Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

Basement membrane-related MMP14 predicts poor prognosis and response to immunotherapy in bladder cancer.

BACKGROUND: Basement membrane (BM) is an important component of the extracellular matrix, which plays an important role in the growth and metastasis of tumor cells. However, few biomarkers based on BM have been developed for prognostic assessment and prediction of immunotherapy in bladder cancer (BLCA). METHODS: In this study, we used the BLCA public database to explore the relationship between BM-related genes (BMRGs) and prognosis. A novel molecular typing of BLCA was performed using consensus clustering. LASSO regression was used to construct a signature based on BMRGs, and its relationship with prognosis was explored using survival analysis. The pivotal BMRGs were further analyzed to assess its clinical characteristics and immune landscape. Finally, immunohistochemistry was used to detect the expression of the hub gene in BLCA patients who underwent surgery or received immune checkpoint inhibitor (ICI) immunotherapy in our hospital. RESULTS: We comprehensively analyzed the relationship between BMRGs and BLCA, and established a prognostic-related signature which was an independent influence on the prognostic prediction of BLCA. We further screened and validated the pivotal gene-MMP14 in public database. In addition, we found that MMP14 expression in muscle invasive bladder cancer (MIBC) was significantly higher and high MMP14 expression had a poorer response to ICI treatment in our cohort. CONCLUSIONS: Our findings highlighted the satisfactory value of BMRGs and suggested that MMP14 may be a potential biomarker in predicting prognosis and response to immunotherapy in BLCA.

Development of a Corticosteroid-Immunosuppressed Mouse Model to Study the Pathogenesis and Therapy of Influenza-Associated Pulmonary Aspergillosis.

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Redox-Dependent Activation of Lung Epithelial STAT3 Is Required for Inducible Protection against Bacterial Pneumonia.

The lung epithelium is dynamic, capable of considerable structural and functional plasticity in response to pathogen challenges. Our laboratory has demonstrated that an inhaled combination of a Toll-like receptor (TLR) 2/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonias. We have previously shown that intact epithelial TLR signaling and generation of multisource epithelial reactive oxygen species (ROS) are required for inducible protection. Further investigating the mechanisms underlying this phenomenon of inducible resistance, reverse-phase protein array analysis demonstrated robust STAT3 (signal transducer and activator of transcription 3) phosphorylation following treatment of lung epithelial cells. We show here that Pam2ODN-induced STAT3 phosphorylation is IL-6-independent. We further found that therapeutic epithelial STAT3 activation is required for inducible protection against Pseudomonas aeruginosa pneumonia. Additional studies showed that inhibiting epithelial dual oxidases or scavenging ROS significantly reduced the Pam2ODN induction of STAT3 phosphorylation, suggesting a proximal role for ROS in inducible STAT3 activation. Dissecting these mechanisms, we analyzed the contributions of redox-sensitive kinases and found that Pam2ODN activated epithelial growth factor receptor in an ROS-dependent manner that is required for therapeutically inducible STAT3 activation. Taken together, we demonstrate that epithelial STAT3 is imperative for Pam2ODN's function and describe a novel redox-based mechanism for its activation. These key mechanistic insights may facilitate strategies to leverage inducible epithelial resistance to protect susceptible patients during periods of peak vulnerability.

A Hybrid Genetic Algorithm Based on Imitation Learning for the Airport Gate Assignment Problem.

