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Gliomas cause high mortality around the world. The metabolic pattern of the tumor was previously suggested to be associated with the patient's survival outcome and immune activity. Yet, this relationship in glioma remains unknown. This study systematically evaluated the immune landscape in different phenotypes classified by metabolic-related pathways of 3068 glioma samples and 33 glioblastoma single-cell sequencing samples. Machine learning prediction analysis of microarray with R (pamr) was used for validating clustering results. A total of 5842 pan-cancer samples were used for external validation of the metabolic clusters. Cell Counting Kit-8 (CCK8) assay, cell clone assay, EdU assay, wound healing assay, Transwell assay, and co-culture assay were performed to verify the distinction in molecular characteristics among metabolic clusters. Metabolomics and RNA sequencing were performed on HS683 and U251 cells to annotate potential hyaluronic acid (HA)-mediated pathways. Three distinct metabolic phenotypes were identified. Metabolic cluster 1 correlated with a high number of immune infiltrating cells and poor survival of glioma patients. Metabolic clusters were proved with different levels of the macrophage markers CD68 and CD163 by multiplex immunofluorescence staining. Glioma cells from other metabolic clusters also expressed various levels of HA. HA was further found to mediate glioma proliferation, progression, and invasion. Moreover, HA potentially promoted macrophage recruitment and M2 polarization through the IL-1/CHI3L1 and TGF-b/CHI3L1 axes. HA also regulated the expression of PD-L1. This work revealed the significant connection between metabolic patterns, especially HA, and tumor immune infiltration in gliomas.

Data are sparse regarding tree nut-induced anaphylaxis (TNA).To characterize rate, clinical characteristics, and management of TNA in children (0-17 years old) across Canada and evaluate factors associated with severe reactions and epinephrine use.Between April 2011 and May 2020, data were collected on children presenting to 5 emergency departments in Canada. Multivariate logistic analysis was used to evaluate factors associated with severe reactions (stridor, cyanosis, circulatory collapse, or hypoxia) and epinephrine use.Among 3096 cases of anaphylaxis, 540 (17%) were induced by tree nut. The median age was 5.2 (interquartile range, 2.5-9.5) years and 65.4% were of male sex. Among all reactions, 7.0% were severe. The major tree nuts accounting for anaphylaxis were cashew (32.8%), hazelnut (20.0%), and walnut (11.5%). Cashew-induced anaphylaxis was more common in British Columbia (14.0% difference [95% confidence interval (CI), 1.6-27.6]) vs Ontario and Quebec, whereas pistachio-induced anaphylaxis was more common in Ontario and Quebec (6.3% difference [95% CI, 0.5-12.2]). Prehospital and emergency department intramuscular epinephrine administration was documented in only 35.2% and 52.4% of cases, respectively. Severe reactions were more likely among of male sex (adjusted odds ratio [aOR], 1.05 [95% CI, 1.01-1.10]), older children (aOR, 1.00 [95% CI, 1.00-1.01]), and in reactions triggered by macadamia (aOR, 1.27 [95% CI, 1.03-1.57]).Different TNA patterns in Canada may be because of differences in lifestyle (higher prevalence of Asian ethnicity in British Columbia vs Arabic ethnicity in Ontario and Quebec). Intramuscular epinephrine underutilization urges for epinephrine autoinjector stocking in schools and restaurants, patient education, and consistent policies across Canada.

Sesame can cause severe allergic reactions and is a priority allergen in Canada.To assess clinical characteristics and management of pediatric sesame-induced anaphylaxis and identify factors associated with epinephrine treatment.Between 2011 and 2021, children with sesame-induced anaphylaxis presenting to 7 emergency departments (ED) in 4 Canadian provinces and 1 regional emergency medical service were enrolled in the Cross-Canada Anaphylaxis Registry. Standardized recruitment forms provided data on symptoms, severity, triggers, and management. Multivariate logistic regression evaluated associations with epinephrine treatment pre-ED and multiple epinephrine dosages.Of all food-induced anaphylactic reactions (n = 3279 children), sesame accounted for 4.0% (n = 130 children), of which 61.5% were boys, and the average (SD) age was 5.0 (4.9) years. Hummus containing sesame paste triggered 58.8% of reactions. In the pre-ED setting, 32.3% received epinephrine, and it was more likely to be used in boys (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.08-1.50) and those with a known food allergy (aOR, 1.36; 95% CI, 1.11-1.68]). In the ED, 47.7% of cases received epinephrine, with older children more likely to receive multiple epinephrine doses (aOR, 1.00; 95% CI, 1.00-1.02).In Canada, hummus is the major trigger of sesame-induced anaphylaxis. Knowledge translation focused on prompt epinephrine use and product-labeling policies are required to limit sesame reactions in communities.

Traditional Chinese medicine (TCM) has long been used to treat diabetes mellitus and angina. It has also gained widespread clinical applications in China as a common adjuvant treatment. Although there is high-quality evidence that TCM is effective in regulating glucose and lipid metabolism, the cardiovascular protective effect of TCM in the treatment of diabetes mellitus has not been fully elucidated, especially in patients with both diabetes mellitus and coronary heart disease (CHD). We systematically assessed the efficacy and safety of TCM for the adjuvant treatment of patients with CHD and diabetes mellitus and examined the pharmacological effects and potential mechanisms of TCM medication/herbs on diabetes mellitus with CHD. We found that TCM could improve the control effect of conventional treatment on cardiac function, hemorheology, blood glucose, blood lipid, and inflammation, thus reducing the frequency of angina and the incidence of cardiovascular events and all-cause mortality. These findings indicate that TCM may be used as a complementary approach for patients with diabetes mellitus and CHD. Nevertheless, more rigorously designed randomized controlled trials and long-term evaluations are needed to support these findings.

Hypoxia and angiogenesis are the leading causes of tumor progression, and their strong correlation has been discovered in many cancers. However, their collective function’s prognostic and biological roles were not reported in gastric cancer. Hence, we aimed to investigate the effects of hypoxia and angiogenesis on gastric cancer via sequencing data. This study used weighted gene coexpression network analysis and random forest regression to build a hypoxia-angiogenesis-related model (HARM) via the TCGA-STAD lncRNA data. It estimated the HARM’s correlation with clinical features and its accuracy for survival prediction. Sequential functional analyses were conducted to investigate its biological role, and we next sought the immune landscape status and immunological function variation by ESTIMATE score calculation and GSVA, respectively. Seven different algorithms were conducted to assess the immunocyte infiltration, and TIDE score and immune checkpoint levels were compared between the high- and low-HARM groups. As a result, we found that HARM predicted patient survival with high accuracy and was correlated with higher stages of gastric cancer. Various cancer-associated pathways and macrophage-related regulations were upregulated in the high-HRAM group. The high-HARM group harbored higher immune levels, and M2 macrophages and cancer-associated fibroblasts were particularly highly unfiltered. Furthermore, globally upregulated immune checkpoints and higher TIDE scores were observed in the high-HARM group. Finally, we filtered eight drugs with lower IC50 in the high-HARM group as potential drugs for the HARM-targeted therapy. We believe this study opens up novel perspectives into the interaction between hypoxia-angiogenesis and immunosuppression and will provide novel insights for gastric cancer immunotherapy.

