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Background: Spaceflight or microgravity conditions cause myocardial atrophy and dysfunction, contributing to post-flight orthostatic intolerance. However, the underlying mechanisms remain incompletely understood and preventive approaches are limited. This study investigated whether and how losartan, a blocker of angiotensin-II receptor, preserved cardiomyocyte size and prevented myocardial dysfunction during microgravity.Method: Adult male mice were suspended with their tails to simulate microgravity. Echocardiography was performed to assess myocardial function. Heart weight and cardiomyocyte size were measured. NADPH oxidase activation was determined by analyzing membrane translocation of its cytosolic subunits including p47phox, p67phox and Rac1. Heart tissues were also assayed for oxidative stress, p47phox phosphorylation (Ser345), MuRF1 protein levels and angiotensin-II production.Results: Tail-suspension for 28 days increased angiotensin-II production in hearts, decreased cardiomyocyte size and heart weight, and induced myocardial dysfunction. Administration of losartan preserved cardiomyocyte size and heart weight, and prevented myocardial dysfunction in tail-suspended mice. These cardioprotective effects of losartan were associated with inhibition of p47phox phosphorylation (Ser345), NADPH oxidase and oxidative stress in tail-suspended mouse hearts. Additionally, the NADPH oxidase inhibitor, apocynin, also reduced oxidative stress, preserved cardiomyocyte size and heart weight, and improved myocardial function in tail-suspended mice. Furthermore, losartan but not apocynin attenuated tail-suspension-induced up-regulation of MuRF1 protein in mouse hearts.Conclusions: Administration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction under microgravity by blocking p47phox phosphorylation and NADPH oxidase activation, and by inhibiting MuRF1 expression. Thus, losartan may be a useful drug to prevent microgravity-induced myocardial abnormalities. [ABSTRACT FROM AUTHOR]

Background: Patients treated with anti-CD20 monoclonal antibodies could have a higher risk of adverse outcomes of coronavirus disease 2019 (COVID-19). The novel anti-CD20 monoclonal antibody obinutuzumab has shown greater B-cell depletion and superior in vitro efficacy than rituximab. We aimed to assess whether obinutuzumab would result in worse COVID-19 outcomes than rituximab., Methods: We retrospectively reviewed 124 patients with B-cell lymphoma, 106 of whom received rituximab treatment and 18 of whom received obinutuzumab treatment. The adverse outcomes of COVID-19 were compared between patients in the two cohorts., Results: The proportions of patients who were hospitalized (55.6% vs. 20.8%, p = 0.005), experienced prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (38.9% vs. 2.9%, p < 0.001), and developed severe COVID-19 (33.3% vs. 4.7%, p < 0.001) were higher in patients with obinutuzumab than in those with rituximab. Multivariate analyses showed that obinuzumab treatment was associated with higher incidences of prolonged SARS-CoV-2 infection (OR 27.05, 95% CI 3.75-195.22, p = 0.001) and severe COVID-19(OR 15.07, 95% CI 2.58-91.72, p = 0.003)., Conclusions: Our study suggested that patients treated with obinutuzumab had a higher risk of prolonged SARS-CoV-2 infection and severe COVID-19 than those treated with rituximab., (© 2024. The Author(s).)

Background: Tracheal tube cuff pressure will increase after pneumoperitoneum when the cuff is inflated with air, high pressure can cause tracheal mucosal damage. This prospective trial aimed to assess if inflating with normal saline or lidocaine can prevent increase of tracheal tube cuff pressure and tracheal mucosal damage in laparoscopic surgeries with general anesthesia. Whether changes of tracheal tube cuff transverse diameter (CD) can predict changes of tracheal tube cuff pressure., Methods: Ninety patients scheduled for laparoscopic resection of colorectal neoplasms under general anesthesia were randomly assigned to groups air (A), saline (S) or lidocaine (L). Endotracheal tube cuff was inflated with room-temperature air in group A (n = 30), normal saline in group S (n = 30), 2% lidocaine hydrochloride injection in group L (n = 30). After intubation, tracheal tube cuff pressure was monitored by a calibrated pressure transducers, cuff pressure was adjusted to 25 cmH 2 O (T 0.5 ). Tracheal tube cuff pressure at 15 min after pneumoperitoneum (T 1 ) and 15 min after exsufflation (T 2 ) were accessed. CD were measured by ultrasound at T 0.5 and T 1 , the ability of ΔCD (T 1-0.5 ) to predict cuff pressure was accessed. Tracheal mucous injury at the end of surgery were also recorded., Results: Tracheal tube cuff pressure had no significant difference among the three groups at T 1 and T 2 . ΔCD had prediction value (AUC: 0.92 [95% CI: 0.81-1.02]; sensitivity: 0.99; specificity: 0.82) for cuff pressure. Tracheal mucous injury at the end of surgery were 0 (0, 1.0) in group A, 0 (0, 1.0) in group S, 0 (0, 0) in group L (p = 0.02, group L was lower than group A and S, p = 0.03 and p = 0.04)., Conclusions: Compared to inflation with air, normal saline and 2% lidocaine cannot ameliorate the increase of tracheal tube cuff pressure during the pneumoperitoneum period under general anesthesia, but lidocaine can decrease postoperative tracheal mucosa injury. ΔCD measured by ultrasound is a predictor for changes of tracheal tube cuff pressure., Trial Registration: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021., (© 2024. The Author(s).)

