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Plasmacytoid dendritic cells (pDCs) are commonly associated with myeloid malignancies. The association between lymphoblastic leukemia and pDCs has been little explored.Here, we report a novel case of early T-cell precursor lymphoblastic leukemia (ETP-ALL) accompanied by prominent proliferation of blastic pDCs mimicking BPDCN. The diagnosis was established based on a comprehensive analysis of morphology, immunophenotype and clinical implications. We also present a literature review and discussion on the differential expression of reactive and neoplastic pDCs, the functional role of pDCs in lymphoblastic leukemia, and the etiological association of normal pDCs and BPDCN.The current case demonstrates for the first time that prominent pDC proliferation can be associated with lymphoid neoplasms and can exhibit blastic morphology and immunophenotype. The underlying mechanism of the coexistence of these two blastic populations remains unknown. Further genetic profiling may be required to denote the progressive development of tumor stem cells to the lymphoid, myeloid or dendritic cell lineage. Moreover, the prognostic value of pDCs in hematological neoplasms needs further investigation.

Hepatitis B virus (HBV) has posed a threat to public health, mainly resulting in liver damage. With long-term accumulation of extracellular matrix, patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma. The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality. With deeper understanding of the bidirectional interaction between the liver and the gut (gut-liver axis), there is a growing consensus that the human health closely relates to the gut microbiota. Supported by animal and human studies, the gut microbiota alters as the HBV-related liver fibrosis initials and progresses, characterized as the decrease of the ratio between "good" and "potentially pathogenic" microbes. When the primary disease is controlled

Peritoneal recurrence is the predominant pattern of relapse after curative-intent surgery for gastric cancer and portends a dismal prognosis. Accurate individualised prediction of peritoneal recurrence is crucial to identify patients who might benefit from intensive treatment. We aimed to develop predictive models for peritoneal recurrence and prognosis in gastric cancer.In this retrospective multi-institution study of 2320 patients, we developed a multitask deep learning model for the simultaneous prediction of peritoneal recurrence and disease-free survival using preoperative CT images. Patients in the training cohort (n=510) and the internal validation cohort (n=767) were recruited from Southern Medical University, Guangzhou, China. Patients in the external validation cohort (n=1043) were recruited from Sun Yat-sen University Cancer Center, Guangzhou, China. We evaluated the prognostic accuracy of the model as well as its association with chemotherapy response. Furthermore, we assessed whether the model could improve the ability of clinicians to predict peritoneal recurrence.The deep learning model had a consistently high accuracy in predicting peritoneal recurrence in the training cohort (area under the receiver operating characteristic curve [AUC] 0·857; 95% CI 0·826-0·889), internal validation cohort (0·856; 0·829-0·882), and external validation cohort (0·843; 0·819-0·866). When informed by the artificial intelligence (AI) model, the sensitivity and inter-rater agreement of oncologists for predicting peritoneal recurrence was improved. The model was able to predict disease-free survival in the training cohort (C-index 0·654; 95% CI 0·616-0·691), internal validation cohort (0·668; 0·643-0·693), and external validation cohort (0·610; 0·583-0·636). In multivariable analysis, the model predicted peritoneal recurrence and disease-free survival independently of clinicopathological variables (p0·0001 for all). For patients with a predicted high risk of peritoneal recurrence and low survival, adjuvant chemotherapy was associated with improved disease-free survival in both stage II disease (hazard ratio [HR] 0·543 [95% CI 0·362-0·815]; p=0·003) and stage III disease (0·531 [0·432-0·652]; p0·0001). By contrast, chemotherapy had no impact on disease-free survival for patients with a predicted low risk of peritoneal recurrence and high survival. For the remaining patients, the benefit of chemotherapy depended on stage: only those with stage III disease derived benefit from chemotherapy (HR 0·637 [95% CI 0·484-0·838]; p=0·001).The deep learning model could allow accurate prediction of peritoneal recurrence and survival in patients with gastric cancer. Prospective studies are required to test the clinical utility of this model in guiding personalised treatment in combination with clinicopathological criteria.None.

To compare the clinical effectiveness of different mesh fixation techniques in Lichtenstein tension-free repair using network meta-analysis.Cochrane Library, Medline, EMBASE, and Web of Science databases were searched until 1 December 2020, and randomized controlled trials (RCTs) comparing outcomes between different mesh fixation techniques were included. The primary endpoints were chronic postoperative inguinal pain (CPIP) and hernia recurrence. The second endpoint was seroma and infection. Data were processed using Stata MP16.0, and R x64 3.6.1.The results demonstrated that 32 RCTs (n = 6362) were eligible for pooling. Six types of mesh fixation techniques were used: non-absorbable suture, absorbable suture, chemical glue, fibrin glue, self-gripping mesh, and staple fixation. Network meta-analysis indicated that the incidence of CPIP with fibrin glue was lower than that with non-absorbable sutures (relative risk [RR] = 0.23, 95% credibility interval [95%CrI] [0.09, 0.50]), absorbable sutures (RR = 0.24, 95%CrI [0.08, 0.60]), chemical glue (RR = 0.36, 95%CrI [0.13, 0.87]), and self-gripping mesh (RR = 0.27 95%CrI [0.09, 0.62]). Self-gripping mesh was superior to non-absorbable sutures (RR = 0.44, 95%CrI [0.23, 0.74]) in reducing postoperative infection.This network meta-analysis suggests that fibrin glue might be best for reducing CPIP and recurrence. However, a large-scale RCT is warranted to confirm the results.