The aim of the study was to analyze perioperative complications and postoperative mortality in patients of acute Stanford type A aortic dissection(ATAAD)combined with cardiac tamponade (TMP).In this study, we identified a total of 242 ATAAD patients who underwent surgery from January 2016 to December 2020. Of the 242 patients, 44(18.2%) patients were combined with TMP and 198(81.8%) patients without TMP. We compared perioperative complications and postoperative mortality between the two groups.The postoperative mortality was significantly higher in patients with TMP (29.5% vs 14.1%, p = 0.014). The incidence of postoperative acute kidney injury (75.0% vs 51.5%, p = 0.005), acute hepatic injury (45.5% vs 20.7%, p = 0.001), cerebral infarction (27.3% vs 13.1%, p = 0.020), low cardiac output syndrome (50.0% vs 33.3%, p = 0.038) and respiratory failure (36.4% vs 22.2%, p = 0.049) in patients with TMP was significantly higher than those without TMP. Binary logistic regression analysis showed that age [odds ratio(OR) 1.063, 95% confidence interval (CI) 1.023∼1.105; p = 0.002], surgical time[odds ratio(OR)1.393, 95% confidence interval (CI) 1.006∼1.929; p = 0.046], cardiac tamponade[odds ratio(OR)3.010, 95% confidence interval (CI) 1.166∼7.767; p = 0.023], circulatory arrest time[odds ratio(OR)1.044, 95% confidence interval (CI) 1.001∼1.088; p = 0.045] were independent risk factors for postoperative mortality in ATAAD patients.Cardiac tamponade increases the difficulty of perioperative management in ATAAD patients, the incidence of postoperative complications and postoperative mortality, which requires the cooperation of anesthesiologists, intensivists and surgeons to save and improve patients' lives.

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.

The use of COVID-19 vaccines has been prioritised to protect the most vulnerable-notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses.This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud - Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6-10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain [RBD] of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable.The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer-BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units [BAU]/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations.Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability.Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force.For the French translation of the abstract see Supplementary Materials section.

Gliomas are the common type of brain tumors originating from glial cells. Epidemiologically, gliomas occur among all ages, more often seen in adults, which males are more susceptible than females. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), standard of care and prognosis of gliomas can be dramatically different. Generally, circumscribed gliomas are usually benign and recommended to early complete resection, with chemotherapy if necessary. Diffuse gliomas and other high-grade gliomas according to their molecule subtype are slightly intractable, with necessity of chemotherapy. However, for glioblastoma, feasible resection followed by radiotherapy plus temozolomide chemotherapy define the current standard of care. Here, we discuss novel feasible or potential targets for treatment of gliomas, especially IDH-wild type glioblastoma. Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failure due to complex regulatory network. There is ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor associated macrophage, dendritic cell vaccine, CAR-T), tumor microenvironment, and combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options.

Although functional and structural abnormalities in brain regions involved in the neurobiology of fear and anxiety have been observed in patients with social anxiety disorder (SAD), the findings have been heterogeneous due to small sample sizes, demographic confounders, and methodological differences. Besides, multimodal neuroimaging studies on structural-functional deficits and couplings are rather scarce. Herein, we aimed to explore functional network anomalies in brain regions with structural deficits and the effects of structure-function couplings on the SAD diagnosis. High-resolution structural magnetic resonance imaging (MRI) and resting-state functional MRI images were obtained from 49 non-comorbid patients with SAD and 53 demography-matched healthy controls. Whole-brain voxel-based morphometry analysis was conducted to investigate structural alterations, which were subsequently used as seeds for the resting-state functional connectivity analysis. In addition, correlation and mediation analyses were performed to probe the potential roles of structural-functional deficits in SAD diagnosis. SAD patients had significant gray matter volume reductions in the bilateral putamen, right thalamus, and left parahippocampus. Besides, patients with SAD demonstrated widespread resting-state dysconnectivity in cortico-striato-thalamo-cerebellar circuitry. Moreover, dysconnectivity of the putamen with the cerebellum and the right thalamus with the middle temporal gyrus/supplementary motor area partially mediated the effects of putamen/thalamus atrophy on the SAD diagnosis. Our findings provide preliminary evidence for the involvement of structural and functional deficits in cortico-striato-thalamo-cerebellar circuitry in SAD, and may contribute to clarifying the underlying mechanisms of structure-function couplings for SAD. Therefore, they could offer insights into the neurobiological substrates of SAD.

Ovarian cancer is the most lethal gynecological malignancy. Recurrence and chemoresistance are tough challenges leading to poor prognosis. HJURP is a molecular chaperone of CENP-A, which is associated with aggressive progression in multiple tumors. However, the function of HJURP in ovarian cancer has not been elucidated. In our study, we found HJURP was over-expressed in ovarian cancer and high expression of HJURP was correlated to unfavorable prognosis. HJURP knockdown could inhibit proliferation, metastasis and induce G0/G1 stagnation of ovarian cancer cells. Besides, next-generation sequencing (NGS) unveiled that WEE1 was down-regulated by silencing HJURP. Further mechanistic research revealed that HJURP regulated WEE1 through MYC, and luciferase assay indicated that MYC was a transcription factor of WEE1. Additionally, we investigated that silencing HJURP increased sensitivity of ovarian cancer cells to cisplatin via MYC/WEE1 axis, and HJURP participated in DNA repair of cisplatin-induced damage. More interestingly, silencing HJURP could enhance sensitivity of ovarian cancer cells to AZD1775 and improve the synergistic effect of cisplatin plus AZD1775 combined therapy. Collectively, our data displays that HJURP promotes tumor progression and chemoresistance of ovarian cancer, and HJURP has potential to be a novel therapeutic target in the combined treatment with cisplatin and AZD1775 in ovarian cancer.

Sex differences in kidney graft loss rates were reported in the United States. Whether these differences are present in other countries is unknown.We estimated the association between recipient sex and death-censored graft loss in patients of all ages recorded in the Scientific Registry of Transplant Recipients, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study registries who received a first deceased donor kidney transplant (1988-2019). We used multivariable Cox regression models, accounting for the modifying effects of donor sex and recipient age, in each registry separately; results were combined using individual patient data meta-analysis.We analyzed 438 585 patients. Young female patients 13-24 y old had the highest crude graft loss rates (female donor: 5.66; male donor: 5.50 per 100 person-years). Among young recipients of male donors, females showed higher graft loss risks than males (0-12 y: adjusted hazard ratio [aHR] 1.42, (95% confidence interval [CI], 1.17-1.73); 13-24 y: 1.24 (1.17-1.32); 25-44 y: 1.09 (1.06-1.13)). When the donor was female, there were no significant differences by recipient sex among those of age45 y; however, the aHR for females was 0.93 (0.89-0.98) in 45-59 y-old and 0.89 (0.86-0.93) in ≥ 60 y-old recipients. Findings were similar for all 3 registries in most age intervals; statistically significant heterogeneity was seen only among 13-24-y-old recipients of a female donor (I2 = 71.5%, P = 0.03).There is an association between recipient sex and kidney transplantation survival that is modified by recipient age and donor sex.

[Objective] This study evaluates the epidemiological characteristics, ophthalmological manifestations, and different therapeutic options available for patients with multiple sclerosis (MS) in China, Spain, and Cuba., [Methods] A self-designed questionnaire was used to conduct a comparable descriptive cross-sectional study on patients with MS. The survey included patients' demographic data, ocular manifestations related to MS, and treatment methodology followed in the three countries. The online survey was designed using the Wenjuanxing survey platform, and a survey link was circulated through WhatsApp, WeChat, and emails. Quantitative data were expressed as mean and standard deviation, the Kruskal-Wallis test was used for non-parametric variables. Qualitative data were expressed as numerical and percentage. The chi-square test (χ2) was used to compare the group's response categories. The statistical difference was considered significant when p < 0.05., [Results] The female-to-male ratio in all the three countries was 2-3:1, and relapsing-remitting MS (RRMS) was the most frequent in all three countries. Vision loss was slow and progressive in half of the patients from the three countries, with no significant differences (p = 0.524). A higher percentage of steroid treatment was observed in Chinese patients in comparison with the patients from other two countries (p < 0.001), and a similar trend was seen in the use of traditional medicines. Almost one-third of patients who did not receive any treatment recovered spontaneously in all the three countries (p = 0.097)., [Conclusions] MS occurs more frequently in the relapsing-remitting clinical form and there is a clear female predominance. The first ocular crisis or clinical debut of MS is characterized by slow and progressive visual impairment, increasing and adding to other ocular manifestations during its evolutionary course. Spontaneous recovery of vision after an attack of optic neuritis in the course of MS is possible.

