Structure-Guided Discovery and Preclinical Assessment of Novel (Thiophen-3-yl)aminopyrimidine Derivatives as Potent ERK1/2 Inhibitors.

The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.

Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. Currently, there are no effective drugs for the treatment of DN. Although several studies have reported the therapeutic potential of mesenchymal stem cells, the underlying mechanisms remain largely unknown. Here, we report that both human umbilical cord MSCs (UC-MSCs) and UC-MSC-derived exosomes (UC-MSC-exo) attenuate kidney damage, and inhibit epithelial-mesenchymal transition (EMT) and renal fibrosis in streptozotocin-induced DN rats. Strikingly, the Hedgehog receptor, smoothened (SMO), was significantly upregulated in the kidney tissues of DN patients and rats, and positively correlated with EMT and renal fibrosis. UC-MSC and UC-MSC-exo treatment resulted in decrease of SMO expression. In vitro co-culture experiments revealed that UC-MSC-exo reduced EMT of tubular epithelial cells through inhibiting Hedgehog/SMO pathway. Collectively, UC-MSCs inhibit EMT and renal fibrosis by delivering exosomes and targeting Hedgehog/SMO signaling, suggesting that UC-MSCs and their exosomes are novel anti-fibrotic therapeutics for treating DN.

A Preliminary Study on the Application of Contrast-Enhanced Ultrasonography in Children With Peripheral Neuroblastic Tumors.

The purpose of this study was to retrospectively analyze the characteristics of contrast-enhanced ultrasound (CEUS) images and quantitative parameters of time-intensity curves (TICs) in children's peripheral neuroblastic tumors (pNTs). By comparing the imaging features and quantitative parameters of the TICs of neuroblastoma (NB) and ganglioneuroblastoma (GNB) patients, we attempted to identify the distinguishing points between NB and GNB. A total of 35 patients confirmed to have pNTs by pathologic examination were included in this study. Each child underwent CEUS with complete imaging data (including still images and at least 3 min of video files). Twenty-four patients were confirmed to have NB, and 11 were considered to have GNB according to differentiation. The CEUS image features and quantitative parameters of the TICs of all lesions were analyzed to determine whether there were CEUS-related differences between the two types of pNT. There was a significant difference in the enhancement patterns of the CEUS features (χ2 = 5.303, p < 0.05), with more "peripheral-central" enhancement in the NB group and more "central-peripheral" enhancement in the GNB group. In the TIC, the rise time and time to peak were significantly different (p < 0.05). The receiver operating characteristic curve showed that the probability of ganglion cell NB increased significantly after RT > 15.29, with a sensitivity of 0.636 and a specificity of 0.958. When the peak time was greater than 16.155, the probability of NB increased significantly, with a sensitivity of 0.636 and a specificity of 0.958. The CEUS features of NB and GNB patients are very similar, and it is difficult to distinguish them. Rise time and time to peak may be useful in identifying GNB and NB, but the sample size of this study was small, and the investigation was only preliminary; a larger sample size is needed to support these conclusions.

Scutellarin inhibits oleic acid induced vascular smooth muscle foam cell formation via activating autophagy and inhibiting NLRP3 inflammasome activation.

