Genus Shewanella: A Potential Intestinal Colonizer Associated With Post-Operative Surgical Site Infections in Coastal Regions.

Background: This study aims to elucidate the clinical characteristics of Shewanella-related surgical site infections (SSIs) and assess the risk of mortality in patients by establishing a predictive model. Patients and Methods: A retrospective analysis of medical history and laboratory data of Shewanella-related SSI patients over the past decade was conducted via the electronic medical record (EMR) system. A predictive model for mortality risk in Shewanella-related SSI patients was established using plasma interleukin-6 (IL-6) levels combined with the Howell-PIRO scoring system. Results: Over the past 10 years, 45 strains of Shewanella were isolated from specimens such as bile, drainage fluid, and whole blood in patients with digestive tract SSIs. Among them, 21 of 45 (46.67%) patients underwent malignant tumor resection of the digestive system, 14 of 45 (31.11%) underwent endoscopic retrograde cholangiopancreatography (ERCP) common bile duct exploration or the stone removal, and seven of 45 (15.56%) were trauma repair patients with fractures and abdominal injuries. Among the 45 Shewanella-related SSI patients, 10 died within 30 days of infection, six cases involved infections with more than two other types of bacteria. The combined use of IL-6 and Howell-PIRO scores for mortality risk assessment yielded an receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.9350, a positive predictive value of 92.71%, a negative predictive value of 94.58%, a diagnostic sensitivity of 95.35%, and a diagnostic specificity of 92.14%-all higher than the model using IL-6 or Howell-PIRO scores alone. Conclusions: We found that residents in coastal areas faced an increased risk of Shewanella-related SSI. Moreover, the higher the number of concurrent microbial infections occurring alongside Shewanella-related SSI, the greater the mortality rate among patients. The combined application of plasma IL-6 levels and the Howell-PIRO scoring system is beneficial for assessing patient mortality risk and guiding timely and proactive clinical interventions.

Analysis of clinical characteristics of infections caused by shewanella species.

PURPOSE: The Shewanella genus is a rare pathogen of marine origin. In recent years, there has been a continuous increase in infection cases caused by this bacterium, and we have observed the uniqueness of infections caused by this microorganism. MATERIALS AND METHODS: This study conducted a retrospective analysis of the medical history and laboratory examination data of patients infected with the Shewanella genus over the past decade. Additionally, it employed bioinformatics methods to analyze the relevant virulence factors and antibiotic resistance genes associated with the Shewanella genus. RESULTS: Over the past 10 years, we have isolated 51 cases of Shewanella, with 68.82% being Shewanella putrefaciens (35/51 cases) and 31.37% being Shewanella algae (16/51 cases). Infected individuals often had underlying diseases, with 39.22% (20/51) having malignant tumors and 25.49% (13/51) having liver and biliary system diseases primarily characterized by stones. The majority of patients, 62.74% (32/51), exhibited mixed infections, including one case with a combination of infections from three other types of bacteria and five cases with a combination of infections from two other types of bacteria. The identified microorganisms were commonly resistant to ticarcillin-clavulanic acid (23.5%), followed by cefoperazone-sulbactam (19.6%), ciprofloxacin (17.6%), and cefotaxime (17.6%). Bioinformatics analysis indicates that Shewanella can express bile hydrolysis regulators and fatty acid metabolism regulators that aid in adapting to the unique environment of the biliary tract. Additionally, it expresses abundant catalase, superoxide dismutase, and two-component signal transduction system proteins, which may be related to environmental adaptation. Shewanella also expresses various antibiotic resistance genes, including beta-lactamases and aminoglycoside modification enzymes. Iron carriers may be one of its important virulence factors. CONCLUSIONS: We speculate that the Shewanella genus may exist as a specific colonizer in the human body, and under certain conditions, it may act as a pathogen, leading to biliary infections in the host.

Developing a clinical-radiomic prediction model for 3-year cancer-specific survival in lung cancer patients treated with stereotactic body radiation therapy.