Background: Social alienation refers to the state of feeling isolated, helpless, and unsatisfied due to maintaining distance from others or avoiding social interaction and activities. This phenomenon is caused by a lack of social skills, social anxiety, physical health problems, and other reasons. Older maintenance hemodialysis patients are exposed to a higher risk of social alienation. However, previous studies have been performed using the total score of the scale, which does not allow the identification of the characteristics of various patient groups with different levels of social alienation. In contrast, latent profile analysis can classify individuals into different categories based on continuous observational indicators, which improves accuracy and provides a more objective assessment by accounting for the uncertainty of variables. Given the concealed nature of social alienation and the differences in characteristics and treatment measures between different profiles, developing a predictive model for social alienation in older maintenance hemodialysis patients holds significance., Objective: To explore the latent profile analysis of social alienation in older maintenance hemodialysis patients and to develop and validate a predictive model for social alienation in this population., Methods: A total of 350 older maintenance hemodialysis patients were selected as the study subjects using convenience sampling. A cross-sectional survey was conducted using a general information questionnaire, the Generalized Alienation Scale, and the Self-Perceived Burden Scale. Based on the results of the Generalized Alienation Scale, a latent profile analysis was performed, followed by univariate analysis and multinomial logistic regression to develop a predictive model. The effectiveness of the predictive model was evaluated in terms of its authenticity, reliability, and predictive ability., Results: Three hundred nineteen valid questionnaires were collected. The social alienation of older maintenance hemodialysis patients based on latent profile analysis were divided into three profiles, which were named the low/medium/high-symptom groups, comprising 21%, 38.9%, and 40.1% of participants, respectively. Based on male, monthly social activity hours, Age-Adjusted Charlson Comorbidity Index, dialysis age, and Self-Perceived Burden Scale, a predictive model of social alienation for older maintenance hemodialysis patients was developed, and the Hosmer-Lemeshow tests showed no statistical significance (P > 0.05). The model has high predictive efficiency in authenticity, reliability and predictability., Conclusion: Older maintenance hemodialysis patients exhibited moderate to high levels of social alienation. The latent profile analysis based method was used to divide patients into low/medium/high-symptom profiles, and the predictive model demonstrates excellent authenticity, reliability, and predictability., (© 2024. The Author(s).)

Background: Cuproptosis is a newly identified form of unprogrammed cell death. As a pivotal metabolic regulator, glutaminase (GLS) has recently been discovered to be linked to cuproptosis. Despite this discovery, the oncogenic functions and mechanisms of GLS in various cancers are still not fully understood., Methods: In this study, a comprehensive omics analysis was performed to investigate the differential expression levels, diagnostic and prognostic potential, correlation with tumor immune infiltration, genetic alterations, and drug sensitivity of GLS across multiple malignancies., Results: Our findings revealed unique expression patterns of GLS across various cancer types and molecular subtypes of carcinomas, underscoring its pivotal role primarily in energy and nutrition metabolism. Additionally, GLS showed remarkable diagnostic and prognostic performance in specific cancers, suggesting its potential as a promising biomarker for cancer detection and prognosis. Furthermore, we focused on uterine corpus endometrial carcinoma (UCEC) and developed a novel prognostic model associated with GLS, indicating a close correlation between GLS and UCEC. Moreover, our exploration into immune infiltration, genetic heterogeneity, tumor stemness, and drug sensitivity provided novel insights and directions for future research and laid the foundation for high-quality verification., Conclusion: Collectively, our study is the first comprehensive investigation of the biological and clinical significance of GLS in pan-cancer. In our study, GLS was identified as a promising biomarker for UCEC, providing valuable evidence and a potential target for anti-tumor therapy. Overall, our findings shed light on the multifaceted functions of GLS in cancer and offer new avenues for further research., (© 2024. The Author(s).)

Background: Anemia is a common complication of total hip arthroplasty (THA). In this study, we evaluated the preoperative risk factors for postoperative anemia after THA and developed a nomogram model based on related preoperative and intraoperative factors., Methods: From January 2020 to May 2023, 927 THA patients at the same medical center were randomly assigned to either the training or validation cohort. The correlation between preoperative and intraoperative risk factors and postoperative anemia after THA was evaluated using univariate and multivariate logistic regression analysis. A nomogram was developed using these predictive variables. The effectiveness and validation for the clinical application of this nomogram were evaluated using the concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA)., Results: Through univariate and multivariate logistic regression analysis, 7 independent predictive factors were identified in the training cohort: Lower body mass index (BMI), extended operation time, greater intraoperative bleeding, lower preoperative hemoglobin level, abnormally high preoperative serum amyloid A (SAA) level, history of cerebrovascular disease, and history of osteoporosis. The C-index of the model was 0.871, while the AUC indices for the training and validation cohorts were 84.4% and 87.1%, respectively. In addition, the calibration curves of both cohorts showed excellent consistency between the observed and predicted probabilities. The DCA curves of the training and validation cohorts were high, indicating the high clinical applicability of the model., Conclusions: Lower BMI, extended operation time, increased intraoperative bleeding, reduced preoperative hemoglobin level, elevated preoperative SAA level, history of cerebrovascular disease, and history of osteoporosis were seven independent preoperative risk factors associated with postoperative anemia after THA. The nomogram developed could aid in predicting postoperative anemia, facilitating advanced preparation, and enhancing blood management. Furthermore, the nomogram could assist clinicians in identifying patients most at risk for postoperative anemia., (© 2024. The Author(s).)