Abnormalities in vascular smooth muscle cells (VSMCs) are pivotal in the pathogenesis of cardiovascular pathologies such as atherosclerosis and hypertension. Scutellarin (Scu), a flavonoid derived from marigold flowers, exhibits a spectrum of biological activities including anti-inflammatory, antioxidant, antitumor, immunomodulatory and antimicrobial effects. Notably, Scu has demonstrated the capacity to mitigate vascular endothelial damage and prevent atherosclerosis via its antioxidative properties. Nevertheless, the influence of Scu on the formation of VSMC-derived foam cells remains underexplored. In this study, Scu was evidenced to efficaciously attenuate oleic acid (OA)-induced lipid accumulation and the upregulation of adipose differentiation-associated protein Plin2 in a dose- and time-responsive manner. We elucidated that Scu effectively diminishes OA-provoked VSMC foam cell formation. Further, it was established that Scu pretreatment augments the protein expression of LC3B-II and the mRNA levels of Map1lc3b and Becn1, concurrently diminishing the protein levels of the NLRP3 inflammasome compared to the OA group. Activation of autophagy through rapamycin attenuated NLRP3 inflammasome protein expression, intracellular lipid droplet content and Plin2 mRNA levels. Scu also counteracted the OA-induced decrement of LC3B-II levels in the presence of bafilomycin-a1, facilitating the genesis of autophagosomes and autolysosomes. Complementarily, in vivo experiments revealed that Scu administration substantially reduced arterial wall thickness, vessel wall cross-sectional area, wall-to-lumen ratio and serum total cholesterol levels in comparison to the high-fat diet model group. Collectively, our findings suggest that Scu attenuates OA-induced VSMC foam cell formation through the induction of autophagy and the suppression of NLRP3 inflammasome activation.

Transgluteal Ultrasonography in Spica Cast in the Post-reduction Assessment of Hip Developmental Dysplasia.

OBJECTIVE: Concentric circle reduction is one of the outcomes after reduction of developmental dysplasia of the hip (DDH). Radiography and magnetic resonance imaging (MRI) are used to confirm the reduction results. In this study, we evaluated the reduction results of the coronal section of the hip using transgluteal ultrasonography. METHODS: We enrolled 46 children admitted to our hospital for closed or open reduction plaster fixation of DDH between January 2021 and December 2022. Thirty-eight patients had unilateral DDH, and eight patients had bilateral DDH. Transgluteal ultrasonography, radiography and MRI were done on the patients during the 7 d after reduction, and the results were interpreted by different radiologists. The covering of the femoral head and the distance between the medial margin of the femoral head and the acetabulum (HSD) were measured after calculating the maximum coronal surface of the iliac bone. MRI is regarded as the gold standard for determining hip reduction or dislocation. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of ultrasound and radiography were determined and compared. RESULTS: The sensitivity, specificity, PPV and NPV of transgluteal ultrasonography were 100% (confidence interval [CI]: 69.2%-100%), 97.7% (CI: 88%-99.9%), 90.9% (CI: 59%-98.6%) and 100%, respectively, higher than those of radiography, which were 50% (CI: 18.7%-81.3%), 86.4% (CI: 72.6%-94.8%), 45.5% (CI: 24%-68.7%) and 88.4% (CI: 80.2%-93.5%), respectively. Ultrasonography had a higher sensitivity (100% vs. 50%, p < 0.01) and positive predictive rate (90.9% vs. 45.5%, p < 0.01) than radiography. Ultrasonography revealed that a distance between the head and socket (HSD) >8 mm indicated a strong suspicion for a poor reduction. CONCLUSION: Transgluteal coronal ultrasound scan with semiquantitative assessment of acetabular femoral head coverage and measurement of HSD can effectively monitor the reduction relationship between the two in children after DDH reduction.

Small molecules targeting protein-protein interactions for cancer therapy.

Protein-protein interactions (PPIs) are fundamental to many biological processes that play an important role in the occurrence and development of a variety of diseases. Targeting the interaction between tumour-related proteins with emerging small molecule drugs has become an attractive approach for treatment of human diseases, especially tumours. Encouragingly, selective PPI-based therapeutic agents have been rapidly advancing over the past decade, providing promising perspectives for novel therapies for patients with cancer. In this review we comprehensively clarify the discovery and development of small molecule modulators of PPIs from multiple aspects, focusing on PPIs in disease, drug design and discovery strategies, structure-activity relationships, inherent dilemmas, and future directions.

Enhancing Prediction for Tumor Pathologic Response to Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Cancer by Dynamic Parameters from Clinical Assessments.

