Natural compounds protect against the pathogenesis of osteoarthritis by mediating the NRF2/ARE signaling

Osteoarthritis (OA), a chronic joint cartilage disease, is characterized by the imbalanced homeostasis between anabolism and catabolism. Oxidative stress contributes to inflammatory responses, extracellular matrix (ECM) degradation, and chondrocyte apoptosis and promotes the pathogenesis of OA. Nuclear factor erythroid 2-related factor 2 (NRF2) is a central regulator of intracellular redox homeostasis. Activation of the NRF2/ARE signaling may effectively suppress oxidative stress, attenuate ECM degradation, and inhibit chondrocyte apoptosis. Increasing evidence suggests that the NRF2/ARE signaling has become a potential target for the therapeutic management of OA. Natural compounds, such as polyphenols and terpenoids, have been explored to protect against OA cartilage degeneration by activating the NRF2/ARE pathway. Specifically, flavonoids may function as NRF2 activators and exhibit chondroprotective activity. In conclusion, natural compounds provide rich resources to explore the therapeutic management of OA by activating NRF2/ARE signaling

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation

Treatment experience for different risk groups of Kaposiform hemangioendothelioma

BackgroundKaposiform hemangioendothelioma (KHE) is a rare vascular tumor with a high risk of mortality. Few studies with large samples of KHE have been reported. KHE may develop into the Kasabach–Merritt phenomenon (KMP), which is characterized by thrombocytopenia and consumptive coagulopathy. The features of severe symptomatic anemia and life-threatening low platelets make the management of KHE associated with KMP challenging.ObjectiveThe aim of this study was to examine the clinical characteristics of patients with KHE and discuss the treatment experience for different risk groups of KHE.MethodsThrough a retrospective review of 70 patients diagnosed with KHE between 2017 and 2022 in our center, we classify lesions into three clinicopathological stages based on the tumor involving depth, and divided the severity of KHE into three levels by estimating clinicopathological stages and severity of thrombocytopenia. Treatments of different severity groups were estimated with sufficient data.ResultsIn our cohort, 27% were neonates, and KHE lesion occurred at birth in 84% of patients. There was a slight male predominance (32 girls and 38 boys). Common clinical characteristics included associated coagulation disorder (100%), locally aggressive cutaneous blue–purple mass (89%), thrombocytopenia (78%), and local pain or joint dysfunction (20%). The lower extremities were the dominant location (35%), followed by the trunk (29%), the maxillofacial region and neck (24%), and the upper extremities (10%). Of the total cohort, 78% developed KMP; the median age at which thrombocytopenia occurred was 27.8 days. The median platelet count of patients who were associated with KMP was 24,000/µL in our cohort. Ninety-two percent of patients were given surgery treatment and 89% of these patients were given high-dose methylprednisolone (5-6 mg/kg daily) before surgery. In 55 patients with KMP, 36% were sensitive to high-dose corticosteroid therapy. Patients from the low-risk group (eight cases) underwent operation, all of whom recovered without recurrence after a maximum follow-up of 5 years. Out of 26 patients from the high-risk group, 25 underwent surgery treatment, with 1 case undergoing secondary surgery after recurrence and 1 case taking sirolimus. Out of 36 cases from the extremely high-risk group, 32 underwent surgery (including 2 cases who underwent external carotid artery ligation and catheterization), 3 of whom underwent secondary operation after recurrence, and the remaining 4 cases took medicine. The mean length of having sirolimus was 21 months; two cases stopped taking sirolimus due to severe pneumonia. Two cases died at 1 and 3 months after discharge.ConclusionsOur study describes the largest assessment of high-risk patients with KHE who have undergone an operation to date, with 5 years of follow-up to track recovery, which provides invaluable knowledge for the future treatment of patients with KHE and KMP from different risk groups: Early surgical intervention may be the most definitive treatment option for most patients with KHE; multimodality treatment is the best choice for the extremely high-risk group

Overcapacity-driven regional waste incineration facility network planning with residential land value maximization involved: a case study of Shanghai, China