Background: Although cervical intervertebral disc (IVD) degeneration is closely associated with neck pain, its cause remains unclear. In this study, an animal model of cervical disc degeneration and discogenic neck pain induced by a low concentration of Propionibacterium acnes (P. acnes-L) is investigated to explore the possible mechanisms of cervical discogenic pain., Methods: Cervical IVD degeneration and discitis was induced in 8-week-old male rats in C3-C6 IVDs through the anterior intervertebral puncture with intradiscal injections of low and high concentrations of P. acnes (P. acnes-L, n = 20 and P. acnes-H, n = 15) or Staphylococcus aureus (S. aureus, n = 15), compared to control (injection with PBS, n = 20). The structural changes in the cervical IVD using micro-CT, histological evaluation, and gene expression assays after MRI scans at 2 and 6 weeks post-modeling. The P. acnes-L induced IVD degeneration model was assessed for cervical spine MRI, histological degeneration, pain-like behaviors (guarding behavior and forepaw von Frey), nerve fiber growth in the IVD endplate region, and DRG TNF-α and CGRP., Results: IVD injection with P. acnes-L induced IVD degeneration with decreased IVD height and MRI T2 values. IVD injection with P. acnes-H and S. aureus both lead to discitis-like changes on T2-weighted MRI, trabecular bone remodeling on micro-CT, and osseous fusion after damage in the cartilage endplate adjacent to the injected IVD. Eventually, rats in the P. acnes-L group exhibited significant nociceptive hypersensitivity, nerve fiber ingrowth was observed in the IVD endplate region, inflammatory activity in the DRG was significantly increased compared to the control group, and the expression of the pain neurotransmitter CGRP was significantly upregulated., Conclusion: P. acnes-L was validated to induce cervical IVD degeneration and discogenic pain phenotype, while P. acnes-H induced was identified to resemble septic discitis comparable to those caused by S. aureus infection., (© 2024. The Author(s).)

Background: Previous studies achieved low microbial detection rates in lymphoma patients with interstitial pneumonia (IP) after chemotherapy. However, the metagenomic next-generation sequencing (mNGS) is a comprehensive approach that is expected to improve the pathogen identification rate. Thus far, reports on the use of mNGS in lymphoma patients with chemotherapy-related IP remain scarce. In this study, we summarized the microbial detection outcomes of lymphoma patients with chemotherapy-related IP through mNGS testing of bronchoalveolar lavage fluid (BALF)., Methods: Fifteen lymphoma patients with chemotherapy-related IP were tested for traditional laboratory microbiology, along with the mNGS of BALF. Then, the results of mNGS and traditional laboratory microbiology were compared., Results: Of the 15 enrolled patients, 11 received rituximab and 8 were administered doxorubicin hydrochloride liposome. The overall microbial yield was 93.3% (14/15) for mNGS versus 13.3% (2/15) for traditional culture methods (P ≤ 0.05). The most frequently detected pathogens were Pneumocystis jirovecii (12/15, 80%), Cytomegalovirus (4/15, 26.7%), and Epstein-Barr virus (3/15, 20%). Mixed infections were detected in 10 cases. Five patients recovered after the treatment with antibiotics alone without glucocorticoids., Conclusion: Our findings obtained through mNGS testing of BALF suggested a high microbial detection rate in lymphoma patients with IP after chemotherapy. Notably, there was an especially high detection rate of Pneumocystis jirovecii. The application of mNGS in patients with chemotherapy-related IP was more sensitive., (© 2023. The Author(s).)

Background: Lung cancer is a major global threat to public health for which a novel predictive nomogram is urgently needed. Non-small cell lung cancer (NSCLC) which accounts for the main port of lung cancer cases is attracting more and more people's attention., Patients and Methods: Here, we designed a novel predictive nomogram using a design dataset consisting of 515 pulmonary nodules, with external validation being performed using a separate dataset consisting of 140 nodules and a separate dataset consisting of 237 nodules. The selection of significant variables for inclusion in this model was achieved using a least absolute shrinkage and selection operator (LASSO) logistic regression model, after which a corresponding nomogram was developed. C-index values, calibration plots, and decision curve analyses were used to gauge the discrimination, calibration, and clinical utility, respectively, of this predictive model. Validation was then performed with the internal bootstrapping validation and external cohorts., Results: A predictive nomogram was successfully constructed incorporating hypertension status, plasma fibrinogen levels, blood urea nitrogen (BUN), density, ground-glass opacity (GGO), and pulmonary nodule size as significant variables associated with nodule status. This model exhibited good discriminative ability, with a C-index value of 0.765 (95% CI: 0.722-0.808), and was well-calibrated. In validation analyses, this model yielded C-index values of 0.892 (95% CI: 0.844-0.940) for external cohort and 0.853 (95% CI: 0.807-0.899) for external cohort 2. In the internal bootstrapping validation, C-index value could still reach 0.753. Decision curve analyses supported the clinical value of this predictive nomogram when used at a NSCLC possibility threshold of 18%., Conclusion: The nomogram constructed in this study, which incorporates hypertension status, plasma fibrinogen levels, BUN, density, GGO status, and pulmonary nodule size, was able to reliably predict NSCLC risk in this Chinese cohort of patients presenting with pulmonary nodules., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown., Methods: PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches., Results: The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle., Conclusions: Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: This research aimed to evaluate the influence of Modic changes (MCs) on disc degeneration at the same and adjacent cephalad levels in the cervical spine., Methods: This research retrospectively reviewed 1036 patients with neck pain, upper limb pain, or numbness who were treated at our out-patient clinic and underwent cervical MRI and cervical anteroposterior/lateral radiography from Jan, 2016 to Jan, 2021. MCs and disc degeneration parameters at same and nearby cephalad levels of MCs were evaluated. Discs were divided into the MCs, adjacent, and control groups, and the association between MCs and disc degeneration at the same and adjacent cephalad levels was investigated., Results: Of the 1036 patients whose MRI scans were reviewed, 986 met the inclusion criteria (503 women and 483 men; average age, 62.8 years; scope of 35-79 years). The prevalence of MCs in the cervical spine was 13.0% (128/986). Type I, II, III changes were observed in 38 (29.69%), 82 (64.06%), and 8 (6.25%) patients, respectively. MCs were most frequently identified at the C5-6 (59/986; 5.98%) and C6-7 (38/986; 3.85%) levels. Disc with MCs showed worse outcomes with regard to disc degeneration grade, anterior osteophyte formation than the adjacent and control groups (p < 0.05), whereas they were more severe in the adjacent group compared to normal group., Conclusion: Our findings indicate that MCs increased disc degeneration at the same and nearby cephalad levels in cervical spine, and the severity of degeneration at the same segment was more serious than that at the cephalad level., (© 2023. The Author(s).)