To develop accurate and accessible prediction methods for assessing pathologic response following NICT prior to surgery, we conducted a retrospective study including 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after two cycles of NICT between January 2019 and March 2022 at our center. We collected clinical parameters to evaluate the dynamic changes in the primary tumor. Univariate and multivariate analyses were performed to determine the correlations between these parameters and the pathologic response of the primary tumor. Subsequently, we constructed prediction models for pCR and MPR using multivariate logistic regression. The MPR prediction Model 2 was internally validated using bootstrapping and externally validated using an independent cohort from our center. The univariate logistic analysis revealed significant differences in clinical parameters reflecting tumor regression among patients with varying pathologic responses. The clinical models based on these assessments demonstrated excellent predictive performance, with the training cohort achieving a C-index of 0.879 for pCR and 0.912 for MPR, while the testing cohort also achieved a C-index of 0.912 for MPR. Notably, the MPR prediction Model 2, with a threshold cut-off of 0.74, exhibited 92.7% specificity and greater than 70% sensitivity, indicating a low rate of underestimating residual tumors. In conclusion, our study demonstrated the high accuracy of clinical assessment-based models in pathologic response prediction, aiding in decision-making regarding organ preservation and radiotherapy adjustments after induction immunochemotherapy.

Decreased serum 4-Hydroxynonenal level as a biomarker for the progression of steroid-induced osteonecrosis of the femoral head.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is becoming a prevalent global health problem. 4-Hydroxynonenal (4-HNE) serves as a common marker of oxidative stress. This study aims to study the potential role of 4-HNE in the progression of steroid-induced osteonecrosis of the femoral head (SIONFH). METHOD: Between April 2021 and December 2021, 64 subjects were enrolled in this cross-sectional case‒control study. Thirty-six patients were grouped based on the Association Research Circulation Osseous (ARCO) classification, and 28 healthy volunteers without hip pain or any lesions shown in anteroposterior and frog-leg lateral pelvic radiographs served as the normal control group. Bone hematoxylin-eosin (HE) staining, microcomputed tomography (micro-CT), immunohistochemistry, and levels of plasma 4-HNE were evaluated. RESULTS: The 4-HNE level was higher in the SIONFH group than in the normal control group (P < 0.001), and 4-HNE levels were significantly higher in SIONFH patients in the early stage of disease (stage II). The 4-HNE level was negatively correlated with ARCO stage (r = - 0.6875, P < 0.001). Immunohistochemistry revealed the presence of 4-HNE in the trabecular bone, osteocytes, and bone marrow. CONCLUSION: The 4-HNE level is negatively associated with ARCO stages. Lower levels of 4-HNE may serve as a critical biomarker for the progression of SIONFH.

Association between immunity and different clinical symptoms in patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a disease with endocrine and metabolic disorders. The main symptoms are hyperandrogenemia (HA), insulin resistance (IR), and ovulation disorder. However, the pathogenesis and pathophysiological process of these major symptoms in PCOS are still not well defined. In recent studies, the chronic low-grade inflammatory state has become one of the factors affecting PCOS. Some alterable immune factors in PCOS, such as interleukin-15 and interleukin-1, have been identified to be related to androgen synthesis and insulin resistance in PCOS. In addition, a disturbed immune microenvironment in the ovary leads to impaired follicular growth and ovulation. Previous studies have roughly reviewed the relationship between immunity and PCOS. However, the link between the different clinical manifestations of PCOS and immunity has not been well explored and analyzed. The clinical presentation of each patient is diverse, and symptomatic treatment is mainly used. Therefore, this article reviews several representative immunological factors that affect these three symptoms to explore the underlying mechanism, which will be beneficial for developing new treatment strategies.

LEARN algorithm: a novel option for predicting non-alcoholic steatohepatitis.

