 to 72.2 mg/dl (RT10 mg groups). A continuous increase in FCT from baseline to 12 months was observed in both groups (p

Dental stem/progenitor cells are a promising cell sources for alveolar bone (AB) regeneration because of their same embryonic origin and superior osteogenic potential. However, their molecular processes during osteogenic differentiation remain unclear. The objective of this study was to identify the responsiveness of dental follicle cells (DFCs) and AB marrow-derived mesenchymal stem cells (ABM-MSCs) to recombinant human bone morphogenetic protein-2 (rhBMP-2). These cells expressed vimentin and MSC markers and did not express cytokeratin and hematopoietic stem cell markers and showed multilineage differentiation potential under specific culture conditions. DFCs exhibited higher proliferation and colony-forming unit-fibroblast efficiency than ABM-MSCs; rhBMP-2 induced DFCs to differentiate toward a cementoblast/osteoblast phenotype and ABM-MSCs to differentiate only toward a osteoblast phenotype; and rhBMP-2-induced DFCs exhibited higher osteogenic differentiation potential than ABM-MSCs. These cells adhered, grew, and produced extracellular matrix on nanohydroxyapatite/collagen/poly(l-lactide) (nHAC/PLA). During a 14-day culture on nHAC/PLA, the extracellular alkaline phosphatase (ALP) activity of DFCs decreased gradually and that of ABM-MSCs increased gradually; rhBMP-2 enhanced their extracellular ALP activity, intracellular osteocalcin (OCN), and osteopontin (OPN) protein expression; and DFCs exhibited higher extracellular ALP activity and intracellular OCN protein expression than ABM-MSCs. When implanted subcutaneously in severe combined immunodeficient mice for 3 months, DFCs+nHAC/PLA+rhBMP-2 obtained higher percentage of bone formation area, OCN, and cementum attachment protein expression and lower OPN expression than ABM-MSCs+nHAC/PLA+rhBMP-2. These results showed that DFCs possessed superior proliferation and osteogenic differentiation potential in vitro, and formed higher quantity and quality bones in vivo. It suggested that DFCs might exhibit a more sensitive responsiveness to rhBMP-2, so that DFCs enter a relatively mature stage of osteogenic differentiation earlier than ABM-MSCs after rhBMP-2 induction. The findings imply that these dental stem/progenitor cells are alternative sources for AB engineering in regenerative medicine, and developing dental tissue may provide better source for stem/progenitor cells.

Objective To evaluate the diagnostic efficacy of gastric juice-based genotypic methods for Helicobacter pylori detection and antibiotic resistance testing. Methods We used electronic databases including Medline, Embase, Web of Science and the Cochrane Central Register of Controlled Trial for literature survey using keywords such as "gastric juice", "Helicobacter pylori" and their synonyms. The quality of the studies was assessed using QUADAS-2. Summary performance measures (sensitivity, specificity, positive predictive values, negative predictive values, diagnostic odds ratio, and area under the summary receiver operating characteristic curve) and HSROC curves were produced. In addition, fagan plots were applied to illustrate the relationship among the prior test probability, PLR/NLR, and posterior test probability. Results Our study cohort comprised eight studies with 1235 participants (617 participants of H. pylori infection and 618 participants of non-H. pylori infection). Pooled sensitivity and specificity with a corresponding 95% confidence interval (CI) of gastric juice-based genotypic methods reflected values of 94% (95%CI, 86% - 98%) and 98% (95%CI, 85% - 100%), respectively. The global sensitivity and specificity of clarithromycin resistance were 92% (95%CI, 85% - 96%) and 90% (95%CI, 80% - 95%), respectively. Conclusion Gastric juice-based genotypic methods can be used for diagnostic prediction of H. pylori infection as well as clarithromycin resistance testing.

RecurIndex, a multigene profiling assay, can predict the risk of local recurrence and distant metastasis in female breast cancer (FBC), but its role in male breast cancer (MBC) remains unclear. In this study, the clinicopathological data of 43 consecutive MBC patients undergoing surgeries between 2009 and 2018 were retrospectively analysed. Their paraffin-embedded tissue sections were examined by RecurIndex test which comprised 2 models: recurrence index for local recurrence (RI-LR) and recurrence index for distant recurrence (RI-DR). Of 43 patients, there were 26 low-risk and 17 high-risk patients assessed by RI-LR, while 17 low-risk and 26 high-risk patients by RI-DR. For RI-LR, tumor N stage showed statistically significant (P P = 0.033), T stage (P = 0.043) and N stage (P = 0.003). In terms of clinical outcomes, the overall survival (OS) of low- and high-risk patients stratified by RI-LR showed no statistically significant differences (P = 0.460), while high-risk patients identified by RI-DR had a significantly worse distant recurrence-free survival (DRFS) (P = 0.035), progression-free survival (PFS) (P = 0.019) and OS (P = 0.044) than low-risk patients. Overall, RI-DR can effectively predict the DRFS, PFS and OS of MBC patients and identify those at low risk of recurrence, which may serve as a potential prognostic tool for MBC.