PURPOSE: The study aims to develop and validate a combined model for predicting 3-year cancer-specific survival (CSS) in lung cancer patients treated with stereotactic body radiation therapy (SBRT) by integrating clinical and radiomic parameters. METHODS: Clinical data and pre-treatment CT images were collected from 102 patients treated with lung SBRT. Multivariate logistic regression and the least absolute shrinkage and selection operator were used to determine the clinical and radiomic factors associated with 3-year CSS. Three prediction models were developed using clinical factors, radiomic factors, and a combination of both. The performance of the models was assessed using receiver operating characteristic curve and calibration curve. A nomogram was also created to visualize the 3-year CSS prediction. RESULTS: With a 36-month follow-up, 40 patients (39.2%) died of lung cancer and 62 patients (60.8%) survived. Three clinical factors, including gender, clinical stage, and lymphocyte ratio, along with three radiomic features, were found to be independent factors correlated with 3-year CSS. The area under the curve values for the clinical, radiomic, and combined model were 0.839 (95% CI 0.735-0.914), 0.886 (95% CI 0.790-0.948), and 0.914 (95% CI 0.825-0.966) in the training cohort, and 0.757 (95% CI 0.580-0.887), 0.818 (95% CI 0.648-0.929), and 0.843 (95% CI 0.677-0.944) in the validation cohort, respectively. Additionally, the calibration curve demonstrated good calibration performance and the nomogram created from the combined model showed potential for clinical utility. CONCLUSION: A clinical-radiomic model was developed to predict the 3-year CSS for lung cancer patients treated with SBRT.

Developing a Prediction Model for Radiation Pneumonitis in Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy Combined With Clinical, Dosimetric Factors, and Laboratory Biomarkers.

BACKGROUND: The study aims to identify the risk factors and develop a model for predicting grade ≥2 radiation pneumonitis (RP) for lung cancer patients treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: Clinical data, dosimetric data, and laboratory biomarkers from 186 patients treated with lung SBRT were collected. Univariate and multivariate logistic regression were performed to determine the predictive factors for grade ≥2 RP. Three models were developed by using the clinical, dosimetric, and combined factors, respectively. RESULTS: With a median follow-up of 36 months, grade ≥2 RP was recorded in 13.4% of patients. On univariate logistic regression analysis, clinical factors of age and lung volume, dosimetric factors of treatment durations, fractional dose and V10, and laboratory biomarkers of neutrophil, PLT, PLR, and Hb levels were significantly associated with grade ≥2 RP. However, on multivariate analysis, only age, lung volume, fractional dose, V10, and Hb levels were independent factors. AUC values for the clinical, dosimetric, and combined models were 0.730 (95% CI, 0.660-0.793), 0.711 (95% CI, 0.641-0.775) and 0.830 (95% CI, 0.768-0.881), respectively. The combined model provided superior discriminative ability than the clinical and dosimetric models (P < .05). CONCLUSION: Age, lung volume, fractional dose, V10, and Hb levels were demonstrated to be significant factors associated with grade ≥2 RP for lung cancer patients after SBRT. A novel model combining clinical, dosimetric factors, and laboratory biomarkers improved predictive performance compared with the clinical and dosimetric model alone.

Investigations of the distant metastatic non-small cell lung cancer without local lymph node involvement: Real world data from a large database.

INTRODUCTION: This study aimed to investigate the presentations and survival outcomes of the distant metastatic non-small cell lung cancer (NSCLC) without lymph node involvement to obtain a clearer picture of this special subgroup of metastatic NSCLC. METHOD: A least absolute shrinkage and selection operator (LASSO) penalized Cox regression analysis was used to select the prognostic variables. A nomogram and corresponding risk-classifying systems were constructed. The C-index and calibration curves were used to evaluate the performance of the model. Overall survival (OS) curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare OS differences between groups. Propensity score matching (PSM) was performed to reduce bias. RESULT: A total of 12 610 NSCLC patients with M1 category (N0 group: 3045 cases; N1-3 group: 9565 cases) were included. Regarding the N0 group, multivariate analysis demonstrated that age, sex, race, surgery, grade, tumor size, and M category were independent prognostic factors. A nomogram and corresponding risk-classifying systems were formulated. Favorable validation results were obtained from the C-index, calibration curves, and survival comparisons. Survival curves demonstrated that N0 NSCLC patients had better survival than N1-3 NSCLC patients both before and after PSM. Furthermore, the survival of resected N0M1 patients was superior to that of those without surgery. CONCLUSION: In this study, a prognostic nomogram and risk-classifying systems designed for the T1-4N0M1 NSCLC patients showed acceptable performance. Primary lung tumor resection might be a feasible treatment for this population subset. Additionally, we proposed that lymph node stage might have a place in the forthcoming tumor-node-metastasis (TNM) staging proposal for NSCLC patients with M1 category.

