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In regenerative medicine, cells, tissues and organs are often replaced, engineered or regrown in order to restore their function after they have been damaged or lost. Local anesthetics, corticosteroids and contrast agents are commonly employed for both diagnostic and therapeutic objectives in interventional pain and musculoskeletal treatments for regenerative medicine. There is growing evidence that routine injectables promote catabolism and disease processes. Thus, understanding the effects of these compounds on regenerative medicine injectates and target tissues such as tenocytes, chondrocytes, nucleus pulposus and ligamentous tissue is critical. This review includes the current research on the effects of local anesthetics and contrast agents, as well as their use and recommendations in regenerative medicine operations.In regenerative medicine, various human organs are often modified to restore their function after being damaged. Various substances are commonly injected in pain and musculoskeletal treatments for regenerative medicine. A growing body of literature indicates that common injectable substances may promote cellular destruction and pathologies. Therefore, understanding their effects on various musculoskeletal tissue and cellular components is critical. This review includes the current research on the effects of local anesthetics and contrast agents, as well as their use and recommendations in regenerative medicine operations.

Background The Quick Mild Cognitive Impairment (Qmci) test has been suggested to be an easy-to-use and precise screening tool for detecting postoperative cognitive dysfunction (POCD). To provide essential information for future POCD studies in Taiwan, the present study provided data regarding the Taiwan version of the Qmci (Qmci-TW) test conducted in the normative Taiwanese population and changes in them over time. Methods The present study recruited adult native Taiwanese volunteers without known neurologic or psychiatric diseases. All enrolled participants received protocolized serial Qmci-TW test at baseline, 2-day follow-up, and 6-month follow-up. Results In total, 30 participants, 15 men and 15 women, were enrolled in this study. The baseline Qmci-TW score ranged from 55 to 80, with a mean of 68.9 and a standard deviation (SD) of 7. At 2-day follow-up, the mean Qmci-TW test score was significantly higher (by 5.3; SD = 7.3) than that at baseline (P = 0.001). At 6-month follow-up, the mean Qmci-TW score was 71.3 (SD = 6.1), with no significant difference compared with that at baseline. The decline in Qmci-TW scores by > 9 points on postoperative day 1 and by > 11 points at 6-month follow-up was the criterion for POCD. Conclusion The present study provided data regarding the Qmci-TW test conducted in the normative Taiwanese population and its time trajectory during the 6-month follow-up.

The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA-associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target.Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient-derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target.PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers. Mechanistic studies showed that c-Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR-mitogen-activated protein kinase (MAPK) signaling activation, which resulted in FOS-related antigen 1 (FRA-1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels.PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer. c-Myc-driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR-MAPK-FRA-1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.

To establish and validate a CT radiomics model for prediction of induction chemotherapy (IC) response and progression-free survival (PFS) among patients with locally advanced hypopharyngeal carcinoma (LAHC).One hundred twelve patients with LAHC (78 in training cohort and 34 in validation cohort) who underwent contrast-enhanced CT (CECT) scans prior to IC were enrolled. Least absolute shrinkage and selection operator (LASSO) was used to select the crucial radiomic features in the training cohort. Radiomics signature and clinical data were used to build a radiomics nomogram to predict individual response to IC. Kaplan-Meier analysis and log-rank test were used to evaluate ability of radiomics signature in progression-free survival risk stratification.The radiomics signature consisted of 6 selected features from the arterial and venous phases of CECT images and demonstrated good performance in predicting the IC response in both two cohorts. The radiomics nomogram showed good discriminative performance, and the C-index of nomogram was 0.899 (95% confidence interval (CI), 0.831-0.967) and 0.775 (95% CI, 0.591-0.959) in the training and validation cohorts, respectively. Survival analysis indicated that low-risk and high-risk groups defined by the value of radiomics signature had significant difference in PFS (3-year PFS 66.4% vs 29.7%, p0.001).Multiparametric CT-based radiomics model could be useful for predicting treatment response and PFS in patients with LAHC who underwent IC.• CT radiomics can predict IC response and progression-free survival in hypopharyngeal carcinoma. • We combined significant radiomics signature with clinical predictors to establish a nomogram to predict individual response to IC. • Radiomics signature could divide patients into the high-risk and low-risk groups based on the PFS.

Onychomycosis is a common fungal infection of the nail. Laser and topical antifungal agent combination therapy is an emerging treatment for onychomycosis. The objective of this study was to systematically evaluate the efficacy and safety of laser and topical antifungal agent combination therapy for onychomycosis.The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang and VIP databases were searched from inception to November 2021. Randomised controlled trials (RCTs) on laser therapy combined with topical antifungal agents for onychomycosis were included. The Cochrane Collaboration tool was used to assess the risk of bias, and Revman 5.3 software was used in the meta-analysis.Twelve studies involving 869 patients were included in this meta-analysis. The results showed that compared with topical antifungal agents alone, laser and topical antifungal agent combination therapy was superior in terms of the complete cure rate (RR 6.04,95% CI (2.17, 16.85), P = 0.0006), mycological cure rate (RR 1.27, 95% CI (1.10, 1.48), P = 0.001), clinical effective rate (RR 1.38, 95% CI (1.20, 1.57), P 0.00001) and patient satisfaction rate (RR 1.47,95% CI (1.17, 1.84), P = 0.0009).The subgroup analysis of outcome indicators, including mycological cure rate and clinical effective rate, demonstrated that both carbon dioxide (COThe present study indicated that laser and topical antifungal agent combination therapy is effective for onychomycosis. However, more large-scale and well-designed RCTs are warranted.

The tumor immunosuppressive microenvironment can influence treatment response and outcomes. A previously validated immunosuppression scoring system (ISS) assesses multiple immune checkpoints in gastric cancer (GC) using tissue-based assays. We aimed to develop a radiological signature for non-invasive assessment of ISS and treatment outcomes.A total of 642 patients with resectable GC from three centers were divided into four cohorts. Radiomic features were extracted from portal venous-phase CT images of GC. A radiomic signature for predicting ISS (RISS) was constructed using the least absolute shrinkage and selection operator (LASSO) regression method. Moreover, we investigated the value of the RISS in predicting survival and chemotherapy response.The RISS, which consisted of 10 selected features, showed good discrimination of immunosuppressive status in three independent cohorts (area under the curve = 0.840, 0.809, and 0.843, respectively). Multivariate analysis revealed that the RISS was an independent prognostic factor for both disease-free survival (DFS) and overall survival (OS) in all cohorts (all p 0.05). Further analysis revealed that stage II and III GC patients with low RISS exhibited a favorable response to adjuvant chemotherapy (OS: hazard ratio [HR] 0.407, 95% confidence interval [CI] 0.284-0.584); DFS: HR 0.395, 95% CI 0.275-0.568). Furthermore, the RISS could predict prognosis and select stage II and III GC patients who could benefit from adjuvant chemotherapy independent of microsatellite instability status and Epstein-Barr virus status.The new, non-invasive radiomic signature could effectively predict the immunosuppressive status and prognosis of GC. Moreover, the RISS could help identify stage II and III GC patients most likely to benefit from adjuvant chemotherapy and avoid overtreatment.

To explore the diagnostic performance and interreader agreement of CEUS LI-RADS in diagnosing ≤ 30 mm liver nodules with different experienced radiologists.Between January 2018 and October 2020, 244 patients at high-risk for HCC who underwent CEUS were enrolled. Two novice radiologists and two expert radiologists independently evaluated LI-RADS categories and main features. Kappa (κ) and Kendall's tests were employed to evaluate the interreader agreement of CEUS LI-RADS. The diagnostic performance was determined based on sensitivity, specificity, accuracy, PPV and NPV.The interreader agreement for arterial phase hyperenhancement, late and mild washout, early washout, and rim hyperenhancement was moderate to almost perfect (κ, 0.44-0.93) among the different levels of radiologists. The interreader agreement for the LI-RADS categories was substantial to almost perfect (κ, 0.78-0.88). However, the interreader agreement for marked washout was fair to moderate (κ, 0.28-0.50). When CEUS LR-5 was used as a diagnostic criterion for HCC, there were no statistical differences in sensitivity, specificity, accuracy, PPV and NPV among the radiologists (p 0.05), except for the differences between Reader 4 and the remaining three radiologists in terms of accuracy and sensitivity (p 0.05).CEUS LI-RADS has good diagnostic agreement for ≤ 30 mm liver nodules among experienced radiologists.