Background Circular RNAs (CircRNAs) have been found to possess vital functions in tumorigenesis of various cancer types, including non-small cell lung cancer (NSCLC). The aim of this study was to identify and explore the diagnostic values of the newly found Toll interacting protein (TOLLIP)-derived circRNA (circTOLLIP) for liquid biopsy in NSCLC. Methods RNase R and actinomycin D assays were conducted to confirm the existence and stability of circTOLLIP. RT-qPCR was performed to identify the expression levels of circTOLLIP in NSCLC tumor tissues, whole blood, and cell lines. The diagnostic values were evaluated by receiver operating characteristic (ROC) curve analysis. Results CircTOLLIP was screened as a candidate biomarker and was found to be significantly down-regulated in both NSCLC tissues and cell lines. Interestingly, circulating circTOLLIP was also lower-expressed in the whole blood of patients with NSCLC compared to that of patients with benign lung disease and healthy controls. Importantly, the circulating circTOLLIP represented better diagnostic values in comparison to the traditional tumor markers (NSE, CYFR21-1, and CA72-4), and showed higher stability even though the whole blood was exposed to various tough conditions. Conclusions Our findings indicate that circTOLLIP can be used as a non-invasive biomarker to distinguish early-stage NSCLC from benign lung diseases and from healthy controls, suggesting the potential application of circTOLLIP for liquid biopsy in NSCLC.

Background To compare the clinical outcomes of C3 laminectomy and C3 laminoplasty at the C3 segment during French-door laminoplasty. Methods The Cochrane Library, PubMed, Embase, and Web of Science databases were searched from inception to November 10, 2020 for studies comparing the clinical outcomes of two types of French-door laminoplasty in the treatment of multilevel cervical spondylotic myelopathy (MCSM). Review Manager 5.3 was used to analyze the following outcomes: operative time, intraoperative blood loss, preoperative and postoperative Japanese Orthopaedic Association (JOA) scores, recovery rate, cervical curvature, cervical range of motion (ROM), incidence of axial symptoms (AS), and C2-3 bony fusion rate. Results A total of eight studies involving 776 patients were included; there were 424 patients in the C3 laminectomy group and 352 patients in the C3 laminoplasty group. The results of the meta-analysis showed that the C3 laminectomy group was superior to the C3 laminoplasty group in terms of operative time (P < 0.00001), cervical ROM (P = 0.04), and incidence of AS (P < 0.0001). However, no statistically significant differences between the two groups were noted regarding intraoperative bleeding (P = 0.44), preoperative JOA score (P = 0.57), postoperative JOA score (P = 0.09), recovery rate (P = 0.25), cervical curvature (P = 0.22), and C2-3 bony fusion rate (P = 0.06). Conclusion This meta-analysis demonstrated that both C3 laminoplasty and C3 laminectomy could effectively improve neurological function in patients with MCSM in French-door laminoplasty. However, C3 laminectomy can reduce the operative time, preserve cervical ROM, and reduce the incidence of postoperative AS. Trial registration PROSPERO registration number is CRD42021230798. Date of registration: February 11, 2021.

Background Current methods for cervical cancer screening result in an increased number of referrals and unnecessary diagnostic procedures. This study aimed to develop and evaluate a more accurate model for cervical cancer screening. Methods Multiple predictors including age, cytology, high-risk human papillomavirus (hrHPV) DNA/mRNA, E6 oncoprotein, HPV genotyping, and p16/Ki-67 were used for model construction in a cross-sectional population including women with normal cervix (N = 1085), cervical intraepithelial neoplasia (CIN, N = 279), and cervical cancer (N = 551) to predict CIN2+ or CIN3+. A base model using age, cytology, and hrHPV was calculated, and extended versions with additional biomarkers were considered. External validations in two screening cohorts with 3-year follow-up were further conducted (NCohort-I = 3179, NCohort-II = 3082). Results The base model increased the area under the curve (AUC, 0.91, 95% confidence interval [CI] = 0.88–0.93) and reduced colposcopy referral rates (42.76%, 95% CI = 38.67–46.92) compared to hrHPV and cytology co-testing in the cross-sectional population (AUC 0.80, 95% CI = 0.79–0.82, referrals rates 61.62, 95% CI = 59.4–63.8) to predict CIN2+. The AUC further improved when HPV genotyping and/or E6 oncoprotein were included in the base model. External validation in two screening cohorts further demonstrated that our models had better clinical performances than routine screening methods, yielded AUCs of 0.92 (95% CI = 0.91–0.93) and 0.94 (95% CI = 0.91–0.97) to predict CIN2+ and referrals rates of 17.55% (95% CI = 16.24–18.92) and 7.40% (95% CI = 6.50–8.38) in screening cohort I and II, respectively. Similar results were observed for CIN3+ prediction. Conclusions Compared to routine screening methods, our model using current cervical screening indicators can improve the clinical performance and reduce referral rates.

This study aimed to evaluate the levels and phenomenology of equivalent black carbon (eBC) at the city center of Augsburg, Germany (01/2018 to 12/2020). Furthermore, the potential health risk of eBC based on equivalent numbers of passively smoked cigarettes (PSC) was also evaluated, with special emphasis on the impact caused by the COVID19 lockdown restriction measures. As it could be expected, peak concentrations of eBC were commonly recorded in morning (06:00-8:00 LT) and night (19:00-22:00 LT) in all seasons, coinciding with traffic rush hours and atmospheric stagnation. The variability of eBC was highly influenced by diurnal variations in traffic and meteorology (air temperature (T), mixing-layer height (MLH), wind speed (WS)) across days and seasons. Furthermore, a marked "weekend effect" was evidenced, with an average eBC decrease of ∼35% due to lower traffic flow. During the COVID19 lockdown period, an average ∼60% reduction of the traffic flow resulted in ∼30% eBC decrease, as the health risks of eBC exposure was markedly reduced during this period. The implementation of a multilinear regression analysis allowed to explain for 53% of the variability in measured eBC, indicating that the several factors (e.g., traffic and meteorology) may contribute simultaneously to this proportion. Overall, this study will provide valuable input to the policy makers to mitigate eBC pollutant and its adverse effect on environment and human health., The work is funded by National Natural Science Foundation of China (42101470), Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five–year Plan (CIT&TCD201904037), the RI-URBANS project (Research Infrastructures Services Reinforcing Air Quality Monitoring Capacities in European Urban & Industrial Areas, European Union's Horizon 2020 research and innovation program, Green Deal, European Commission, contract 101036245), the dtec.bw -Digitalization and Technology Research Center of the Bundeswehr (project MORE), and Peiyang Future Scholar Scholarship (6120000246). We would like to thank to the Administration of Augsburg City for giving access to the traffic data (Tiefbauamt, Markus Furnier). We also would like to thank Prof. Dr. Stefan Emeis from Institute of Meteorology and Climate Research - Atmospheric Environmental Research (IMK-IFU) of Karlsruhe Institute of Technology for providing a ceilometer.

BackgroundImmune checkpoint inhibitors (ICIs) are dramatically changing the treatment landscape of a variety of cancers. Nevertheless, the variability in ICI responses highlight the importance in identifying predictive biomarkers. PTPRD and PTPRT (PTPRD/PTPRT) are the phosphatases of JAK-STAT signaling, a critical pathway in anti-cancer immunity regulation. However, the pan-cancer association between PTPRD/PTPRT mutation and the efficacy of ICIs remains unclear across pan-cancer patients.MethodsWe analyzed the association between PTPRD/PTPRT mutations and patient outcomes using clinical data and genomic mutations from TCGA pan-cancer cohort. Furthermore, the ICI-treatment cohort was used to evaluate the relationship between PTPRD/PTPRT mutation and the efficacy of ICIs. Another ICIs-treatment cohort was used to validate the findings. The TCGA pan-cancer dataset was analyzed to explore the correlation between PTPRD/PTPRT mutations and immune signatures. Moreover, we combined four factors to construct a nomogram model that could be used to predict the survival of pan-cancer patients receiving ICI treatment. The calibration curves and area under the curve were applied to assess the performance of the model.ResultsPTPRD/PTPRT mutations were shown to be associated with a worse prognosis in TCGA cohort (P < 0.05). In the Samstein cohort, prolonged overall survival (OS) was observed in PTPRD/PTPRT mutant cancers, compared with wild-type cancers (mOS: 40.00 vs 16.00 months, HR = 0.570, 95%CI: 0.479-0.679, P < 0.0001). In the validation cohort, significant OS advantage was observed in PTPRD/PTPRT mutant patients (mOS: 31.32 vs 15.53 months, HR = 0.658, 95%CI: 0.464-0.934, P = 0.0292). Furthermore, PTPRD/PTPRT mutations were associated with a higher tumor mutational burden, MSI score, and TCR score (P < 0.0001). Enhanced immune signatures were found in the PTPRD/PTPRT mutant cancers (P < 0.05). Finally, we successfully established a nomogram model that could be used to predict the survival of NSCLC patients who received ICI treatment. Based on the risk score of the model, patients in the low-risk group showed a better mOS than those in the high-risk group (mOS: 2.75 vs 1.08 years, HR = 0.567, 95%CI: 0.492-0.654; P < 0.001).ConclusionsPTPRD/PTPRT mutations may be a potential biomarker for predicting ICI treatment responsiveness in multiple cancer types.