Airport gates are the main places for aircraft to receive ground services. With the increased number of flights, limited gate resources near to the terminal make the gate assignment work more complex. Traditional solution methods based on mathematical programming models and iterative algorithms are usually used to solve these static situations, lacking learning and real-time decision-making abilities. In this paper, a two-stage hybrid algorithm based on imitation learning and genetic algorithm (IL-GA) is proposed to solve the gate assignment problem. First of all, the problem is defined from a mathematical model to a Markov decision process (MDP), with the goal of maximizing the number of flights assigned to contact gates and the total gate preferences. In the first stage of the algorithm, a deep policy network is created to obtain the gate selection probability of each flight. This policy network is trained by imitating and learning the assignment trajectory data of human experts, and this process is offline. In the second stage of the algorithm, the policy network is used to generate a good initial population for the genetic algorithm to calculate the optimal solution for an online instance. The experimental results show that the genetic algorithm combined with imitation learning can greatly shorten the iterations and improve the population convergence speed. The flight rate allocated to the contact gates is 14.9% higher than the manual allocation result and 4% higher than the traditional genetic algorithm. Learning the expert assignment data also makes the allocation scheme more consistent with the preference of the airport, which is helpful for the practical application of the algorithm.

Genetic variants in NPAS2 gene and clinical outcomes of resectable non-small-cell lung cancer.

Background: A series of studies have demonstrated that NPAS2 plays a critical role in the development and progression of several cancers. However, the association between genetic variants in the NPAS2 gene and the clinical outcome of patients with non-small-cell lung cancer (NSCLC) has not been investigated. Methods: Six functional SNPs in NPAS2 were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 484 Chinese NSCLC patients undergoing surgery. Multivariate Cox proportional hazards model were used for the prognosis analysis. Results: We found that SNP rs2305158 exhibited a significant association with overall survival of NSCLC patients in the dominant model (hazard ratio [HR]: 0.68; 95% CI: 0.49-0.95; p = 0.02). Lymph node metastasis was significantly associated with increased death risk (HR: 1.73; 95% CI: 1.24-2.40; p = 0.001) in patients with the homozygous wildtype (WW) genotype of rs2305158. However, no significant association was observed between them in patients carrying a heterozygous variant (WV) or homozygous variant (VV) genotype of rs2305158. Finally, in the joint and interaction analysis, the patients carrying homozygous wildtype (WW) genotype and lymph node metastasis from N1 to N3 conferred a significant increased effect on death (HR: 2.29; 95% CI: 1.40-3.76; p = 0.001). Conclusions: Our results suggest that NPAS2 polymorphisms may serve as an independent prognostic marker for NSCLC patients.

Molecular identification and phylogenetic analysis of fungal pathogens isolated from diseased fish in Xinjiang, China.

The outbreaks of fungal diseases in cultured fish have been severe in recent years, which is harmful to the healthy and sustainable development of fish farming. In this study, an investigation was conducted for significant fungal infections of 12 species of fish in four regions in Xinjiang, China, to understand the distribution of local fish fungal pathogens. Twenty-six fungal strains with pathogenicity were isolated, and the challenge experiment showed that eight strains from Changji area had high infection rate to fish eggs. Based on internal transcribed spacer sequence data and molecular analysis, the 26 strains were classified into nine different species of six fungal genera. Phylogenetic analysis showed that all strains were divided into two clades, namely Cluster 1 (contains only the genus Mucor) and Cluster 2 (consists of five small branches), and the distribution of strains from the same region was scattered in two clusters. There is no strict host selectivity for these fungi to infect fish. Mucor sp. are the main fungal pathogen of fish in these four regions, whereas Hypophthalmichthys molitrix and Carassius auratus are two types of fish that were susceptible to pathogen. In addition, the environmental adaptability experiments showed that eight highly pathogenic strains have different adaptability to the environment, and their optimum temperature and pH were 25°C and 7.0, respectively, whereas the concentration of NaCl was negatively correlated with the growth of strains. Therefore, these results indicated that the coinfection of multiple fungal pathogens in a culture region should be considered in the future study.

All-optical logic gates based on unidirectional surface plasmon polaritons.