Background Docetaxel (DTX) exhibits antitumor effects against breast cancer by stabilizing microtubules and increasing the accumulation of reactive oxygen species (ROS). DTX extravasation during infusion often causes skin injury. The present study aimed to investigate the effects and mechanisms of icaritin (ICT) on DTX‐induced skin injury. Methods The effects of ICT on the viability and apoptosis of HaCaT cells were measured by SRB assay and flow cytometry, respectively. Endogenous LC3 puncta and microtubules were determined by immunofluorescence. The number of mitochondria was measured by MitoTracker orange staining. ROS were determined by dihydroethidium staining. The expression of markers of ROS and autophagy were measured by western blotting. Chloroquine, compound D, and tamoxifen were employed as the inhibitor for autophagy and AMPK, estrogen receptors (ERs) modulator, respectively. Results DTX inhibited the viability and decreased apoptosis of HaCaT cells, which can be rescued by ICT. ICT decreased microtubule bundles, increased the number of mitochondria, and attenuated ROS of HaCaT cells induced by DTX. ICT blocks autophagy and the autophagic flux. Compound C or tamoxifen diminished the protection effects of ICT on DTX‐treated HaCaT cells. Conclusion ICT alleviates DTX‐induced skin injury by suppressing ROS, reducing microtubule bundles, and blocking autophagy via ERs. Our study indicated that ICT may be a potential candidate for DTX‐induced skin injury., ICT alleviates DTX‐induced skin injury by alleviating the microtubule bundles, while the specific mechanism is unknown. At the same time, ICT, as an ER modulator, promotes the phosphorylation of the α subunit of AMPK to activate AMPK, thereby regulating the level of autophagy. ICT also reduces the level of ROS by acting as an ER modulator to reduce cell apoptosis.

ObjectivesTo investigate the incidence, predisposing factors, diagnosis and management of subcapsular renal haematoma (SRH) after ureteroscopic lithotripsy (URSL).DesignRetrospective observational study.SettingShandong Provincial Hospital, a 4500-bed tertiary hospital in China.ParticipantsThe data from 1535 consecutive patients treated with URSL (including rigid URSL and flexible URSL) between January 2015 and October 2020 were retrospectively analysed.Main outcome measuresSRH after URSL confirmed via CT. The characteristics, operative data and outcomes of these patients were documented and compared.ResultsSix patients were confirmed to have an SRH after URSL on CT. The total incidence of SRH after URSL was 0.39%. The incidences of SRH after rigid URSL and flexible URSL were 0.38% and 0.41%, respectively. Unendurable ipsilateral flank pain and a significant decrease in haemoglobin after surgery were the typical clinical manifestations of SRH after URSL. There were no significant differences in age, sex, history of diabetes mellitus, preoperative hypertension, body mass index, stone laterality or perfusion pressure (p>0.05). However, SRH was significantly associated with the stone size, stone location, degree of hydronephrosis and operative duration (pConclusionsSRH is a rare but potentially serious complication of URSL. Severe hydronephrosis and a thin renal cortex preoperatively and prolonged operative duration are strong predisposing factors for SRH. Laparoscopic ureterolithotomy should be considered as an alternative surgery for patients with severe ureteral tortuosity. SRH is treated based on patients’ clinical manifestations. Most patients can be managed with conservative treatment or percutaneous drainage alone.

Summary: Background: The tumour stroma microenvironment plays an important part in disease progression and its composition can influence treatment response and outcomes. Histological evaluation of tumour stroma is limited by access to tissue, spatial heterogeneity, and temporal evolution. We aimed to develop a radiological signature for non-invasive assessment of tumour stroma and treatment outcomes. Methods: In this multicentre, retrospective study, we analysed CT images and outcome data of 2209 patients with resected gastric cancer from five independent cohorts recruited from two centres (Nanfang Hospital of Southern Medical University [Guangzhou, China] and Sun Yat-sen University Cancer Center [Guangzhou, China]). Patients with histologically confirmed gastric cancer, at least 15 lymph nodes harvested, preoperative abdominal CT available, and complete clinicopathological and follow-up data were eligible for inclusion. Tumour tissue was collected for patients in the training cohort (321 patients), internal validation cohort one (246 patients), and external validation cohort one (128 patients). Four stroma classes were defined according to the protein expression of α-smooth muscle actin and periostin assessed by immunohistochemistry. The primary objective was to predict the histologically based stroma classes by using preoperative CT images. We trained a deep convolutional neural network model using the training cohort and tested the model in the internal and external validation cohort one. We evaluated the model's association with prognosis in the training cohort, two internal, and two external validation cohorts and compared outcomes of patients who received or did not receive adjuvant chemotherapy. Findings: The deep-learning model achieved a high diagnostic accuracy for assessing tumour stroma in both internal validation cohort one (area under the receiver operating characteristic curve [AUC] 0·96–0·98]) and external validation cohort one (AUC 0·89–0·94). The stromal imaging signature was significantly associated with disease-free survival and overall survival in all cohorts (p

The tumor immune microenvironment (TIME) is associated with tumor prognosis and immunotherapy response. Here we develop and validate a CT-based radiomics score (RS) using 2272 gastric cancer (GC) patients to investigate the relationship between the radiomics imaging biomarker and the neutrophil-to-lymphocyte ratio (NLR) in the TIME, including its correlation with prognosis and immunotherapy response in advanced GC. The RS achieves an AUC of 0.795–0.861 in predicting the NLR in the TIME. Notably, the radiomics imaging biomarker is indistinguishable from the IHC-derived NLR status in predicting DFS and OS in each cohort (HR range: 1.694–3.394, P