Background The effect of socioeconomic status (SES) on hepatocellular carcinoma (HCC) is still unclear, and there is no nomogram integrated SES and clinicopathological factors to predict the prognosis of HCC. This research aims to confirm the effects of SES on predicting patients’ survival and to establish a nomogram to predict the prognosis of HCC. Methods The data of HCC patients were collected from the Surveillance, Epidemiology, and Final Results (SEER) database from 2011 to 2015. SES (age at diagnosis, race and sex, median family income, education level, insurance status, marital status, residence, cost of living index, poverty rate) and clinicopathological factors were included in univariate and multivariate Cox regression analysis. Nomograms for predicting 1‐, 3‐, and 5‐year cancer‐specific survival (CSS) and overall survival (OS) were established and evaluated by the concordance index (C‐index), the receiver operating characteristic curve (ROC), the calibration plot, the integrated discrimination improvement (IDI), and the net reclassification improvement (NRI). Results A total of 33,670 diagnosed HCC patients were involved, and nomograms consisting of 19 variables were established. The C‐indexes of the nomograms are higher than TNM staging system, which predicts the CSS (0.789 vs. 0.692, p, The impacts of socioeconomic status (SES), including: age at diagnosis, race and sex, median family income, education level, insurance status, marital status, residence, cost of living index, poverty rate on hepatocellular carcinoma (HCC) are still unclear. This research collected the data of 33,670 diagnosed HCC patients from the Surveillance, Epidemiology, and Final Results (SEER) database, and nomograms for 1‐, 3‐, and 5‐year survival rates based on the SES and clinical factors were constructed.

As two common mental disorders during the period of adolescence that extend to early adulthood, attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) have considerable diagnostic co-occurrence and shared neuropsychological impairments. Our study aimed to identify overlapping and distinct brain structural abnormalities associated with ADHD and SUDs among adolescents and young adults. A systematic literature search on voxel-based morphometry (VBM) studies of ADHD and SUDs was conducted in PubMed and Web of Science. Data were extracted and analyzed to identify brain abnormalities using Seed-based d-Mapping software. Data-driven functional decoding was conducted to identify the psychophysiological functioning associated with brain alterations. 13 and 14 VBM studies for ADHD (619 patients and 483 controls) and SUDs (516 patients and 413 controls), respectively, were included. Patterns of decreased gray matter volume (GMV) were found in the left precentral gyrus, bilateral superior frontal gyri, and left inferior frontal gyrus in the ADHD group compared to the control group. In contrast, individuals with SUDs, relative to controls, were characterized by increased GMV in the left putamen and insula. Comparative analysis indicated larger regional GMV in the right inferior parietal lobule and smaller volumes in the left putamen and left precentral gyrus in the ADHD group than in the SUDs group. Dissociable brain structural abnormalities in adolescents and young adults with ADHD and SUDs potentially implicate different pathogeneses and provide a reference for differential diagnosis and early detection for shared symptomology and comorbidity.

BackgroundJMJD8 has recently been identified as a cancer-related gene, but current studies provide limited information. We aimed to clarify its roles and the potential mechanisms in pan-cancer.MethodsPan-cancer bulk sequencing data and online web tools were applied to analyze JMJD8’s correlations with prognosis, genome instability, cancer stemness, DNA repair, and immune infiltration. Moreover, single-cell datasets, SpatialDB database, and multiple fluorescence staining were used to validate the association between JMJD8 expression and M2 macrophages. Further, we utilized ROCplotter and cMap web tool to analyze the therapeutic responses and screened JMJD8-targeted compounds, respectively, and we used AlphaFold2 and Discovery Studio to conduct JMJD8 homology modeling and molecular docking.ResultsWe first noticed that JMJD8 was an oncogene in many cancer types. High JMJD8 was associated with lower genome stability. We then found that high JMJD8 correlated with high expression of mismatch repair genes, stemness, homologous repair gene signature in more than 9 cancers. ESTIMATE and cytokine analyses results presented JMJD8’s association with immunosuppression. Also, immune checkpoint CD276 was positively relevant to JMJD8. Subsequently, we validated JMJD8 as the M2 macrophage marker and showed its connection with other immunosuppressive cells and CD8+ T-cell depression. Finally, potential JMJD8-targeted drugs were screened out and docked to JMJD8 protein.ConclusionWe found that JMJD8 was a novel oncogene, and it correlated with immunosuppression and DNA repair. JMJD8 was highly associated with immune checkpoint CD276 and was an M2 macrophage biomarker in many cancers. This study will reveal JMJD8’s roles in pan-cancer and its potential as a novel therapeutic target.

BackgroundChina ranks 53rd out of 81 countries in the Quality of Death Index for 2021. Although hospice care demand is increasing, the progress remains slow. It is of great significance to explore the acceptances and associated influencing factors of hospice care.MethodsA cross-sectional survey by quota sampling was conducted in China from July 10th to September 15th, 2021. We collected demographic data and hospice care acceptance. A stepwise linear regression analysis was used.ResultsThis survey contained 11,031 valid questionnaire results to investigate the hospice care acceptance. It was found that individuals with undergraduate or above (β = 0.04), more properties [2 (β = 0.02), 3 (β = 0.01)], and higher reimbursement types of medical insurance [employee health insurance and commercial health (β = 0.03), government insurance (β = 0.04)] had higher hospice acceptance willingness, while males (β = −0.02) were less willing to accept than females. Psychological conditions [mild anxiety (β = 0.03), moderate anxiety (β = 0.01), moderate stress (β = 0.05), and severe stress (β = 0.06)] also played an important role. The Self-Management Scale (SHMS) (β = 0.12), EuroQol Five Dimensions Questionnaire (EQ-5D) (β = 0.05), EuroQol Visual Analog Scale (EQ-VAS) (β = 0.21), Short-Form Family Health Scale (FHS-SF) (β = 0.12), higher scores of the Short-Form Health Literacy Instrument (HLS-SF12) (β = 0.16), and Perceived Social Support Scale (PSSS) (β = 0.10) also contributed. Gender subgroup showed that in the male group, age, highest educational level, marital status, number of properties, whether having children, psychological conditions, the SHMS, EQ-5D, EQ-VAS, HLS-SF12, and PSSS showed significant difference. Urban and rural subgroups showed that age, highest educational level, number of properties, whether having chronic disease or psychological conditions, the SHMS, EQ-VAS, HLS-SF12, and PSSS were contributing factors in rural areas.ConclusionThe average score of acceptance of hospice care was 65.02 points. Gender, house, anxiety, pressure, social support, and health literacy were the main influencing factors on residents' attitudes.