To establish and validate a radiomics signature for stratifying the risk of progression-free survival (PFS) in patients with locally advanced hypopharyngeal carcinoma (LAHC) undergoing induction chemotherapy (IC).We extracted radiomics features from baseline contrast-enhanced computed tomography (CECT) images. We enrolled 112 LAHC patients (78 in the training cohort and 34 in the validation cohort). We used cox regression model and random survival forests variable hunting (RSFVH) algorithm for feature selection and radiomics signature building. The radiomics signature was established in the training cohort and tested in the validation cohort. We used the Kaplan-Meier analysis and log-rank test to evaluate the ability of radiomics signature in PFS risk stratification among patients with different IC responses and constructed a radiomics nomogram to predict individual PFS risk.The radiomics signature performed well in stratifying patients into highrisk and low-risk groups of progression in both the training and validation cohorts. The radiomics nomogram showed good discriminative ability for predicting PFS. Survival outcome analysis of subsets indicated that the radiomics signature performed well in stratifying the risk of PFS in patients with LAHC with different IC responses.The radiomics signature was a pretreatment predictor for PFS in patients with LAHC who exhibited different responses to IC.

Among the recently described subtypes in childhood B-lymphoblastic leukemia (B-ALL) were DUX4- and PAX5-altered (PAX5alt). By using whole transcriptome RNA sequencing in 377 children with B-ALL from the Malaysia-Singapore ALL 2003 (MS2003) and Malaysia-Singapore ALL 2010 (MS2010) studies, we found that, after hyperdiploid and ETV6-RUNX1, the third and fourth most common subtypes were DUX4 (n = 51; 14%) and PAX5alt (n = 36; 10%). DUX4 also formed the largest genetic subtype among patients with poor day-33 minimal residual disease (MRD; n = 12 of 44). But despite the poor MRD, outcome of DUX4 B-ALL was excellent (5-year cumulative risk of relapse [CIR], 8.9%; 95% confidence interval [CI], 2.8%-19.5% and 5-year overall survival, 97.8%; 95% CI, 85.3%-99.7%). In MS2003, 21% of patients with DUX4 B-ALL had poor peripheral blood response to prednisolone at day 8, higher than other subtypes (8%; P = .03). In MS2010, with vincristine at day 1, no day-8 poor peripheral blood response was observed in the DUX4 subtype (P = .03). The PAX5alt group had an intermediate risk of relapse (5-year CIR, 18.1%) but when IKZF1 was not deleted, outcome was excellent with no relapse among 23 patients. Compared with MS2003, outcome of PAX5alt B-ALL with IKZF1 codeletion was improved by treatment intensification in MS2010 (5-year CIR, 80.0% vs 0%; P = .05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 codeletion.

Graphical Abstract Engineering approaches for growth factor delivery have been considerably advanced for tissue regeneration, yet most of them fail to provide a complex combination of signals emulating a natural healing cascade, which substantially limits their clinical successes. Herein, we aimed to emulate the natural bone healing cascades by coupling the processes of angiogenesis and osteogenesis with a hybrid dual growth factor delivery system to achieve vascularized bone formation. Basic fibroblast growth factor (bFGF) was loaded into methacrylate gelatin (GelMA) to mimic angiogenic signalling during the inflammation and soft callus phases of the bone healing process, while bone morphogenetic protein-2 (BMP-2) was bound onto mineral coated microparticles (MCM) to mimics osteogenic signalling in the hard callus and bone remodelling phases. An Initial high concentration of bFGF accompanied by a sustainable release of BMP-2 and inorganic ions was realized to orchestrate well-coupled osteogenic and angiogenic effects for bone regeneration. In vitro experiments indicated that the hybrid hydrogel markedly enhanced the formation of vasculature in human umbilical vein endothelial cells (HUVECs), as well as the osteogenic differentiation of mesenchymal stem cells (BMSCs). In vivo results confirmed the optimal osteogenic performance of our F/G-B/M hydrogel, which was primarily attributed to the FGF-induced vascularization. This research presents a facile and potent alternative for treating bone defects by emulating natural cascades of bone healing. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01173-z.

Competency-based public communication skills are not systematically taught in most medical curricula, reflecting a gap between medical knowledge and holistic patient care as trainees transition into clinicians. We sought to investigate the efficacy of technology, entertainment, and design (TED) talks in postgraduate year (PGY) training programs.The authors organized an official internal TEDx event in which six PGY trainees volunteered as speakers. Two experienced physicians and two administrators also participated as speakers to provide trainees a didactic shadow learning experience. The remaining PGY trainees, along with clerks, physicians, nurses, pharmacists, and administrators, attended the conference. Before the event, speakers undertook individual training sessions and learned the principles of the presentation structure and storytelling mode. At the end of the event, a survey evaluating overall satisfaction in communication skills and professionalism was administered to all of the attendees.Survey participants totaled 104, with a response rate of 97.2%. TEDx talks improved trainees' levels of patient care, communication, and professionalism. Speakers reported the high level of satisfaction with the event (mean 4.96 on a 5-point Likert scale; standard deviation 0.20). Participants agreed that the shadowing experience was useful and that the event encouraged them to pursue interests outside the medical field.This study highlights that TED is successful in terms of participant satisfaction and training in communication and professionalism. Engaging and training PGY trainees through TED-style events could bridge the gap between acquired knowledge and professional competencies. The authors recommend the implementation of TED-style events in medical training programs.

Regulatory T cell (Treg) stability is necessary for the proper control of immune activity and tissue homeostasis. However, it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions. Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability. Here, we demonstrate that to maintain Foxp3 protein expression, Tregs require cell-to-cell contact, which is mediated by the CD147-CD98 interaction. As Tregs are produced, CD147, which is expressed on their surface, is stimulated by CD98, which is widely expressed in the physiological environment. As a result, CD147’s intracellular domain binds to CDK2 and retains it near the membrane, leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation. In addition, the optimal distribution of Foxp3+ Tregs under both pathological and physiological conditions depends on CD98 expression. Thus, our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment. More importantly, Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability, which has guiding significance for the application of Tregs in immunotherapy.

Objective This study investigated the role of radiomics in evaluating the alterations of oncogenic signaling pathways in head and neck cancer. Methods Radiomics features were extracted from 106 enhanced computed tomography images with head and neck squamous cell carcinoma. Support vector machine-recursive feature elimination was used for feature selection. Support vector machine algorithm was used to develop radiomics scores to predict genetic alterations in oncogenic signaling pathways. The performance was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve. Results The alterations of the Cell Cycle, HIPPO, NOTCH, PI3K, RTK RAS, and TP53 signaling pathways were predicted by radiomics scores. The AUC values of the training cohort were 0.94, 0.91, 0.94, 0.93, 0.87, and 0.93, respectively. The AUC values of the validation cohort were all greater than 0.7. Conclusions Radiogenomics is a new method for noninvasive acquisition of tumor molecular information at the genetic level.