Purpose: To present the clinical features of thyroid-associated ophthalmopathy (TAO) with different CT types, and to report the outcomes of endoscopic orbital decompression combined with fat decompression (EOD-FD)., Patients and Methods: Thirty-four patients with TAO who underwent EOD-FD between December 2020 and March 2022 in the Ophthalmology Department of Li Huili Hospital Affiliated with Ningbo University, were included in this retrospective interventional case series. Patients were categorized into two groups based on the results of computerized tomography (CT) scans: muscle expansion type and fat hyperplasia type., Results: Thirty-four TAO patients (55 eyes) were included in this study, and the mean age was 38.62 years (range 22-60 years). The average eye protrusion (EP) reduced from preoperative 23.20 mm to postoperative 19.66 mm (p < 0.0001). Mean intraocular pressure (IOP) decreased from 20.11 mmHg at baseline to 17.29 mmHg postoperatively (p < 0.0001), with a reduction of 2.84 mmHg (14.12%). Twenty cases of muscle expansion and fourteen cases of fat hyperplasia were definite by CT imaging. The mean IOP in the muscle expansion group was higher than that in the fat hyperplasia group (p < 0.05). Elevated intraocular pressure (IOP) occurred in 23 eyes (36.11%), and it was associated with extraocular muscle involvement, gender, and EP. In 3 cases of impaired vision, the mean best corrected visual acuity (VA) improved from 0.4 preoperatively to 0.84 postoperatively (p < 0.01). There were 8 cases with visual field (VF) damage and/or corneal epithelium damage, and all these damages were reversible., Conclusion: In this study, we describe the clinical features and experience of EOD-FD in patients with TAO. EOD-FD is an effective technique in reducing IOP and proptosis, with a low incidence of postoperative diplopia., (© 2023. The Author(s).)

Background: Bushenhuoxue (BSHX) formula, a ten-compound herbal decoction, is widely used to treat postmenopausal osteoporosis (PMOP) in China. However, the mechanism is not clear yet., Methods: The underlying biological processes and signaling pathways were predicted by network pharmacology. In vivo experimental study, 24 female C57BL/6 J mice were randomly divided into sham, ovariectomized (OVX) and BSHX formula groups. Mice in the latter two groups were subjected to bilateral ovariectomy, and mice in the BSHX formula group were extra treated by BSHX formula at an oral dosage of 0.2 mL/10 g for 8 weeks. The femur samples were harvested for tissue analyses including μCT assay, histology and immunohistochemical (IHC) staining of VEGF signaling., Results: A total of 218 active ingredients and 274 related targets were identified in BSHX formula. After matching with 292 targets of PMOP, 64 overlapping genes were obtained. GO and KEGG enrichment analyses on these 64 genes revealed that angiogenesis and VEGF signaling were considered as the potential therapeutic mechanism of BSHX formula against PMOP. Animal experiments showed that mice in the BSHX formula-treated group presented increased bone mass, microstructural parameters, blood vessel numbers and an activation of VEGF signaling (VEGF, COX2, eNOS and CD31) compared to the OVX mice., Conclusion: This study revealed that BSHX formula exerts anti-PMOP effects possibly through activating VEGF signaling-mediated angiogenesis., (© 2023. The Author(s).)

Background: We evaluated the value of electrophysiological indicators by external anal sphincter electromyography (EAS-EMG), sympathetic skin response (SSR), R-R interval variation (RRIV), and Bulbocavernosus Reflex (BCR) in differential diagnosis of multiple system atrophy (MSA) and Parkinson's disease (PD)., Methods: A total of 41 patients with MSA and 32 patients with PD were enrolled. The electrophysiological changes of autonomic dysfunction were assessed with BCR, EAS-EMG, SSR, and RRIV, and the abnormal rate of each indicator was calculated. The diagnostic value of each indicator was analyzed with ROC curve., Results: The incidence rate of autonomic dysfunction in MSA group was significantly higher than that in PD group (p < 0.05). The abnormal rates of BCR and EAS-EMG indicators in MSA group were higher than those in PD group (p < 0.05). The abnormal rates of SSR and RRIV indicators in MSA group and PD group were high; however, there was no significant difference between MSA and PD groups (p > 0.05). The sensitivity of BCR combined with EAS-EMG indicators in differential diagnosis of MSA and PD were 92.3% in males and 86.7% in females, respectively, and the specificity was 72.7% in males and 90% in females, respectively., Conclusions: Combined analysis of BCR and EAS-EMG has high sensitivity and specificity for differential diagnosis of MSA and PD., (© 2023. The Author(s).)