Background To investigate the stress changes between different bone cement forms and injection volumes in adjacent vertebrae after percutaneous kyphoplasty (PKP) by establishing a three-dimensional finite element model of osteoporosis. Methods A male healthy volunteer was selected. CT of scans L1 to L3 vertebrae were imported into Mimics 21.0 software.The vertebral model of osteoporosiswas established based on previous literature reference. The models were divided into three groups: unilateral, bilateral integration and bilateral separation groups, with each group injecting 2 ml, 4,ml and 6 ml of bone cement, respectively. In all models, a vertical compressive load of 500 N, anterior flexion/posterior extension, left/right bending, and left/right rotation were applied with a moment of 7.5 N/m, of which 85% was applied to the anterior mid-column and 15% to the posterior column. The stress changes between adjacent vertebrae under different conditions were calculated. Results After percutaneous kyphoplasty was applied to the L2 vertebral body, some differences can be found between the effects of different cement injection volumes and cement morphology on adjacent structures. There was no major difference between the groups when the bone cement injection volume was 2 ml. When the amount of bone cement injected was 4 ml, the bone cement morphology of the bilateral integration group (BIG) produced less stress between adjacent vertebral bodies. The minimum stress was 14.95 MPa in the L3 vertebral body in posterior extension. Whereas the stress levels on adjacent intervertebral structures, BIG shaped bone cement shows some superiority. In addition, the adjacent vertebrae and intervertebral structures are subjected to less stress during left and right rotation. Conclusions The present finite element study suggested that bilateral integration bone cement is a suitable form of cement injection, and when the injection volume is 4 ml, reduces stress on adjacent segments by approximately 15% while maintaining the stability of the injected vertebral body.

Aging has a significant role in the proliferation and development of cancers. This study explored the expression profiles, prognostic value, and potential roles of aging-related genes in gliomas. We designed risk score and cluster models based on aging-related genes and glioma cases using LASSO Cox regression analysis, consensus clustering analysis and univariate cox regression analyses. High risk score was related to malignant clinical features and poor prognosis based on 10 datasets, 2953 cases altogether. Genetic alterations analysis revealed that high risk scores were associated with genomic aberrations of aging-related oncogenes. GSVA analysis exhibited the potential function of the aging-related genes. More immune cell infiltration was found in high-risk group cases, and glioma patients in high-risk group may be more responsive to immunotherapy. Knock-down of CTSC, an aging-related gene, can inhibit cell cycle progression, colony formation, cell proliferation and increase cell senescence in glioma cell lines in vitro. Indeed, high expression of CTSC was associated with poor prognosis in glioma cases. In conclusion, this study revealed that aging-related genes have prognostic potential for glioma patients and further identified potential mechanisms for aging-related genes in tumorigenesis and progression in gliomas.

Retinal degeneration, characterised by the progressive death of retinal neurons, is the most common cause of visual impairment. Oxysterols are the cholesterol derivatives produced via enzymatic and/or free radical oxidation that regulate cholesterol homeostasis in the retina. Preclinical and clinical studies have suggested a connection between oxysterols and retinal degeneration. Here, we summarise early and recent work related to retina oxysterol-producing enzymes and the distribution of oxysterols in the retina. We examine the impact of loss of oxysterol-producing enzymes on retinal pathology and explore the molecular mechanisms associated with the toxic or protective roles of individual oxysterols in different types of retinal degeneration. We conclude that increased efforts to better understand the oxysterol-associated pathophysiology will help in the development of effective retinal degeneration therapies. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Tamoxifen resistance remains the major obstacle to the estrogen receptor positive breast cancer endocrine therapy. Placenta-specific 8 (PLAC8) has been implicated in epithelial-mesenchymal transition and tumorigenesis. However, the molecular mechanisms underlying PLAC8 function in the context of tamoxifen resistance are unclear. Curcumin has attracted considerable attention in the last decades. It is isolated from Curcuma longa and has beneficial effects in cancer therapy. We studied this property by using MCF-7 and tamoxifen-resistant breast cancer cells (MCF-7/TAM) cell lines. PLAC8 can regulate MCF-7/TAM cell drug sensitivity through the MAPK/ERK pathway and shows the potential effects of curcumin or as a possible druggable target against tamoxifen failure. Supplementary Information The online version contains supplementary material available at 10.1007/s00109-021-02047-5.

To overcome the shortcoming of conventional transarterial chemoembolization (cTACE) like high systemic release, a novel droplet-based flow-focusing microfluidic device was fabricated and the biocompatible poly(lactic-co-glycolic acid) (PLGA) magnetic drug-eluting beads transarterial chemoembolization (TACE) microspheres with tunable size and shell thickness were prepared via this device. Paclitaxel, as a model active, was loaded through O/O/W emulsion method with high efficiency. The size and the shell thickness vary when adjusting the flow velocity and/or solution concentration, which caters for different clinical requirements to have different drug loading and release behavior. Under the designed experimental conditions, the average diameter of the microspheres is 60 ± 2 μm and the drug loading efficiency has reached 6%. The drug release behavior of the microspheres shows the combination of delayed release and smoothly sustained release profiles and the release kinetics differ within different shell thickness. The microspheres also own the potential of magnetic resonance imaging (MRI) visuality because of the loaded magnetic nanoparticles. The microsphere preparation method and device we proposed are simple, feasible, and effective, which have a good application prospect.

Resumen: El confinamiento debido a la pandemia de la COVID-19, realizado a nivel mundial, ha tenido consecuencias casi siempre negativas en los pacientes con esclerosis múltiple (EM). Objetivo: Hemos comparado el efecto sociolaboral que el confinamiento ha podido tener en pacientes con EM de dos poblaciones tan diferentes como son España y China. Método: Se elaboraron unos cuestionarios a lo que respondieron un grupo de pacientes de EM que son revisados en la unidad de EM del hospital Vithas (Fundación DINAC) en Sevilla, y pacientes con EM atendidos en varias provincias de China durante el mes de abril de 2020, con el objetivo de analizar las diferencias y similitudes del efecto sociolaboral entre ambas poblaciones. Para llevar a cabo este análisis se creó una base de datos que se analizó posteriormente. Resultados: La población china tiene una mayor proporción de pacientes más jóvenes y no hay diferencia respecto al género. La mayoría de las variables estudiadas se comportaron de igual forma en los pacientes con EM tanto españoles como chinos. Los pacientes españoles presentaron menos impacto (30,7%) en su situación socioeconómica que los chinos (44%), p

Triple-negative breast cancer is still a difficult point in clinical treatment at present, and a deep study of its pathogenesis has great clinical value. Therefore, our research mainly focuses on exploring the progression of triple-negative breast cancer and determines the important role of the HJURP/YAP1/NDRG1 transcriptional regulation axis in triple-negative breast cancer. We observed significantly increased HJURP expression levels in triple-negative breast cancer compared to other subtypes. HJURP could affect the level of ubiquitination modification of YAP1 protein and then regulate its downstream transcriptional activity. Mechanistically, we found that YAP1 positively regulates NDRG1 transcription by binding the promoter region of the NDRG1 gene. And HJURP/YAP1/NDRG1 axis could affect cell proliferation and chemotherapy sensitivity in triple-negative breast cancer. Taken together, these findings provide insights into the transcriptional regulation axis of HJURP/YAP1/NDRG1 in triple-negative breast cancer progression and therapeutic response.