Background: There is an unmet need for accurate non-invasive methods to diagnose non-alcoholic steatohepatitis (NASH). Since impedance-based measurements of body composition are simple, repeatable and have a strong association with non-alcoholic fatty liver disease (NAFLD) severity, we aimed to develop a novel and fully automatic machine learning algorithm, consisting of a deep neural network based on impedance-based measurements of body composition to identify NASH [the bioeLectrical impEdance Analysis foR Nash (LEARN) algorithm]. Methods: A total of 1,259 consecutive subjects with suspected NAFLD were screened from six medical centers across China, of which 766 patients with biopsy-proven NAFLD were included in final analysis. These patients were randomly subdivided into the training and validation groups, in a ratio of 4:1. The LEARN algorithm was developed in the training group to identify NASH, and subsequently, tested in the validation group. Results: The LEARN algorithm utilizing impedance-based measurements of body composition along with age, sex, pre-existing hypertension and diabetes, was able to predict the likelihood of having NASH. This algorithm showed good discriminatory ability for identifying NASH in both the training and validation groups [area under the receiver operating characteristics (AUROC): 0.81, 95% CI: 0.77-0.84 and AUROC: 0.80, 95% CI: 0.73-0.87, respectively]. This algorithm also performed better than serum cytokeratin-18 neoepitope M30 (CK-18 M30) level or other non-invasive NASH scores (including HAIR, ION, NICE) for identifying NASH (P value <0.001). Additionally, the LEARN algorithm performed well in identifying NASH in different patient subgroups, as well as in subjects with partial missing body composition data. Conclusions: The LEARN algorithm, utilizing simple easily obtained measures, provides a fully automated, simple, non-invasive method for identifying NASH.

Using Normalized Carcinoembryonic Antigen and Carbohydrate Antigen 19 to Predict and Monitor the Efficacy of Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are established prognostic biomarkers for patients with gastric cancer. However, their potential as predictive markers for neoadjuvant chemotherapy (NACT) efficacy has not been fully elucidated. METHODS: We conducted a retrospective analysis to determine values of CEA and CA19-9 prior to NACT (pre-NACT) and after NACT (post-NACT) in 399 patients with locally advanced gastric cancer (LAGC) who received intended NACT and surgery. RESULTS: Among the 399 patients who underwent NACT plus surgery, 132 patients (33.1%) had elevated pre-NACT CEA/CA19-9 values. Furthermore, either pre-NACT or post-NACT CEA /CA19-9 levels were significantly associated with prognosis (p = 0.0023) compared to patients with non-elevated levels. Moreover, among the patients, a significant proportion (73/132, 55.3%) achieved normalized CEA/CA19-9 following NACT, which is a strong marker of a favorable treatment response and survival benefits. In addition, the patients with normalized CEA/CA19-9 also had a prolonged survival compared to those who underwent surgery first (p = 0.0140), which may be attributed to the clearance of micro-metastatic foci. Additionally, the magnitude of CEA/CA19-9 changes did not exhibit a statistically significant prognostic value. CONCLUSIONS: Normalization of CEA/CA19-9 is a strong biomarker for the effectiveness of treatment, and can thus be exploited to prolong the long-term survival of patients with LAGC.

Multifunctional protein-based self-assembled nanoplatform: overcoming hypoxic tumor microenvironment for enhanced imaging-guided photodynamic therapy.

Photodynamic therapy (PDT) has emerged as a promising modality for cancer treatment, but its efficacy is often limited by tumour hypoxia. Here, we report the development of a novel protein-based, self-assembled nanoplatform, CAT-I-BODIPY NPs (CIB NPs), to address this limitation. We first design and synthesize an I-BODIPY photosensitizer based on the heavy atom effect and modification of the electron-donating group, which exhibits excellent capabilities in generating reactive oxygen species and enabling near-infrared (NIR) fluorescence imaging. The incorporation of an oxygen-producing enzyme, catalase (CAT), within these nanoassemblies enables in situ oxygen generation to counteract hypoxic constraints. Controllable self-assembly by multiple supramolecular interactions into highly ordered architecture not only guarantees CAT's catalytic activity but also leads to excellent NIR fluorescence imaging ability and enhanced PDT efficacy. Notably, the visualization of optimal accumulation of CIB NPs within tumour sites 18 h post-injection offers precise PDT application guidance. Both in vitro and in vivo studies corroborate the remarkable anti-tumour efficacy of CIB NPs under NIR illumination, providing a significant advancement in PDT. The favourable biosafety profile of CIB NPs further emphasizes their potential for clinical application in hypoxic tumour therapy.