Background: Pancreatic metastasis from colorectal cancer is extremely rare. Here, we report a case of colorectal cancer with lung and pancreatic metastasis and analyze the histopathology, immunohistochemistry, and next-generation sequencing (NGS) to generate a differential diagnosis and treatment of metastatic colon cancer., Case Presentation: AC1 A 78-year-old man was admitted because of a recently elevated carcinoembryonic antigen. This patient had undergone laparoscopic right hemicolectomy for cecal cancer IIA (T3N0M0) 5 years before admission, and thoracoscopic left upper lung wedge resection for primary colon cancer lung metastasis 2 years before admission. At that time, the patient was thought to have pancreatic metastasis from colon cancer. He underwent laparoscopic distal pancreatectomy (combined with splenectomy). Postoperative pathology revealed colon cancer metastasis. We performed NGS on tumor samples at three loci and found colon cancer's most common oncogenic driver genes (KRAS, APC, and TP53). One month after surgery, the patient was given capecitabine for six cycles of chemotherapy. At present, no high adverse reactions have been reported., Discussion: For patients with pancreatic space-occupying, such as a previous history of colorectal cancer, and recent carcinoembryonic antigen elevation, we should highly suspect pancreatic metastatic colorectal cancer. NGS is an essential auxiliary for identifying metastatic tumors. Surgery combined with postoperative chemotherapy is an effective treatment., (© 2022. The Author(s).)

Objectives: To analyze the changes of gene expression at different timepoints after spinal cord injury (SCI) with tenth segment thoracic injury., Methods: Two SCI models, the complete paraplegia (H) and Allen's strike (D) methods were applied to induce SCI in rats, and transcriptome sequencing was performed 1, 3, 7, 14, 56, and 70 days after SCI, respectively. Principal component analysis, differentially expressed gene analysis, and hierarchical clustering analysis were applied to analyze the differentially expressed genes (DEGs). Gene Ontology GO enrichment analysis, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and Gene Set Enrichment Analysis revealed the pathway of gene enrichment., Results: There were 1,907, 3,120, 3,728, 978, 2,319, and 3,798 DEGs in the complete paraplegia group and 2,380, 878, 1,543, 6,040, 1,945, and 3,850 DEGs in the Allen's strike method group and after SCI at 1, 3, 7, 14, 56, and 70 days, respectively. The transcriptome contours of D1, H1, D3, and H14 were clustered with C; the H56, D56, H70, and D70 transcriptome contours were similar and clustered together. H3, D7, and H7 were clustered together, and D14 was clustered separately. The transcriptome differences of the two SCI models were mainly concentrated during the first 2 weeks after SCI. The DEGs after SCI in the complete paraplegia group were more concentrated. Most of the early transcriptional regulation stabilized within 2 weeks after injury., Conclusions: There were DEGs between the two SCI models. Through the gene changes and pathway enrichment of the entire time period after SCI, the molecular mechanism of SCI repair was revealed in depth, which provided a reference for SCI treatment in the future., (© 2022. The Author(s).)

Background: The incidence of postoperative delirium (POD) is high in elderly patients with one-lung ventilation, which is mostly related to the impairment of cerebral oxygen supply/demand balance during operation. (Surgical) stress can cause changes to normal physiological function and increase oxygen supply to the brain. When cerebral oxygen supply/demand is unbalanced, other organs may have already suffered from hypoperfusion or even hypoxic damages leading to increased release of inflammatory factors. Regional saturation of cerebral oxygenation (rScO 2 ) monitoring can noninvasively monitor the variation of regional cerebral oxygen supply/demand balance in real time, and it has a good correlation with the occurrence of POD. S-100β is one of the markers commonly used to predict and diagnose POD, and lactate is one of the important indicators for the quality of tissue perfusion. The study explores whether the goal-directed therapy based on rScO 2 monitoring can reduce perioperative inflammatory factor levels and POD incidence in elderly patients with one-lung ventilation and improve tissue perfusion., Methods: The study is registered on Chinese Clinical Trial Registry (ChiCTR2100054888). A total of 159 patients scheduled for thoracoscopic lobectomy under general anesthesia were divided into the control group (n = 81) and the goal-directed therapy group (GDT group, n = 78). On the basis of the conventional management in the control group, the GDT group applied goal-directed rScO 2 monitoring to maintain rScO 2 at ±20% baseline level during one-lung ventilation. The levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, and lactate; the intensity of postoperative pain; and the incidence of POD before anesthesia (T1), at the end of operation (T2), on day 1 after operation (T3), on day 3 after operation (T4), and on day 7 after operation or before discharge (T5) were compared respectively between the two groups., Results: The incidence of POD at T3 and the awakening time in the GDT group were lower than those in the control group (P < 0.05). During T2 to T4, the levels of inflammatory factors and lactate concentration in the control group were higher than those in the GDT group (P < 0.05). During T3 to T4, the levels of C-reactive protein and lactate in the control group were higher than those in the GDT group (P < 0.05). During T2 to T3, the levels of S-100β in the control group were higher than those in the GDT group (P < 0.05). The levels of inflammatory factors and lactate concentration in both groups during T2 to T4 were higher than those at T1 and T5 (P < 0.05), and there was no statistical difference at T1 versus T5 (P > 0.05). There was no significant difference in postoperative pain intensity, the incidence of agitation during awakening, and postoperative hospital stays between the two groups., Conclusion: Goal-directed therapy based on rScO 2 monitoring can reduce perioperative inflammatory factor levels, postoperative delirium incidence, and postoperative awakening time and improve tissue perfusion in elderly patients with one-lung ventilation., Trial Registration: The Chinese Clinical Trial Registry ChiCTR2100054888 . Registered on 28 December 2021., (© 2022. The Author(s).)