This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up.This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18-45 years, with intact cervix and 1-4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18-26 and 27-45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006.Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2-100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9-99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination.The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention.National Natural Science Foundation of China, National Key RD Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease. Current treatment strategies are limited by their efficacy and/or side effect profile and the need for safer and effective alternatives is undeniable. We aimed to conduct a systematic review focusing on the efficacy and safety of omalizumab in BP patients. Embase, PubMed, Cochrane, and clinicaltrials.gov were searched for English and French articles published from inception to July 1, 2021, using search terms “omalizumab” OR “Xolair” OR “IGE025” OR “olizumab” AND “bullous pemphigoid.” Screening and data extraction was performed by two raters independently. The primary outcome was complete response (CR), and secondary outcomes were partial response (PR), flare-ups, adverse events/vital status. In total, 22 articles were included, with a total of 56 patients. All patients had a refractory BP with mean disease duration of 13.5 ± 20.2 months (Standard Deviation (SD)) and failed 3.1 ± 1.6 therapies and many remained corticosteroids dependent. Overall, 87.5% of patients responded to treatment (55.4% CR and 32.1% PR), 7.1% discontinued the protocol and only 5.4% were non responders. A third of patients were able to discontinue all other therapies and most others were able to discontinue or taper systemic corticosteroids to

Cancer-associated fibroblast (CAF) secretes extracellular vesicle (EV)-encapsulated microRNAs (miRNAs) which have been underlined great promise for therapeutic target for diseases and cancers. Our study aimed to explore the role of EV-encapsulated miR-10a-5p from CAFs in angiogenesis in cervical cancer. Expression of miR-10a-5p in clinical samples of cervical cancer and cancer cells was detected by in situ hybridization and RT-qPCR. Results demonstrated that miR-10a-5p expression was upregulated in both cancer tissues and cells. CAFs and normal fibroblasts (NFs) from cervical cancer patient tissues were characterized under transmission electron microscopy, followed by EV isolation from CAFs. The EVs labeled with PKH67 were cultured with cervical squamous cell carcinoma (CSCC) cell line (SiHa) and HUVECs. Data indicated that CAF-EVs were internalized by cancer cells and promoted cell proliferation and tube formation. CAF-EVs then were transfected with miR-10a-5p inhibitor and then injected into nude mice. While injection of CAF-EVs promoted tumor growth and increased VEGFR and CD31 expression level, miR-10a-5p inhibitor-treated CAF-EVs resulted in decreased tumor volume and amount of vessel around tumor. Of note, dual-luciferase reporter gene assay and bioinformatic analysis indicated TBX5 as a target gene of miR-10a-5p. Moreover, EV-derived miR-10a-5p promoted angiogenesis in vivo and in vitro through activation of Hedgehog signaling via downregulation of TBX5. Taken altogether, miR-10a-5p in CAF-EVs promoted CSCC cell angiogenesis and tumorigenicity via activation of Hh signaling by inhibition of TBX5, providing insight into novel treatment based on miR-10a-5p against CSCC.

N2 non-small cell lung cancer (NSCLC) without N1 involvement, also known as skip metastases (pN0N2), has been suggested as a subgroup of heterogeneous N2 disease with better survival. This real-world observational study aimed to elucidate the prognostic impacts of skip N2 metastases using a large number of pathologic N2 NSCLC from 10 participating centers in China.Medical records of pN2 NSCLC patients after surgical resection at 10 thoracic surgery centers between January 2014 and September 2017 were retrospectively reviewed based on the LinkDoc database. Clinical data on patient demographics, tumor characteristics, treatments and clinical outcomes were collected. Overall survival of patients with and without skip metastases was evaluated and compared by Kaplan-Meier method and Log-rank test. Cox proportional hazard model was established to identify potential prognostic predictors. Subgroup analysis was carried out to further explore the prognostic significance of skip metastases.Among 2653 surgically resected N2 patients, 881 (33.2%) had skip metastases. Patients with skip N2 had a significant better overall survival (P = 0.0019). Multivariate COX regression analysis showed borderline significance of skip metastases (HR = 0.81, 95%CI: 0.645-1.017, P = 0.0698) after adjustment for other covariates. Other independent prognostic predictors included smoking history, tumor location, stage and N2 station involved (P 0.05). Subgroup analysis demonstrated significant survival benefits of skip N2 in most subpopulations.This study suggested a prognostic benefit of skip N2 metastases in real world practice. Further subdivision of N2 disease is warranted for better patient management and prognostic prediction (NCT03429192).

Thermal ablation is a point-of-care ablative treatment technique for cervical intraepithelial neoplasia (CIN). However, limited information is available about its efficacy in low- and middle-income countries. We evaluated the efficacy of thermal ablation in treatment of CIN detected through high-risk human papillomavirus (HPV) screening in China. Women positive on high-risk HPV and having colposcopically suspected lesions eligible for ablation underwent colposcopy, biopsy and thermal ablation in one visit. Women ineligible were recalled for large loop excision of transformation zone (LLETZ) when histopathology results were high-grade CIN. Posttreatment follow-up at 6 months or more was with HPV test and cytology followed by colposcopy and biopsy for HPV and/or cytology-positive women. Cure was defined as either negative cytology and HPV test or absence of histopathology proved CIN in any positive women. Of total 218 HPV-positive women treated with thermal ablation (n = 170) or LLETZ (n = 48), 196 reported for follow-up evaluation. For women with histologically confirmed CIN at baseline (thermal ablation-104; LLETZ-38), cure rates were 84.6% for thermal ablation and 86.8% for LLETZ. Cure rates after thermal ablation were 90.3% for CIN grade one (CIN1) and 76.2% for CIN grade two or worse (CIN2+). HPV clearance rate was 80.4% in women undergoing thermal ablation, which was lower for HPV16/18 compared to other oncogenic types (67.6% vs 85.7%). HPV test had a negative predictive value (NPV) of 98.7% to detect CIN2+ at follow-up and the positive predictive value (PPV) was 40.4%. Thermal ablation is effective to treat CIN as well as to clear the high-risk HPV infection. HPV test has high PPV and NPV in following up patients posttreatment.

SARS-CoV-2 has caused a worldwide pandemic that began with an outbreak of pneumonia cases in the Hubei province of China. Knowledge of those most at risk is integral for treatment, guideline implementation, and resource allocation. We conducted a systematic review and meta-analysis to evaluate comorbidities associated with severe and fatal cases of COVID-19. A search was conducted on PubMed and EmBase on 20 April 2020. Pooled estimates were collected using a random-effects model. Thirty-three studies were included in the systematic review and twenty-two in the meta-analysis. Of the total cases 40.80% (95%CI: 35.49%, 46.11%) had comorbidities, while fatal cases had 74.37% (95%CI: 55.78%, 86.97%). Hypertension was more prevalent in severe [47.65% (95%CI: 35.04%, 60.26%)] and fatal [47.90% (95%CI: 40.33%, 55.48%)] cases compared to total cases [14.34% (95%CI: 6.60%, 28.42%)]. Diabetes was more prevalent among fatal cases [24.89% (95%CI: 18.80%, 32.16%)] compared to total cases [9.65% (95%CI: 6.83%, 13.48%)]. Respiratory diseases had a higher prevalence in fatal cases [10.89% (95%CI: 7.57%, 15.43%)] in comparison to total cases [3.65% (95%CI: 2.16%, 6.1%)]. Studies assessing the mechanisms accounting for the associations between severe cases and hypertension, diabetes, and respiratory diseases are crucial in understanding this new disease, managing patients at risk, and developing policies and guidelines that will reduce future risk of severe COVID-19 disease.

Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin β4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-κB pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.

Bisphenol A (BPA) is a widely spreading environmental endocrine disruptor . Its characteristics, including small doses and frequent contact, make it easy to enter human body through drinking water, food, air and other pathways, leading to tumors, infertility, and liver damage. The present review summarizes the underlying mechanism of oxidative stress and its related effects induced by BPA in the liver. The progress of the mechanism for oxidative stress induced by BPA is summarized, including mitochondrial dysfunction, lipid peroxidation and inflammation reaction, liver dyslipidemia, apoptosis, and cell death mechanism. In the future, it is necessary to elucidate the molecular mechanisms and timing of oxidative stress to clarify the effects on different exposures to different genders and growth stages. Besides, studying the toxic effects on BPA surrogates, BPA metabolites and BPA combined with other pollutants in the environment is beneficial to clarify the environmental and human health effects of BPA and provide technical reference for the development of practical control measures.