Background 46,XX male disorders of sex development are rare. Approximately 80% of cases of testicular tissue differentiation may be due to translocation of SRY to the X chromosome or an autosome. SRY-negative 46,XX males show overexpression of pro-testis genes, such as SOX9 and SOX3, or failure of pro-ovarian genes, such as WNT4 and RSPO1, which induces testis differentiation, however, almost all testicles exhibit dysgenesis. Following inadequate exposure to androgens during the embryo stage, remnants of the Mullerian duct and incomplete closure of the urogenital sinus lead to enlargement of prostatic utricles. This condition is associated with proximal hypospadias and disorders of sex development. Many cases are asymptomatic, but show increased rates of postoperative complications and surgical failure. Case presentation A 5-year-old Chinese boy with scrotal hypospadias and bilateral cryptorchidism with prostatic utricles was presented. Gonadal histology showed ovo-testicular tissue on the right side and testicular tissue on the left side; all testicular tissue exhibited dysgenesis. Furthermore, chromosome karyotype analysis revealed 46,XX and, the presence of SRY was ruled out by polymerase chain reaction analysis. Whole-genome analysis showed the boy has a 1.4-Mb duplication in the Xq27.1q27.2 region (arr[hg19]Xq27.1q27.2:139585794–140996652) involving SOX3. No SOX3 duplication was observed in the parents, who had a normal phenotype. Conclusions We report the first case of an SRY-negative 46 XX male with prostatic utricle caused by SOX3 duplication. SOX3 duplication may cause sex reversal, and all 46,XX SRY-negative males should be screened for SOX3 mutations. Gonadal biopsy is recommended to evaluate ovarian and testicular tissue development. Testicular dysgenesis and low exposure to male hormones during fetal development can lead to enlarged prostatic utricles. Thus endoscopic examination should be performed preoperatively to detect prostatic utricles in SRY-negative 46,XX males to determine the surgical plan and reduce postoperative complications.

Purpose: There is still no standard nonsurgical regimen for conventional chondrosarcoma (CHS). We aimed to identify whether any CHSs have a favored microenvironment for immunotherapy via multidimensional evaluation of the immunologic characteristics of this tumor. Experimental Design: We obtained 98 newly-diagnosed CHS fresh tumors from several institutions and performed comprehensive analysis of data from CyTOF, whole-exome sequencing, and flow cytometry in 22 cases. Clinical data from immunotherapy responders and nonresponders were compared to explore possible biomarkers of immunotherapy response. Mechanism studies were conducted to interpret the biomarker phenotype. Results: Based on the integrated data of single-cell CyTOF and flow cytometry, the CHS immune-microenvironment phenotypes were classified into three groups: subtype I, the “granulocytic–myeloid-derived suppressor cell (G-MDSC) dominant” cluster, with high number of HLA-DR− CD14− myeloid cells; subtype II, the “immune exhausted” cluster, with high exhausted T-cell and dendritic-cell infiltration; and subtype III, the “immune desert” cluster, with few immune cells. Immune cell–rich subtypes (subtype I and II) were characterized by IDH mutation, pathologic high grade, and peritumoral edema, while subtype I cases were exclusively featured by myxoid transformation. In clinical practice involving 12 individuals who received PD-1 antibody immunotherapy, all of the 3 cases with controlled diseases were retrospectively classified as subtype II. In mechanism, IDH mutation significantly elevated chemokine levels and immune-cell infiltration in immune-inactivated tumors. Conclusions: This study is the first to provide immune characterization of CHS, representing a major step to precise immunotherapy against this malignancy. Immunotherapy is promising for the “immune exhausted” subtype of patients with CHS.

High-grade gliomas are notorious for a high recurrence rate even after curative resection surgery. Studies regarding the influence of scalp block on high-grade gliomas have been inconclusive, possibly because the condition’s most important genetic mutation profile, namely the isocitrate dehydrogenase 1 (IDH1) mutation, had not been analyzed. Therefore, we conducted a single-center study including patients with high-grade glioma who underwent tumor resection between January 2014 and December 2019. Kaplan–Meier survival analysis revealed that scalp block was associated with longer progression-free survival (PFS; 15.17 vs. 10.77 months, p = 0.0018), as was the IDH1 mutation (37.37 vs. 10.90 months, p = 0.0149). Multivariate Cox regression analysis revealed that scalp block (hazard ratio: 0.436, 95% confidence interval: 0.236–0.807, p = 0.0082), gross total resection (hazard ratio: 0.405, 95% confidence interval: 0.227–0.721, p = 0.0021), and IDH1 mutation (hazard ratio: 0.304, 95% confidence interval: 0.118–0.784, p = 0.0138) were associated with better PFS. Our results demonstrate that application of scalp block, regardless of IDH1 profile, is an independent factor associated with longer PFS for patients with high-grade glioma.

Background Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. Methods Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. Results A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. Conclusions Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Femoral shaft fractures (FSFs) are associated with significant blood loss, resulting in anemia and hemorrhagic shock. However, there has been limited data for the blood loss of FSFs during the whole perioperative period. Our primary aim is to quantify the blood loss associated with FSFs treated with intramedullary nail or locking compression plate fixation, as well as to identify the relative affecting factors for perioperative hidden blood loss (HBL).131 consecutive patients with FSFs were enrolled in the retrospective study between January 2009 and January 2020, including 90 cases for intramedullary nail (Nail group) and 41 cases for locking compression plate fixation (Plate group). Demographics and perioperative data were collected and analyzed. Total blood loss (TBL), visible blood loss (VBL), HBL, and percentage of HBL (PHBL) were calculated based on hematocrit (Hct) changes.There was a large drop of hemoglobin (Hb) during the perioperative time. Of all 131 patients, the average HBL was 1445.5 ± 443.2 mL, accounting for 78.7% of TBL (1815.1 ± 446.3 mL). TBL and HBL in Nail group were 1886.1 ± 438.6 mL and 1546.0 ± 424.7 mL; while TBL and HBL in Plate group were 1659.5 ± 427.9 mL and 1225.1 ± 405.7 mL. The differences between the two groups were statistically significant (p = 0.007, p0.001, respectively). Besides, statistical significance (p0.05, p0.05, respectively) was also reported in HBL between Type-A and Type-C, and between Type-B and Type-C (1395.8 ± 444.8 mL vs. 1651.6 ± 495.7 mL; and 1411.2 ± 383.4 mL vs. 1651.6 ± 495.7 mL, respectively).Patients of FSFs had significant TBL and HBL, the amount of which was much larger than that observed intra-operatively. Moreover, two readily available preoperative factors for nail fixation and Type-C were associated with a higher likelihood of more HBL. Therefore, it was argued that regular perioperative monitoring and timely blood transfusion were crucially important for patients to avoid possible risks of anemia and facilitate recovery.

Hepatoblastoma is a kind of extreme malignancy frequently diagnosed in children. Although surgical resection is considered as the first-line treatment for hepatoblastoma, a relatively large population of patients have lost the preferred opportunity for surgery. Administration of locoregional ablation enables local tumor control but with the deficiency of insufficient ablation, residual tumor, and rapid progression. In this study, we integrated 219 hepatoblastoma and 121 non-cancer liver tissues to evaluate the expression of NR2F6, from which a higher NR2F6 level was found in hepatoblastoma compared with non-cancer livers with a standard mean difference (SMD) of 1.04 (95% CI: 0.79, 1.29). The overexpression of NR2F6 also appeared to be an efficient indicator in distinguishing hepatoblastoma tissues from non-cancer liver tissues from the indication of a summarized AUC of 0.90, with a pooled sensitivity of 0.76 and a pooled specificity of 0.89. Interestingly, nude mouse xenografts provided direct evidence that overexpressed NR2F6 was also detected in residual tumor compared to untreated hepatoblastoma. Chromatin immunoprecipitation-binding data in HepG2 cells and transcriptome analysis of HepG2 xenografts were combined to identify target genes regulated by NR2F6. We finally selected 150 novel target genes of NR2F6 in residual tumor of incomplete ablation, and these genes appeared to be associated with the biological regulation of lipid metabolism-related pathway. Accordingly, targeting NR2F6 holds a therapeutic promise in treating residual recurrent hepatoblastoma after incomplete ablation., GRAPHICAL ABSTRACT