Background: The programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling pathway is significantly upregulated in influenza virus infection, which impairs the antiviral response. Blocking this signaling pathway may reduce the damage, lower the virus titer in lung tissue, and alleviate the symptoms of infection to promote recovery. In addition to the enhanced viral immune response, using of immune checkpoint inhibitors in influenza virus infection is controversial, the aim of this study was to identify the key factors and regulatory mechanisms in the PD-1 checkpoint blockade response microenvironment in influenza infection., Methods: A BALB/c mouse model of influenza A/PR8(H1N1) infection was established then constructed, and whole-transcriptome sequencing including mRNAs, miRNAs (microRNAs), lncRNAs (long noncoding RNAs), and circRNAs (circular RNAs) of mice treated with PD-1 checkpoint blockade by antibody treatment and IgG2a isotype control before infection with A/PR8(H1N1) were performed. Subsequently, the differential expression of transcripts between these two groups was analyzed, followed by functional interaction prediction analysis to investigate gene-regulatory circuits., Results: In total, 84 differentially expressed dif-mRNAs, 36 dif-miRNAs, 90 dif-lncRNAs and 22 dif-circRNAs were found in PD-1 antagonist treated A/PR8(H1N1) influenza-infected lungs compared with the controls (IgG2a isotype control treated before infection). In spleens between the above two groups, 45 dif-mRNAs, 36 dif-miRNAs, 57 dif-lncRNAs, and 24 dif-circRNAs were identified. Direct function enrichment analysis of dif-mRNAs and dif-miRNAs showed that these genes were mainly involved in myocardial damage related to viral infection, mitogen activated protein kinase (MAPK) signaling pathways, RAP1 (Ras-related protein 1) signaling pathway, and Axon guidance. Finally, 595 interaction pairs were obtained for the lungs and 462 interaction pairs for the spleens were obtained in the competing endogenous RNA (ceRNA) complex network, in which the downregulated mmu-miR-7043-3p and Vps39-204 were enriched significantly in PD-1 checkpoint blockade treated A/PR8(H1N1) infection group., Conclusions: The present study provided a basis for the identification of potential pathways and hub genes that might be involved in the PD-1 checkpoint blockade response microenvironment in influenza infection., (© 2022. The Author(s).)

Background: Massive, delayed bleeding (DB) is the most common major complication of Rubber Band Ligation (RBL) for internal hemorrhoids caused by premature band slippage. In this study we modified conventional RBL to prevent early rubber band slippage and evaluated its clinical efficacy and safety., Methods: Study participants were consecutive patients with grade II or III internal hemorrhoids treated with RBL at Ningbo Medical Center of Lihuili Hospital from January 2019 to December 2020. Postoperative minor complications such as pain, swelling, anal edema, prolapse recurrence and major complications like DB were retrospectively reviewed., Results: A total of 274 patients were enrolled, including 149 patients treated with modified RBL and 125 treated with conventional RBL. There was no statistically significant difference between the two groups at baseline. Five cases of postoperative DB have been observed in the conventional RBL group, compared to none in the modified ones, with a significant difference (P < 0.05). Within three months after surgery, 8 cases in the modified RBL group experienced a recurrence rate of 5.4%, whereas 17 patients in the conventional RBL group experienced a recurrence rate of 13.6%. The difference was statistically significant (P < 0.05). The VAS score, edema, and incidence of sensation of prolapse between the two groups were not significantly different at 3 and 7 days after surgery (P < 0.05). There were also no significant differences in HDSS and SHS scores between the two groups after surgery (P > 0.05)., Conclusion: Modified RBL may be associated with a lower rate of complications, especially with lower DB rate in comparison with standard RBL. Further studies in larger samples and different design are necessary to confirm these results., (© 2022. The Author(s).)

Purpose: The purpose of this study was to explore the clinical features, risk factors, and outcomes of mixed Candida albicans/bacterial bloodstream infections (mixed-CA/B-BSIs) compared with monomicrobial Candida albicans bloodstream infection (mono-CA-BSI) in adult patients in China., Methods: All hospitalized adults with Candida albicans bloodstream infection (CA-BSI) were recruited for this retrospective observational study from January 1, 2013, to December 31, 2018., Results: Of the 117 patients with CA-BSI, 24 patients (20.5%) had mixed-CA/B-BSIs. The most common copathogens were coagulase-negative Staphylococcus (CNS) (24.0%), followed by Klebsiella pneumoniae (20.0%) and Staphylococcus aureus (16.0%). In the multivariable analysis, a prior ICU stay > 2 days (adjusted odds ratio [OR], 7.445; 95% confidence interval [CI], 1.152-48.132) was an independent risk factor for mixed-CA/B-BSIs. Compared with patients with mono-CA-BSI, patients with mixed-CA/B-BSIs had a prolonged length of mechanical ventilation [17.5 (4.5, 34.8) vs. 3.0 (0.0, 24.5), p = 0.019] and prolonged length of ICU stay [22.0 (14.3, 42.2) vs. 8.0 (0.0, 31.5), p = 0.010]; however, mortality was not significantly different., Conclusions: There was a high rate of mixed-CA/B-BSIs cases among CA-BSI cases, and CNS was the predominant coexisting species. A prior ICU stay > 2 days was an independent risk factor for mixed -CA/B-BSIs. Although there was no difference in mortality, the outcomes of patients with mixed -CA/B-BSIs, including prolonged length of mechanical ventilation and prolonged length of ICU stay, were worse than those with mono-CA-BSI; this deserves further attention from clinicians.

