Search

Abstract: Brain diseases, including Alzheimer's disease (AD), brain tumors and Parkinson's disease (PD), pose heavy pressure on the public healthcare system. The main obstacle to vanquish brain diseases is the blood-brain barrier (BBB), which is a selective barrier mainly formed by brain endothelial cells. BBB prevents almost all drugs from reaching the brain, thereby hindering drug delivery. Over the past few decades, considerable signs of progress have been made in crossing the BBB and treating brain diseases. Gold nanoparticles (AuNPs) demonstrate the characteristics of adjustable size, unique optical properties, flexible surface modification, and good biocompatibility, which all contribute AuNPs as a promising candidate in biomedical fields. This article reviews the structure and properties of BBB, and discusses main transport routes through the BBB. Besides, nanoparticles, specially AuNPs applied in brain diseases as main drug delivery platforms, are systematically summarized, emphasizing several methods to modify AuNPs, including tuning particle size and surface modification, which are aimed at promoting BBB penetration or prolonging circulation time of AuNPs. In addition, AuNPs utilized in brain diseases are introduced in detail from the aspects of brain imaging, AD, brain tumors, and PD. Prospects and challenges that need to be considered in further investigations and clinical transformation of AuNPs used in brain diseases are also included, hoping to bring new insights into the applications of AuNPs in brain diseases.

Spatiotemporal manipulation of protein distributions, abundances, and functions based on molecular level remains a significant challenge in studying biological systems and developing therapeutics. Particularly, such a nanotherapeutic platform though both specific and internal way is extremely lacking. Herein, we put forward a click chemistry-driven protein sorting (PROCLISORT) strategy, which acted in a cell space station (CSS) to achieve the sequential regulation of specific protein along the entire PD-1 immune checkpoint axis. From the spatial dimension, CSS could achieve comprehensive recognition, anchoring and blocking PD-L1/PD-L2 as well as transport PD-L1 among organelles at the subcellular level. From the time dimension, through the booting control via click reaction, the occurrence of these biological regulatory events became controllable and sequential, thus resulting in rapid and durable down-regulation of PD-L1. Through these smart tasks, this CSS stimulated a satisfactory tumor-immune-therapy effect both in vitro and in vivo. With a rational design, this multistage booting nanoplatform holds promise for molecular manipulation along the disease-related pathway in various living systems.

Explore the application value of pulmonary perfusion imaging and delayed imaging for evaluating pulmonary capillary permeability.After establishing a rat model of pulmonary contusion, changes in the metabolic index of technetium-99m macroaggregated albumin (99mTC-MAA) in the lungs of model rats were evaluated for two consecutive days. 99mTC-MAA metabolic indices of rat lungs with pulmonary contusion of varying severity (mild, moderate, and severe) were correlated with lung wet/dry weight ratio (W/D) and Evans blue extravasation. Finally, the method was validated in patients with pulmonary contusion and one healthy volunteer.The 99mTC-MAA metabolic index was 23.56% ± 2.44% in healthy control (HC) rat lung, 8.56% ± 3.42% immediately after lung contusion (d0), 8.35% ± 3.20% after 1 day (d1), and 17.45% ± 6.44% after 2 days (d2); indices at d0 and d1 were significantly higher than those at HC (P0.05). The metabolic index of 99mTC-MAA in lung had significant negative correlations with W/D (r = -0.8025; P = 0.0092) and Evans blue extravasation (r = -0.9356; P = 0.0002). Metabolic and oxygenation indices of 99mTC-MAA exhibited a significant positive linear correlation in patients with pulmonary contusion (r = 0.8925; P = 0.0416).Pulmonary perfusion and delayed imaging of 99mTC-MAA have potential value for evaluating pulmonary capillary permeability.

Background Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days. Methods This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis. Results A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups. Conclusions In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

RNA interference is a promising way to treat cancer and the construction of a stable drug delivery system is critically important for its application. Gelatin nanospheres (GNs) comprise a biodegradable drug vehicle with excellent biocompatibility, but there are limited studies on its delivery and role in the stabilization of miRNA and siRNA. Breast cancer is the most diagnosed type of female cancer worldwide. Abnormal miRNA expression is closely related to the occurrence and progression of estrogen receptor-positive (ER+) breast cancer. In this study, miR-4458 was upregulated in ER+ breast cancer and could inhibit MCF-7 cell viability, colony formation, migration, and invasion. Collagen type XI alpha 1 (COL11A1) was identified as a directly interacting protein of miR-4458 and an important component of the extracellular matrix. High COL11A1 expression was positively correlated with poor prognosis, lower overall survival, disease-free survival, and a late tumor-node-metastasis stage. COL11A1 knockdown could inhibit MCF-7 cell migration and invasion. GNs were used to load a miR-4458 mimic or COL11A1 siRNA (si-COL11A1) to achieve sustained and controlled release in xenograft nude mice. Their tumor volume was decreased, tumor cell apoptosis was promoted, and hepatic metastasis was significantly inhibited. Moreover, the DDR2/SRC signaling pathway was inactivated after transfection with the miR-4458 mimic and si-COL11A1. In conclusion, GNs can be potentially used to deliver siRNA or miRNA, and miR-4458 and COL11A1 can be possible targets for ER+ breast cancer treatment.

Background: Cardiometabolic Index (CMI) was associated with several risk factors for stroke; however, few studies assessed the role of CMI in stroke risk. Objective: This study aimed to assess the association between CMI and stroke in a population- based cross-sectional study. Methods: This study included 4445 general residents aged ≥40 years selected by multistage stratified random cluster sampling. CMI was calculated as the product of the ratio of waist circumference to height (WHtR) and the ratio of triglyceride levels to high-density lipoprotein cholesterol levels (TG/HDL-C). Participants were categorized according to CMI quartiles: quartile 1 (Q1), quartile 2 (Q2), quartile 3 (Q3), and quartile 4 (Q4). Multivariate logistic regression analysis and receiver operating characteristic (ROC) curves were used to assess the association between CMI and stroke. Results: A total of 4052 participants were included in the study, with an overall stroke prevalence of 7.2%. The prevalence of stroke increased with CMI quartiles, ranging from 4.4% to 9.2% (p for trend Conclusion: Although there was a strong and independent association between CMI and stroke in the general population, CMI had limited discriminating ability for stroke. Thus, new parameters should be developed.