Oesophageal squamous cell carcinoma (ESCC) is a malignant tumour of the digestive system that is associated with high morbidity and mortality rates worldwide. With the increased use of immunotherapy in cancer treatment, there is an urgent need to elucidate the immune-related mechanisms in ESCC and other digestive system carcinomas.In our study, single-sample gene set enrichment analysis (ssGSEA) was first performed to analyse the expression profile downloaded from the NCBI Gene Expression Omnibus (GEO) database. Then,Our analyses showed that the numbers of infiltrating macrophages were obviously higher in advanced stages in ESCC compared with other types of immunocytes. MEOX2 was identified as a biomarker correlated with macrophage infiltration in ESCC and other types of digestive system carcinomas. And MEOX2 expression was strongly associated with the mRNA expression of colony-stimulating factor 1 (CSF-1) and CSF-1 receptor (CSF-1R) in these kinds of carcinomas.We speculated that MEOX2 could facilitate macrophage infiltration

N6-methyladenosine (m6A) is the most common modification on endogenous RNA transcripts in mammalian cells. Currently, the lack of precise single-nucleotide RNA modification tools makes it challenging to understand the relationship between site-specific RNA methylation and the corresponding phenotypic outcomes. Here, we developed a bidirectional dCasRx epitranscriptome editing platform composed of a nucleus-localized dCasRx conjugated with either a methyltransferase, METTL3, or a demethylase, ALKBH5, to manipulate methylation events at targeted m6A sites in HEK293T and glioma stem cells. This platform specifically and efficiently edited m6A modifications at targeted sites, modulating both gene expression and cell proliferation. We then employed the dCasRx epitranscriptomic editor to further elucidate the molecular function of m6A-binding proteins YTH (DF1, DF2, DF3) family and found that the YTH paralogs act together to mediate RNA degradation. These findings collectively demonstrate that the dCasRx epitranscriptome perturbation platform reported in this study can be employed as site-specific m6A editors for delineating the functional roles of individual m6A modifications in the mammalian epitranscriptome.

Dysregulation of glucose homeostasis contributes to insulin resistance and type 2 diabetes. Whilst exercise stimulated activation of AMP-activated protein kinase (AMPK), an important energy sensor, has been highlighted for its potential to promote insulin-stimulated glucose uptake, the underlying mechanisms for this remain largely unknown. Here we found that AMPK positively regulates the activation of Rab5, a small GTPase which is involved in regulating Glut4 translocation, in both myoblasts and skeletal muscles. We further verified that TBC1D17, identified as a potential interacting partner of Rab5 in our recent study, is a novel GTPase activating protein (GAP) of Rab5. TBC1D17-Rab5 axis regulates transport of Glut1, Glut4, and transferrin receptor. TBC1D17 interacts with Rab5 or AMPK via its TBC domain or N-terminal 1-306 region (N-Ter), respectively. Moreover, AMPK phosphorylates the Ser 168 residue of TBC1D17 which matches the predicted AMPK consensus motif. N-Ter of TBC1D17 acts as an inhibitory region by directly interacting with the TBC domain. Ser168 phosphorylation promotes intra-molecular interaction and therefore enhances the auto-inhibition of TBC1D17. Our findings reveal that TBC1D17 acts as a molecular bridge that links AMPK and Rab5 and delineate a previously unappreciated mechanism by which the activation of TBC/RabGAP is regulated.

Background Although the incidence of lymph node (LN) metastasis (LNM) along the left gastric artery is high, its relationship with the prognosis in postoperative patients with esophageal squamous cell carcinoma (ESCC) is rarely reported. This study clarified the prognostic impact of LNM along the left gastric artery in postoperative patients with ESCC. Methods This study assessed data of 1521 patients with ESCC who underwent esophagectomy at the Sun Yat-sen University Cancer Center between March 1992 and March 2012. A chi-squared test and Mann-Whitney U test were used to explore the preliminary correlation between clinical factors and LNM along the left gastric artery. Univariate and multivariate Cox regression analyses were used to assess whether LNM along the left gastric artery was an independent predictor of overall survival. Kaplan–Meier analysis and the log-rank test were used to present a classifying effect based on LN status. Results LNM was observed in 598 patients (39.3%) and was found along the branches of the left gastric artery in 256 patients (16.8%). The patients were classified into two groups based on the presence of LNM along the left gastric artery. Patients without LNM along the left gastric artery had better cancer-specific survival than those with positive LNs (P Conclusions This study indicated that LNM along the left gastric artery was an important independent prognostic factor for long-term survival among ESCC patients (P = 0.011).

Objective The aim of this evidence implementation project was to identify the barriers and omissions affecting adequacy of hemodialysis and to develop implementable strategies to maintain hemodialysis adequacy among hemodialysis patients with end-stage renal disease. Introduction Assessing adequacy of hemodialysis and improving quality of life are important issues for patients with end-stage renal disease. However, they are often inadequately addressed, and evidence-based practices are not always followed. Methods A clinical audit was undertaken using the Joanna Briggs Institute Practical Application of Clinical Evidence System and Getting Research into Practice approaches. Seven audit criteria that represent best practice recommendations for maintaining hemodialysis adequacy among hemodialysis patients were used. A baseline audit was performed, which was followed by the implementation of multiple improvement strategies over 20 weeks and the outcomes finalized using a follow-up audit to determine the change to be implemented in practice. Results The baseline audit results showed that most audit criteria were less than 77% in practice. The compliance rates for nurses who had received education regarding hemodialysis, checking the prescription order for each patient at each session, and using the prescribed dialyzer for every session were determined to have reached 100% at the follow-up audit. The compliance rates for completion prehemodialysis checks, using a sterile technique when inserting an arteriovenous catheter, matching a blood flow rate with the prescription, and maintaining a blood flow rate throughout the treatment session were found to be 73-95% at the follow-up audit. The most significant finding was the proportion of hemodialysis patients with inadequate urea reduction ratio was reduced from 4.6 to 3.2% after implementation of the best practice approaches. Conclusion The implementation of institution-specific evidence-based resources brought about immediate improvements in hemodialysis adequacy management and practice. A variety of strategies contributed to the success of this implementation project, such as scenario simulation education, Objective Structured Clinical Examination, the interrelation response system Kahoot, the use of hemodialysis International Organization for Standardization job descriptions, regular weekly audits, and collaboration with physicians when caring for patients during clinical practice.

OBJECTIVE: To explore the feasibility of using the threshold of neural response telemetry(NRT) to guide postoperative machine adjustment by analyzing the regularity and correlation between the threshold of subjective behavior test and NRT in cochlear implant patients with normal cochlear morphology and inner ear malformation. METHODS: Thirty cochlear implant patients with normal cochlear morphology and 12 cochlear implant patients with inner ear malformation were selected for NRT test and subjective behavior test, respectively. Electrode 1 representing high frequency, electrode 11 representing medium frequency and electrode 22 representing low frequency were selected to analyze the correlation between NRT threshold and T value and C value. RESULTS: The mean NRT threshold values of the cochlear normal group and the inner ear malformation group were both greater than T value, close to and slightly smaller than C value. The T value, C value and NRT threshold of the inner ear malformation group were slightly higher than those of the cochlear normal group. The NRT thresholds of high, middle and low frequency bands were significantly correlated with C and T values in the normal cochlear group and the inner ear malformation group. Compared with the normal cochlear group, the regression coefficients B of NRT threshold and T value in the high, medium and low frequency groups were 20.90%, 3.02%, 9.68%, and the K coefficients were 13.01%, 3.92%, 5.28%. The regression coefficients B of NRT threshold and C value of the two groups were 15.74%, 2.51%, 0.53%, and K were 14.44%, 0.24%, 4.09%, respectively. It can be seen that the correlation between NRT threshold and T value and C value of the two groups was significantly different in the high frequency band, but similar in the low and middle frequency band. CONCLUSION: The NRT threshold is significantly correlated with the threshold of subjective behavior test. The linear regression equation obtained can be used to guide the cochlear implant tuning machine, especially for the high frequency band T and C values of patients with inner ear malformation implantation. Different regression equations should be used to estimate the T and C values of patients with normal cochlea, so as to obtain more accurate T and C values.