Background: AT-rich interactive domain-containing protein 1A (ARID1A) is a subunit of the mammary SWI/SNF chromatin remodeling complex and a tumor suppressor protein. The loss of ARID1A been observed in several types of human cancers and associated with poor patient prognosis. Previously, we have reported that ARID1A protein was rapidly ubiquitinated and destructed in gastric cancer cells during DNA damage response. However, the ubiquitin e3 ligase that mediated this process remains unclear., Materials and Methods: The interaction between ARID1A and β-TRCP was verified by co-immunoprecipitation (Co-IP) assay. The degron site of ARID1A protein was analyzed by bioinformatics assay. Short hairpin RNAs (shRNAs) were used to knockdown (KD) gene expression., Results: Here we show that DNA damage promotes ARID1A ubiquitination and subsequent destruction via the ubiquitin E3 ligase complex SCFβ-TRCP. β-TRCP recognizes ARID1A through a canonical degron site (DSGXXS) after its phosphorylation in response to DNA damage. Notably, genetic inactivation of the Ataxia Telangiectasia Mutated (ATM) kinase impaired DNA damage-induced ARID1A destruction., Conclusions: Our studies provide a novel molecular mechanism for the negative regulation of ARID1A by β-TRCP and ATM in DNA damaged gastric cancer cells., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: Pseudomonas aeruginosa (PA) is a leading cause of nosocomial infections, and carbapenem non-susceptible strains are a major threat to patient safety., Methods: A single center, retrospective comparative analysis of carbapenem-non-susceptible PA (CnSPA) and carbapenem-susceptible PA (CSPA) bloodstream infections (BSIs) was conducted between January 1, 2007, and December 31, 2016. Prevalence and risk factors associated with CnSPA BSIs were examined., Results: The study enrolled 340 patients with PA BSIs; 30.0% ( N  = 101) of patients had CnSPA. High APACHE II scores (≥15), central venous catheterization, and delayed application of appropriate definitive therapy were independently associated with higher risk of mortality in PA BSIs. Multivariate analysis revealed that respiratory disease and exposure to carbapenems within the previous 90 days to onset of BSI were independent risk factors for acquisition of CnSPA BSIs. Overall all-cause 30-day mortality associated with PA BSIs was 26.8% (91/340). In addition, mortality was higher in patients with CnSPA than in those with CSPA (37.6% vs. 22.2%, respectively; P  = 0.003). Corticosteroid therapy and delayed receipt of effective definitive therapy were independent risk factors for death from CnSPA BSIs., Conclusion: Increased incidence of CnSPA BSIs was observed during the study period, with higher mortality seen in patients with these infections. Respiratory disease and exposure to carbapenems were independent risk factors for development of CnSPA BSIs. Appropriate definitive therapy reduced mortality rates. BLBLIs were as effective as carbapenems as a treatment for PA BSIs., Competing Interests: Ethics approval for this study was submitted and approved through Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (Reference Number 1028).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Tobacco is widely planted as an important nonfood economic crop throughout the world, and large amounts of tobacco wastes are generated during the tobacco manufacturing process. Tobacco and its wastes contain high nicotine content. This issue has become a major concern for health and environments due to its toxicity and complex physiological effects. The microbial transformation of nicotine into valuable functionalized pyridine compounds is a promising way to utilize tobacco and its wastes as a potential biomass resource. Agrobacterium tumefaciens S33 is able to degrade nicotine via a novel hybrid of the pyridine and pyrrolidine pathways, in which several intermediates, such as 6-hydroxynicotine, can be used as renewable precursors to synthesize drugs and insecticides. This provides an opportunity to produce valuable chemical 6-hydroxynicotine from nicotine via biocatalysis using strain S33., Results: To accumulate the intermediate 6-hydroxynicotine, we firstly identified the key enzyme decomposing 6-hydroxynicotine, named 6-hydroxynicotine oxidase, and then disrupted its encoding gene in A. tumefaciens S33. With the whole cells of the mutant as a biocatalyst, we tested the possibility to produce 6-hydroxynicotine from the nicotine of tobacco and its wastes and optimized the reaction conditions. At 30 °C and pH 7.0, nicotine could be efficiently transformed into 6-hydroxynicotine by the whole cells cultivated with glucose/ammonium/6-hydroxy-3-succinoylpyridine medium. The molar conversion and the specific catalytic rate reached approximately 98% and 1.01 g 6-hydroxynicotine h -1  g -1 dry cells, respectively. The product could be purified easily by dichloromethane extraction with a recovery of 76.8%, and was further confirmed by UV spectroscopy, mass spectroscopy, and NMR analysis., Conclusions: We successfully developed a novel biocatalytic route to 6-hydroxynicotine from nicotine by blocking the nicotine catabolic pathway via gene disruption, which provides an alternative green strategy to utilize tobacco and its wastes as a biomass resource by converting nicotine into valuable hydroxylated-pyridine compounds.