Targeting integrin α5ß1 in urological tumors: opportunities and challenges.

Urological tumors, such as prostate cancer, renal cell carcinoma, and bladder cancer, have shown a significant rise in prevalence in recent years and account for a significant proportion of malignant tumors. It has been established that metastasis to distant organs caused by urological tumors is the main cause of death, although the mechanisms underlying metastasis have not been fully elucidated. The fibronectin receptor integrin α5ß1 reportedly plays an important role in distant metastasis and is closely related to tumor development. It is widely thought to be an important cancer mediator by interacting with different ligands, mediating tumor adhesion, invasion, and migration, and leading to immune escape. In this paper, we expound on the relationship and regulatory mechanisms of integrin α5ß1 in these three cancers. In addition, the clinical applications of integrin α5ß1 in these cancers, especially against treatment resistance, are discussed. Last but not least, the possibility of integrin α5ß1 as a potential target for treatment is examined, with new ideas for future research being proposed.

Factors Associated with Lesion Recurrence Following Cervical Conization.

Objective: To investigate the factors influencing lesion recurrence during the follow-up after cervical conization and evaluate the clinical value of human papillomavirus (HPV) testing and thinprep cytology test (TCT) in postoperative follow-up patients undergoing cervical conization. Methods: A total of 289 patients with cervical lesions who underwent primary cervical conization at our hospital between January 1, 2018, and December 31, 2019, were included in this study. TCT, HPV testing, and colposcopy were performed every 6 months for a follow-up period of 3 years. Based on the follow-up results, the patients were divided into recurrence and non-recurrence groups. The basic and colposcopic data of the two groups were analyzed to identify factors influencing lesion recurrence. Additionally, the clinical value of HPV testing and TCT in postoperative follow-up and recurrence diagnosis of patients undergoing cervical conization was assessed. Results: The recurrence group showed significantly higher age of onset, concurrent rate of other chronic diseases, and parity, as well as a markedly lower barrier contraceptive rate compared to the non-recurrence group, with statistically significant differences (P < .05). In the recurrence group, the type III transformation zone (TZ) predominated (59.26%), which significantly differed from the non-recurrence group (P < .05). The detection rates of abnormal TCT findings and HPV infections in postoperative reexaminations were significantly higher in the recurrence group compared to the non-recurrence group (P < .05), whereas no significant differences were observed between the two groups before cervical conization (P > .05). Among the recurrence group (n = 54), 52 cases (96.3%) had HPV infections, and 29 cases (53.7%) had abnormal TCT findings, with a significantly higher detection rate for HPV infections (P < .05). The area under the receiver operating characteristic (ROC) curve (AUC) for HPV testing, TCT, and combined HPV testing with TCT after cervical conization were 0.861, 0.712, and 0.882, respectively. These results indicate that HPV testing alone performs similarly to combined HPV testing with TCT and significantly outperforms TCT alone in predicting lesion recurrence after cervical conization. Conclusions: Factors influencing lesion recurrence after cervical conization include patient age, barrier contraceptive rate, concurrent rate of other chronic diseases, parity, and type of transformation zone. HPV testing alone is more sensitive and accurate than TCT in predicting lesion recurrence during postoperative follow-up of patients undergoing cervical conization. This finding can reduce missed diagnoses and provide a significant theoretical basis for postoperative follow-up of patients undergoing cervical conization.