Optical logic gates are important elements in optical computing and optical circuits. In this study, all-optical logic gates, including OR, XOR, XNOR, NAND, and NOT gates, are obtained in a composite structure composed of gyroelectric material and metal based on the interference and absorption of surface waves. In the composite structure, a Y-shaped channel through which surface plasmon polaritons propagate unidirectionally is formed. Through the ingenious one-way surface plasmon polaritons, backscattering and side-scattering generated by the composite structure and influencing the surrounding devices are prohibited effectively. The precisely controlled optical phase difference ensures the realization of five different logic gates with high contrast ratios. The maximum contrast ratios for XOR, XNOR, NAND, and NOT gates are 31.64 dB, 43.47 dB, 31.47 dB, and 43.47 dB, respectively. The output logic states "1"or "0" obtained by different logic inputs have nearly the same light intensity. Our research results provide the possibility for constructing all-optical integrated logic devices.

Pure retroperitoneal natural orifice translumenal endoscopic surgery (NOTES) transvaginal nephrectomy using standard laparoscopic instruments: a safety and feasibility study in a porcine model.

BACKGROUND: Among the different organs used for NOTES (natural orifice translumenal endoscopic surgery) technique, the transvaginal approach may be the optimal choice because of a simple and secure closure of colpotomy site. Pure and hybrid NOTES transvaginal operations were routinely performed via transperitoneal access. In this study, we investigate the safety and feasibility of pure retroperitoneal natural orifice translumenal endoscopic surgery (NOTES) transvaginal nephrectomy using conventional laparoscopic techniques in a porcine model. METHODS: Six female pigs, weighing an average of 30 kg, were used in this study. Under general anesthesia, pure retroperitoneal NOTES transvaginal nephrectomy was conducted using standard laparoscopic instruments. Posterolateral colpotomy was performed, and the incision was enlarged laterally using blunt dissection and pneumatic dilation. A single-port device was inserted to construct the operative channel. The retroperitoneal space was created using sharp and blunt dissection under endoscopic guidance up to the level of the kidney. Dissection and removal of the kidney were performed according to standard surgical procedure, and the colpotomy site was closed using interrupted sutures. The survival and complications were observed 1 week postoperatively. RESULTS: Our results showed that two cases failed because of peritoneal rupture. One case was successful, but required the assistance of an extra 5 mm laparoscopic trocar inserted in the flank. Three cases of pure retroperitoneal NOTES transvaginal nephrectomy were completed, and survived 1 week after the operation. In these three cases, no intra- or postoperative complications were observed. CONCLUSIONS: All findings confirmed the safety and feasibility of the retroperitoneal pure retroperitoneal NOTES transvaginal nephrectomy using standard laparoscopic instruments, which suggested the possibility of clinical application in human beings in the future.

Optical-phase demodulation using zero-index metamaterials.

We theoretically demonstrate that zero-index materials junction with three ports can realize functions of optical interferometer in optical phase demodulator to finish a critical step of phase demodulation. When the junction is made up of ε-near-zero (ENZ) materials, performances of the proposed structure get worse due to impedance mismatch, which result in distortion and decrease of final demodulation outputs. To improve performances, three approaches including narrowing the ENZ junction, embedding proper defect, and using anisotropy ENZ junction are proposed. Our work provides an effective way for optical phase demodulation based on zero-index metamaterials.

Copper-oxygen adducts: new trends in characterization and properties towards C-H activation.

This review summarizes the latest discoveries in the field of C-H activation by copper monoxygenases and more particularly by their bioinspired systems. This work first describes the recent background on copper-containing enzymes along with additional interpretations about the nature of the active copper-oxygen intermediates. It then focuses on relevant examples of bioinorganic synthetic copper-oxygen intermediates according to their nuclearity (mono to polynuclear). This includes a detailed description of the spectroscopic features of these adducts as well as their reactivity towards the oxidation of recalcitrant Csp3 -H bonds. The last part is devoted to the significant expansion of heterogeneous catalytic systems based on copper-oxygen cores (i.e. within zeolite frameworks).

Propensity score-matched analysis examining the role of obesity on outcomes in retroperitoneal laparoscopic adrenalectomy: a cohort study.