Breast cancer is a kind of malignant tumor that occurs in breast tissue, which is the most common cancer in women. Cellular metabolism is a critical determinant of the viability and function of cancer cells in tumor microenvironment. In this study, based on the gene expression profile of metabolism-related genes, the prognostic value of 20 metabolic pathways in patients with breast cancer was identified. A universal risk stratification signature that relies on 20 metabolic pathways was established and validated in training cohort, two testing cohorts and The Cancer Genome Atlas pan cancer cohort. Then, the relationship between metabolic risk score subtype, prognosis, immune infiltration level, cancer genotypes and their impact on therapeutic benefit were characterized. Results demonstrated that the patients with the low metabolic risk score subtype displayed good prognosis, high level of immune infiltration and exhibited a favorable response to neoadjuvant chemotherapy and immunotherapy. Taken together, the work presented in this study may deepen the understanding of metabolic hallmarks of breast cancer, and may provide some valuable information for personalized therapies in patients with breast cancer.

As a new type of nanomaterials, the gold nanoclusters (AuNCs) perform many special physical and chemical properties, such as large Stokes shift, relatively simple preparation, good water solubility, low toxicity, and good biocompatibility, which make them show infinite potential in various fields, especially in cancer treatment. In recent years, great progress has been made in the preparation, functionalization, and biomedical applications of the AuNCs. In this article, the latest research progress and synthesis methods of the AuNCs have been summarized, emphasizing the preparation using the “bottom- up” synthesis strategy. Furthermore, we introduced the in vivo pharmacokinetic performance of the AuNCs. In the last part, we exemplified the applications of the AuNCs in biomedicine, including photothermal therapy (PTT), bioimaging, drug delivery, and radiotherapy sensitization, which further confirmed the great potential of the AuNCs in tumor treatment.

Background Ensuring high accuracy in multimodal image fusion for oral and maxillofacial tumors is crucial before further application. The aim of this study was to explore the factors influencing the accuracy of multimodal image fusion for oral and maxillofacial tumors. Methods Pairs of single-modality images were obtained from oral and maxillofacial tumor patients, and were fused using a proprietary navigation system by using three algorithms (automatic fusion, manual fusion, and registration point-based fusion). Fusion accuracy was evaluated including two aspects—overall fusion accuracy and tumor volume fusion accuracy—and were indicated by mean deviation and fusion index, respectively. Image modality, fusion algorithm, and other characteristics of multimodal images that may have potential influence on fusion accuracy were recorded. Univariate and multivariate analysis were used to identify relevant affecting factors. Results Ninety-three multimodal images were generated by fusing 31 pairs of single-modality images. The interaction effect of image modality and fusion algorithm (P = 0.02, P = 0.003) and thinner slice thickness (P = 0.006) were shown to significantly influence the overall fusion accuracy. The tumor volume (P P = 0.007), and image modality (P = 0.01) were significant influencing factors for tumor volume fusion accuracy. Conclusions To ensure high overall fusion accuracy, manual fusion was not preferred in CT/MRI image fusion, and neither was automatic fusion in image fusion containing PET modality. Using image sets with thinner slice thickness could increase overall fusion accuracy. CT/MRI fusion yielded higher tumor volume fusion accuracy than fusion containing PET modality. The tumor volume fusion accuracy should be taken into consideration during image fusion when the tumor volume is small and the tumor is located in the mandible.

Programmed death ligand 1 (PD-L1) has been shown to be inducibly expressed on neutrophils to suppress host immunity during polymicrobial sepsis, virus and parasite infections. However, the role of PD-L1 on neutrophil-mediated antifungal immunity remains wholly unknown. Here, we show that the expression of PD-L1 on murine and human neutrophils was upregulated upon the engagement of C-type lectin receptor Dectin-1 with its ligand β-glucans, exposed on fungal pathogen Candida albicans yeast. Moreover, β-glucan stimulation induced PD-L1 translocation into nucleus to regulate the production of chemokines CXCL1 and CXCL2, which control neutrophil mobilization. Importantly, C. albicans infection-induced expression of PD-L1 leads to neutrophil accumulation in bone marrow, through mediating their autocrine secretion of CXCL1/2. Furthermore, neutrophil-specific deficiency of PD-L1 impaired CXCL1/2 secretion, which promoted neutrophil migration from bone marrow into the peripheral circulation, thereby conferring host resistance to C. albicans infection. Finally, either PD-L1 blockade or pharmacological inhibition of PD-L1 expression significantly increased neutrophil release from bone marrow to enhance host antifungal immunity. Our data together indicate that activation of Dectin-1/PD-L1 cascade by β-glucans inhibits neutrophil release from bone marrow reserve, contributing to the negative regulation of antifungal innate immunity, which functions as a potent immunotherapeutic target against life-threatening fungi infections.