Background: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure., Results: We show that both non-tumorigenic (MCF 10A, MCF-12A) and tumorigenic (MCF7) breast epithelial cells exposed to cigarette smoke acquire mesenchymal properties such as fibroblastoid morphology, increased anchorage-independent growth, and increased motility and invasiveness. Moreover, transplantation experiments in mice demonstrate that treatment with cigarette smoke extract renders MCF 10A cells more capable to survive and colonize the mammary ducts and MCF7 cells more prone to metastasize from a subcutaneous injection site, independent of cigarette smoke effects on the host and stromal environment. The extent of transformation and the resulting phenotype thus appear to be associated with the differentiation state of the cells at the time of exposure. Analysis by flow cytometry showed that treatment with CSE leads to the emergence of a CD44(hi)/CD24(low) population in MCF 10A cells and of CD44+ and CD49f + MCF7 cells, indicating that cigarette smoke causes the emergence of cell populations bearing markers of self-renewing stem-like cells. The phenotypical alterations induced by cigarette smoke are accompanied by numerous changes in gene expression that are associated with epithelial to mesenchymal transition and tumorigenesis., Conclusions: Our results indicate that exposure to cigarette smoke leads to a more aggressive and transformed phenotype in human mammary epithelial cells and that the differentiation state of the cell at the time of exposure may be an important determinant in the phenotype of the final transformed state.

Background: The transcription factor, CCAAT enhancer binding protein-β (C/EBPβ), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation. Increases in the ratio of LIP/LAP are associated with aggressive, metastatic breast cancer; however, little is known regarding the molecular mechanisms that regulate LIP expression or the biological actions of an increase in the LIP/LAP ratio. Metastasis is highly dependent upon the suppression of anoikis and the role of C/EBPβ and LIP in this anchorage-independent, survival process is currently not known in mammary epithelial cells. IGF-1R signaling is important for the survival of breast cancer cells and crosstalk between IGF-1R and EGFR signaling pathways have been implicated in the development of more aggressive disease. We therefore evaluated in mammary epithelial cells whether IGF-1R signaling regulates the LIP/LAP ratio, analyzed the potential interplay between EGFR and IGF-1R signaling and addressed the biological significance of increased LIP expression in cellular survival and suppression of anoikis., Results: Our data provide the first evidence that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. Although crosstalk between IGF-1R signaling and EGFR signaling is detectable in MCF10A cells, this crosstalk is not required for the IGF-1 mediated regulation of LIP expression. Rather, the critical regulator of IGF-1 induced LIP expression appears to be EGFR-independent, Akt activity. Our data also demonstrate that increases in LIP expression promote cell survival via suppression of anoikis. Likewise, knockdown of total C/EBPβ leads to increased cell death and suggest that C/EBPβ expression is important for survival and resistance to anoikis. IGF-1 treatment can partially rescue vector control cells from anoikis; however, cells with reduced C/EBPβ expression do not survive anoikis., Conclusions: Taken together, our data demonstrate that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. C/EBPβ expression and elevations in LIP play an important role in regulating cellular survival via suppression of anoikis, in an IGF-1R mediated context or in a manner independent of IGF-1R signaling.

Background: Aminoglycoside ototoxicity is one of the common health problems. Mitochondrial 12S rRNA mutations are one of the important causes of aminoglycoside ototoxicity. However, the incidences of 12S rRNA mutations associated with aminoglycoside ototoxicity are less known., Methods: A total of 440 Chinese pediatric hearing-impaired subjects were recruited from two otology clinics in the Ningbo and Wenzhou cities of Zhejiang Province, China. These subjects underwent clinical, genetic evaluation and molecular analysis of mitochondrial 12S rRNA. Resultant mtDNA variants were evaluated by structural and phylogenetic analysis., Results: The study samples consisted of 227 males and 213 females. The age of all participants ranged from 1 years old to 18 years, with the median age of 9 years. Ninety-eight subjects (58 males and 40 females) had a history of exposure to aminoglycosides, accounting for 22.3% cases of hearing loss in this cohort. Molecular analysis of 12S rRNA gene identified 41 (39 known and 2 novel) variants. The incidences of the known deafness-associated 1555A > G, 1494C > T and 1095T > C mutations were 7.5%, 0.45% and 0.91% in this entire hearing-impaired subjects, respectively, and 21.4%, 2% and 2% among 98 subjects with aminoglycoside ototoxicity, respectively. The structural and phylogenetic evaluations showed that a novel 747A > G variant and known 839A > G, 1027A > G, 1310C > T and 1413T > C variants conferred increased sensitivity to aminoglycosides or nonsyndromic deafness as they were absent in 449 Chinese controls and localized at highly conserved nucleotides of this rRNA. However, other variants were polymorphisms. Of 44 subjects carrying one of definite or putative deafness-related 12S rRNA variants, only one subject carrying the 1413T > C variant harbored the 235DelC/299DelAT mutations in the GJB2 gene, while none of mutations in GJB2 gene was detected in other 43 subjects., Conclusions: Mutations in mitochondrial 12S rRNA accounted for ~30% cases of aminoglycoside-induced deafness in this cohort. Our data strongly support the idea that the mitochondrial 12S rRNA is the hot spot for mutations associated with aminoglycoside ototoxicity. These data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside antibiotic therapy, and eventually to decrease the incidence of deafness.