Polystyrene nanoplastics (PS NPs) contamination is a serious problem for human and animal health. Excessive exposure to PS NPs can affect the structure and function of the heart. And lipopolysaccharide (LPS) induces myocardial damage, leading to myocardial fibrosis (MF). To investigate whether PS NPs exacerbate LPS-induced myocardial autophagy and fibrosis, we established in vivo and in vitro models of PS NPs/LPS exposure alone and in combination. We found that PS NPs/LPS exposure disrupts myocardial structure, significantly increases reactive oxygen species (ROS), triggers oxidative stress, promotes TGF-β1/Smad pathway activation, and leads to elevated levels of fibrotic proteins and collagen. Meanwhile, activation of AMPK/mTOR/ULK1 signaling pathway induced autophagy onset, and combined exposure of PS NPs/LPS exacerbated MF and autophagy. H9C2 cells were used for in vitro experiments, and the experimental results showed that the addition of TGF-β receptor inhibitor LY2109761 to the exposed group not only inhibited the upregulation of fibrotic genes but also effectively reduced the expression of autophagic signals, indicating that combined exposure of PS NPs and LPS mediates and regulates cardiac autophagy through TGF-β1. The above results suggest that PS NPs exacerbate LPS-induced MF and autophagy in mice via ROS/TGF-β1/Smad. Our study provides some new evidence to clarify the potential mechanisms of PS NPs-induced cardiotoxicity.

Precise timing of macrophage polarization plays a pivotal role in immunomodulation of tissue regeneration, yet most studies mainly focus on M2 macrophages for their anti-inflammatory and regenerative effects while the essential proinflammatory role of the M1 phenotype on the early inflammation stage is largely underestimated. Herein, a superparamagnetic hydrogel capable of timely controlling macrophage polarization is constructed by grafting superparamagnetic nanoparticles on collagen nanofibers. The magnetic responsive hydrogel network enables efficient polarization of encapsulated macrophage to the M2 phenotype through the podosome/Rho/ROCK mechanical pathway in response to static magnetic field (MF) as needed. Taking advantage of remote accessibility of magnetic field together with the superparamagnetic hydrogels, a temporal engineered M1 to M2 transition course preserving the essential role of M1 at the early stage of tissue healing, as well as enhancing the prohealing effect of M2 at the middle/late stages is established via delayed MF switch. Such precise timing of macrophage polarization matching the regenerative process of injured tissue eventually leads to optimized immunomodulatory bone healing in vivo. Overall, this study offers a remotely time-scheduled approach for macrophage polarization, which enables precise manipulation of inflammation progression during tissue healing.

Metal-organic framework (MOF) derivatives with unique physicochemical and electronic properties have seen a tremendous growth in diverse applications. Organic optobioelectronics have long been pursued in modern electronics for next-generation bio-relevant implementations. The intersection of these two disciplines could be an appealing way to pursue better performance of materials and devices. Herein this work reports the exploration of MOF derivatives and its ionic modulation for gating organic photoelectrochemical transistor (OPECT) biosensing. In the representative system of poly(ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) gated by zeolitic-imidazolate-framework (ZIF)-8-derived Cd

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can be effectively controlled by rapid and accurate identification of SARS-CoV-2-infected cases through large-scale screening. Hypercube pooling polymerase chain reaction (PCR) is frequently used as a pooling technique because of its high speed and efficiency. We attempted to implement the hypercube pooling strategy and found it had a large quantization effect. This raised two questions: is hypercube pooling with edge = 3 actually the optimal strategy? If not, what is the best edge and dimension? We used a C++ program to calculate the expected number of PCR tests per patient for different values of prevalence, edge, and dimension. The results showed that every edge had a best performance range. Then, using C++ again, we created a program to calculate the optimal edge and dimension required for pooling samples when entering prevalence into our program. Our program will be provided as freeware in the hope that it can help governments fight the SARS-CoV-2 pandemic.

The importance of supplementary motor area (SMA) for motor function and compensation for primary motor area (M1) has received increased attention. We used diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS) to evaluate structure and function of corticospinal projection originating from SMA. Fibers of corticospinal projection originating from M1 (CST) and SMA (ACST) were analyzed. ACST originating from mesial SMA area formed separate white matter bundles leaving the anterior part of M1 area, which then entered the posterior limb of the internal capsule. Projection and overlap of both CST and ACST were detected on medulla. Fibers of contralesional ACST were more than that of ipsilesional ACST in patients with SMA tumors (p

Background To explore the postoperative prognosis of esophageal squamous cell carcinoma (ESCC) patients with stage IB/IIA, using a prognostic score (PS). Methods Stage IB/IIA ESCC patients who underwent esophagectomy from 1999 to 2010 were included. We retrospectively recruited 153 patients and extracted their medical records. Moreover, we analyzed the programmed death ligand-1 (PD-L1) expression of their paraffin tissue. The cohort were randomly divided into a training group (N = 123) and a validation group (N = 30). We selected overall survival (OS) as observed endpoint. Prognostic factors with a multivariable two-sided P Results Univariable and multivariable analyses identified pTNM stage, the number of lymph nodes (NLNs) and PD-L1 expression as independent OS predictors. Primary prognostic score which comprised above three covariates adversely related with OS in two cohorts. PS discrimination of OS was comparable between the training and internal validation cohorts (C-index = 0.774 and 0.801, respectively). In addition, the PS system had an advantage over pTNM stage in the identification of high-risk patients (C-index = 0.774 vs. C-index = 0.570, P Conclusion Our study suggested a PS for significant clinical stratification of IB/IIA ESCC to screen out subgroups with poor prognosis.

Objective To investigate the incidence and risk factors of bone cement implantation syndrome (BCIS) in bone tumor surgeries. Methods This was a retrospective observational study. We investigated patients who underwent bone tumor surgeries requiring cementation as part of the surgery between March 2016 and January 2018. We reviewed medical records, including formal anesthesia records and operation notes. Patients with complete data files were included. To investigate the general incidence of BCIS in tumor surgeries, patients of all ages, genders and tumor types were included. Vital signs, including oxygen saturation, blood pressure, heart rate, and respiratory rate, were checked and recorded once every 1–2 min after cementation. Accurate time points of cementation were recorded on formal anesthesia record sheets by the anesthesiologists. The definition and severity of BCIS were based on the classification system proposed in previous studies: grade I, moderate hypoxia (SpO2 20%); grade II, severe hypoxia (SpO2 40%) or unexpected loss of consciousness; and grade III, cardiovascular collapse requiring cardiopulmonary resuscitation. We also compared the incidence of BCIS between those patients with and without possible risk factors, including intraoperative blood loss, arthroplasty, use of an intramedullary device, patient age, gender, tumor location, and preexisting lung cancer or lung metastasis. Results A total of 88 patients were included. BCIS occurred in 23 patients, with an incidence of 26.1%. Among them, 19 had grade I and 4 had grade II BCIS. There was no patients with grade III BCIS. The lowest blood pressure occurred within 10 min in 21 (87.5%) patients and within 20 min for all patients. A total of 9 grade I BCIS were self‐limiting. The other 10 grade I hypotension cases and all grade II hypotension cases recovered after administration of a vasoconstrictor medication. Preexisting lung cancer or lung metastasis was the risk factor for BCIS; 40.0% of patients (16 in 40 patients) with preexisting lung cancer or metastasis had BCIS, whereas only 14.6% of patients (7 in 48 patients) without lung lesions had BCIS. There was no risk difference in terms of arthroplasty, old age, and increased blood loss. Apart from grades I and II bone cement implantation syndrome, there were no other major complications, including death, cardiovascular events, or cerebrovascular events. Conclusion Bone cement implantation syndrome is not unusual in bone tumor surgeries, and preexisting lung cancer or lung metastasis is a risk factor., The incidence of bone cement implantation syndrome (BCIS) in bone tumor surgeries was 26%. The incidence of grade I and grade II BCIS was 22% and 4%, respectively.