The purpose of this study was to explore the correlations between patients’ opioid-taking self-efficacy, social support, and their pain management satisfaction, and to evaluate the effect of social support and opioid-taking self-efficacy in explaining the variance in pain management satisfaction. We used a cross-sectional and correlational research design and recruited 123 cancer patients via convenience sampling. We used the following instruments: the Opioid-Taking Self-Efficacy Scale, the Inventory of Socially Supportive Behavior, and the Chinese version of the Pain Treatment Satisfaction Scale. There were significant and negative correlations between opioid-taking self-efficacy and pain management satisfaction (r = − .43, p

Dexmedetomidine sedation has been associated with favourable outcomes after surgery. We aimed to assess whether perioperative dexmedetomidine use is associated with improved survival after cardiac surgery.This retrospective cohort study included 2068 patients undergoing on-pump coronary artery bypass grafting and/or valve surgery. Among them, 1029 patients received dexmedetomidine, and 1039 patients did not. Intravenous dexmedetomidine infusion of 0.007 μg kgThe median age was 63 yr old and the male to female ratio was 71:29 in both groups. Baseline covariates were balanced between groups after adjustment using PSM, IPTW, or overlap weighting. Patients receiving dexmedetomidine in cardiac surgical procedures had higher survival during postoperative 5 yr in unadjusted analysis (hazard ratio [HR]=0.63; 95% confidence interval [CI], 0.51-0.78; P0.001), and after adjustment with PSM (HR=0.63; 95% CI, 0.45-0.89; P=0.009), IPTW (HR=0.70; 95% CI, 0.51-0.95; P=0.023), or overlap weighting (HR=0.67; 95% CI, 0.51-0.89; P=0.006). The 5-yr mortality rate after cardiac surgery was 13% and 20% in the dexmedetomidine and non-dexmedetomidine groups, respectively (PSM adjusted odds ratio=0.61; 95% CI, 0.42-0.89; P=0.010).Perioperative dexmedetomidine infusion was associated with improved 5-yr survival in patients undergoing cardiac surgery.

Plasma cell-rich acute rejection (PCAR), a subtype of T cell-mediated rejection, is a relatively rare type of acute allograft rejection, that is usually associated with a higher rate of graft failure. However, it is difficult to diagnose PCAR precisely.A 45-year-old woman who had received a kidney transplant presented with acute kidney injury and uremic symptoms approximately 1 year after transplantation.A renal biopsy was performed and pathological examination revealed marked inflammation with abundant plasma cells in areas within interstitial fibrosis and tubular atrophy. The patient was diagnosed with PCAR and chronic active T cell-mediated rejection (CA-TCMR) grade IA.Immunosuppressants were administered as tacrolimus (2 mg twice daily), mycophenolate mofetil (250 mg twice daily), and prednisolone (15 mg/day) for suspected PCAR.The patients showed rapid deterioration in kidney function and reached impending graft failure.PCAR is often associated with poor graft outcome. The high variability in tacrolimus levels could contribute to poor patient outcomes, leaving aggressive immunosuppressive therapy as the remaining choice for PCAR treatment.

Overactive bladder (OAB) is a disease that seriously affects patients' quality of life and mental health. To address this issue, more and more researchers are examining the relationship between OAB treatment and urinary microecology. In this study, we sought to determine whether differences in treatment efficacy were related to microbiome diversity and composition as well as the abundance of specific genera. Machine learning algorithms were used to construct predictive models for urine microbiota-based treatment of OAB.Urine samples were obtained from 64 adult female OAB patients for 16S rRNA gene sequencing. Patients' overactive bladder symptom scores (OABSS) were collected before and after mirabegron treatment and patients were divided into effective and ineffective groups. The relationship between the relative abundance of certain genera and OABSS were analyzed. Three machine learning algorithms, including random forest (RF), supporting vector machine (SVM) and eXtreme gradient boosting (XGBoost) were utilized to predict the therapeutic effect of mirabegron based on the relative abundance of certain genera in OAB patients' urine microbiome.The species composition of the two groups differed. For one, the relative abundance ofThe results of this study indicate that urinary microbiota might influence the efficacy of mirabegron, and that

Inconsistent training programs for public health emergency (PHE) have been criticized as a contributing factor in PHE's managerial weak points. In response, to analyze the relevant discrepancies among the medical students in the class of 2021 from Xiangya School of Medicine of Central South University, the present study conducted an online questionnaire survey using convenience sampling. The questionnaire comprised four sections, including the basic information, the subjective cognition in PHE, the rescue knowledge and capabilities of PHE, and the mastery of PHE regulations and psychological intervention abilities. To compare the abovementioned aspects, related data were collected from 235 medical students divided into two groups, namely, clinical medical students (Group A) and preventive medical students (Group B). We found a more positive attitude in PHE (P = 0.014) and a better grasp of the PHE classification (P = 0.027) and the reporting system in group B compared with group A. In addition, even if group B showed the same response capability in communicable diseases as group A, the former had less access to clinical practice, resulting in poorer performance in the noncommunicable diseases during a fire, flood, and traffic accidents (P = 0.002, P = 0.018, P = 0.002). The different emphasis of each training program contributed to the uneven distribution of abilities and cognition. Meanwhile, the lack of an integrated PHE curriculum led to unsystematic expertise. Hence, to optimize the PHE management system, equal attention should be paid to medical students with diverse majors along with a complete integrated PHE curriculum.

Both tumor-cell-targeting and BBB (blood-brain barrier)-penetrating ability are the key characteristics for glioma theranostics. We established one type of nanomicellar probe functionalized with a newly developed peptide WES. The micellar system could enact a series of cascaded functions in living bodies. It could specifically recruit the ApoE corona in blood circulation rather than perform nonspecific protein absorption. Following, it could penetrate into the BBB in an active manner. Finally, and most importantly, it could recognize and target the tumor marker as well as deliver drugs effectively toward glioma. The cascaded micellar system has shown satisfactory therapeutic ability for glioma in both a subcutaneous and orthotopic model, which provides a prospective strategy for brain cancer treatment.

Backgrounds. The prevalence of diabetes has increased with the increase of obesity, and finding indicators to predict diabetes risk has become an urgent need. The purpose of this study is to compare the correlation between four anthropometric indices and the prevalence of diabetes. Methods. A total of 4052 participants aged 40 years and above were selected in Dehui City, Jilin Province, using a multistage stratified whole group sampling method. Face-to-face interviews and physical examinations were conducted. Multivariate logistic analysis was used. The values of BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were divided into quartiles (Q1: study participants ≥ 40 years of age, especially in females.

