The synthesis of 1,2,3-triazoles as binders of D-dopachrome tautomerase (D-DT) for the development of dual-targeting inhibitors.

Despite recent advances in the treatment of cancer, the issue of therapy resistance remains one of the most significant challenges in the field. In this context, signaling molecules, such as cytokines have emerged as promising targets for drug discovery. Examples of cytokines include macrophage migration inhibitory factor (MIF) and its closely related analogue D-dopachrome tautomerase (D-DT). In this study we aim to develop a new chemical class of D-DT binders and subsequently create a dual-targeted inhibitor that can potentially trigger D-DT degradation via the Proteolysis Targeting Chimera (PROTAC) technology. Here we describe the synthesis of a novel library of 1,2,3-triazoles targeting D-DT. The most potent derivative 19c (IC50 of 0.5 ± 0.04 µM with high selectivity toward D-DT) was attached to a cereblon (CRBN) ligand through aliphatic amides, which were synthesized by a remarkably convenient and effective solvent-free reaction. Enzyme inhibition experiments led to the discovery of the compound 10d, which exhibited moderate inhibitory potency (IC50 of 5.9 ± 0.7 µM), but unfortunately demonstrated no activity in D-DT degradation experiments. In conclusion, this study offers valuable insight into the SAR of D-DT inhibition, paving the way for the development of novel molecules as tools to study D-DT functions in tumor proliferation and, ultimately, new therapeutics for cancer treatment.

Advancements in understanding bacterial enteritis pathogenesis through organoids.

Bacterial enteritis has a substantial role in contributing to a large portion of the global disease burden and serves as a major cause of newborn mortality. Despite advancements gained from current animal and cell models in improving our understanding of pathogens, their widespread application is hindered by apparent drawbacks. Therefore, more precise models are imperatively required to develop more accurate studies on host-pathogen interactions and drug discovery. Since the emergence of intestinal organoids, massive studies utilizing organoids have been conducted to study the pathogenesis of bacterial enteritis, revealing new mechanisms and validating established ones. In this review, we focus on the advancements of several bacterial pathogenesis mechanisms observed in intestinal organoid/enteroid models, exploring the host response and bacterial effectors during the infection process. Finally, we address the features that warrant additional investigation or could be enhanced in existing organoid models in order to guide future research endeavors.

Self-reported perceptions of ethical and professional expectations of medical students in China and the influence of voluntary work during the COVID-19: a survey on "Five Characteristics".

In the post-pandemic era, there is a need for medical professionals with creativity, clinical expertise, and social responsibility. The Chinese government issued a directive to enhance the "Five Characteristics" perceptions of medical students, incorporating moral integrity and adeptness in saving lives and aiding the injured, embracing a compassionate approach to medical practice, possessing the knowledge essential for academic distinction, mastering technical expertise, and the artistry of applying scientific methodologies. The purpose of this study was to investigate the opinions related to ethics and professional behaviors of medical students at one Chinese medical school using a validated 19-item survey instrument and analyze its influencing factors. We conducted a survey in a medical university in Anhui Province, China, and collected 1966 valid questionnaires using the "Five Characteristics Rating Scale". The results indicated high perceptions of "Five Characteristics" among Chinese medical students (85.42 ± 8.727). Lower-grade-year medical students (86.59 ± 7.888) had higher "Five Characteristics" perceptions than upper-grade-year medical students (84.29 ± 9.327, P < 0.05). In addition, medical students experiencing voluntary work during the COVID-19 pandemic showed higher perceptions (86.21 ± 8.357) than those without such experience (85.13 ± 8.842, P < 0.05). Grade year and voluntary work experience during the COVID-19 pandemic were influencing factors of "Five Characteristics" perceptions. Our research offers a theoretical foundation for governments and medical schools to cultivate doctors with high ethical standards and professional expectations.

A novel link between circPDE3B and ferroptosis in esophageal squamous cell carcinoma progression.

AIM: To unravel whether ferroptosis involves with the actions by circPDE3B-mediated facilitation of esophageal squamous cell carcinoma (ESCC) progression. METHODS: Human ESCC tissues and cell lines were prepared for the evaluation of ferroptosis. Cellular iron, ROS, GSH, and MDA levels were measured to assess ferroptosis. Flow cytometry was employed to analyze apoptosis and cell cycle. Subcellular fractionation and fluorescence in situ hybridization (FISH) were conducted to validate the localization of circPDE3B. RNA pull-down, RNA immunoprecipitation (RIP), and luciferase assay were subjected to identify the molecular mechanisms. Nude mouse xenograft model was carried out to evaluate the function of circPDE3B/SLC7A11/CBS in vivo. RESULTS: Increased circPDE3B in human ESCC specimens was positively correlated with ferroptosis-related molecules, SLC7A11 and CBS. Functionally, circPDE3B knockdown triggered ferroptosis, apoptosis, and cell cycle arrest in ESCC cells. Whereas, these effects were obviously blocked by miR-516b-5p inhibitor. Mechanistically, not only circPDE3B sponged miR-516b-5p to upregulate CBS, but also directly bound with HNRNPK to stabilize SLC7A11. In mice, depletion of circPDE3B restrained ESCC growth, while this was abolished by overexpression of CBS or SLC7A11. CONCLUSION: In summary, circPDE3B promotes ESCC progression by suppressing ferroptosis through recruiting HNRNPK/SLC7A11 and miR-516b-5p/CBS axes.