Chemoresistance remains the primary challenge of clinical treatment of gastric cancer (GC), making the biomarkers of chemoresistance crucial for treatment decision. Our previous study has reported that p21-actived kinase 6 (PAK6) is a prognostic factor for selecting which patients with GC are resistant to 5-fluorouracil/oxaliplatin chemotherapy. However, the mechanistic role of PAK6 in chemosensitivity remains unknown. The present study identified PAK6 as an important modulator of the DNA damage response (DDR) and chemosensitivity in GC. Analysis of specimens from patients revealed significant associations between the expression of PAK6 and poorer stages, deeper invasion, more lymph node metastases, higher recurrence rates, and resistance to oxaliplatin. Cells exhibited chemosensitivity to oxaliplatin after knockdown of PAK6, but showed more resistant to oxaliplatin when overexpressing PAK6. Functionally, PAK6 mediates cancer chemoresistance by enhancing homologous recombination (HR) to facilitate the DNA double-strand break repair. Mechanistically, PAK6 moves into nucleus to promote the activation of ATR, thereby further activating downstream repair protein CHK1 and recruiting RAD51 from cytoplasm to the DNA damaged site to repair the broken DNA in GC. Activation of ATR is the necessary step for PAK6 mediated HR repair to protect GC cells from oxaliplatin-induced apoptosis, and ATR inhibitor (AZD6738) could block the PAK6-mediated HR repair, thereby reversing the resistance to oxaliplatin and even promoting the sensitivity to oxaliplatin regardless of high expression of PAK6. In conclusion, these findings indicate a novel regulatory mechanism of PAK6 in modulating the DDR and chemoresistance in GC and provide a reversal suggestion in clinical decision.

Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer-associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction-sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD-1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level."

De novo and acquired resistance, which are mainly mediated by genetic alterations, are barriers to effective routine chemotherapy. However, the mechanisms underlying gastric cancer (GC) resistance to chemotherapy are still unclear. We showed that the long noncoding RNA CRNDE was related to the chemosensitivity of GC in clinical samples and a PDX model. CRNDE was decreased and inhibited autophagy flux in chemoresistant GC cells. CRNDE directly bound to splicing protein SRSF6 to reduce its protein stability and thus regulate alternative splicing (AS) events. We determined that SRSF6 regulated the PICALM exon 14 skip splice variant and triggered a significant S-to-L isoform switch, which contributed to the expression of the long isoform of PICALM (encoding PICALML). Collectively, our findings reveal the key role of CRNDE in autophagy regulation, highlighting the significance of CRNDE as a potential prognostic marker and therapeutic target against chemoresistance in GC. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-020-01299-y.

Bone formation is important in the development of osteoporosis (OP). X–inactive specific transcript (XIST), a lncRNA, is involved in this process; however, mode of its action is not known. We compared the serum levels of XIST and miR-29b-3p among the patients with and without OP. In rat bone marrow mesenchymal stem cells (BMSCs), during osteogenic differentiation, XIST expression was detected first, followed by overexpression or suppression of miR-29b-3p and NNMT. Expression of osteogenic genes, ALP (electrochemical alkaline phosphatase) and RUNX2 (Runt-related transcription factor 2) were detected by RT-qPCR and western blots, and the calcium nodules in BMSCs were detected by staining. The relationships of XIST, miR-29b-3p, and NNMT were characterized by dual-luciferase reporter assay. Serum XIST was significantly upregulated in patients of OP. XIST downregulated the ALP and Runx2 levels and inhibited calcium nodules, whereas low expression of XIST reversed these events. MiR-29b-3p was inhibited by XIST sponge and lowered the levels of ALP, Runx2, and calcium nodules. NNMT was negatively regulated by miR-29b-3p, promoting the osteogenic differentiation of BMSCs. In conclusion, XIST is highly expressed in OP, and regulates NNMT by sponging miR-29b-3p to suppress the osteogenic differentiation of BMSCs.

Berberine (BBR), an isoquinoline alkaloid isolated from Rhizoma coptidis, is reported to possess antiviral activity. Our previous study has shown that BBR alleviates Coxsackievirus B3 (CVB3) replication in HeLa cells. However, the anti-CVB3 activity of BBR is still unclear in vivo. In this study, we explored the effect of BBR on CVB3-induced viral myocarditis in mice. These results demonstrated a beneficial effect of BBR on alleviating CVB3-induced myocarditis in vivo, which sheds new light on the utility of BBR as a therapeutic strategy against CVB3-induced viral myocarditis. This article is protected by copyright. All rights reserved.

Little is known about the relation between perioperative inflammatory changes and long-term survival in cancer patients. The aim of the study was to assess the association of perioperative serum interleukin-6 (IL6) and tumor necrosis factor-The 135 eligible patients in one center of Nanfang Hospital were retrieved from CLASS-01 trial (NCT01609309), an open-label, multicenter, randomized clinical noninferiority trial conducted at 14 centers in China. Serum IL6 and TNFHigh levels of IL6_0 (≥3.67 pg/mL) and TNFPerioperative high serum IL6 and TNF