Introduction Withholding the malignant bone tumors disclosure from patients is common in China. The purpose of the study was to explore the perceptions of patients, families, doctors, and nurses regarding the disclosure of malignant bone tumors in China. Method Semistructured interviews were conducted with 25 cases, consisting of 69 participants (14 patients, 25 family members, 17 doctors, and 13 nurses), and the transcripts were analysed using Colaizzi’s (1978) descriptive phenomenological analysis process. Results Five themes were identified: (1) doctors preferred to inform the family members first, (2) family members’ decisions depended on different situations, (3) the patients agreed that disclosure should be different for each person/personally, (4) care from nurses reduced the overreaction of patients, and (5) key points improve the informing quality. Discussion Family participatory cancer disclosure and multidisciplinary teams could improve the quality of cancer disclosure. Culturally congruent health care and culturally sensitive interventions in cancer disclosure are suggested.

Objective The aim of this study was to determine the clinical outcomes and long-term stability of individualized titanium mesh combined with free flap for orbital floor reconstruction after maxillectomy and to identify the risk factors for titanium mesh exposure. Material and methods The data of 66 patients who underwent maxillectomy and orbital floor defect reconstruction by individualized titanium mesh in Peking University School and Hospital of Stomatology between 2011 and 2019 were retrospectively reviewed. Postoperative ophthalmic function and success of aesthetic restoration were assessed. Titanium mesh exposure was recorded and the risk factors were identified. Results Mean follow-up was for 24.8 months (range, 6-92 months). Ophthalmic function was successfully restored in 63/66 patients. Aesthetic restoration was not considered satisfactory by 10 patients. Titanium mesh exposure occurred in six patients (exposure rate, 9.1%). Preoperative radiotherapy was identified as an independent risk factor for mesh exposure (OR = 28.8, P = 0.006). Previous surgery, postoperative radiotherapy, pathological type of the primary lesion, the type of tissue flap applied, and the use of intraoperative navigation were not significant risk factors. Six patients with titanium mesh exposure underwent second surgery, but mesh exposure recurred in two patients due to insufficient soft tissue coverage. Conclusion Individualized titanium mesh with free flap can effectively restore maxilla-orbital defects. Preoperative radiotherapy is an independent predictor of postoperative titanium mesh exposure. Adequate soft tissue coverage of the mesh may reduce the risk of mesh exposure. Level of evidence Level 4 (case-control study) Laryngoscope, 2021.

Background Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications. Methods We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Results Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM. Conclusions TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

In the past two decades, three coronaviruses with ancestral origins in bats have emerged and caused widespread outbreaks in humans, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first SARS epidemic in 2002–2003, the appreciation of bats as key hosts of zoonotic coronaviruses has advanced rapidly. More than 4,000 coronavirus sequences from 14 bat families have been identified, yet the true diversity of bat coronaviruses is probably much greater. Given that bats are the likely evolutionary source for several human coronaviruses, including strains that cause mild upper respiratory tract disease, their role in historic and future pandemics requires ongoing investigation. We review and integrate information on bat–coronavirus interactions at the molecular, tissue, host and population levels. We identify critical gaps in knowledge of bat coronaviruses, which relate to spillover and pandemic risk, including the pathways to zoonotic spillover, the infection dynamics within bat reservoir hosts, the role of prior adaptation in intermediate hosts for zoonotic transmission and the viral genotypes or traits that predict zoonotic capacity and pandemic potential. Filling these knowledge gaps may help prevent the next pandemic., Bats harbour a multitude of coronaviruses and owing to their diversity and wide distribution are prime reservoir hosts of emerging viruses. Ruiz-Aravena, McKee and colleagues analyse the currently available information on bat coronaviruses and discuss their role in recent and potential future spillovers.

Background The human brain is a highly complex and nonlinear system, nonlinear complexity measures such as approximate entropy (ApEn) and sample entropy (SampEn) can better reveal characteristics of brain dynamics. However, no studies report complexity of perioperative physiological signals to reveal how brain complexity associates with age, varies along with the development of surgery and postoperative neurological complications. Aim This study examined the complexity of intraoperative regional cerebral oxygen saturation (rSO2), aiming to reveal brain dynamics during surgery. Methods This retrospective cohort study enrolled patients who scheduled for robot-assisted urological surgery. Intraoperative rSO2 was continuously monitored throughout the surgery. Postoperative delirium (POD) was diagnosed by the Confusion Assessment Method. ApEn and SampEn were used to characterize the complexity of rSO2. Pearson correlation coefficients were used to measure the correlation between complexity of rSO2 and age. The association between complexity of rSO2 and POD was examined using T tests. Results A total of 68 patients (mean [SD] age, 63.0 (12.0) years; 47 (69.1%) males) were include in this analysis. There was a significant reverse relationship between the complexity of rSO2 and age (The correlation coefficients range between − 0.32 and − 0.28, all p 2 than the other two groups. Older age remained an independent factor influencing complexity of rSO2 after adjusting for a number of covariates. Six patients (8.8%) developed POD, and POD patients had lower complexity of rSO2 compared with non-POD patients. Conclusions The complexity of rSO2 may serve as a new candidate marker of aging and POD prediction.

This secondary analysis of the Keynote 048 trial examines treatment with pembrolizumab in patients with recurrent and metastatic head and neck squamous cell carcinoma.