A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche.

Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4+ lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the VSIg4+ lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.

Emergency surgery for a patient with a thoracic spinal epidural abscess: a case report and literature review.

A man in his early 40s visited the Emergency Department because of no motor function in his lower limbs for 10 hours. Magnetic resonance imaging of his thoracic spine showed that the thoracic spinal canal (T2-T6) was occupied, and the thoracic spinal cord was compressed. In view of the severe symptoms, we quickly completed preoperative preparations and performed a thoracic laminectomy within 24 hours of paralysis of both lower limbs. Postoperatively, the patient underwent rehabilitation exercise. Four weeks later, the patient's lower limbs had full 5/5 strength. We reviewed the related literature to summarize the clinical guidelines with spinal surgeons. Timely diagnosis of thoracic spinal epidural abscess, early surgical treatment, and anti-infection management and rehabilitation exercise are essential for the full recovery of lower limb muscle strength.

A cross-sectional study of the association between heavy metals and pan-cancers associated with sex hormones in NHANES 1999-2018.

Given the complexity of tumorigenesis, numerous studies have also shown that excessive exposure to heavy metals increases the risk of cancers and disrupts the secretion of sex hormones. However, the specific effects of heavy metals on cancers remain to be proven. To confirm the association between heavy metals and pan-cancer sex hormone levels among adults, 94,337 individuals from the National Health and Nutrition Examination Survey were assessed. We examined the associations between pan-cancers associated with sex hormones (ovarian, testicular, breast, and prostate cancers) and heavy metals in blood/urine. The methods (the WQS (weighted quantile sums) and SVYGLM (survey generalized linear model) regressions) were used to evaluate the association between sex hormone-related cancers and each metal category by incorporating covariates. To evaluate the overall effect of heavy metals and detect the dose-response relationship between the prevalence of pan-cancers associated with sex hormones and heavy metals, RCS (restricted cubic splines) were applied. Environmental exposure to heavy metals may be associated with pan-cancers associated with sex hormones in adults in the USA. Prostate cancer was inversely associated with blood cadmium while positively associated with blood lead, urinary tin, and thallium. Breast cancer was inversely associated with blood lead. Ovarian cancer was positively associated with blood cadmium. We also found a non-linear dose-response relationship between pan-cancers associated with sex hormones and heavy metals, which was non-parametric, using RCS models. The OR for breast cancer decreased along with the increase in lead concentration under approximately 20 µg/dl, while the OR for prostate cancer increased between urine thallium levels of approximately 0.17-1.1 ng/ml. Pan-cancers associated with sex hormones are associated with exposure to heavy metals. Considering the design of the NHANES study, further studies need to be conducted on other nationally representative surveys.

Association between urinary nickel with obesity status in adults: A cross-sectional study.

Objectives: The prevalence of obesity is on the rise and is connected to numerous factors. However, the relationship between obesity and nickel has never been investigated. Our study aimed to explore the association between urinary nickel and obesity Status in adults. Methods: From the 2017-2018 National Health and Nutrition Examination Surveys (NHANES), 1,705 participants ≥18 years of age were enrolled. To explore further the relationship among urinary nickel, body mass index (BMI), and waist circumference(WC), Weighted multivariate linear regression analyses and further subgroup analyzes were conducted. Results: Urinary nickel does not correlate with BMI level but positively correlates with WC. In the subgroup analyzed according to sex, Urinary nickel has a positive correlation with BMI and WC in males but has a negative correlation in females. Secondary stratification analysis according to sex and race, Urinary nickel positively correlates with BMI in White males. It also positively correlates with WC in both White and Black males. Conclusions: A correlation was found between urinary nickel levels and BMI and WC in adult males. Adult men, especially those already obese, may need to reduce nickel exposure.

Risk factors, clinical features, and outcomes of premature acute myocardial infarction.