Background Raltitrexed is a specific inhibitor of thymidylate synthase and a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In this study, we investigated the effect of raltitrexed on the proliferation of HGC-27 human gastric cancer cells and its potential underlying molecular mechanism(s). Methods RT-qPCR and western blotting were used to quantify RSK4 levels. Colony formation and flow cytometry assays were used to assess HGC-27 cell proliferation, cell cycle progression, mitochondrial membrane potential, and apoptosis. The expression of cell cycle and apoptosis markers were determined by western blotting. Results Our results demonstrate that raltitrexed upregulated RSK4 mRNA and protein levels in HGC-27 cells. Moreover, raltitrexed significantly inhibited tumor cell colony formation, arrested the cell cycle, decreased the mitochondrial membrane potential, and induced apoptosis. We observed that raltitrexed was capable of upregulating the expression of Bax, cyclin A1, and CDK3, and downregulating the expression of Bcl-2 and cleaved caspase-3. Importantly, siRNA-mediated RSK4 knockdown significantly reduced the inhibitory effect of raltitrexed on cell proliferation and its promotion of cell apoptosis. Moreover, silencing of RSK4 inhibited the raltitrexed-induced upregulation of cytochrome C. In addition, the changes in molecular markers related to the cell cycle and apoptosis induced by raltitrexed were reduced upon RSK4 depletion. Conclusion Our study shows that RSK4 is a key target of raltitrexed in the regulation of gastric cancer cell proliferation, cell cycle progression, and apoptosis.

Data on sofosbuvir-based therapy for pregnant women and infants with severe chronic hepatitis C (CHC) are lacking. Two late pregnant women and one female infant with severe CHC were enrolled for treatment. Pregnant Women 1 and 2 and Infant 3 were 30, 33, and 1.2 years old, respectively; the gestational ages of pregnant Women 1 and 2 were 31 and 26 weeks, respectively. Notably, pregnant Women 1 and 2 and Infant 3 had hepatitis C virus (HCV) RNA levels of 139 000, 198 000, and 8 450 000 IU/ml; alanine aminotransferase levels of 420, 781, and 220 U/L; and received sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, and sofosbuvir/ledipasvir for 12 weeks, respectively. All three patients were safely cured with favorable tolerance, and two newborns were both breastfeeding and were consistently negative for the anti-HCV antibody during the 1-year follow-up after birth. Additionally, two newborns and Infant 3 had normal growth parameters during the follow-up year one. In conclusion, this case series study found that sofosbuvir-based therapy for pregnant women and infants with severe CHC is safe and effective. The data may fill the gap and provide evidence of the use of sofosbuvir-based therapy as a reference when similar severe CHC situations are encountered during clinical practice.

Fetal exposure to multiple organic contaminants (OCs) is a public concern because of the adverse effects of OCs on early life development. Infant hair has the potential to be used as an alternative matrix to identify susceptible fetuses, owing to its reliability, sensitivity, and advantages associated with sampling, handling, and ethics. However, the applicability of infant hair for assessing in utero exposure to OCs is still limited. In this study, 57 infant hair samples were collected in Guangzhou, South China, to evaluate the levels and compositions of typical OCs in the fetus. Most of the target OCs were detected in infant hair, with medians of 144 μg/g, 17.7 μg/g, 192 ng/g, 46.9 ng/g, and 1.36 ng/g for phthalate esters (PAEs), alternative plasticizers (APs), organophosphorus flame retardants (OPFRs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs), respectively. Meanwhile, paired maternal hair (0-9 cm from the scalp) was collected to examine the associations between maternal and infant hair for individual compounds. Low-brominated PBDEs tended to deposit in infant hair, with median concentrations approximately two times higher than those in maternal samples. Levels of PBDEs and 4,4'-dichlorodiphenyldichloroethylene (p,p'-DDE) in paired maternal and infant hair showed strong positive correlations (p 0.05), while most plasticizers (PAEs and APs) were poorly correlated between paired hair samples. Exposure sources were responsible for the variation in correlation between OC levels in the paired infant and maternal samples. Crude relationships between fetal exposure to OCs and birth size were examined using the Bayesian kernel machine regression (BKMR) model. BDE-28 was found to be adversely associated with the birth size. This study provides referential information for evaluating in utero exposure to OCs and their health risks based on infant hair.

The high geological background and the residual pollution of historical zinc smelting in the karst area of northwest Guizhou has led to serious soil heavy metal pollution. In order to understand the characteristics of soil heavy metal pollution in agricultural land, wasteland, and forestland, 126 surface and profile soil samples were collected from a typical zinc powder factory-polluted small watershed in Weining County, Northwest Guizhou Province. The concentrations and distribution characteristics of Cd, As, Pb, Cu, and Zn in soils were studied. The results showed that the average

Present study has aimed to understand the intervention and prevention of the mental health crisis of college students. For this purpose, this study has checked the effect of trust in wellbeing information on preventive behavior and mental wellbeing. The target population taken for this study is the students of colleges situated in Mainland in China. The data was collected from the 458 students of the college. Smart PLS has been employed on the data to get the results using partial least square structural equation modeling. For this purpose, the data were analyzed in two stages, i.e., measurement model stage and the structural model stage. Results of this study have revealed that trust in wellbeing information plays a significant and positive role in setting preventive behavior and the mental wellbeing of students. Further, it has also been revealed that preventive behavior also plays a significant and positive role in mental wellbeing. Additionally, preventive behavior has been found as an important mediating variable among the relationship of trust in wellbeing information and mental wellbeing. Moreover, family support is crucial by positively moderating the relationship between preventive behavior and mental wellbeing. Many practical implications have been found among which the foremost is that the education institutes must undertake those efforts that aim to ensure the fairness in the information spread regarding the mental wellbeing during seminars, workshops and administration should play a positive role responsible for strengthening the mental health of students by managing ideas, improving student education management, innovating management techniques and methods.