Bisphenol A (BPA) is a widely used raw material that can be detected both in the environment and in the human body. Due to its estrogen-like effects, wide concerns have been raised about the potential role of BPA in the initiation and development of hormone-dependent cancers. Ovarian cancer is the most common reproductive system cancer and has a high mortality rate in women. Despite recent investigations into BPA's carcinogenic effects, studies on its role in ovarian cancer development remain limited. In this study, we aimed to assess the effect of BPA at various environmentally relevant concentrations on proliferation and metastasis of ovarian cancer cells. We discovered that BPA can stimulate proliferation of OVCAR-3 ovarian cancer cells after exposure for up to 5 days. Strikingly, BPA enhanced ovarian cancer cell migration, invasion, and adhesion (to vascular endothelial cells) through upregulation of matrix metalloproteinase-2 (MMP-2), MMP-9, and intercellular cell adhesion molecule-1 (IMAC-1). The stimulatory effects of BPA on cancer cell proliferation and metastasis were reversed by treatment with an ERα inhibitor, but not by treatment with an ERβ inhibitor. Together, these results suggest that BPA induces proliferation and metastasis of ovarian cancer cells through ERα signaling pathways. This study provides new insights into the carcinogenic effects of BPA with regard to ovarian cancer.

c‐Jun activation domain‐binding protein‐1 (Jab1) is aberrantly overexpressed in multiple cancers and plays an oncogenic role in cancer progression. We examined the association between Jab1 expression and prognosis in patients with cancer by conducting a meta‐analysis. A comprehensive search strategy was performed using the PubMed, Web of Science, Ovid and EMBASE in July 2020. Eligible studies were enrolled according to definite criteria. Twenty‐seven studies involving 2609 patients were enrolled in this meta‐analysis. A significant association between high Jab1 expression and poor overall survival (pooled hazard ratio [HR] 2.344, 95% confidence interval [CI]: 2.037‐2.696) was observed. Subgroup analyses of the type of cancer, sample size, follow‐up period, Jab1 detection method and preoperative treatment did not alter the significance. On pooling data from Cox multivariate analyses, high Jab1 expression was found to be an independent prognostic indicator for overall survival. In addition, high Jab1 expression was found to be associated with advanced clinicopathological features such as clinical stage, lymphatic metastasis, histological grade and distant metastasis in cancers. Our meta‐analysis is the first to demonstrate that high Jab1 expression may be a promising indicator of poor prognosis and has an independent prognostic value for overall survival in patients with cancer.

Background Previous research has revealed that skewed X chromosome inactivation (SXCI) and androgen receptor (AR) CAG polymorphisms are associated with increased risk of recurrent pregnancy loss (RPL); however, the results are conflicting, and the underlying mechanisms remain unclear. This study investigated the role of SXCI and AR CAG polymorphisms in patients with RPL and explored whether the underlying mechanisms were related to the ovarian reserve and preimplantation embryo aneuploidy. Methods This was a prospective case-control study carried out in a tertiary hospital-based reproductive medicine center. An external validation RPL cohort was recruited during the study period. Data on baseline and cycle characteristics were collected. X-chromosome inactivation (XCI) was measured using a human AR assay. AR polymorphisms were assessed using quantitative fluorescent polymerase chain reactions and direct sequencing. Blastocysts of the patients with RPL were tested by single nucleotide polymorphism microarray based preimplantation genetic testing for aneuploidy. Results In total, 131 patients with idiopathic RPL and 126 controls were included for the case-control study. Patients with RPL exhibited a significantly more skewed XCI distribution pattern (67.71 ± 10.50 vs. 64.22 ± 10.62, p = 0.011), as well as significantly shorter bi-allelic mean (18.56 ± 1.97 vs. 19.34 ± 2.38, p = 0.005) and X-weighted bi-allelic mean (18.46 ± 2.02 vs. 19.38 ± 2.53, p = 0.001) of AR CAG repeats. Multivariate logistic regression models indicated that CAG repeat Conclusion SXCI and AR CAG polymorphisms are related to RPL; however, these two factors do not lead to RPL by affecting the ovarian reserve or increasing embryo aneuploidy. The roles of SXCI and AR CAG in RPL may involve other mechanisms that require further investigation. Trial registration: NCT02504281, https://www.clinicaltrials.gov (Date of registration, 21/07/2015; date of enrolment of the first subject, 30/07/2015).