[Advances in organoids of the digestive system].

Organoid is a newly developed cellular there-dimensional culture system in recent years. Organoids have a three-dimensional structure, which is similar to that of the real organs. Together with the characteristics of self-renewal and reproduction of tissue origin, organoids can better simulate the function of real organs. Organoids provide a new platform for the study of organogenesis, regeneration, disease pathogenesis, and drug screening. The digestive system is an essential part of the human body and performs important functions. To date, organoid models of various digestive organs have been successfully established. This review summarizes the latest research progress of organoids of taste buds, esophagi, stomachs, livers and intestines, and prospects future application of organoids.

A Segmentation Method of Serialized Human Body Slices Based on Matting Strategy and Skeleton Extraction.

INTRODUCTION: In this paper, a semiautomatic image segmentation method for the serialized body slices of the Visible Human Project (VHP) is proposed. METHOD: In our method, we first verified the effectiveness of the shared matting method for the VHP slices and utilized it to segment a single image. Then, to meet the need for the automatic segmentation of serialized slice images, a method based on the parallel refinement method and flood-fill method was designed. The ROI (region of interest) image of the next slice can be extracted by using the skeleton image of the ROI in the current slice. RESULT: Utilizing this strategy, the color slice images of the Visible Human body can be continuously and serially segmented. This method is not complex but is rapid and automatic with less manual participation. CONCLUSION: The experimental results show that the primary organs of the Visible Human body can be accurately extracted.

Dynamics and hydrodynamic efficiency of diving beetle while swimming.

Diving beetle, an excellent biological prototype for bionic underwater vehicles, can achieve forward swimming, backward swimming, and flexible cornering by swinging its two powerful hind legs. An in-depth study of the propulsion performance of them will contribute to the micro underwater vehicles. In this paper, the kinematic and dynamic parameters, and the hydrodynamic efficiency of the diving beetle are studied by analysis of swimming videos using Motion Capture Technology, combined with CFD simulations. The results show that the hind legs of diving beetle can achieve high propulsion force and low return resistance during one propulsion cycle at both forward and backward swimming modes. The propulsion efficiencies of forward and backward swimming are 0.47 and 0.30, respectively. Although the efficiency of backward swimming is lower, the diving beetle can reach a higher speed in a short time at this mode, which can help it avoid natural enemies. At backward swimming mode, there is a long period of passive swing of hind legs, larger drag exists at higher speed during the recovery stroke, which reduces the propulsion efficiency to a certain extent. Reasonable planning of the swing speed of the hind legs during the power stroke and the recovery stroke can obtain the highest propulsion efficiency of this propulsion method. This work will be useful for the development of a bionic propulsion system of micro underwater vehicle.

Sideband cooling of a trapped ion in strong sideband coupling regime.

Conventional theoretical studies on the ground-state laser cooling of a trapped ion have mostly focused on the weak sideband coupling (WSC) regime, where the cooling rate is inverse proportional to the linewidth of the excited state. In a recent work [New J. Phys.23, 023018 (2021)10.1088/1367-2630/abe273], we proposed a theoretical framework to study the ground state cooling of a trapped ion in the strong sideband coupling (SSC) regime, under the assumption of a vanishing carrier transition. Here we extend this analysis to more general situations with nonvanishing carrier transitions, where we show that by properly tuning the coupling lasers a cooling rate proportional to the linewidth can be achieved. Our theoretical predictions closely agree with the corresponding exact solutions in the SSC regime, which provide an important theoretical guidance for sideband cooling experiments.

A novel 3D lumbar vertebrae location and segmentation method based on the fusion envelope of 2D hybrid visual projection images.

In recent years, fast and precise lumbar vertebrae segmentation technology have been one of the important topics in practical medical diagnosis and assisted medical surgery scenarios. However, most of the existing vertebral segmentation methods are based on the whole vertebral scanning space, which, up to some extent, is difficult to meet the clinical needs because of its large time complexity and space complexity. Different from the existing methods, for better exploiting the real time of lumbar segmentation, meanwhile ensuring its accuracy, a novel 3D lumbar vertebrae location and segmentation method based on the fusion envelope of 2D hybrid visual projection images (LVLS-HVPFE) is proposed in this paper. Firstly, a 2D projection location network of lumbar vertebrae based on fusion envelope of hybrid visual projection images is proposed to obtain the accurate location of each intact lumbar vertebra in the coronal and sagittal planes respectively. Among them, the envelope dataset of hybrid visual projection images (EDHVPs) is established to enhance feature representation and suppress interference in the process of dimensionality reduction projection. An envelope deep neural network (EDNN) for EDHVPs is established to effectively obtain depth envelope structure features with three different sizes, and a dimension reduction fusion mechanism is proposed to increase the sampling density of features and ensure the mutual independence of multi-scale features. Secondly, the concept of 3D localization criterion with spatial dimensionality reduction (SDRLC) is first proposed as a measure to verify the distribution consistency of vertebral targets in coronal and sagittal planes of a CT scan, and it can directionally guide for the subsequent 3D lumbar segmentation. Thirdly, under the condition of 3D positioning subspace of each intact lumbar vertebra, the 3D segmentation network based on spatial orientation guidance is used to realize an accurate segmentation of corresponding lumbar vertebra. The proposed method is evaluated with three representative datasets, and experimental results show that it is superior to the state-of-the-art methods.