Aims: To investigate the risk factors, clinical features, and prognostic factors of patients with premature acute myocardial infarction (AMI). Materials and methods: A retrospective cohort study of patients with AMI included in data from the West China Hospital of Sichuan University from 2011 to 2019 was divided into premature AMI (aged < 55 years in men and < 65 years in women) and non-premature AMI. Patients' demographics, laboratory tests, Electrocardiography (ECG), cardiac ultrasound, and coronary angiography reports were collected. All-cause death after incident premature MI was enumerated as the primary endpoint. Results: Among all 8,942 AMI cases, 2,513 were premature AMI (79.8% men). Compared to the non-premature AMI group, risk factors such as smoking, dyslipidemia, overweight, obesity, and a family history of coronary heart disease (CHD) were more prevalent in the premature AMI group. The cumulative survival rate of patients in the premature AMI group was significantly better than the non-premature AMI group during a mean follow-up of 4.6 years (HR = 0.27, 95% CI 0.22-0.32, p < 0.001). Low left ventricular ejection fraction (LVEF) (Adjusted HR 3.00, 95% CI 1.85-4.88, P < 0.001), peak N-terminal pro-B-type natriuretic peptide (NT-proBNP) level (Adjusted HR 1.34, 95% CI 1.18-1.52, P < 0.001) and the occurrence of in-hospital major adverse cardiovascular and cerebrovascular events (MACCEs) (Adjusted HR 2.36, 95% CI 1.45-3.85, P = 0.001) were predictors of poor prognosis in premature AMI patients. Conclusion: AMI in young patients is associated with unhealthy lifestyles such as smoking, dyslipidemia, and obesity. Low LVEF, elevated NT-proBNP peak level, and the occurrence of in-hospital MACCEs were predictors of poor prognosis in premature AMI patients.

Genome-wide comparison and in silico analysis of splicing factor SYF2/NTC31/p29 in eukaryotes: Special focus on vertebrates.

The gene SYF2-an RNA splicing factor-can interact with Cyclin D-type binding protein 1 (GICP) in many biological processes, including splicing regulation, cell cycle regulation, and DNA damage repair. In our previous study we performed genome-wide identification and functional analysis of SYF2 in plant species. The phylogenetic relationships and expression profiles of SYF2 have not been systematically studied in animals, however. To this end, the gene structure, genes, and protein conserved motifs of 102 SYF2 homologous genes from 91 different animal species were systematically analyzed, along with conserved splicing sites in 45 representative vertebrate species. A differential comparative analysis of expression patterns in humans and mice was made. Molecular bioinformatics analysis of SYF2 showed the gene was conserved and functional in different animal species. In addition, expression pattern analysis found that SYF2 was highly expressed in hematopoietic stem cells, T cells, and lymphoid progenitor cells; in ovary, lung, and spleen; and in other cells and organs. This suggests that changes in SYF2 expression may be associated with disease development in these cells, tissues, or organs. In conclusion, our study analyzes the SYF2 disease resistance genes of different animal species through bioinformatics, reveals the relationship between the SYF2 genotype and the occurrence of certain diseases, and provides a theoretical basis for follow-up study of the relationship between the SYF2 gene and animal diseases.

Modified Perineal Reconstruction Combined with Anal Sphincter Repair for Obstetric Anal Sphincter Injuries.

Objective: The aim of this study was to investigate the clinical effectiveness of modified perineal reconstruction combined with anal sphincter repair in the treatment of obstetric anal sphincter injuries (OASIS). Methods: Twenty consecutive patients with an OASI who underwent modified perineal reconstruction combined with anal sphincter repair in the Department of Colorectal and Anal Surgery of the First Hospital of Jilin University from October 2015 to September 2017 were retrospectively enrolled in this study. Anal function was evaluated using the Williams grade, the Wexner score, anorectal manometry, and transrectal ultrasound. Results: Differences in both the Williams grade and the Wexner score prior to operation and following surgery indicated that anal function had improved, and these differences were statistically significant (P < 0.05). These indices also showed further improvement six months after surgery as compared with values at one month, and again, these differences were statistically significant (P < 0.05). In addition, anorectal manometry at six months following surgery showed statistically significant differences in the maximum anal resting pressure, maximum anal systolic pressure, and anal defecation pressure as compared with values prior to operation (P < 0.05). Postoperative endorectal ultrasound revealed that the anal sphincter presented with close imbricated overlapping. Conclusion: Modified perineal reconstruction combined with anal sphincter repair in the treatment of female perineal defect is associated with a good clinical outcome, strengthening anal function, and reconstructing the perineum, and is a possible method for clinical treatment.

Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial.

BACKGROUND: Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine. METHODS: We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine-Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0 × 1011 viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0 × 1011 viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259. FINDINGS: Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (p<0·0001). The low dose group had a serum NAb GMT of 744·4 (95% CI 520·1-1065·6) and the high dose group had a GMT of 714·1 (479·4-1063·7) 14 days after booster dose, significantly higher than the GMT in the CoronaVac group (78·5 [60·5-101·7]; p<0·0001). INTERPRETATION: We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination. FUNDING: National Natural Science Foundation of China and Jiangsu Provincial Key Research and Development Program.

Reconstruction of complex chest wall defects: A case report.

BACKGROUND: Chronic radiative chest wall ulcers are common in patients undergoing radiation therapy. If not treated early, then symptoms such as erosion, bleeding and infection will appear on the skin. In severe cases, ulcers invade the ribs and pleura, presenting a mortality risk. Small ulcers can be repaired with pedicle flaps. Because radioactive ulcers often invade the thorax, surgeons need to remove large areas of skin and muscle, and sometimes ribs. Repairing large chest wall defects are a challenge for surgeons. CASE SUMMARY: A 74-year-old female patient was admitted to our department with chest wall skin ulceration after radiation therapy for left breast cancer. The patient was diagnosed with chronic radioactive ulceration. After multidisciplinary discussion, the authors performed expansive resection of the chest wall ulcers and repaired large chest wall defects using a deep inferior epigastric perforator (DIEP) flap combined with a high-density polyethylene (HDPE) patch. The patient was followed-up 6 mo after the operation. No pigmentation or edema was found in the flap. CONCLUSION: DIEP flap plus HDPE patch is one of the better treatments for radiation-induced chest wall ulcers.

Functional Adaptation of Vocalization Revealed by Morphological and Histochemical Characteristics of Sonic Muscles in Blackmouth Croaker (Atrobucca nibe).

Sound production in the blackmouth croaker (Atrobucca nibe) was characterized using acoustic, morphological, and histochemical methods. Their calls consisted of a train of two to seven pulses; the frequency ranged from 180 to 3000 Hz, with a dominant frequency of 326 ± 40 Hz. The duration of each call ranged from 80 to 360 ms. Male A. nibe possess a pair of bilaterally symmetric sonic muscles attached to the body wall adjacent to the swim bladder. The average diameter of the sonic muscle fibers was significantly shorter than that of the abdominal muscle fibers. Semithin sections of the sonic muscle fibers revealed a core-like structure (central core) and the radial arrangement of the sarcoplasmic reticulum and myofibrils. Numerous mitochondria were distributed within the central core and around the periphery of the fibers. Most of the fibers were identified as Type IIa on the basis of their myosin adenosine triphosphatase activities, but a few were identified as Type IIc fibers. All sonic muscle fibers exhibited strong oxidative enzyme activity and oxidative and anaerobic capabilities. The features suggest that the sonic muscles of A. nibe are morphologically and physiologically adapted for fast twitching and fatigue resistance, which support fish vocalization.

The Clinical Outcomes, Prognostic Factors and Nomogram Models for Primary Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