Bladder cancer is a common tumor type of the urinary system, which has high levels of morbidity and mortality. The first‑line treatment is cisplatin‑based combination chemotherapy, but a significant proportion of patients relapse due to the development of drug resistance. Therapy‑induced senescence can act as a 'back‑up' response to chemotherapy in cancer types that are resistant to apoptosis‑based anticancer therapies. The circadian clock serves an important role in drug resistance and cellular senescence. The aim of the present study was to investigate the regulatory effect of the circadian clock on paclitaxel (PTX)‑induced senescence in cisplatin‑resistant bladder cancer cells. Cisplatin‑resistant bladder cancer cells were established via long‑term cisplatin incubation. PTX induced apparent senescence in bladder cancer cells as demonstrated via SA‑β‑Gal staining, but this was not observed in the cisplatin‑resistant cells. The cisplatin‑resistant cells entered into a quiescent state with prolonged circadian rhythm under acute PTX stress. It was identified that the circadian protein cryptochrome1 (CRY1) accumulated in these quiescent cisplatin‑resistant cells, and that CRY1 knockdown restored PTX‑induced senescence. Mechanistically, CRY1 promoted p53 degradation via increasing the binding of p53 with its ubiquitin E3 ligase MDM2 proto‑oncogene. These data suggested that the accumulated CRY1 in cisplatin‑resistant cells could prevent PTX‑induced senescence by promoting p53 degradation.

Coronavirus disease-2019 (COVID-19) has become a pandemic disease globally. The First Affiliated Hospital of Chengdu Medical College has adopted telestroke to make stroke care accessible in remote areas. During the period January 2020 to March 2020, there was no COVID-19 case reported in our stroke center. A significant reduction of stroke admission was observed between the ischemic stroke group (235 vs. 588 cases) and the intracerebral hemorrhage group (136 vs. 150 cases) when compared with the same period last year (p < 0.001). The mean door-to-needle time (DNT) and door-to-puncture time (DPT) was 62 and 124 min, respectively. Compared to the same period last year, a significant change was observed in DNT (62 ± 12 vs. 47 ± 8 min, p = 0.019) but not in DPT (124 ± 58 vs. 135 ± 23 min, p = 0.682). A total of 46 telestroke consultations were received from network hospitals. Telestroke management in the central hospital was performed on 17 patients. Of them, 3 (17.6%) patients had brain hernia and died in hospital and 8 (47.1%) patients were able to ambulation at discharge and had a modified Rankin Scale of 0–2 at 3 months. The COVID-19 pandemic impacted stroke care significantly in our hospital, including prehospital and in-hospital settings, resulting in a significant drop in acute ischemic stroke admissions and a delay in DNT. The construction of a telestroke network enabled us to extend health-care resources and make stroke care accessible in remote areas. Stroke education and public awareness should be reinforced during the COVID-19 pandemic.

Background:. Minimal change nephropathy (MCD) is a common pathological type of nephrotic syndrome and is often associated with acute kidney injury (AKI). This study aimed to investigate the clinical characteristics and related factors of AKI in patients with MCD and nephrotic syndrome. Methods:. Patients from Chinese People's Liberation Army General Hospital who were diagnosed with pathological renal MCD with clinical manifestations of nephrotic syndrome were included from January 1, 2013 to December 31, 2017. Patients diagnosed with membranous nephropathy (MN) by renal biopsy from January 1, 2013 to December 31, 2017 are included as a control population. We retrospectively analyzed the clinical and pathological characteristics of patients as well as the percentages and clinical characteristics of AKI in different age groups. We assessed the correlation of pathological characteristics with serum creatinine using multivariate linear regression analysis. Results:. A total of 367 patients with MCD were included in the analysis, with a sex ratio of 1.46: 1 (male: female) and an age range of 6 to 77 years. Among all the patients, 109 developed AKI (29.7%), and of these patients, 85 were male (78.0%). In the 586 patients with MN, 27 (4.6%) patients developed AKI. The percentage of AKI in MCD patients was significantly higher than that in MN patients (χ2 = 41.063, P

In the auditory system, ribbon synapses are vesicle-associated structures located between inner hair cells (IHCs) and spiral ganglion neurons that are implicated in the modulation of trafficking and fusion of synaptic vesicles at the presynaptic terminals. Synapse loss may result in hearing loss and difficulties with understanding speech in a noisy environment. This phenomenon happens without permanent hearing loss; that is, the cochlear synaptopathy is “hidden.” Recent studies have reported that synapse loss might be critical in the pathogenesis of hidden hearing loss. A better understanding of the molecular mechanisms of the formation, structure, regeneration, and protection of ribbon synapses will assist in the design of potential therapeutic strategies. In this review, we describe and summarize the following aspects of ribbon synapses: (1) functional and structural features, (2) potential mechanisms of damage, (3) therapeutic research on protecting the synapses, and (4) the role of synaptic regeneration in auditory neuropathy and the current options for synapse rehabilitation.

Microscopic type-1 tympanoplasty (T1T) is a classical method for the treatment of chronic otitis media. However, it has its limitations. The development of otoendoscopy provided a new method for T1T.To investigate the difference between endoscopic T1T and microscopic T1T.Seventy-four patients who underwent T1T were evaluated retrospectively. About 52 cases underwent endoscopic T1T, and 22 cases accepted microscopic T1T. Parameters including operative duration, incision size, graft site, duration of postoperative hospitalization, visual analog scale (VAS) score, complications, hearing improvement, and expenses were compared.Operative duration of endoscopic T1T (47.0 ± 8.2 min) was shorter than microscopic T1T (58.0 ± 9.3 min) (Endoscopic T1T is a minimally invasive surgery with similar graft success rate, comparable hearing improvement, fast recovery, low cost, and high patient satisfaction compared to microscopic T1T.

Zongqiu Wang,1,* Jiwen Hou,2,* Yu Shi,3 Qiaowen Tan,1 Lin Peng,1 Zhiying Deng,1 Zhihong Wang,1 Zongjun Guo1 1Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Geriatrics, The Affiliated Hospital of Chengdu University, Chengdu, People’s Republic of China; 3Department of Critical Medicine, Weihai Central Hospital, Weihai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zongjun GuoDepartment of Geriatrics, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong 266003, People’s Republic of ChinaEmail guozjj@163.comObjective: To explore the effects of different lifestyle choices on mild cognitive impairment (MCI) and to establish a decision tree model to analyse their predictive significance on the incidence of MCI.Methods: Study participants were recruited from geriatric and physical examination centres from October 2015 to October 2019: 330 MCI patients and 295 normal cognitive (NC) patients. Cognitive function was evaluated by the Mini-Mental State Examination Scale (MMSE) and Clinical Dementia Scale (CDR), while the Barthel Index (BI) was used to evaluate life ability. Statistical analysis included the χ2 test, logistic regression, and decision tree. The ROC curve was drawn to evaluate the predictive ability of the decision tree model.Results: Logistic regression analysis showed that low education, living alone, smoking, and a high-fat diet were risk factors for MCI, while young age, tea drinking, afternoon naps, social engagement, and hobbies were protective factors for MCI. Social engagement, a high-fat diet, hobbies, living condition, tea drinking, and smoking entered all nodes of the decision tree model, with social engagement as the root node variable. The importance of predictive variables in the decision tree model showed social engagement, a high-fat diet, tea drinking, hobbies, living condition, and smoking as 33.57%, 27.74%, 22.14%, 11.94%, 4.61%, and 0%, respectively. The area under the ROC curve predicted by the decision tree model was 0.827 (95% CI: 0.795∼ 0.856).Conclusion: The decision tree model has good predictive ability. MCI was closely related to lifestyle; social engagement was the most important factor in predicting the occurrence of MCI.Keywords: lifestyle, behaviours habit, mild cognitive impairment, influencing factors, decision tree model