Sepsis is the major culprit of death among critically ill patients who are hospitalized in intensive care units (ICUs). Although sepsis-related mortality is steadily declining year-by-year due to the continuous understanding of the pathophysiological mechanism on sepsis and improvement of the bundle treatment, sepsis-associated hospitalization is rising worldwide. Surviving Sepsis Campaign (SSC) guidelines are continuously updating, while their content is extremely complex and comprehensive for a precisely implementation in clinical practice. As a consequence, a standardized step-by-step approach for the diagnosis and treatment of sepsis is particularly important. In the present study, we proposed a standardized step-by-step approach for the diagnosis and treatment of sepsis using our daily clinical experience and the latest researches, which is close to clinical practice and is easy to implement. The proposed approach may assist clinicians to more effectively diagnose and treat septic patients and avoid the emergence of adverse clinical outcomes.

Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5′-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

In this study, we have constructed a binary supramolecular nanoassembly composed of α-cyclodextrin-modified hyaluronic acid and an azobenzene-modified diphenylalanine derivative with a positively charged imidazole group. This nanoassembly can bind with siRNA through electrostatic interactions and efficiently delivered them into cancer cells and inhibited their growth.

Human nails have been increasingly used as a biomarker for human exposure to persistent organic pollutants (POPs). In the present study, the fingernails of e-waste-dismantling workers from Longtang town, Qingyuan city, rural residents from Shijiao town, Qingyuan city, and urban residents from Guangzhou city, respectively, were collected from South China to monitor the human burdens of polybrominated diphenyl ether (PBDEs) and polychlorinated biphenyl (PCBs). The median concentrations of in the nails of the e-waste-dismantling workers, and urban and rural residents were 412, 129, and 82.1 ng g-1, respectively, and the median concentrations of were 108, 8.4, and 22.1 ng g-1, respectively. The levels of PCBs and PBDEs in the nails of e-waste-dismantling workers were significantly higher as compared to those for urban and rural residents (p < 0.05), implying the continuous and greater exposure to these chemicals in the e-waste recycling areas. BDE 209 (92-98%) was the major congener of PBDEs and CB 52 (26-51%) was the main congener of PCB in nail samples. However, no significant gender difference was observed for PBDE and PCB levels in nails from all three investigated areas, and no significant correlation was found between their levels and the age of the participants. The enantiomer fractions (EFs) of CBs 95 and 132 indicated that the external sources (e.g. dust and/or air) were the primary sources for CBs 95 and 132 in human nails from the e-waste area, while the contribution from the internal sources (e.g. serum) could be in a small percentage. The results of this study indicate that human nails can be used as a proper indicator of human exposure to PCBs and PBDEs, and further studies are needed by a comprehensive investigation of the relationships between the PCB and PBDE levels in the nails and serum and/or other internal tissues.

The sources and chemical components of urban air particles exhibit seasonal variations that may affect their hazardousness to human health. Our aims were to investigate winter and spring variation in particulate matter (PM) sources, components and toxicological responses of different PM size fractions from samples collected in Guangzhou, China. Four size-segregated PM samples (PM

Rhinoplasty is one of the most commonly performed aesthetic surgical procedures. The current study aimed to use bibliometric analysis to qualitatively and quantitatively evaluate rhinoplasty research and determine the research trends and hotspots in this field.Publications on rhinoplasty research were extracted from the web of science core collection database. VOSviewer1.6.18 was used to analyze the co-authorship, co-occurrence, the citations of countries, institutions, authors, and hotspot keywords, and the journals in which the studies were published.On April 8, 2022, 11,130 records of rhinoplasty research published between 1945 and 2021 were collected. Most of the retrieved studies were original research articles (n = 8309, 74.65%), and 1950 (17.52%) papers were available in an open-access format. The annual publication output increased annually. Research groups in the USA were the main contributors and had a strong academic reputation in this field. University of California System was the institution with the greatest contribution (4.17%, with 464 publications). Plastic and Reconstructive Surgery (1248 publications, 11.21%) published the most research in this field and was also the most frequently co-cited journal (33,894 citations, total link strength [TLS]: 722,672). R. J. Rohrich (140 publications) was the most prolific author and the most frequently co-cited author (2562 citations, TLS: 56,624). The following rhinoplasty research hotspots were identified: cleft rhinoplasty, nasal reconstruction, nasal tip, revision rhinoplasty, septorhinoplasty, nasal prosthesis, hyaluronic acid, and preservation rhinoplasty.Our results provide a general overview of the major directions in rhinoplasty research. Preservation rhinoplasty, rib graft, nonsurgical rhinoplasty, hyaluronic acid, FACE-Q, fillers, and three-dimensional technology may be future research hotspots.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background Lymph node metastasis (LNM) is an important factor for both treatment and prognosis of early gastric cancer (EGC). Current methods are insufficient to evaluate LNM in EGC due to suboptimal accuracy. Herein, we aim to identify methylation signatures for LNM of EGC, facilitate precision diagnosis, and guide treatment modalities. Methods For marker discovery, genome-wide methylation sequencing was performed in a cohort (marker discovery) using 47 fresh frozen (FF) tissue samples. The identified signatures were subsequently characterized for model development using formalin-fixed paraffin-embedded (FFPE) samples by qPCR assay in a second cohort (model development cohort, n = 302, training set: n = 151, test set: n = 151). The performance of the established model was further validated using FFPE samples in a third cohorts (validation cohort, n = 130) and compared with image-based diagnostics, conventional clinicopathology-based model (conventional model), and current standard workups. Results Fifty LNM-specific methylation signatures were identified de novo and technically validated. A derived 3-marker methylation model for LNM diagnosis was established that achieved an AUC of 0.87 and 0.88, corresponding to the specificity of 80.9% and 85.7%, sensitivity of 80.6% and 78.1%, and accuracy of 80.8% and 83.8% in the test set of model development cohort and validation cohort, respectively. Notably, this methylation model outperformed computed tomography (CT)-based imaging with a superior AUC (0.88 vs. 0.57, p Conclusions A novel 3-marker methylation model was established and validated that shows diagnostic potential to identify LNM in EGC patients and thus reduce unnecessary gastrectomy in EGC.