Engineered Biosynthesis through the Adenylation Domains from Nonribosomal Peptide Synthetases.

Nonribosomal peptide synthetases, consisted of multiple catalytic domains, are involved in the biosynthesis of an important family of bioactive natural products in a coordinated manner. Among the functional domains, adenylation domains are specifically responsible for recognizing carboxylic acid building blocks and synthesizing aminoacyl adenylates. Given their critical roles in the biosynthesis of the growing peptide, A-domains are also referred to as the "gatekeeper". In this review, very recent developments on the A-domains from NRPSs are reviewed to expand the fundamental knowledge of the A domain, including knowledge on the structures, functions, and molecular interactions. Several recent examples were also discussed to highlight the great potential of A-domain engineering. This study should provide a framework for the combinatorial biosynthesis or synthetic biology-driven microbial production of novel nonribosomal peptides.

Global trends and performances in diabetic retinopathy studies: A bibliometric analysis.

Objective: The objective of this study is to conduct a comprehensive bibliometric analysis to identify and evaluate global trends in diabetic retinopathy (DR) research and visualize the focus and frontiers of this field. Methods: Diabetic retinopathy-related publications from the establishment of the Web of Science (WOS) through 1 November 2022 were retrieved for qualitative and quantitative analyses. This study analyzed annual publication counts, prolific countries, institutions, journals, and the top 10 most cited literature. The findings were presented through descriptive statistics. VOSviewer 1.6.17 was used to exhibit keywords with high frequency and national cooperation networks, while CiteSpace 5.5.R2 displayed the timeline and burst keywords for each term. Results: A total of 10,709 references were analyzed, and the number of publications continuously increased over the investigated period. America had the highest h-index and citation frequency, contributing to the most influence. China was the most prolific country, producing 3,168 articles. The University of London had the highest productivity. The top three productive journals were from America, and Investigative Ophthalmology Visual Science had the highest number of publications. The article from Gulshan et al. (2016; co-citation counts, 2,897) served as the representative and symbolic reference. The main research topics in this area were incidence, pathogenesis, treatment, and artificial intelligence (AI). Deep learning, models, biomarkers, and optical coherence tomography angiography (OCTA) of DR were frontier hotspots. Conclusion: Bibliometric analysis in this study provided valuable insights into global trends in DR research frontiers. Four key study directions and three research frontiers were extracted from the extensive DR-related literature. As the incidence of DR continues to increase, DR prevention and treatment have become a pressing public health concern and a significant area of research interest. In addition, the development of AI technologies and telemedicine has emerged as promising research frontiers for balancing the number of doctors and patients.

[A novel lateral classification of osteonecrosis of femoral head based on CT recons-truction of necrotic area and its clinical verification].