The Roche Cobas (Cobas) and BD Onclarity (Onclarity) human papillomavirus (HPV) assays are convenient, PCR-based, HPV DNA tests; currently, data on performance of Onclarity in Chinese women is limited. We aimed to evaluate the clinical performance of Onclarity for detecting cervical lesions in Chinese women.In total, 1122 women were enrolled into this study. Exfoliated cervical cells were collected in PreservCyt medium and were tested using Cobas and Onclarity. Cytology and histology were interpreted by senior cytologists and a panel of pathologists, respectively, at Cancer Hospital, Chinese Academy of Medical Sciences.The assays showed excellent concordance for HPV16 (kappa = 0.91, 95% CI: 0.85-0.97) and for 12 other high-risk types (HPV31/33/35/39/45/51/52/56/58/59/66/68, kappa = 0.84, 95% CI: 0.78-0.90), and very good concordance for HPV18 (kappa = 0.75, 95% CI: 0.69-0.81). No difference for ≥CIN2 sensitivity was observed between Onclarity and Cobas (both 90.5%); and theCIN2 specificity for detection was similar between Onclarity (84.2%, 95% CI: 81.6-86.4) and Cobas (80.4%, 95% CI: 77.6-82.8). When combined with cytology triage, the colposcopy referral rate point estimate was slightly lower for Onclarity (9.0%) than for Cobas (11.0%), with the same ≥CIN2 sensitivity of 75.0% (95% CI: 53.1-88.8) for Onclarity and Cobas.Onclarity exhibited comparable screening performance and triage efficiency compared to Cobas in detection of cervical lesions in Chinese women.

Objective. This study describes a randomized controlled trial that assesses percutaneous endoscopic lumbar discectomy (PELD) combined with a polyetheretherketone (PEEK) rod in patients with GLDH (herniation affecting 50% of the sagittal diameter of the spinal canal) and reports the 2-year follow-up outcome. Methods. In all, 243 patients were randomly assigned to undergo PELD or PELD combined with a PEEK rod by generating random numbers with a random number generator. Clinical outcome data, including the numerical rating scale (NRS), were used to assess the patients’ back and leg pain, while the Oswestry Disability Index (ODI) was used to quantify pain and disability. Imaging data included intervertebral disc height (IDH), range of motion (ROM), and modified Pfirrmann grades. Results. At the final follow-up, the NRS for back and leg pain and the ODI scores were significantly decreased in both groups. The NRS for back pain and the ODI scores in the PELD + PEEK group (1.32 ± 0.70, 14.10 ± 4.74) were better than those in the PELD group (1.91 ± 0.69, 16.93 ± 4.33) (P<0.05). The IDH of the PELD + PEEK group (10.54 ± 1.62) was significantly higher than that in the PELD group (9.98 ± 1.90) (P=0.025). The ROM of the PELD + PEEK group (2.39 ± 0.90) was significantly lower than that of the PELD group (9.49 ± 1.62) (P<0.001). Conclusion. For symptomatic patients with GLDH, both PELD and PELD combined with a PEEK rod showed good efficacy. However, the long-term effect of PELD combined with a PEEK rod is better than that of PELD alone. Moreover, PELD combined with a PEEK rod can effectively reduce the recurrence rate. Maximum benefit can be gained if we adhere to strict selection criteria for PELD combined with a PEEK rod.

Objective To estimate long-term outcomes of biopsy-confirmed cervical intraepithelial neoplasia grade 1 (CIN1) or normal cervix and identify the cofactors during disease progression. Methods In 1999, a cervical cancer screening cohort in Shanxi, China, enrolled 1997 women aged 35–45. They were followed up at year 6, 11, and 15 after enrollment with high-risk human papillomavirus (hrHPV) DNA testing, liquid-based cytology, and visual inspection with acetic acid. Progression, persistence, and regression rates were calculated, stratified by baseline hrHPV and cytological status. Risk factors associated with hrHPV acquisition, persistence, and progression were examined. Results The cumulative rates of progression to CIN2+ among CIN1 over 6, 11, and 15 years were 7.5%, 21.4%, and 24.0%, respectively; the regression rates to normal cervix were 85.0%, 76.7%, and 72.9%, respectively. Over 6, 11, and 15 years, 0.7%, 2.9%, and 5.2% of normal cervix developed CIN2+, respectively, but over 90% remained normal after 15 years. CIN1 or normal cervix positive for hrHPV had significantly higher progression rates to CIN2+ than those without hrHPV. Similarly, the severity of cytological status was found to be associated with an increased risk of developing CIN2+. Women who had an earlier sexual debut were at a higher risk of acquiring new HPV infection and repeated HPV infections. Conclusions Clinical follow-up strategies for women with CIN1 or normal cervix could be adjusted accordingly based on hrHPV/cytology status.

This study aimed to compare the treatment response, complications and prognosis in mid-low locally advanced rectal cancer (LARC) patients who underwent stepwise neoadjuvant chemoradiotherapy (SCRT) or traditional neoadjuvant chemoradiotherapy (CRT).The medical records of patients with mid-low rectal cancer who underwent SCRT or CRT were retrospectively analyzed. Differences in the treatment response, pathologic complete response (pCR), R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation, defunctioning stoma, treatment-emergent adverse events (TEAEs), overall survival (OS) and disease-free survival (DFS) between patients who underwent SCRT and CRT were compared.A total of 430 medical records were investigated, including 194 patients in the SCRT group and 236 patients in the CRT group. There was no significant difference in the rates of treatment response, pCR, R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation or TEAEs between the two groups. However, the rate of defunctioning stoma in the SCRT group was significantly lower than that in the CRT group (20.1% vs. 44.1%, respectively, P 0.01). Moreover, the median OS time of the SCRT and CRT groups was 44.0 and 50.5 months, respectively (P = 0.17). The median DFS time of the SCRT and CRT groups was 41.0 and 46.8 months, respectively (P = 0.32).Compared with the CRT group, the SCRT group had a similar treatment response, local control and long-term prognosis, and more importantly, a portion of the patients in the SCRT group were exempted from excessive radiation.

Human papillomavirus (HPV) test, self-sampling and thermal ablation for cervical intraepithelial neoplasia (CIN) have been developed separately to increase screening coverage and treatment compliance of cervical cancer screening programmes. A large-scale study in rural China screened 9,526 women with their combinations to explore the optimal cervical cancer-screening cascade in the real-world. Participants received careHPV and polymerase chain reaction (PCR) HPV tests on self-collected samples. Women positive on either HPV test underwent colposcopy, biopsy and thermal ablation in a single visit. Samples positive on either HPV test were retested for genotyping. Absolute and relative performance of HPV tests, triage strategies, 'colposcopy and thermal ablation' approach were statistically evaluated. PCR HPV test detected 33.3% more CIN grade two or worse (CIN2+) at a cost of 28.1% more colposcopies compared to careHPV. Sensitivities of PCR HPV and careHPV tests to detect CIN2+ were 96.7 and 72.5%. Specificities for the same disease outcome were 82.1 and 86.0%. Triaging HPV-positive women with HPV16/18 genotyping considerably improved the positive predictive value for CIN2+ (4.8-5.0 to 18.2-19.2%). Ninety-six women positive on HPV and having abnormal colposcopy were eligible for thermal ablation and all accepted same-day treatment, contributing to 64.6% being treated appropriately (CIN1+ on histopathology), which reached up to 84.8% among women positive on HPV 16/18 triage. No serious side-effects/complications were reported. The combination of PCR HPV test followed by HPV 16/18 triaging on self-collected samples and colposcopy of triage positive women followed by immediate thermal ablation might be the appropriate screening cascade for rural China.

Transmembrane proteins (TMPs) play important roles in many biological processes, such as cell recognition and communication. Their structures are crucial for revealing complex functions but are hard to obtain. A variety of computational algorithms have been proposed to fill the gap by predicting structures from primary sequences. In this study, we mainly focus on α-helical TMP and develop a multiscale deep learning pipeline, MemBrain 3.0, to improve topology prediction. This new protocol includes two submodules. The first module is transmembrane helix (TMH) prediction, which features the capability of accurately predicting TMH with the tail part through the incorporation of tail modeling. The prediction engine contains a multiscale deep learning model and a dynamic threshold strategy. The deep learning model is comprised of a small-scale residue-based residual neural network and a large-scale entire-sequence-based residual neural network. Dynamic threshold strategy is designed to binarize the raw prediction scores and solve the under-split problem. The second module is orientation prediction, which consists of a support vector machine (SVM) classifier and a new Max-Min assignment (MMA) strategy. One typical merit of MemBrain 3.0 is the decision mode composed of the dynamic threshold strategy and the MMA strategy, which makes it more effective for hard TMHs, such as half-TMH, back-to-back TMH, and long-TMH. Systematic experiments have demonstrated the efficacy of the new model, which is available at: www.csbio.sjtu.edu.cn/bioinf/MemBrain/.