Background: There is inconsistent evidence regarding obesity's effect on surgical outcomes following retroperitoneal laparoscopic adrenalectomy (RLA). This study aimed to investigate the influence of obesity on surgical outcomes in patients undergoing RLA, with an emphasis on operative time, drainage tube removal time, postoperative hospital stays and perioperative complications. Methods: In this retrospective, single-center, observational study, all consecutive cases of unilateral RLA for adrenal disease from January 2012 to December 2021 were incorporated. The patients were divided into two groups based on their body mass index (BMI) of 28 kg/m2. To mitigate selection bias, propensity score matching (PSM) was conducted, using logistic regression to calculate propensity scores for balancing baseline characteristics. A multivariate logistic regression analysis was performed to assess how obesity affects operative time and intraoperative blood loss as well. The linear correlation between BMI and surgical outcomes, including prolonged operative time and increased intraoperative blood loss, was also examined using restricted cubic spline (RCS) analysis. Results: A total of 569 patients who underwent RLA were included. After PSM, 122 patients were apportioned to each group. Statistically significant differences were observed between the obese and non-obese group in operative time (97.5 vs. 115 min, P<0.001). There were no statistically significant differences between the two groups regarding hospital stay (6.7 vs. 6.8 days, P=0.58), drainage tube removal time (3.0 vs. 3.0 days, P=0.19), nor postoperative complications (9.0% vs. 12.3%, P=0.41). Furthermore, univariate logistic regression analysis revealed that, obese patients undergoing RLA were linked to prolonged operative time and increased intraoperative blood loss. After adjusting for potential confounders, the obese group showed a 67% increased risk of prolonged operative time and a 69% increased intraoperative blood loss. The RCS analysis revealed that BMI had a linear relationship with operative time (P for nonlinearity =0.47) and blood loss during surgery (P for linearity =0.89). Conclusions: In patients undergoing RLA, obesity exerts a significant influence on surgical outcomes, particularly with regard to operative time and intraoperative blood loss, as shown in multivariable logistic regression analysis and PSM to balance baseline characteristics.

Discovery of LWY713 as a potent and selective FLT3 PROTAC degrader with in vivo activity against acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) has been validated as a therapeutic target for acute myeloid leukemia (AML). While a number of FLT3 kinase inhibitors have been approved for AML treatment, the clinical data revealed that they cannot achieve complete and sustained suppression of FLT3 signaling at the tolerated dose. Here we report a series of new, potent and selective FLT3 proteolysis targeting chimera degraders. The optimal compound LWY713 potently induced the degradation of FLT3 with a DC50 value of 0.64 nM and a Dmax value of 94.8% in AML MV4-11 cells with FLT3-internal tandem duplication (ITD) mutation. Mechanistic studies demonstrated that LWY713 selectively induced FLT3 degradation in a cereblon- and proteasome-dependent manner. LWY713 potently inhibited FLT3 signaling, suppressed cell proliferation, and induced cell G0/G1-phase arrest and apoptosis in MV4-11 cells. Importantly, LWY713 displayed potent in vivo antitumor activity in MV4-11 xenograft models.

Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader.

Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC50 value of 20 nM and a Dmax value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.

Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1.

Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound LLC355 potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.

Evolutionary analysis of the OSCA gene family in sunflower (Helianthus annuus L) and expression analysis under NaCl stress.