Background Pubic ramus fracture was an injury of anterior pelvic ring, the anterior pelvic ring plays an important role in maintaining the stability of the pelvis. The purpose of this study was to investigate the effect and indication of percutaneous retrograde pubic screw fixation assisted by hollow pedicle finder for pubic ramus fractures. Methods The clinical data of 68 patients with pubic ramus fracture treated with cannulated screw from March 2008 to March 2020 were retrospectively analyzed. According to the surgical methods, they were divided into traditional surgery group (32 cases in group A, with traditional retrograde pubic screw fixation) and modified surgery group (36 cases in group B, with percutaneous retrograde pubic screw fixation assisted by hollow open circuit device). Operation time, blood loss, incision length, screw length and complications were recorded and compared between the two groups. On the second day after surgery, the maximum fracture displacement over plain radiographs, entrance radiographs and exit radiographs of the pelvis was evaluated according to Matta criteria to evaluate the postoperative fracture reduction. Majeed score was used to evaluate the hip function at 12 months after surgery. Results The operations were successfully completed in both groups. The operation time, blood loss and incision length in group B were significantly less than those in group A (P 0.05). In group A, there were 3 cases of incision infection, 1 case of incision fat liquefaction and 2 cases of lower extremity deep venous thrombosis, and the complication rate was 18.8%. There was only 1 case of lower extremity deep vein thrombosis in group B, and the complication rate was 2.8%, which was significantly lower than that in group A. The fracture in one case after surgery was found to be displaced in group A and no fracture was found in group B. There was no significant difference between the two groups in Matta imaging evaluation on the next day after surgery and Majeed function evaluation at 12 months after surgery (P > 0.05). Conclusion Percutaneous retrograde pubic ramus screw fixation assisted by hollow pedicle finder is effective in the treatment of pelvic pubic ramus fracture. It has the advantages of less incision, shorter operation time, less blood loss and lower incidence of complications compared with traditional methods. However, correct surgical indications should be required when we apply this surgical method.

The epithelial-to-mesenchymal transition (EMT) describes a biological process in which polarized epithelial cells are converted into highly motile mesenchymal cells. It promotes cancer cell dissemination, allowing them to form distal metastases, and also involves drug resistance in metastatic cancers. Transforming growth factor β (TGFβ) is a multifunctional cytokine that plays essential roles in development and carcinogenesis. It is a major inducer of the EMT. The MIR31 host gene (

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a–regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.

Background We sought to compare the prognostic significance of different preoperative complete blood count cell ratios in patients with oral cavity squamous cell carcinoma (OSCC) treated with surgery and postoperative radiotherapy (PORT). Methods We retrospectively reviewed the clinical records of 890 patients with OSCC who were treated with surgery and PORT. The following preoperative complete blood count cell ratios were collected: neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR). Overall survival (OS), local control, regional control, and distant control (DC) served as the main outcomes of interest. Results The results of multivariate analysis in the entire study cohort revealed that a low NLR was the only independently favorable marker of both OS (adjusted hazard ratio [HR]: 0.794, 95% confidence interval (CI): 0.656–0.961, bootstrap p = 0.028) and DC (adjusted HR: 0.659, 95% CI: 0.478–0.909, bootstrap p = 0.015). Both LMR and PLR were not retained in the model as independent predictors. Subgroup analyses in high‐risk patients (i.e., those bearing T4 disease, N3 disease, or poor differentiation) revealed that a high NLR was a significant adverse risk factor for both OS and DC (all p, This relatively large cohort reports a comparative result: pretreatment high neutrophil‐to‐lymphocyte ratio (NLR) was an independent unfavorable risk factor for both overall survival and distant metastasis in patients with oral cavity squamous cell carcinoma (OSCC) who underwent surgery and postoperative radiotherapy. Lymphocyte‐to‐monocyte ratio (LMR) and platelet‐to‐lymphocyte ratio (PLR) were not significant.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

Background Proton beam radiation therapy (PBRT) has dosimetric advantages compared to photon radiation therapy for the treatment of major salivary gland tumors (MSGTs). Methods Patients with non-metastatic MSGTs treated at a single proton therapy center from October 2013 to October 2018 were retrospectively reviewed. Results Sixty-eight patients with MSGTs were included and the most common site and histology were the parotid gland (75.0%) and adenoid cystic carcinoma (22.1%), respectively. The 3-year rates of locoregional control, progression-free survival, and overall survival were 95.1% (95% CI: 89.9%-100.0%), 80.7% (70.2%-92.7%), and 96.1% (95% CI: 90.9%-100.0%), respectively. Conclusion In a large cohort of MSGTs treated with PBRT, the rates of locoregional control were high in short-term follow-up and treatment was well tolerated.

Screening and therapeutic programs for colorectal cancer (CRC) are invasive or not effective and unable to meet patient needs. Major advances in immunogenomics may change this status but need more exploration. Differentially expressed genes and immune-related genes (IRGs) were identified by computational methods. A prognostic model was established and validated based on survival-related IRGs via stepwise multivariate Cox regression analysis. Nine IRGs were selected and identified as survival-related genes. A 7-gene prognostic model could offer a preliminary and valid determination of risk in CRC patients. The area under the curve of the receiver operating characteristic was 0.672. The 7-gene prognostic model might be used as a novel prognostic tool in CRC patients.

Background Shear wave elastography (SWE) directly quantifies the local arterial wall stiffness by calculating the elastic modulus. However, whether carotid wall elastic modulus can predict obstructive coronary artery disease (CAD) is not well known. We aimed to investigate the value of carotid wall elastic modulus measured using SWE in identifying obstructive CAD. Materials and methods We prospectively enrolled 61 patients without carotid plaque referred for clinically indicated coronary angiography. Twenty-seven (44.3%) patients were diagnosed with obstructive CAD (≥50% coronary stenosis). The elastic modulus of common carotid artery was quantified using SWE. Ankle--brachial index (ABI) and echocardiographic global cardiac calcium score (GCCS) were measured. Results Patients with obstructive CAD had significantly higher elastic modulus than those without obstructive CAD. The maximum elastic modulus (EMmax) was independently associated with obstructive CAD after adjusting for the Framingham risk score, ABI, and GCCS. EMmax had the highest area under the curve (AUC) to identify obstructive CAD (AUC 0.70; P = 0.003). In the nested models, the model based on the Framingham risk score and ABI (χ2 = 3.74) improved by adding GCCS (χ2 = 9.95) and further improved by adding EMmax (χ2 = 15.86). Adding EMmax to the combined ABI and GCCS model increased integrated discrimination index from 0.10 to 0.19. Conclusion Carotid wall elastic modulus measured using SWE is a useful predictor of obstructive CAD in patients without carotid plaque. We demonstrated the incremental and independent value of carotid wall elastic modulus in identifying obstructive CAD compared with clinical risk factors and other imaging predictors, including ABI and GCCS. Video abstract Please see the video, in Supplemental Digital Content 1, http://links.lww.com/HJH/B551 for more insights from the authors.