Purpose: Stereotactic body radiation therapy (SBRT) is a standard treatment for early primary lung cancer patients. However, there are few simple models for predicting the clinical outcomes of these patients. Our study analyzed the clinical outcomes, identified the prognostic factors, and developed prediction nomogram models for these patients. Materials and Methods: We retrospectively analyzed 114 patients with primary lung cancer treated with SBRT from 2012 to 2020 at our institutions and assessed patient's clinical outcomes and levels of toxicity. Kaplan-Meier analysis with a log-rank test was used to generate the survival curve. The cut-off values of continuous factors were calculated with the X-tile tool. Potential independent prognostic factors for clinical outcomes were explored using cox regression analysis. Nomograms for clinical outcomes prediction were established with identified factors and assessed by calibration curves. Results: The median overall survival (OS) was 40.6 months, with 3-year OS, local recurrence free survival (LRFS), distant disease-free survival (DDFS) and progression free survival (PFS) of 56.3%, 61.3%, 72.9% and 35.8%, respectively, with grade 3 or higher toxicity rate of 7%. The cox regression analysis revealed that the clinical stage, immobilization device, and the prescription dose covering 95% of the target area (D95) were independent prognostic factors associated with OS. Moreover, the clinical stage, and immobilization device were independent prognostic factors of LRFS and PFS. The smoking status, hemoglobin (Hb) and immobilization device were significant prognostic factors for DDFS. The nomograms and calibration curves incorporating the above factors indicated good predictive accuracy. Conclusions: SBRT is effective and safe for primary lung cancer. The prognostic factors associated with OS, LRFS, DDFS and PFS are proposed, and the nomograms we proposed are suitable for clinical outcomes prediction.

Destabilization of macrophage migration inhibitory factor by 4-IPP reduces NF-κB/P-TEFb complex-mediated c-Myb transcription to suppress osteosarcoma tumourigenesis.

BACKGROUND: As an inflammatory factor and oncogenic driver protein, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) plays a crucial role in the osteosarcoma microenvironment. Although 4-iodo-6-phenylpyrimidine (4-IPP) can inactivate MIF biological functions, its anti-osteosarcoma effect and molecular mechanisms have not been investigated. In this study, we identified the MIF inhibitor 4-IPP as a specific double-effector drug for osteosarcoma with both anti-tumour and anti-osteoclastogenic functions. METHODS: The anti-cancer effects of 4-IPP were evaluated by wound healing assay, cell cycle analysis, colony formation assay, CCK-8 assay, apoptosis analysis, and Transwell migration/invasion assays. Through the application of a luciferase reporter, chromatin immunoprecipitation assays, and immunofluorescence and coimmunoprecipitation analyses, the transcriptional regulation of the NF-κB/P-TEFb complex on c-Myb- and STUB1-mediated proteasome-dependent MIF protein degradation was confirmed. The effect of 4-IPP on tumour growth and metastasis was assessed using an HOS-derived tail vein metastasis model and subcutaneous and orthotopic xenograft tumour models. RESULTS: In vitro, 4-IPP significantly reduced the proliferation and metastasis of osteosarcoma cells by suppressing the NF-κB pathway. 4-IPP hindered the binding between MIF and CD74 as well as p65. Moreover, 4-IPP inhibited MIF to interrupt the formation of downstream NF-κB/P-TEFb complexes, leading to the down-regulation of c-Myb transcription. Interestingly, the implementation of 4-IPP can mediate small molecule-induced MIF protein proteasomal degradation via the STUB1 E3 ligand. However, 4-IPP still interrupted MIF-mediated communication between osteosarcoma cells and osteoclasts, thus promoting osteoclastogenesis. Remarkably, 4-IPP strongly reduced HOS-derived xenograft osteosarcoma tumourigenesis and metastasis in an in vivo mouse model. CONCLUSIONS: Our findings demonstrate that the small molecule 4-IPP targeting the MIF protein exerts an anti-osteosarcoma effect by simultaneously inactivating the biological functions of MIF and promoting its proteasomal degradation. Direct destabilization of the MIF protein with 4-IPP may be a promising therapeutic strategy for treating osteosarcoma.

Coagulants put phosphate-accumulating organisms at a competitive disadvantage with glycogen-accumulating organisms in enhanced biological phosphorus removal system.

Enhanced biological phosphorus removal (EBPR) process is susceptible to the changed operation condition, which results in an unstable treatment performance. In this work, long-term effect of coagulants addition, aluminum salt for the reactor R1 and iron salt for the reactor R2, on EBPR systems was comprehensively evaluated. Results showed that during the initial 30 days' coagulant addition, effluent chemical oxygen demand and phosphorus can be reduced below 25 and 0.5 mg·L-1, respectively. Further supply of metal salts would stimulate microbial extracellular polymeric substance excretion and induce reactive oxygen species accumulation, which destroyed the cell membrane integrity and deteriorated the phosphorus removal performance. Moreover, coagulants would decrease the relative abundance of Candidatus Accumulibacter while increase the relative abundance of Candidatus Competibacter, leading phosphors accumulating organisms in a disadvantage position. The results of this work might be valuable for the operation of chemical assisted biological phosphorus removal bioreactor.