Spontaneous ventilation video-assisted thoracic surgery (SV-VATS) is reported to have superior or equal efficacy on postoperative recovery to mechanical ventilation VATS (MV-VATS). However, perioperative safety of the SV-VATS blebectomy is not entirely demonstrated.We performed a noninferiority, randomized controlled trial (No. NCT03016858) for primary spontaneous pneumothorax patients aged 16 to 50 years undergoing a SV-VATS and the MV-VATS procedure. The trial was conducted at 10 centers in China from April 2017 to January 2019. The primary outcome was the comparison of intra- and postoperative complications between SV-VATS and MV-VATS procedures. Secondary outcomes included total analgesia dose, change of vital sign during surgery, procedural duration, recovery time, postoperative visual analog pain scores, and hospitalization length.In this study, 335 patients were included. There was no significant difference between the SV-VATS group and the MV-VATS group in the intra- and postoperative complication rates (17.90% vs 22.09%; relative risk, 0.81; 95% confidence interval, 0.52-1.26; P = .346). The SV-VATS group was associated with significantly decreased total dose of intraoperative opioid agents; that is, sufentanil (11.37 μg vs 20.92 μg; P .001) and remifentanil (269.78 μg vs 404.96 μg; P .001). The SV-VATS procedure was also associated with shorter extubation time (12.28 minutes vs 17.30 minutes; P .001), postanesthesia care unit recovery time (25.43 minutes vs 30.67 minutes; P = .02) and food intake time (346.07 minute vs 404.02 minutes; P = .002). Moreover, the SV-VATS procedure deceased the anesthesia cost compared with the MV-VATS ($297.81 vs $399.81; P .001).SV-VATS was shown to be noninferior to MV-VATS in term of complication rate and in selected patients undergoing blebectomy for primary spontaneous pneumothorax.

Background The effect of comorbid hypertension and type 2 diabetes mellitus (T2DM) on coronary artery plaques examined by coronary computed tomography angiography (CCTA) is not fully understood. We aimed to comprehensively assess whether comorbid hypertension and T2DM influence coronary artery plaques using CCTA. Materials and methods A total of 1100 T2DM patients, namely, 277 normotensive [T2DM(HTN−)] and 823 hypertensive [T2DM(HTN +)] individuals, and 1048 normotensive patients without T2DM (control group) who had coronary plaques detected on CCTA were retrospectively enrolled. Plaque type, coronary stenosis, diseased vessels, the segment involvement score (SIS) and the segment stenosis score (SSS) based on CCTA data were evaluated and compared among the groups. Results Compared with patients in the control group, the patients in the T2DM(HTN−) and T2DM(HTN +) groups had more partially calcified plaques, noncalcified plaques, segments with obstructive stenosis, and diseased vessels, and a higher SIS and SSS (all P values 3 (OR = 2.233 and 3.769; both P values 5 (OR = 2.057 and 3.580; both P values 3 (OR = 1.647; P = 0.001) and an SSS > 5 (OR = 1.625; P = 0.001). Conclusion T2DM is related to the presence of partially calcified plaques, obstructive CAD, and more extensive coronary artery plaques. Comorbid hypertension and diabetes further increase the risk of partially calcified plaques, and more extensive coronary artery plaques.

A fibrotic stroma accumulates in advanced cancers, and invasive cancer cells migrate along collagen fibers that facilitate dissemination from the primary tumor. However, the ways in which tumor cells govern these processes remain unclear. Here, we report that the epithelial-mesenchymal transition-activating transcription factor ZEB1 increased type I collagen (Col1) secretion and enhanced tumor cell adherence to Col1. Mechanistically, ZEB1 increased the levels of α1β1 integrin (encoded by Itga1 and Itgb1) by inhibiting PP2A activity, which reduced nuclear accumulation of HDAC4 and, thereby, derepressed Itga1 gene transcription. In parallel, ZEB1 relieved the miRNA-148a-mediated silencing of Itga1. High levels of Itga1 enhanced tumor cell adherence to Col1 and were essential for Col1-induced tumor growth and metastasis. Furthermore, ZEB1 enhanced Col1 secretion by increasing the expression of a kinesin protein that facilitated transport and secretion of Col1-containing vesicles. Our findings elucidate a transcriptional mechanism by which lung adenocarcinoma cells coordinate a collagen deposition and adhesion process that facilitates tumor progression.

Background Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects. Methods EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee. Results Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: − 23.7%; 80% confidence interval [CI] − 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups. Conclusions The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov (NCT02696902) on 11th February 2016 and on EudraCT (2015-001706-34) on 7th March 2016.

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays in vitro. Among them, compounds H34, H42, H48, and H52 displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays in vitro and in vivo proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound H52 exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.HIGHLIGHTSStructural fusion was used to screen brain penetrating PARP-1 inhibitors.55 benzodiazepines were evaluated for their PARP-1 inhibition activity.Four compounds displayed acceptable inhibition effects on breast cancer cells.The benzodiazepine PARP-1 inhibitors were proved to be brain permeable. Structural fusion was used to screen brain penetrating PARP-1 inhibitors. 55 benzodiazepines were evaluated for their PARP-1 inhibition activity. Four compounds displayed acceptable inhibition effects on breast cancer cells. The benzodiazepine PARP-1 inhibitors were proved to be brain permeable.