Hyperosmolality-gated calcium-permeable channels (OSCA) are Ca2 + nonselective cation channels that contain the calcium-dependent DUF221 domain, which plays an important role in plant response to stress and growth. However, the OSCA gene has not been fully identified and analyzed in sunflowers. In this study, we comprehensively analyzed the number, structure, collinearity, and phylogeny of the OSCA gene family in the sunflower, six Compositae species (Arctium lappa, Chrysanthemum morifolium, Cichorium endivia, Cichorium intybus, Lactuca sativa var. Angustata, and Carthamus tinctorius), and six other plants (soybean, Arabidopsis thaliana, rice, grape, and maize). The expression of the sunflower OSCA gene in nine different tissues, six different hormones, and NaCl stress conditions were analyzed based on transcriptome data and qRT-PCR. A total of 15 OSCA proteins, distributed on 10 chromosomes, were identified in the sunflower, and all of them were located in the endoplasmic reticulum. Using the phylogenetic tree, collinearity, gene structure, and motif analysis of the six Compositae species and six other plants, we found that the sunflower OSCA protein had only three subfamilies and lacked the Group 4 subfamily, which is conserved in the evolution of Compositae and subject to purification selection. The OSCA gene structure and motif analysis of the sunflower and six Compositae showed that there was a positive correlation between the number of motifs of most genes and the length of the gene, different subfamilies had different motifs, and the Group 4 subfamily had the smallest number of genes and the simplest gene structure. RNA-seq and qRT-PCR analysis showed that the expression levels of most OSCA genes in the sunflower changed to varying degrees under salt stress, and HaOSCA2.6 and HaOSCA3.1 were the most important in the sunflower's response to salt stress. The coexpression network of the sunflower genes under salt stress was constructed based on weighted gene co-expression network analysis (WGCNA). In conclusion, our findings suggest that the OSCA gene family is conserved during the sunflower's evolution and plays an important role in salt tolerance. These results will deepen our understanding of the evolutionary relationship of the sunflower OSCA gene family and provide a basis for their functional studies under salt stress.

Development and validation of a circulating tumor cells-related signature focusing on biochemical recurrence and immunotherapy response in prostate cancer.

Background: Studies have shown that the circulating tumor cells (CTCs) play a key role for invasion and formation of distant metastases in prostate cancer (PCa). However, few CTCs-related genes (CRGs) have been developed for biochemical recurrence (BCR) prediction and clinical applications of PCa patients. Materials and methods: Bioinformatics analysis with public PCa datasets were used to investigate the relationship between the differentially expressed CRGs and BCR. Lasso-COX regression analysis was used to constructed and validated a CRGs-based BCR prediction signature for PCa. Single-cell data were used to validate the expression levels of signature genes in different cell types and then explored the cell-cell communication relationships. Finally, the expression levels of signature genes were verified and the CRGs involved in immunotherapy response were further identified. Results: Thirteen CRGs were differentially expressed and closely associated with BCR in PCa. Then we constructed and validated a BCR prediction signature for PCa patients based on 3 differentially expressed CRGs (EMID1, SPP1 and UBE2C), and the signature was an independent factor to predict BCR for PCa. Single-cell data showed the specific expression patterns of the signature genes, while the SPP1 pathway plays an important role in cell-cell communication. Further analyses suggested UBE2C was highly expressed in BCR group and high expression of UBE2C had a better response for patients who received immunotherapy. Moreover, the expression levels of UBE2C in CTCs were higher than other cells and tissues, indicated that UBE2C may affect the BCR event of PCa patients through CTCs. Conclusion: Our findings demonstrated that CRGs were significantly associated with BCR and immunotherapy efficacy in PCa and CRGs may influence the BCR event through CTCs.

A Specific High Toxicity of Xinjunan (Dioctyldiethylenetriamine) to Xanthomonas by Affecting the Iron Metabolism.