DNA-functionalized nanoparticle (DfNP) technology, the integration of DNA with nanotechnology, has emerged over recent decades as a promising biofunctionalization tool in the light of biotechnological approaches. The development of DfNPs has exhibited significant potential for several biological and biomedical applications. In this review, we focus on the mechanism of a series of DNA-NP nanocomposites and highlight the superstructures of DNA-based NPs. We also summarize the applications of these nanocomposites in cell imaging, cancer therapy and bioanalytical detection.

Ferroptosis, which is characterized by intracellular iron accumulation and lipid peroxidation, is a newly described form of regulated cell death that may play a key role in tumour suppression. In the present study, we investigated the expression profiles and biological effects of fascin actin-bundling protein 1 (Fascin, gene name FSCN1) in breast cancer. In addition, bioinformatics analysis of the TCGA cancer database and gain- and loss-of-function studies showed that Fascin enhances sensitivity to erastin-induced ferroptosis. Mechanistically, Fascin directly interacts with cysteine/glutamate transporter (xCT, gene name SLC7A11) and decreases its stability via the ubiquitin-mediated proteasome degradation pathway. Furthermore, we observed that Fascin is substantially upregulated in tamoxifen-resistant breast cancer cell lines, and drug-resistant cells were also more vulnerable to erastin-induced ferroptosis. Taken together, our findings reveal a previously unidentified role of Fascin in ferroptosis by regulating xCT. Thus, ferroptosis activation in breast cancer with high Fascin level may serve as a potential treatment.

Background Cold urticaria (coldU) is associated with substantial morbidity and risk of fatality. Data on coldU in children are sparse. We aimed to evaluate the clinical characteristics, management, risk of associated anaphylaxis, and resolution rate of coldU in a pediatric cohort. Additionally, we sought to compare these metrics to children with chronic spontaneous urticaria (CSU). Methods We prospectively enrolled children with coldU from 2013-2021 in a cohort study at the Montreal Children’s Hospital and an affiliated allergy clinic. Data for comparison with participants with solely CSU were extracted from a previous study. Data on demographics, comorbidities, severity of presentation, management, and laboratory values were collected at study entry. Patients were contacted yearly to assess for resolution. Results Fifty-two children with cold urticaria were recruited, 51.9% were female and the median age of symptom onset was 9.5 years. Most patients were managed with second generation H1-antihistamines (sgAHs). Well-controlled disease on sgAHs was negatively associated with concomitant CSU (adjusted odds ratio (aOR)=0.69 [95%CI: 0.53, 0.92]). Elevated eosinophils were associated with cold-induced anaphylaxis (coldA) (aOR=1.38 [95%CI: 1.04, 1.83]), which occurred in 17.3% of patients. The resolution rate of coldU was 4.8 per 100 patient-years, which was lower than that of CSU (adjusted hazard ratio=0.43 [95%CI: 0.21, 0.89], P

Gliomas are aggressive tumors in the central nervous system and glioblastoma is the most malignant type. Ferroptosis is a programmed cell death that can modulate tumor resistance to therapy and the components of tumor microenvironment. However, the relationship between ferroptosis, tumor immune landscape, and glioblastoma progression is still elusive. In this work, data from bulk RNA-seq analysis, single cell RNA-seq analysis, and our own data (the Xiangya cohort) are integrated to reveal their relationships. A scoring system is constructed according to ferroptosis related gene expression, and high scoring samples resistant to ferroptosis and show worse survival outcome than low scoring samples. Notably, most of the high scoring samples are aggressive glioblastoma subtype, mesenchymal, and classical, by calculating RNA velocity. Cross-talk between high scoring glioblastoma cells and immunocytes are explored by R package ‘celltalker’. Ligand–receptor pairs like the TRAIL or TWEAK signaling pathway are identified as novel bridges implying how ferroptosis modulate immunocytes’ function and shape tumor microenvironment. Critically, potential drugs target to high scoring samples are predicted, namely, SNX2112, AZ628, and bortezomib and five compounds from the CellMiner database. Taken together, ferroptosis associates with glioblastoma aggressiveness, cross-talk with immunocytes and offer novel chemotherapy strategy.

Sensitive detection of biomarkers is highly desirable for disease diagnosis and postoperative examination. As a signal amplification technique, nonlinear hybridization chain reactions (NHCR) based on DNA self-assembly has been widely adopted to versatile biosensor platforms for signal output and sensitivity enhancement. Herein, we proposed a novel hairpin-free NHCR based flow cytometric immunoassay for prostate specific antigen (PSA) detection. In this study, Ab1-Ag-Ab2-streptavidin-trigger DNA complexes were formed on the magnetic beads (MBs), and each trigger DNA initiated a round of NHCR amplification to form dendritic DNA nanostructures with many fluorescent signal molecules. The robust flow cytometric fluorescent analysis was finally employed for the quantitation of target protein on the MBs. As far as we know, this is the first time to combine the hairpin-free NHCR strategy with fluorescent immunoassay on MBs to detect protein biomarkers. In addition to the high selectivity of immunoassay itself, the characteristics of isothermal, enzyme-free, and exponential amplification efficiency of hairpin-free NHCR endow this developed immunoassay with a detection limit that exceeds 100-folds that of commercially available PSA kits. Moreover, this MBs-based platform of this immunoassay is also amenable to target enrichment and removal of spontaneous NHCR signal through magnetic separation, greatly eliminating the background signal interference. With our efforts, this newly developed biosensor exhibits a detection limit of 1.92 pg/mL and shows high selectivity. It has also been successfully applied to the quantitative detection of PSA in serum samples. With these merits, this convenient biosensor platform has the potential for medical research and disease diagnosis.

Early diagnosis of tuberculosis meningitis (TBM) remains a great challenge during clinical practice. The diagnostic efficacies of cerebrospinal fluid (CSF)-based mycobacterial growth indicator tube (MGIT) culture, modified Ziehl-Neelsen (ZN) staining, Xpert MTB/RIF, and metagenomic next-generation sequencing (mNGS) for TBM remained elusive.A total of 216 adult patients with suspicious TBM were retrospectively enrolled in this multi-cohort study. The diagnostic performances for MGIT, modified ZN staining, Xpert MTB/RIF, and mNGS using CSF samples were evaluated.Uniform clinical case definition classified 88 (40.7%) out of 216 patients as the definite TBM, 5 (2.3%) patients as probable TBM cases, and 24 (11.1%) patients as possible TBM cases. The sensitivities of MGIT, modified ZN staining, Xpert MTB/RIF, and mNGS for TBM diagnosis against consensus uniform case definition for definite TBM were 25.0%, 76.1%, 73.9%, and 84.1%, respectively. Negative predictive values (NPVs) were 66.0%, 85.9%, 84.8%, and 90.1%, respectively. The sensitivities of MGIT, modified ZN staining, Xpert MTB/RIF, and mNGS for TBM diagnosis against consensus uniform case definition for definite, probable, and possible TBM were 18.8%, 57.3%, 55.5%, and 63.2%, respectively. Negative predictive values (NPVs) were 51.0%, 66.4%, 65.6%, and 69.7%, respectively. mNGS combined with modified ZN stain and Xpert could cover TBM cases against a composite microbiological reference standard, yielding 100% specificity and 100% NPV.Metagenomic next-generation sequencing detected TBM with higher sensitivity than Xpert, ZN staining and MGIT culture, but mNGS cannot be used as a rule-out test. mNGS combined with Xpert or modified ZN staining could enhance the sensitivity of diagnostic tests for TBM.