Human hair has increasingly been used as a noninvasive biomonitoring matrix for assessment of human exposure to various organic contaminants (OCs). However, the accumulation processes of OCs in hair remains unclear thus far, which raised concerns on the reliability of hair analysis results for OCs. Herein, Chinese population was selected as the study subject, the effects of changes in hair biological characteristics, including length and color, on the accumulation of OCs in hair was investigated. With the growing of hair shaft and the increased distance from the scalp, a significant increasing trend was found for levels of polychlorinated biphenyls (PCBs) and organophosphate flame retardants (PFRs) along the hair shafts (p 0.05). Source identification using Chemical Mass Balance model indicated that PCBs in hair were mainly from exogenous sources (air and dust). The accumulation rates of PCB and PFR individuals in the hair shaft decreased with increasing of log K

Objective: We sought to identify tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2/TNFAIP8L2) expression in bladder cancer and its relationship to clinicopathological findings and prognosis.Methods: Immunohistochemical (IHC) staining for TIPE2 was performed on 110 archived radical cystectomy specimens. Ten high-power fields were randomly selected from each specimen to observe and record the percentage of immunoreactive cells of TIPE2 in tumor cells (grade 0–4) and the corresponding immunostaining intensity (grade 0–3). The expression score of TIPE2 was obtained by multiplying the results of the above two scores, which ranged from 0 to 12 points. The cut-off point of the sum of the scores were defined as follows: 0–3 scores were defined as negative expression (-); >3 scores were classified as positive expression, < 7, low expression, ≥7, high expression.Results: In 110 cases, TIPE2 was stained in various degrees in bladder cancer tissues, and expressed in both nucleus and cytoplasm. 4.5% (5/110) showed negative expression, 40.9% (45/110) showed low expression, and 54.5% (60/110) showed high expression. TIPE2 expression was negatively correlated with lymph node metastasis (p = 0.004) and disease progression (p = 0.021). Survival curves were plotted to show that patients with high TIPE2 expression had a progression-free survival curve above those with negative/low TIPE2 expression (p = 0.027). In multivariate Cox proportional hazard regression analysis, TIPE2 was a protective factor for progression-free survival in bladder urothelial carcinoma (p = 0.031), pT stage (p = 0.016) was a risk factor for progression-free survival, and age was a risk factor for overall survival (p = 0.020).Conclusion: TIPE2 may be a new biomarker to predict the disease progression and prognosis of patients with urothelial carcinoma of the bladder.

Background Due to the outbreak and rapid spread of coronavirus disease 2019 (COVID-19), more than 160 million patients have become convalescents worldwide to date. Significant alterations have occurred in the gut and oral microbiome and metabonomics of patients with COVID-19. However, it is unknown whether their characteristics return to normal after the 1-year recovery. Methods We recruited 35 confirmed patients to provide specimens at discharge and one year later, as well as 160 healthy controls. A total of 497 samples were prospectively collected, including 219 tongue-coating, 129 stool and 149 plasma samples. Tongue-coating and stool samples were subjected to 16S rRNA sequencing, and plasma samples were subjected to untargeted metabolomics testing. Results The oral and gut microbiome and metabolomics characteristics of the 1-year convalescents were restored to a large extent but did not completely return to normal. In the recovery process, the microbial diversity gradually increased. Butyric acid-producing microbes and Bifidobacterium gradually increased, whereas lipopolysaccharide-producing microbes gradually decreased. In addition, sphingosine-1-phosphate, which is closely related to the inflammatory factor storm of COVID-19, increased significantly during the recovery process. Moreover, the predictive models established based on the microbiome and metabolites of patients at the time of discharge reached high efficacy in predicting their neutralizing antibody levels one year later. Conclusions This study is the first to characterize the oral and gut microbiome and metabonomics in 1-year convalescents of COVID-19. The key microbiome and metabolites in the process of recovery were identified, and provided new treatment ideas for accelerating recovery. And the predictive models based on the microbiome and metabolomics afford new insights for predicting the recovery situation which benefited affected individuals and healthcare.

Background The association between body mass index (BMI) and the overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) patients remains controversial and unclear, Method A total of 2010 patients from a high-volume center were enrolled in the study. The OS of PDAC patients was evaluated based on restricted cubic spline (RCS), propensity score (PS) and multivariable risk adjustment analyses. Result BMI was linearly related to the OS (total P = 0.004, nonlinear P = 0.124). BMI was analyzed as categorical data based on X-tile software-defined cutoffs and World Health Organization (WHO)-recommended cutoffs. Adjusted with confounding covariates, higher BMI manifested as a positive prognostic predictor. Furthermore, BMI was proven to be associated with the OS in the PS analysis. (UnderweightXtile vs. NormalXtileP = 0.003, OverweightXtile vs. NormalXtileP = 0.019; UnderweightWHO vs. NormalWHOP WHO vs. NormalWHOP = 0.024). It was also revealed that patients with higher BMI benefitted more from chemotherapy. (Adjusted hazard ratio (aHR): UnderweightXtile vs. NormalXtile vs. OverweightXtile: 0.565 vs. 0.474 vs. 0.409; UnderweightWHO vs. NormalWHO vs. OverweightWHO: 0.613 vs. 0.464 vs. 0.425). Conclusion Among PDAC patients, there was a positive association between BMI and the OS, especially in patients treated with chemotherapy.