Objective: To analyze the femoral head collapse and the operation of osteonecrosis of the femoral head (ONFH) in different Japanese Investigation Commitee (JIC) types, in order to summarize the prognostic rules of each type of ONFH, and explore the clinical significance of CT lateral subtypes based on reconstruction of necrotic area of C1 type and verify their clinical effect. Methods: A total of 119 patients (155 hips) with ONFH between May 2004 and December 2016 were enrolled in the study. The total hips consisted of 34 hips in type A, 33 in type B, 57 in type C1, and 31 in type C2, respectively. There was no significant difference in age, gender, affected side, or type of ONFH of the patients with differenct JIC types ( P>0.05). The 1-, 2-, and 5-year femoral head collapse and operation of different JIC types were analyzed, as well as the survival rate (with femoral head collapse as the end point) of hip joint between different JIC types, hormonal/non-hormonal ONFH, asymptomatic and symptomatic (pain duration >6 months or ≤6 months), and combined preserved angle (CPA) ≥118.725° and CPA<118.725°. JIC types with significant differences in subgroup surgery and collapse and with research value were selected. According to the location of the necrotic area on the surface of the femoral head, the JIC classification was divided into 5 subtypes in the lateral CT reconstruction, and the contour line of the necrotic area was extracted and matched to the standard femoral head model, and the necrosis of the five subtypes was presented by thermography. The 1-, 2-, and 5-year outcomes of femoral head collapse and operation in different lateral subtypes were analyzed, and the survival rates (with collapse of the femoral head as the end point) between CPA≥118.725° and CPA<118.725° hip in patients with this subtype were compared, as well as the survival rates of different lateral subtypes (with collapse and surgery as the end points, respectively). Results: The femoral head collapse rate and operation rate in the 1-, 2-, and 5-year were significantly higher in patients with JIC C2 type than in patients with other hip types ( P<0.05), while in patients with JIC C1 type than in patients with JIC types A and B ( P<0.05). The survival rate of patients with different JIC types was significantly different ( P<0.05), and the survival rate of patients with JIC types A, B, C1, and C2 decreased gradually. The survival rate of asymptomatic hip was significantly higher than that of symptomatic hip, and the survival rate of CPA≥118.725° was significantly higher than that of CPA<118.725° ( P<0.05). The lateral CT reconstruction of type C1 hip necrosis area was selected for further classification, including type 1 in 12 hips, type 2 in 20 hips, type 3 in 9 hips, type 4 in 9 hips, and type 5 in 7 hips. There were significant differences in the femoral head collapse rate and the operation rate among the subtypes after 5 years of follow-up ( P<0.05). The collapse rate and operation rate of types 4 and 5 were 0; the collapse rate and operation rate of type 3 were the highest; the collapse rate of type 2 was high, but the operation rate was lower than that of type 3; the collapse rate of type 1 was high, but the operation rate was 0. In JIC type C1 patients, the survival rate of the hip joint with CPA≥118.725° was significantly higher than that with CPA<118.725° ( P<0.05). In the follow-up with femoral head collapse as the end point, the survival rates of types 4 and 5 were all 100%, while the survival rates of types 1, 2, and 3 were all 0, and the difference was significant ( P<0.05). The survival rate of types 1, 4, and 5 was 100%, of type 3 was 0, and of type 2 was 60%, showing significant difference ( P<0.05). Conclusion: JIC types A and B can be treated by non-surgical treatment, while type C2 can be treated by surgical treatment with hip preservation. Type C1 was classified into 5 subtypes by CT lateral classification, type 3 has the highest risk of femoral head collapse, types 4 and 5 have low risk of femoral head collapse and operation, type 1 has high femoral head collapse rate but low risk of operation; type 2 has high collapse rate, but the operation rate is close to the average of JIC type C1, which still needs to be further studied.

Role of CD19+ CD5+ CD1d+ Bregs in maintaining the Th17/Treg balance in mice with systemic lupus erythematosus complicated with atherosclerosis.

OBJECTIVE: In this study, we aimed to investigate Bregs, their regulatory effects on Th17/Treg cell balance, and the release of downstream inflammatory factors in a mouse model of low-density lipoprotein receptor (LDLr)-/- + Pristane. METHODS: After the establishment of the mouse model of systemic lupus erythematosus (SLE) complicated with atherosclerosis (AS), 8-week-old LDLr-/- + Pristane mice (n = 10) were included in the SLE + AS group. Furthermore, 8-week-old MRL/lpr and C57 mice were used as the SLE and normal control groups, respectively (n = 10 per group). After feeding the mice a high-fat diet for 14 weeks, peripheral blood and spleen of mice were collected, and Bregs, Th17, and Treg cells and related inflammatory factors were detected by flow cytometry, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction. RESULTS: The number of Bregs and Tregs in spleen lymphocytes of SLE + AS mice significantly decreased compared with the C57 group (p < .05), whereas the number of Th17 cells significantly increased (p = .000). Furthermore, the proportion of Bregs showed a negative correlation with the Th17/Treg ratio (p = .03). Mice in the SLE + AS group showed higher serum interleukin (IL)-10, IL-17, and tumor necrosis factor-α levels than those in the SLE and C57 groups (p < .05). Furthermore, IL-35 and transforming growth factor (TGF)-ß expression was reduced in the SLE + AS group compared with the C57 group (p < .05). CONCLUSIONS: The proportion of Breg decreases was negatively associated with increased Th17/Treg which was increased in SLE + AS mice, indicating that Bregs may regulate Th17/Treg cell homeostasis and cytokine release via IL-35 and TGF-ß production.