BACKGROUND AND PURPOSE The burden of cervical arterial atherosclerosis, which is an important risk factor of stroke, is huge in China. The visceral adiposity index (VAI) is a convenient index that is related to a series of metabolic abnormalities and a variety of diseases, including cerebrovascular diseases. This study aimed to explore the relationship between VAI and cervical arterial atherosclerosis. METHODS This cross-sectional study used the multistage stratified random cluster sampling method to acquire a representative sample of residents aged ≥40 in the general population of northeast China. All participants completed a detailed questionnaire and provided blood samples. Cervical vascular ultrasound was performed by experienced ultrasound doctors. VAI was calculated by a well-established formula and analyzed by quartiles (Q1-Q4). RESULTS A total of 3688 people aged ≥40 years who underwent cervical arterial ultrasound were finally included, amongst whom 3.2% had increased intima-media thickness (IMT), 48.6% had carotid plaque and 4.0% had cervical artery stenosis (CAS). After adjusting for several parameters, little statistical significance was found between VAI and increased IMT; compared with the VAI-Q1 group, the VAI-Q2, VAI-Q3 and VAI-Q4 groups were more likely to have CAS [odds ratio (OR) 2.01, 95% confidence interval (CI) 1.17-3.43; OR 1.82, 95% CI 1.05-3.15; OR 1.79, 95% CI 1.03-3.12] and the VAI-Q3 and VAI-Q4 groups were at greater risk of carotid plaque (OR 1.30, 95% CI 1.05-1.62; OR 1.34, 95% CI 1.07-1.67). CONCLUSIONS The VAI was related to carotid plaque and CAS in the general population that is older than 40 years.

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 10(9)/L (range, 0.01–2.75 X 10(9)/L) and was significantly higher in patients who achieved complete response (p=0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2–0.8, p=0.007). Low DLIx was independently associated with shorter progression-free (p=0.02) and overall survival (p=0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

Benzotriazole ultraviolet stabilizers (BUVSs) are ubiquitous emerging pollutants that have been reported to show estrogenic disruption effects through interaction with the classic estrogen receptors (ERs) in the fashion of low activity. The present study aims at revealing the potential disruption mechanism via estrogen-related receptors α and γ (ERRα and ERRγ) pathways. By the competitive binding assay, we first found that BUVSs bond to ERRγ ligand binding domain (ERRγ-LBD) with

Chronic wounds such as diabetic feet undergo a lifetime risk of developing into incurable ulcers. Current treatments for chronic wounds remain unsatisfactory due to the lack of ideal wound dressings that integrate facile dressing change, long-acting treatment, and high therapeutic efficacy into one system. Herein, a synergistically detachable microneedle (MN) dressing with a dual-layer structure is presented to enable programmed treatment via one-time dressing application. Such a dual-layer dressing MN system (DDMNS) is composed of chitosan (CS) hydrogel dressing (CSHD) on top of a detachable MN patch with a CS tip and a polyvinyl pyrrolidone (PVP) backing substrate incorporated with magnesium (Mg). The synergistic detachment is achieved with the backing Mg/PVP substrate dissolving within minutes due to the local moist environment of the CSHD enhancing the reaction between Mg and inflammation microenvironment. The combined treatment of Mg and panax notoginseng saponins (PNS) loaded in DDMNS achieves antibacterial, neovascularization, and activating a benign immune response so that the three overlapping periods of the inflammation, tissue proliferation, and tissue remodeling of wound healing reach a dynamic balance. This advanced DDMNS provides a facile approach for the programmed treatment of chronic wound management indicating potential value in wound healing and other related biomedical fields.

This study aimed to examine the current suicidal risk and whether the suicidal risk was associated with a wide range of trauma. The self-administered online questionnaire was adopted to collect suicide risk (SR) such as suicidal ideation, self-harm, suicide attempts, and different trauma information of the adolescents by cluster sampling in Chongqing, China. Multivariable linear regression was presented to assess the association between different risks of trauma and SR scores. Approximately 14.7% of adolescents enrolled reported suicide ideation and more than 10% of adolescents have experienced one kind of trauma during the Coronavirus disease 2019 (COVID-19) pandemic period. After adjusting for confounding variables, adolescents who suffered family hurt had a higher risk score of SR (beta coefficients (β) = 0.289, 95% confidence interval (CI) = 0.115–0.463). A positive association was found among participants from junior and senior school (β = 0.415, 95% CI = 0.152, 0.768), and the SR score was positively associated with sexism among participants from the university/college (β = 0.238, 95% CI = 0.042, 0.434). The most potentially obvious trauma that contributed to SR in junior and senior school adolescents might be cyberbullying. Family neglect or abuse might be a detrimental factor in SR for adolescents whether those in junior school or those in university school in China. More interventions, like education related to cyberbullying and family abuse, should be prioritized to reduce the risk of suicide.

Background Postoperative acute kidney injury (AKI) is associated with poor clinical outcomes. Early identification of high-risk patients of developing postoperative AKI can optimize perioperative renal management and facilitate patient survival. The present study aims to develop and validate a nomogram to predict postoperative AKI after liver resection in older patients. Methods A retrospective observational study was conducted involving data from 843 older patients scheduled for liver resection at a single tertiary high caseload general hospital between 2012 and 2019. The data were randomly divided into training (70%, n = 599) and validation (30%, n = 244) datasets. The training cohort was used to construct a predictive nomogram for postoperative AKI with the logistic regression model which was confirmed by a validation cohort. The model was evaluated by receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis in the validation cohort. A summary risk score was also constructed for identifying postoperative AKI patients. Results Postoperative AKI occurred in 155 (18.4%) patients and was highly associated with in-hospital mortality (5.2% vs. 0.7%, P P = 0.47). Decision curve analysis demonstrated a significant clinical benefit. The summary risk score calculated as the sum of points from the six variables (one point for each variable) performed as well as the nomogram in identifying the risk of AKI (AUC 0.71, 95% CI: 0.66–0.76). Conclusion This nomogram and summary risk score accurately predicted postoperative AKI using six clinically accessible variables, with potential application in facilitating the optimized perioperative renal management in older patients undergoing liver resection. Trial registration NCT04922866, retrospectively registered on clinicaltrials.gov on June 11, 2021.