Purpose: The tumor immune microenvironment (TIME) has an important impact on response to cancer immunotherapy using immune checkpoint inhibitors. Specifically, an “infiltrated-excluded”/“cold” TIME is predictive of poor response. The antidiabetic agent metformin may influence anticancer immunity in esophageal squamous cell carcinoma (ESCC). Experimental Design: We analyzed matched pre- and posttreatment ESCC specimens in a phase II clinical trial of low-dose metformin treatment (250 mg/day) to evaluate direct anti-ESCC activity and TIME reprogramming. Follow-up correlative studies using a carcinogen-induced ESCC mouse model were performed with short-term (1 week) or long-term (12 weeks) low-dose metformin (50 mg/kg/day) treatment. Results: In the clinical trial, low-dose metformin did not affect proliferation or apoptosis in ESCC tumors as assayed by Ki67 and cleaved caspase-3 immunostaining. However, metformin reprogrammed the TIME toward “infiltrated-inflamed” and increased the numbers of infiltrated CD8+ cytotoxic T lymphocyte and CD20+ B lymphocyte. Further, an increase in tumor-suppressive (CD11c+) and a decrease in tumor-promoting (CD163+) macrophages were observed. Metformin augmented macrophage-mediated phagocytosis of ESCC cells in vitro. In the ESCC mouse model, short-term metformin treatment reprogrammed the TIME in a similar fashion to humans, whereas long-term treatment further shifted the TIME toward an active state (e.g., reduction in CD4+ FoxP3+ regulatory T cells) and inhibited ESCC growth. In both humans and mice, metformin triggered AMPK activation and STAT3 inactivation, and altered the production of effector cytokines (i.e., TNFα, IFNγ, and IL10) in the immune cells. Conclusions: Low-dose metformin reprograms the TIME to an activated status and may be a suitable immune response modifier for further investigation in patients with ESCC.

Background Laryngocarcinoma (LC), in most cases a squamous cell carcinoma, accounts for 1 ~ 5% of the incidence of all tumors. At present, laryngocarcinoma is mainly managed with the integration of surgery and radio- and chemo-therapies. The current development trend of treatment is to improve the local control rate of tumor and the quality of life of patients. Intraoperative radiation therapy (IORT) is a radiotherapy that delivers single high dose irradiation at a close range to the tumor bed during the surgical operation process. It has particular radiobiological advantages in protecting normal surrounding tissues by directly applying the irradiation dose to the high-risk tumor bed area. Two forms of IORT, i.e., high dose rate (HDR) brachytherapy and external beam radiotherapy (EBRT, including electron and photono IORT), had been studied before the treatment of head and neck tumors (including laryngocarcinoma). However, no relevant assessment had been carried out on 50KV low-energy X-ray. We are convinced by certain arguments that the application of low-energy X-ray for intraoperative local radiotherapy of laryngocarcinoma can not only achieve the therapeutic effect of IORT but also reduce the incidence of high-energy irradiation related toxic and side effects. The purpose of this study is to observe the safety and short-term efficacy of IORT when used in conjunction with standard of care for the treatment of local advanced laryngocarcinoma (LAL). Methods/design In consideration of the applications of precise targeted IORT in oncosurgery and in line with the application range and reference clinical medical guidances approved by SFDA (ZEISS radiosurgical operation system has been used for the treatment of solid tumors since 31 December, 2013 with an approval from SFDA), we have preliminarily planned the tumors suitable for IORT, determined the members of MDT in our hospital, improved the MDT diagnosis and treatment processes for the tumors, established the standards, indications and contraindications for the application of IORT, determined the indicators to be observed after the treatment of tumors with surgical operations plus IORT, and carried out follow-up visits and statistical analysis. This is a single-arm, prospective Phase II clinical trial of the treatment of LAL patients with IORT + EBRT. The study subjects are followed up for statistics and information of their acute/chronic toxic reactions and local control rate, DFS, and OS etc. The safety and short-term efficacy of the application of IORT as SIB for the treatment of LAL. The sample size of the study is 125 subjects. Discussion The safety and efficacy of IORT for the treatment of head and neck cancers have been proven in studies by multiple institutions (1–3). The purpose of this study is to investigate the maximum safe dose and short-term efficacy of IORT for providing a theoretical basis for clinical trials. Trial registration Trial registration: Clinicaltrials.gov, NCT04278638. Registered 18 February 2020 - prospectively registered, https://clinicaltrials.gov/ct2/show/NCT04278638

Thyroid cancer (TC) is a frequently occurring malignant tumor with a rising steadily incidence. microRNA (miRNA/miR)-193a-3p is an miRNA that is associated with tumors, playing a crucial role in the genesis and progression of various cancers. However, the expression levels of miR-193a-3p and its molecular mechanisms in TC remain to be elucidated. The present study aimed to probe the expression of miR-193a-3p and its clinical significance in TC, including its underlying molecular mechanisms. Microarray and RNA sequencing data gathered from three major databases, specifically Gene Expression Omnibus (GEO), ArrayExpress and The Cancer Genome Atlas (TCGA) databases, and the relevant data from the literature were used to examine miR-193a-3p expression. Meta-analysis was also conducted to evaluate the association between clinicopathological parameters and miR-193a-3p in 510 TC and 59 normal samples from the TCGA database. miRWalk 3.0, and the TCGA and GEO databases were used to predict the candidate target genes of miR-193a-3p. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network enrichment analyses were conducted by using the predicted candidate target genes to investigate the underlying carcinogenic mechanisms. A dual luciferase assay was performed to validate the targeting regulatory association between the most important hub gene cyclin D1 (CCND1) and miR-193a-3p. miR-193a-3p expression was considerably downregulated in TC compared with in the non-cancer controls (P

Background In clinical practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are the most common markers measured before and after surgery for gastric cancer (GC). However, which pre- or post-operative combined tumour markers (CEA and CA19-9) have more prognostic value remains unclear. Methods Consecutive patients undergoing a resection for GC at the Fujian Medical University Union Hospital were included as a discovery database between January 2011 and December 2014. The prognostic impact of pre- and post-operative tumour markers was evaluated using Kaplan–Meier log-rank survival analysis and multivariable Cox regression analysis. The results were then externally validated. Results A total of 735 and 400 patients were identified in the discovery cohort and in the validation cohort, respectively. Overall survival rates decreased in a stepwise manner in association with the number of pre- and post-operative positive tumour markers (both P P Conclusion Pre-operative tumour markers have a better discriminatory ability for post-operative survival in GC patients than post-operative tumour markers, and the normalisation of tumour markers after surgery was associated with better survival.

Osteosarcoma is the most common primary malignant tumor of the bone and the long-term survival of patients with this disease has remained unsatisfactory over the past several decades. Andrographolide, a traditional drug used in Chinese medicine, has been found to exert a significant antitumor effect against several types of cancer. However, relatively little is known about the effect of andrographolide on osteosarcoma and the underlying mechanisms. In the present study, it was shown that andrographolide inhibited osteosarcoma cell proliferation by arresting the cell cycle at the G2/M phase and increasing caspase-mediated apoptosis. Furthermore, treatment with andrographolide induced JNK activation and increased production of reactive oxygen species (ROS). The andrographolide-triggered apoptosis in osteosarcoma cells was partly abrogated by a JNK inhibitor and completely reversed by a ROS scavenger. Additionally, JNK activation and cell cycle arrest at the G2/M phase were prevented by administration of an ROS scavenger. In vivo, it was also found that andrographolide inhibited tumor growth by increasing the levels of ROS and activating JNK; thus inducing cytotoxicity in primary osteosarcoma cells. Together, the results of the present study suggest that andrographolide caused G2/M arrest and induced cell apoptosis via regulation of the ROS/JNK signaling pathway in osteosarcoma cells. Thus, andrographolide may serve as a promising antitumor therapeutic agent against osteosarcoma.