Background The tumor microenvironment (TME) plays an important role in the occurrence and development of gastric cancer (GC) and is widely used to assess the treatment outcomes of GC patients. Immunohistochemistry (IHC) and gene sequencing are the main analysis methods for the TME but are limited due to the subjectivity of observers, the high cost of equipment and the need for professional analysts. Methods The ImmunoScore (IS) was developed in the TCGA cohort and validated in GEO cohorts. The Radiomic ImmunoScore (RIS) was developed in the TCGA cohort and validated in the Nanfang cohort. A nomogram was developed and validated in the Nanfang cohort based on RIS and clinical features. Results For IS, the area under the curves (AUCs) were 0.798 for 2-year overall survival (OS) and 0.873 for 4-year overall survival. For RIS, in the TCGA cohort, the AUCs distinguishing High-IS or Low-IS and predicting prognosis were 0.85 and 0.81, respectively; in the Nanfang cohort, the AUC predicting prognosis was 0.72. The nomogram performed better than the TNM staging system according to the ROC curve (all P Conclusions The RIS and the nomogram can be used to assess the TME, prognosis and adjuvant chemotherapy benefit of GC patients after radical gastrectomy and are valuable additions to the current TNM staging system. High-nomogram GC patients may benefit more from adjuvant chemotherapy than Low-nomogram GC patients.

Atrazine (ATZ) is a widely used herbicide worldwide and is a long-suspected endocrine-disrupting chemical. However, most endocrine-disrupting toxicity studies on ATZ have been based on animal models and those investigating inner mechanisms have only focused on a few genes. Therefore, the possible link between ATZ and endocrine-disrupting toxicity is still unclear. In this study, multi-omics and molecular biology techniques were used to elucidate the possible molecular mechanisms underlying the effect of ATZ exposure on MCF-7 proliferation at environmentally relevant concentrations. Our study is the first report on ATZ-induced one carbon pool by folate metabolic disorder in MCF-7 cells. A concentration of 1 μM ATZ yielded the highest cell viability and was selected for further mechanistic studies. A total of 34 significantly changed metabolites were identified based on metabolomic analysis, including vitamins, amino acids, fatty acids, and corresponding derivatives. Folate and pyridoxal have potential as biomarkers of ATZ exposure. One carbon pool by folate metabolic pathway was identified based on metabolic pathway analysis of the significantly altered pathways. Moreover, FTCD and MTHFD related to this pathway were further identified based on transcriptomic analysis and protein assays. Folate and different forms of 5,6,7,8-tetrahydrofolate, which participate in purine synthesis and associate with methyl groups (SOPC, arachidonic acid, and L-tryptophan) in one carbon pool by the folate metabolic pathway, potentially promote MCF-7 cell proliferation. These findings on the key metabolites and regulation of the related differentially expressed genes in folate metabolism will shed light on the mechanism of MCF-7 cell proliferation after ATZ exposure. Overall, this study provides new insights into the mechanistic understanding of toxicity caused by endocrine-disrupting chemicals.

Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion. Dynamic assembly of focal adhesions and other actin-based cytoskeletal structures on the leading edge of motile cells requires precise spatial and temporal control of protein trafficking. Yet, the way in which EMT-activating transcriptional programs interface with vesicular trafficking networks that effect cell polarity change remains unclear. Here, by utilizing multiple approaches to assess vesicular transport dynamics through endocytic recycling and retrograde trafficking pathways in lung adenocarcinoma cells at distinct positions on the EMT spectrum, we find that the EMT-activating transcription factor ZEB1 accelerates endocytosis and intracellular trafficking of plasma membrane-bound proteins. ZEB1 drives turnover of the MET receptor tyrosine kinase by hastening receptor endocytosis and transport to the lysosomal compartment for degradation. ZEB1 relieves a plus-end-directed microtubule-dependent kinesin motor protein (KIF13A) and a clathrin-associated adaptor protein complex subunit (AP1S2) from microRNA-dependent silencing, thereby accelerating cargo transport through the endocytic recycling and retrograde vesicular pathways, respectively. Depletion of KIF13A or AP1S2 mitigates ZEB1-dependent focal adhesion dynamics, front-rear axis polarization, and cancer cell motility. Thus, ZEB1-dependent transcriptional networks govern vesicular trafficking dynamics to effect cell polarity change., The way in which metastatic tumour cells control endocytic vesicular trafficking networks to establish a front-rear polarity axis that facilitates motility remains unclear. Here, the authors show that the EMT activator ZEB1 influences vesicular trafficking dynamics to execute cell polarity change.

Rationale: Sclerosing thymoma (ST) is quite a rare disease, as denoted in previous literature. Less than 20 cases of ST have been reported to date. However, the combined thymoma, composed of both type AB thymoma and ST, has never been described before. Patient concerns: The subject, a 49-year-old woman, came in with the chief complaint of cough for 10 days. Diagnoses: Both the contrast-enhanced computed tomography scan and the ultrasonography showed a huge mass located in the right thoracic cavity with inhomogeneous contrast accompanied by the invasion of the pericardium and pleura. Subsequently, computed tomography-guided core-needle biopsy revealed type B2 thymoma, and type AB thymoma could not be excluded. Based on postsurgical histopathology and immunohistochemical finding, this tumor was given the final diagnosis of ST and type AB thymoma. Interventions: After 6 months of adjuvant chemotherapy and local radiotherapy, total thymectomy was performed. Outcomes: The patient has been duly followed up for 1 year without any tumor recurrence. Lessons: ST is a very rare mediastinal neoplasm. Moreover, ST in combination with AB thymoma and affecting a large area, is unprecedented. Whether radiotherapy and chemotherapy have a certain effect on ST requires further investigation. In addition, due to the unclear recurrence rate of ST, long-term follow-up evaluation seems necessary.