Synthesis and Cytotoxicity Evaluation of Dehydroepiandrosterone Derivatives by Iron-Catalyzed Stereoselective Hydroamination.

The direct modification of structurally complex natural product dehydroepiandrosterone (DHEA) through iron-catalyzed direct hydroamination of DHEA with various nitro(hetero)arenes was carried out to afford 5α-arylamino-DHEAs (1-25) in good yields (53-72%). Though as a radical reaction, it features high stereoselectivity, and only the 5α-substituted derivatives were produced. The in vitro antiproliferative activity of these synthesized compounds against the human breast cancer MCF-7 cell was evaluated, showing that most of DHEA analogues possessed the moderate cytotoxic activity. The preliminary structure-activity relationship analysis revealed that the electron-withdrawing groups installed at the para-position of arylamine ring had a great contribution to the improvement of the DHEA's cytotoxic potency. Among them, (4-trifluoromethylaniline)-DHEA (4) displayed the most potent cytotoxicity, with an IC50 value of 19.3 µM, which was 2.3-fold more active than DHEA.

Optimal treatment options for uterine submucosal fibroids: Percutaneous microwave ablation versus transcervical resection of myoma.

OBJECTIVES: To compare the efficacy and safety of percutaneous microwave ablation (PMWA) and transcervical resection of myoma (TCRM) for submucosal fibroids. METHODS: From January 2019 to January 2021, we conducted a randomized controlled study involving patients with symptomatic uterine submucosal fibroids. Questionnaires were also used to measure the uterine fibroid symptom (UFS) scores and quality of life (QoL) scores before and after treatment at 3, 6, and 12 months. Outcomes, adverse events, hemoglobin recovery, and submucosal fibroid volume of both groups were also compared. Operation time, amount of bleeding, hospital stay time, and occurrence of complications were compared in groups with fibroids of different lengths. RESULTS: Follow-up after surgery showed that UFS scores at 3, 6, and 12 months were significantly lower in each group, while QoL scores increased significantly. For fibroids less than 3 cm, surgical time was 34.2 ± 9.9 min, incidence of perioperative complications was 4.2%, and both decreased significantly, compared to the surgical time of the PMWA group (40.0 ± 8.1 min) and incidence of perioperative complications (24%; p < .05 for both). For uterine submucosal fibroids >5 cm, the operation time in the PMWA group was 92.7 ± 16.0 min, intraoperative bleeding volume was 22.7 ± 6.4 mL, and hospital stay was 2.7 ± 1.1 days, which were significantly less than the procedural time (107 ± 11.9 min), intraoperative bleeding loss (45.9 ± 12.8 mL), and length of hospital stay (5.0 ± 1.1 days) in the TCRM group. The differences were statistically significant (p < .05). CONCLUSIONS: PMWA and TCRM were both effective treatments for uterine submucosal fibroids. For fibroids shorter than 3 cm in length, especially pedicled submucosal fibroids, TCRM has absolute advantages; however, for uterine submucosal fibroids >5 cm, PMWA avoids perioperative complications, such as uterine perforation, water poisoning syndrome, and the need for repeat surgery, and is considered the preferred mode of treatment. Therefore, personalized treatment should be used for different patients with uterine submucosal fibroids.