Meloxicam (MLX) is a non-steroidal anti-inflammatory drug used to treat rheumatoid arthritis and osteoarthritis. However, its poor water solubility limits the dissolution process and influences absorption. In order to solve this problem and improve its bioavailability, we prepared it in nanocrystals with three different particle sizes to improve solubility and compare the differences between various particle sizes. The nanocrystal particle sizes were studied through dynamic light scattering (DLS) and laser scattering (LS). Transmission electron microscopy (TEM) was used to characterize the morphology of nanocrystals. The sizes of meloxicam-nanocrystals-A (MLX-NCs-A), meloxicam-nanocrystals-B (MLX-NCs-B), and meloxicam-nanocrystals-C (MLX-NCs-C) were 3.262 ± 0.016 μm, 460.2 ± 9.5 nm, and 204.9 ± 2.8 nm, respectively. Molecular simulation was used to explore the distribution and interaction energy of MLX molecules and stabilizer molecules in water. The results of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) proved that the crystalline state did not change in the preparation process. Transport studies of the Caco-2 cell model indicated that the cumulative degree of transport would increase as the particle size decreased. Additionally, plasma concentration–time curves showed that the AUC0–∞ of MLX-NCs-C were 3.58- and 2.92-fold greater than those of MLX-NCs-A and MLX-NCs-B, respectively. These results indicate that preparing MLX in nanocrystals can effectively improve the bioavailability, and the particle size of nanocrystals is an important factor in transmission and absorption.

Retinal segmentation is a prerequisite for quantifying retinal structural features and diagnosing related ophthalmic diseases. Canny operator is recognized as the best boundary detection operator so far, and is often used to obtain the initial boundary of the retina in retinal segmentation. However, the traditional Canny operator is susceptible to vascular shadows, vitreous artifacts, or noise interference in retinal segmentation, causing serious misdetection or missed detection. This paper proposed an improved Canny operator for automatic segmentation of retinal boundaries. The improved algorithm solves the problems of the traditional Canny operator by adding a multi-point boundary search step on the basis of the original method, and adjusts the convolution kernel. The algorithm was used to segment the retinal images of healthy subjects and age-related macular degeneration (AMD) patients; eleven retinal boundaries were identified and compared with the results of manual segmentation by the ophthalmologists. The average difference between the automatic and manual methods is: 2-6 microns (1~2 pixels) for healthy subjects and 3-10 microns (1~3 pixels) for AMD patients. Qualitative method is also used to verify the accuracy and stability of the algorithm. The percentage of “perfect segmentation” and “good segmentation” is 98% in healthy subjects and 94% in AMD patients. This algorithm can be used alone or in combination with other methods as an initial boundary detection algorithm. It is easy to understand and improve, and may become a useful tool for analyzing and diagnosing eye diseases.

Previous event-related potential (ERP) research demonstrated four successive ERP components in the repetition priming of human face recognition: P100, N170, N250r, and N400. While these components correspond, respectively, to the four stages proposed by the interactive activation and competition (IAC) model, there has been no emphasis in past research on how internal and external facial features affect repetition priming and the sensitivity of these ERP components to item interval. This study was designed to address these issues. We used faces of celebrities as targets, including completely familiar faces, familiar internal feature faces, and familiar external feature faces. We displayed a target face either immediately following its prime (immediate repetition) or after a delay with interference from a presentation of two other faces (delayed repetition). ERP differences at P100 and N170 were nearly statistically non-significant; familiar faces and familiar external feature faces were associated with reliable ERP signals of N250r and N400 in the immediate repetition condition. For delayed repetition, however, N250r and N400 signals were only preserved for the familiar external feature faces. The differences of these ERP components suggest that, compared with internal facial features, external features of a previously presented face contribute more to brain-based facial repetition priming, particularly during the last two stages of the IAC model.

BackgroundWe sought to investigate the prognostic impact of missed RT sessions in patients who had undergone surgery for oral cavity squamous cell carcinoma (OCSCC).MethodsThe study sample consisted of 905 patients with surgically treated OCSCC who fulfilled criteria of RT course ≤8 weeks. The study participants were divided into three groups based on the characteristics of missed RT, as follows: 1) early missed RT, 2) late missed RT, and 3) RT as scheduled.ResultsThe 5-year overall survival (OS) rates in the early missed RT, late missed RT, and RT as scheduled groups were 53.0, 58.1, and 64.5%, respectively (p = 0.046). In multivariate analysis, early missed RT was independently associated with both OS (hazard ratio (HR) = 1.486; 95% confidence interval (CI): 1.122–1.966;p = 0.006) and the occurrence of distant metastasis (HR = 1.644; 95% CI: 1.047–2.583;p = 0.031).ConclusionEarly missed RT was independently associated with a higher occurrence of distant metastasis and less favorable OS in patients who had undergone surgery for OCSCC.

Because of the national emergency triggered by the coronavirus disease 2019 (COVID‐19) pandemic, government‐mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in‐person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard‐of‐care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high‐volume cancer center at the domestic epicenter of the COVID‐19 crisis., Cancer care is undeniably affected by the coronavirus disease 2019 (COVID‐19) public health emergency, but quality cancer care must persist. A high‐volume cancer center from the domestic epicenter of the COVID‐19 crisis shares its multidisciplinary approach to integrating current public health restrictions and adopting telemedicine to optimize the care of patients with head and neck cancer; it is hoped that this center's experience will provide helpful insights to oncology colleagues.