The mechanism of olfactory disorder (OD) in patients with COVID-19 is unclear. Our study aimed to elucidate the relationships between inflammatory factors and OD in a sample of patients infected with the Omicron variant, with a high vaccination rate in China.The Sniffin' Sticks 12-item test was performed in a cross-sectional study of 148 recovered patients who were infected with the Omicron variant to evaluate OD severity. We compared demographic, laboratory, and clinical data.A total of 148 patients infected with the Omicron variant were enrolled. A total of 129 cases of OD were detected. Increased inflammation contributed to OD severity, especially in the adult group. OD was shown to be aggravated by an increase in interleukin-6 levels. The adjusted odds ratio (OR) was 2.22 (95% confidence interval 0.98-5.05, P = 0.056) after adjustment for age, sex, and vaccine characteristics.These findings indicated that the prevalence of OD remains high in vaccinated patients infected with the Omicron variant and that the Sniffin' Sticks 12-item test might be a feasible method to screen for OD. Interleukin-6 may play a role in the biochemical and pathological processes underlying OD.

To investigate the impact of station 3A lymph node dissection (LND) on overall survival (OS) and disease-free survival (DFS) in completely resected right-side non-small-cell lung cancer (NSCLC) patients.A total of 1661 cases with completely resected right-side NSCLC were included. Propensity score matching (PSM) was performed to minimize selection bias, and a logistic regression model was conducted to investigate the risk factors associated with station 3A lymph node metastasis (LNM). The Kaplan-Meier method and Cox proportional hazards model were used to evaluate the impact of station 3A LND on survival.For the entire cohort, 503 patients (30.3%) underwent station 3A LND. Of those, 11.3% (57/503) presented station 3A LNM. Univariate and multivariate logistic analyses showed that station 10 LNM, tumor location, and the number of resected lymph nodes were independent risk factors associated with station 3A LNM. Before PSM, patients with station 3A LND had worse 5-year OS (p = 0.002) and DFS (p = 0.011), and more drainage on postoperative day 1 (p = 0.041) than those without. After PSM, however, station 3A LND was not associated with the 5-year OS (65.7% vs. 63.6%, p = 0.432) or DFS (57.4% vs. 56.0%, p = 0.437). The multivariate analysis further confirmed that station 3A LND was not a prognostic factor (OS, p = 0.361; DFS, p = 0.447).Station 3A LND could not improve long-term outcomes and it was unnecessary to dissect station 3A lymph nodes during surgery of right-side NSCLC.

Persistent Müllerian duct syndrome (PMDS) is an autosomal recessive congenital abnormality in which Müllerian derivatives, uterus, cervix, upper two-thirds of the vagina, and fallopian tubes persist in otherwise normally virilized males. Mutations in anti-Müllerian hormone (AMH) and AMH receptor type II (AMHR2) genes have been identified as causative. However, functional experimental analysis of AMHR2 or AMH variants that cause PMDS is still lacking.A Chinese Han family affected by PMDS was identified. To assess the history and clinical manifestations of PMDS, physical, operational, ultrasonographical, pathological, and other examinations were performed on family members. The variant screening was conducted using trio whole-exome sequencing (trio WES) and Sanger sequencing. Complementation-based NanoLuciferase Binary Technology (NanoBiT) was used to examine the interaction between AMH and AMHR2 variants in vivo. The effect of the two variants on the transcriptional activity of the TGFβ/BMP pathway was evaluated using a luciferase assay.Classic phenotypic manifestations of PMDS in a pair of identical twins were described and confirmed by genetic sequence analysis. Molecular studies revealed two novel variants c.118G C [p.(Gly40Arg)], c.1222G C [p.(Ala408Pro)] in the AMHR2 gene. The AMHR2 p.Gly40Arg variant reduces its ability to bind to AMH, while the p.Ala408Pro variant alters the kinase domain structure. Both variants significantly reduce TGFβ/BMP signaling.Two missense AMHR2 variants associated with PMDS were identified. These findings provide novel insights toward better clinical evaluation and further understanding of the molecular basis of PMDS.

To analyze the contrast-enhanced ultrasound (CEUS) manifestations of combined hepatocellular-cholangiocarcinoma (CHC) and to investigate the diagnostic value of the 2017 version of the CEUS Liver Imaging Reporting and Data System (LI-RADS) and serum tumor markers in CHC.A total of 66 pathologically confirmed CHC nodules were retrospectively analyzed. We summarized the CEUS manifestations of CHC and analyzed the relationship between serum tumor markers and the enhancement pattern of CHC. We also classified CHC according to CEUS LI-RADS criteria. The Kappa test was used to assess the interreader agreement of CEUS LI-RADS between radiologists.According to the results, 52 of 62 (83.9%) patients had elevated alpha-fetoprotein (AFP), 19 of 61 (31.1%) had elevated carbohydrate antigen 199 (CA 199), and 13 of 61 (21.3%) had both elevated AFP and CA 199. Of the 66 CHC nodules, 64 (97.0%) were identified as malignant lesions by CEUS, 13 (19.7%) showed a hepatocellular carcinoma-like enhancement pattern, and 21 (31.8%) showed a cholangiocarcinoma-like enhancement pattern. For the CEUS LI-RADS categories, 39 of 53 (73.6%) CHC nodules were classified as LR-M, 12 (22.6%) were classified as LR-5, and 2 (3.8%) were classified as LR-4. The interreader agreement for the LI-RADS categories was 0.60.Although CHC lacks specific CEUS features, CEUS LI-RADS and serum tumor markers can be useful tools for reducing the misdiagnosis of CHC. In addition, due to the relative complexity of the CEUS features involved in CHC, it is necessary for beginning radiologists to learn more about CEUS features.

Target therapy for highly heterogeneous cancers represents a major clinical challenge due to the lack of recurrent therapeutic targets identified in these tumors. Herein, the authors report a tumor-customized targeting photothermal therapy (PTT) strategy for highly heterogeneous cancers, by which 2D supramolecular self-assembled nanodiscs are modified with tumor-specific binding peptides identified by phage display techniques. Taking osteosarcoma (OS) as a model heterogeneous cancer, an OS targeting peptide (OTP) is first selected after biopanning and is demonstrated to successfully bind to this heterogeneous cancer cells/tissues. Successful conjugation of OTP to heptamethine cyanine (Cy7)-based 2D nanodiscs Cy7-TCF (2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran,TCF) enables the 2D nanodiscs to specifically target the heterogeneous tumor. Notably, a single dose injection of this targeted nanodisc (T-ND) not only effectively induces enhanced photothermal tumor ablation under near-infrared light, but also exhibits sevenfold increase of tumor retention time (more than 24 days) compared to generic nanomedicine. Thus, the authors' findings suggest that the combination of phage display-based affinity peptides selection and 2D supramolecular nanodiscs leads to the development of a platform technology for highly heterogeneous cancers precise therapy, offering specific tumor targeting, ultralong tumor retention, and precise PTT.

To help doctors and patients evaluate lumbar intervertebral disc degeneration (IVDD) accurately and efficiently, we propose a segmentation network and a quantitation method for IVDD from T2MRI. A semantic segmentation network (BianqueNet) composed of three innovative modules achieves high-precision segmentation of IVDD-related regions. A quantitative method is used to calculate the signal intensity and geometric features of IVDD. Manual measurements have excellent agreement with automatic calculations, but the latter have better repeatability and efficiency. We investigate the relationship between IVDD parameters and demographic information (age, gender, position and IVDD grade) in a large population. Considering these parameters present strong correlation with IVDD grade, we establish a quantitative criterion for IVDD. This fully automated quantitation system for IVDD may provide more precise information for clinical practice, clinical trials, and mechanism investigation. It also would increase the number of patients that can be monitored.