The effective implementation of garbage classification policies in metropolises appears to bring the government into a new quandary about the overcapacity of regional waste incineration facilities (WIFs). This paper proposes a bi-objective robust optimization model to replan the WIFs’ location and their logistics network toward operational cost minimization and regional residential land value maximization. Shanghai is selected as a real-case, and the garbage classification rate and house price fluctuation coefficient are considered as uncertain parameters. All Pareto solutions depict that the regional residential land value released by WIF's closure and subsequent "Not in My Back Yard" effect mitigation is huge, ranging from 74 to 102 billion yuan. Furthermore, the trade-off's robust solutions show that keeping 3 WIFs in the suburbs essentially maximizes the land value, while keeping 6 WIFs evenly distributed throughout the city has the lowest operating cost. Notably, the robust model has good anti-disturbance and the ability to adapt to external changes. As the population migrates to five new cities from the central city and reaches its peak, similar Pareto solutions are observed as those in the baseline scenario without the influence of policies

Subcritical Water Extraction of Ursolic Acid from Hedyotis diffusa

An efficient and environmental-friendly extraction method has been developed for extraction of ursolic acid (UA) from Hedyotis diffusa by using subcritical water extraction (SWE). The experiments were carried out at different particle sizes (20–100 mesh), extraction temperature (120–200 °C), extraction time (10–50 min), solvent/solid ratio (20–40 mL/g), and extraction pressure (0.6–3.0 MPa). Response surface methodology (RSM) was employed to optimize SWE conditions, and the maximum UA yield was 6.45 mg/g material. Optimal conditions are as follows: Particle size of 80 mesh, extraction temperature at 157 °C and a solvent/solid ratio of 30 mL/g. The model of experimental response was proved to predict the experimental results very well and demonstrated that UA yield was mainly depended on solvent/solid ratio, followed by particle size and temperature. The purified extract was analyzed by electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS). The acquired precursor ion was m/z 455.3532, which is consistent with calculated value of UA. Furthermore, different extraction methods, including maceration extraction, heat reflux extraction, ultrasonic extraction, microwave-assisted extraction, and SWE were comparatively analyzed, which indicated that SWE was a time-saving, cost-saving and environment-friendly extraction technology for extraction of UA from Hedyotis diffusa

Ultrasound microflow patterns help in distinguishing malignant from benign thyroid nodules

Abstract Background Vascular features are not commonly used to evaluate thyroid nodules by conventional ultrasound due to the low sensitivity. Superb Microvascular Imaging (SMI) is a new ultrasonic Doppler technology that specializes in depicting microvessels and low-speed flow. The objective of this study was to explore the value of microflow features on SMI in differentiating malignant from benign thyroid nodules. Methods One hundred and seventy-seven adult patients with thyroid nodules in our center from October 2021 to June 2022 with available histopathological results were recruited, including 125 malignant nodules and 123 benign nodules. Preoperative ultrasound was performed using greyscale, Color Doppler Flow Imaging (CDFI), monochrome SMI (mSMI) and color SMI (cSMI). Vascular features such as flow richness, microflow distribution and microflow patterns of malignant thyroid nodules were compared with those of benign nodules. Results Penetrating vessel ≥ 1 (82.4% in the malignant group vs. 30.9% in the benign group, P < 0.001), the crab claw-like pattern (64.0% vs. 10.6%, P < 0.001) and the root hair-like pattern (8.0% vs. 2.4%, P = 0.049) were common in malignant thyroid nodules, among which the crab claw-like pattern was an independent risk factor for malignant thyroid nodules. The wheel-like pattern (1.6% in the malignant group vs. 33.3% in the benign group, P < 0.001) and the arborescent pattern (0 vs. 19.5%, P < 0.001) were more likely to appear in benign nodules. The diagnostic specificities of the crab claw-like pattern and the root hair-like pattern for malignant thyroid nodules were 0.894, 0.976, and the positive predictive values were 0.860, 0.769. The diagnostic specificities of the wheel-like pattern and the arborescent pattern for benign thyroid nodules were 0.984, 1.000, and the positive predictive values were 0.953, 1.000. Conclusions The crab claw-like pattern and the root hair-like pattern were microflow characteristics of malignant thyroid nodules. The wheel-like pattern and the arborescent pattern could help exclude the diagnosis of thyroid cancer

Table_1_Efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations: Results from phase II and III trials.pdf