L4-to-L4 nerve root transfer for hindlimb hemiplegia after hypertensive intracerebral hemorrhage.

There is no effective treatment for hemiplegia after hypertensive intracerebral hemorrhage. Considering that the branches of L4 nerve roots in the lumbar plexus root control the movement of the lower extremity anterior and posterior muscles, we investigated a potential method of nerve repair using the L4 nerve roots. Rat models of hindlimb hemiplegia after a hypertensive intracerebral hemorrhage were established by injecting autogenous blood into the posterior limb of internal capsule. The L4 nerve root on the healthy side of model rats was transferred and then anastomosed with the L4 nerve root on the affected side to drive the extensor and flexor muscles of the hindlimbs. We investigated whether this method can restore the flexible movement of the hindlimbs of paralyzed rats after hypertensive intracerebral hemorrhage. In a beam-walking test and ladder rung walking task, model rats exhibited an initial high number of slips, but improved in accuracy on the paretic side over time. At 17 weeks after surgery, rats gained approximately 58.2% accuracy from baseline performance and performed ankle motions on the paretic side. At 9 weeks after surgery, a retrograde tracing test showed a large number of fluoro-gold-labeled motoneurons in the left anterior horn of the spinal cord that supports the L4-to-L4 nerve roots. In addition, histological and ultramicrostructural findings showed axon regeneration of motoneurons in the anterior horn of the spinal cord. Electromyography and paw print analysis showed that denervated hindlimb muscles regained reliable innervation and walking coordination improved. These findings suggest that the L4-to-L4 nerve root transfer method for the treatment of hindlimb hemiplegia after hypertensive intracerebral hemorrhage can improve the locomotion of hindlimb major joints, particularly of the distal ankle. Findings from study support that the L4-to-L4 nerve root transfer method can effectively repair the hindlimb hemiplegia after hypertensive intracerebral hemorrhage. All animal experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (No. IACUC-1906009) in June 2019.

Antioxidant and antibacterial insights into the leaves, leaf tea and medicinal roots from Astragalus membranaceus (Fisch.) Bge.

Used as traditional Chinese medicine, Astragalus membranaceus (Fisch.) Bge. (A. membranaceus) roots are also used as tonic food material in a wide range of applications, while the leaves are left in the field, unused. Therefore, comprehensively exploring and utilizing the leaves will inevitably reduce the associated resource waste and environment pollution. In this study, the plant leaves were processed into tea using green tea processing technology. Bioactive components, antioxidant and antibacterial activities of the Leaf Tea (LT) and Dry Leaves (DL) were studied, and compared to that of the Dry Roots (DR). The results showed that the polysaccharides content (POL) in the DR (20.44%) was twice as high as the DL (10.18%) and LT (8.68%). However, the DL contained 36.85% more water-soluble extracts (WSE), 35.09% more ethanol-soluble extracts (ESE), 409.63% more total flavonoid content (TFC), 221.01% more total phenolic content (TPC) and 94.34% more proteins, and the LT contained 26.21% more WSE, 40.64% more ESE, 326.93% more TFC, 191.90% more TPC and 37.71% more proteins. The total amino acid (AA) content in the DR was 8.89%, while in that of the DL and LT were 24.18% and 28.96% respectively, nearly 3-times higher than that of the DR. The antioxidant activity of DR was much lower than those of DL and LT, both of which had antioxidant activity closer to that of Vitamin C (VC) and the antioxidant activities were even stronger when the optimal concentration was reached. Except for Aspergillus niger and Staphylococcus aureus, the DL and DR exhibited inhibition activities to Salmonella, Bacillus subtilis, Escherichia coli and yeast, while the LT had antimicrobial activities against all the strains except for A. niger. In summary, compared with the most commonly used DR, the DL and LT from A. membranaceus contained higher bioactive components, and stronger antioxidant and antimicrobial activities. Producing leaf tea may be an appropriate way to economically and reasonably utilize the plant leaves which are by-products.