Tumor necrosis factor-alpha (TNFα) is an inflammatory cytokine that regulates inflammation and tumor progression in non-small cell lung cancer (NSCLC). The higher levels of TNF α are known to induce expression of several genes such as TNFα-induced protein 2 (TNFAIP2) with a largely unknown role in NSCLC. We provide the preliminary evidence for the role of TNFAIP2 in NSCLC progression and its epigenetic regulation mediated by microRNA, miR-145-5p. The expression of TNFAIP2 was confirmed using quantitative real-time PCR, immunohistochemistry, and Western blot in NSCLC tissue and paired adjacent normal tissue. All in vitro assays were undertaken in A549 and H23 cells and chemoresistance assays were undertaken in A549/Cisplatin (DDP) and H23/DDP cell types. TNFAIP2 silencing was undertaken using lipofectamine transfection of specific siRNA. Cells were co-transfected with miR-145-5p, and TNFAIP2-3' untranslated region (UTR) or TNFAIP2 with mutated 3'UTR using the luciferase vector pGL. Cell viability, transwell migration, and invasion were assessed. The role of caspase 3 proteins in cell viability was ascertained using Western blot. The tumor tissues (and cisplatin-resistant cell lines A549/DDP and H23/DDP) expressed significantly higher levels of TNAIP2 mRNA and protein. Silencing of TNFAIP2 resulted in reduced cell viability, reduced invasion, and migration in vitro. Silencing of TNFAIP2 in A549/DDP and H23/DDP had higher expression of TNFAIP2, reduced cell viability, and increased induction of caspase 3. MiR-145-5p binds to the 3'UTR of TNFAIP2. Overexpression of MiR-145-5p reduced expression of TNFAIP2, decreased cell viability, reduced cell migration and invasion, and significantly reduced expression of caspase 3 protein. TNFAIP2 mediates tumorigenesis in NSCLC through, not completely known pathways. miR-145-5p negatively regulates TNFAIP2 expression. miR-145-5p-mediated therapies may be explored in NSCLC.

Background & Aims Glecaprevir/pibrentasvir is approved for treating adults infected with HCV genotypes 1–6. In clinical trials, glecaprevir/pibrentasvir was associated with high rates of sustained virologic response at post-treatment week 12 (SVR12) and was well tolerated. A systematic review and meta-analysis of the real-world effectiveness and safety of glecaprevir/pibrentasvir were undertaken. Methods Real-world studies reporting SVR12 in adults with HCV infection (n ≥20) treated with glecaprevir/pibrentasvir were identified in journal publications from January 1, 2017, to February 25, 2019, and congress presentations through April 14, 2019. Random-effects meta-analysis was used to determine SVR12 rates using data from ≥2 cohorts; intention-to-treat (ITT) analyses included patients treated with glecaprevir/pibrentasvir who had SVR12 data available, discontinued early, or were lost to follow-up; modified ITT (mITT) analyses excluded those with non-virologic failure. Naive pooling was used to calculate adverse event (AE) rates. Results Overall, 12,531 adults were treated with glecaprevir/pibrentasvir (18 cohorts). Of patients with post-treatment week 12 data, SVR12 rates were 96.7% (95% CI 95.4–98.1) in the ITT population (n = 8,583, 15 cohorts) and 98.1% (95% CI 97.1–99.2) in the mITT population (n = 7,001, 14 cohorts). SVR12 rates were ≥95% across subgroups (HCV genotype, cirrhosis status, treatment history, treatment duration, on-label treatment, and subgroups of interest). AEs were reported in 17.7% (1,271/7,199) of patients (8 cohorts). Serious AEs were reported in 1.0% (55/5,522) of patients (6 cohorts). The most frequent AEs were pruritus, fatigue, and headache. AE-related treatment discontinuations were reported in 0.6% (33/5,595) of patients (6 cohorts). Conclusions Consistent with clinical trials, real-world evidence indicates that glecaprevir/pibrentasvir is a well-tolerated and highly effective pangenotypic treatment for a broad range of HCV-infected patients. Lay summary It is important to assess treatments for hepatitis C virus (HCV) in the real world, as patient populations tend to be more diverse and potentially less adherent to treatment compared to those in clinical trials. Results from 18 studies performed in real-world clinics were pooled and analyzed to investigate the effectiveness and safety of a direct-acting antiviral combination (glecaprevir/pibrentasvir) in routine clinical practice. This analysis showed that glecaprevir/pibrentasvir is highly effective and well tolerated across all HCV genotypes and patient groups studied. It also showed that results seen in the real world are similar to the results seen in clinical trials, even in patients historically considered more challenging to treat.

PurposeThe contribution of rare genetic variation in the development of soft-tissue sarcoma (STS) remains underexplored. To address this gap, we conducted a whole-exome case-control and somatic-germline interaction study to identify and characterise STS susceptible genes.MethodsThe study involved 219 STS cases from The Cancer Genome Atlas and 3507 controls. All cases and controls were matched genetically onEuropean ancestry based on the 1000 Genomes project. Cross-platform technological stratification was performed with XPAT and gene-based association tests with VAAST 2.ResultsNF1 exhibited the strongest genome-wide signal across the six subtypes, with p=1×10−5. We also observed nominally significant association signals for three additional genes of interest, TP53 (p=0.0025), RB1 (p=0.0281), and MSH2 (p=0.0085). BAG1, which has not previously been implicated in STS, exhibited the strongest genome-wide signal after NF1, with p=6×10−5. The association signals for NF1 and MSH2 were driven primarily by truncating variants, with ORs of 39 (95% CI: 7.1 to 220) for NF1 and 33 (95% CI: 2.4 to 460) for MSH2. In contrast, the association signals for RB1 and BAG1 were driven primarily by predicted damaging missense variants, with estimated ORs of 12 (95% CI: 2.4 to 59) for RB1 and 20 (95% CI: 1.4 to 300) for BAG1.ConclusionsOur results confirm that pathogenic variants in NF1, RB1 and TP53 confer large increases in the risk of developing multiple STS subtypes, provide support for the role of MSH2 in STS susceptibility and identify BAG1 as a novel candidate STS risk gene.