ObjectivesThe addition of novel β-lactamase inhibitors to carbapenems restores the activity against multidrug-resistant Gram-negative bacteria. The aim of this study was to summarize the evidence on the efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations.MethodsWe conducted a meta-analysis of clinical trials comparing novel carbapenem–β-lactamase inhibitor combinations with comparators to assess the clinical and microbiological responses, mortality, and adverse events (AEs).ResultsA total of 1,984 patients were included. The pooled risk ratios (RRs) of clinical cure, microbiological eradication, all-cause mortality, and 28-day mortality were 1.11 (95% CI: 0.98–1.26), 0.98 (95% CI: 0.82–1.16), 0.90 (95% CI: 0.49–0.94), and 0.68 (95% CI: 0.49–0.94) between the novel carbapenem–β-lactamase inhibitor combinations and control groups. Sensitivity analysis revealed that the phase II trial of imipenem–cilastatin/relebactam (ICR) against complicated urinary tract infections could be the most important factor of heterogeneity for the microbiological response. The therapeutic effect of novel carbapenem–β-lactamase inhibitor combinations was better in meropenem–vaborbactam (MEV), phase III trials, and number of patients less than 200. The RRs of AEs from any cause and serious adverse events (SAEs) for patients receiving novel carbapenem–β-lactamase inhibitor combinations were 0.98 (95% CI: 0.93–1.04) and 1.01 (95% CI: 0.75–1.36), respectively.ConclusionsICR and MEV were superior to comparators for clinical cure and survival rate in the treatment of complicated infections, and both were as tolerable as the comparators.</p

Image_2_Efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations: Results from phase II and III trials.tif

ObjectivesThe addition of novel β-lactamase inhibitors to carbapenems restores the activity against multidrug-resistant Gram-negative bacteria. The aim of this study was to summarize the evidence on the efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations.MethodsWe conducted a meta-analysis of clinical trials comparing novel carbapenem–β-lactamase inhibitor combinations with comparators to assess the clinical and microbiological responses, mortality, and adverse events (AEs).ResultsA total of 1,984 patients were included. The pooled risk ratios (RRs) of clinical cure, microbiological eradication, all-cause mortality, and 28-day mortality were 1.11 (95% CI: 0.98–1.26), 0.98 (95% CI: 0.82–1.16), 0.90 (95% CI: 0.49–0.94), and 0.68 (95% CI: 0.49–0.94) between the novel carbapenem–β-lactamase inhibitor combinations and control groups. Sensitivity analysis revealed that the phase II trial of imipenem–cilastatin/relebactam (ICR) against complicated urinary tract infections could be the most important factor of heterogeneity for the microbiological response. The therapeutic effect of novel carbapenem–β-lactamase inhibitor combinations was better in meropenem–vaborbactam (MEV), phase III trials, and number of patients less than 200. The RRs of AEs from any cause and serious adverse events (SAEs) for patients receiving novel carbapenem–β-lactamase inhibitor combinations were 0.98 (95% CI: 0.93–1.04) and 1.01 (95% CI: 0.75–1.36), respectively.ConclusionsICR and MEV were superior to comparators for clinical cure and survival rate in the treatment of complicated infections, and both were as tolerable as the comparators.</p

H4K20me3, H3K4me2 and H3K9me2 mediate the effect of ER on prognosis in breast cancer

ABSTRACTPrevious studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment

Image_1_Efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations: Results from phase II and III trials.tif

ObjectivesThe addition of novel β-lactamase inhibitors to carbapenems restores the activity against multidrug-resistant Gram-negative bacteria. The aim of this study was to summarize the evidence on the efficacy and safety of novel carbapenem–β-lactamase inhibitor combinations.MethodsWe conducted a meta-analysis of clinical trials comparing novel carbapenem–β-lactamase inhibitor combinations with comparators to assess the clinical and microbiological responses, mortality, and adverse events (AEs).ResultsA total of 1,984 patients were included. The pooled risk ratios (RRs) of clinical cure, microbiological eradication, all-cause mortality, and 28-day mortality were 1.11 (95% CI: 0.98–1.26), 0.98 (95% CI: 0.82–1.16), 0.90 (95% CI: 0.49–0.94), and 0.68 (95% CI: 0.49–0.94) between the novel carbapenem–β-lactamase inhibitor combinations and control groups. Sensitivity analysis revealed that the phase II trial of imipenem–cilastatin/relebactam (ICR) against complicated urinary tract infections could be the most important factor of heterogeneity for the microbiological response. The therapeutic effect of novel carbapenem–β-lactamase inhibitor combinations was better in meropenem–vaborbactam (MEV), phase III trials, and number of patients less than 200. The RRs of AEs from any cause and serious adverse events (SAEs) for patients receiving novel carbapenem–β-lactamase inhibitor combinations were 0.98 (95% CI: 0.93–1.04) and 1.01 (95% CI: 0.75–1.36), respectively.ConclusionsICR and MEV were superior to comparators for clinical cure and survival rate in the treatment of complicated infections, and both were as tolerable as the comparators.</p