Xanthomonas spp. encompass a wide range of phytopathogens that brings great economic losses to various crops. Rational use of pesticides is one of the effective means to control the diseases. Xinjunan (Dioctyldiethylenetriamine) is structurally unrelated to traditional bactericides, and is used to control fungal, bacterial, and viral diseases with their unknown mode of actions. Here, we found that Xinjunan had a specific high toxicity toward Xanthomonas spp., especially to the Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of rice bacterial leaf blight. Transmission electron microscope (TEM) confirmed its bactericidal effect by morphological changes, including cytoplasmic vacuolation and cell wall degradation. DNA synthesis was significantly inhibited, and the inhibitory effect enhanced with the increase of the chemical concentration. However, the synthesis of protein and EPS was not affected. RNA-seq revealed differentially expressed genes (DEGs) particularly enriched in iron uptake, which was subsequently confirmed by siderophore detection, intracellular Fe content and iron-uptake related genes transcriptional level. The laser confocal scanning microscopy and growth curve monitoring of the cell viability in response to different Fe condition proved that the Xinjunan activity relied on the addition of iron. Taken together, we speculated that Xinjunan exerted bactericidal effect by affecting cellular iron metabolism as a novel mode of action. IMPORTANCE Sustainable chemical control for rice bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae need to be developed due to limited bactericides with high efficiency, low cost, and low toxicity in China. This present study verified a broad-spectrum fungicide named Xinjunan possessing a specific high toxicity to Xanthomonas pathogens, which were further confirmed by affecting the cellular iron metabolism of Xoo as a novel mode of action. These findings will contribute to the application of the compound in the field control of Xanthomonas spp.-caused diseases, and be directive for future development of novel specific drugs for the control of severe bacterial diseases based on this novel mode of action.

Establishment and validation of a nomogram for predicting the surgical difficulty of lateral retroperitoneal laparoscopic adrenalectomy.

Background: Lateral retroperitoneal laparoscopic adrenalectomy (LRLA) is widely performed for the resection of adrenal disorders, but when larger and more malignant lesions are involved, the difficulty of LRLA increases. We aimed to develop and evaluate a predictive model for the surgical difficulty of LRLA. Methods: A retrospective, observational, single-center study was performed involving all consecutive cases of unilateral RLA for adrenal disease from 2012.01 to 2021.12. Cases were randomly divided into training and validation cohorts (split ratio =7:3), then the least absolute shrinkage and selection operator (LASSO) regression was applied to reduce data dimension and select predictors. Multivariate logistic regression followed to develop the prediction nomogram for the surgical difficulty of LRLA. Finally, receiver operating characteristic (ROC) curve, calibration curve plot and decision curve analysis (DCA) were used to evaluate the nomogram's discrimination, calibration, and clinical usefulness, respectively. Results: A total of 621 cases were enrolled with a median age of 53 years and a median tumor diameter of 1.7 cm. After LASSO regression analysis, surgeon's experience, tumor diameter, resection procedure, histological type, patient's sex and body mass index (BMI) were identified to establish the nomogram. The model displayed good discrimination with area under the curve (AUC) in both the training cohort (0.754, 95% CI: 0.701-0.806) and validation cohort (0.742, 95% CI: 0.646-0.838). Additionally, excellent calibration curves were revealed for surgical difficulty evaluation in both the training cohort (P=0.999) and validation cohort (P=0.444). DCA results indicated the prediction model was clinically useful. Conclusions: Our novel and effective predictive model can be used to assess the individual surgical difficulty of LRLA. By stratifying patients at risk of having a difficult LRLA for adrenal disease, the model could contribute to improvements in perioperative strategy and therapy.

Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders.

G1 to S phase transition 1 (GSPT1) is the requisite release factor for the translation termination. GSPT1 is identified as an oncogenic driver of several types of cancer and considered to be a promising cancer therapeutic target. Although two selective GSPT1 degraders were advanced into clinical trials, neither of them has been approved for clinical use. Here we developed a series of new selective GSPT1 degraders, among which the optimal compound 9q potently induced degradation of GSPT1 with a DC50 of 35 nM in U937 cells, and showed good selectivity in the global proteomic profiling study. Mechanism studies revealed that compound 9q induced GSPT1 degradation through the ubiquitin-proteasome system. Consistent with its potent GSPT1 degradation activity, compound 9q displayed good antiproliferative activities against U937 cells, MOLT-4 cells, and MV4-11 cells, with IC50 values of 0.019 µM, 0.006 µM, and 0.027 µM, respectively. Compound 9q also dose-dependently induced G0/G1 phase arrest and apoptosis in U937 cells.