Establishing a jugular-femoral venous route for recanalization of complicated inferior vena cava in Budd-Chiari Syndrome after transfemoral access failure.

Recanalization of inferior vena cava (IVC) with complete obstruction, old thrombosis or long segmental stenosis/obstruction (complicated IVC) via transfemoral access may fail in patients with Budd-Chiari syndrome (BCS). In this study, 34 consecutive patients with BCS underwent recanalization of complicated IVC occlusion via jugular-femoral venous (JFV) route establishment. BCS with complicated IVC was detected by reviewing preoperative color Doppler ultrasonography or computed tomography (CT) venography, and confirmed by intraoperative venography. Clinical data on technical success, complications, and follow-up outcomes were analyzed. Except for one patient received surgical repair of rupture IVC after recanalization, technical success of IVC recanalization was achieved in remaining 33 (97.1%) patients. No perioperative deaths was found. Three complications were observed during recanalization, for a complication rate of 8.8%. Bleeding of the femoral vein was observed in one patient, and two patients showed bleeding of IVC. The IVC lesion diameter and blood flow of the distal IVC increased significantly after the procedure. Twenty-four patients (77.4%) were clinically cured, and four patients (12.9%) showed clinical improvement. The 1-year, 3-year, 5-year primary patency rates were 85.9%, 76.4% and 70.0%, respectively. The 5-year secondary patency rate was 96.8%. There were three deaths during follow up, and the 5-year survival rate was 90.0%. In conclusion, JFV route establishment and angioplasty for complicated IVC is safe and effective for patients with BCS after transfemoral access failure.

Monitoring the lipid oxidation and flavor of Russian sturgeon fillets treated with low temperature vacuum heating: formation and relationship.

BACKGROUND: Sturgeon is one of the most precious fish resources worldwide. Low temperature vacuum heating (LTVH) has been confirmed as a good way of maintaining food quality. However, there is a lack of in-depth studies assessing the impact of LTVH on lipid oxidation and flavor formation. RESULTS: The present study compared the effect of LTVH and traditional cooking on lipid oxidation and flavor of sturgeon fillets. In total, 13 fatty acids were detected, of which polyunsaturated fatty acids content was the highest (P < 0.05). LTVH prevented the formation of conjugated diene and thiobarbituric acid reactive substances (P < 0.05), as manifested by an increased signal intensity of free radicals of electron spin resonance. The characteristic peaks intensity of lipid by Raman at 970 cm-1 , 1080 cm-1 and 1655 cm-1 were reduced, whereas peaks at 1068 cm-1 and 1125 cm-1 displayed the opposite trend. Confocal fluorescence microscopy showed that the lipids particles were reduced and distributed more evenly with an increase in heating temperature. Principal component analysis of electronic nose cannot effectively separate all groups; however, gas chromatography-ion migration spectrometry showed that the volatile flavor compounds were relatively stable during LTVH. Correlation analysis of all the above lipid oxidation indices and characteristic flavor substances showed that each treatment group was located in different quadrants and demonstrated great differentiation. CONCLUSION: Overall, the results of the present study support the view that LTVH is a healthier way of cooking. © 2022 Society of Chemical Industry.

Treatment of biliary stenosis using percutaneous transhepatic cholangiobiopsy with biopsy forceps of varying diameter.

BACKGROUND: The present study aimed to compare the clinical results and pathological diagnostic quality of percutaneous transhepatic cholangiobiopsy for biliary obstruction using biopsy forceps (BFs) of varying diameter. METHODS: A total of 57 patients with obstructive jaundice who underwent percutaneous transhepatic cholangiobiopsy and drainage with 1 of 2 BFs diameters (6.0-mm BFs, n=30; 4.5-mm BFs, n=27) between February 2018 and May 2019 were retrospectively assessed. BFs were compared in terms of their sample quality, diagnostic accuracy, sensitivity, specificity, number of passes, and complication rate. RESULTS: All 57 patients underwent the procedure successfully and the technical success rate was 100%. The 6.0- and 4.5-mm BFs demonstrated a diagnostic accuracy of 80% (24/30) and 85% (23/27), respectively (P=0.733), and a sensitivity of 78% (22/28) and 86% (22/26), respectively (P=0.729). The specificity of both the 6.0- and 4.5-mm BFs was 100%. The complication rate was 10% (3/30) with the 6.0-mm BFs and 19% (5/27) with the 4.5-mm BFs (P=0.456). The mean number of biopsies was 2.9±0.6 with the 6.0-mm BFs compared with 3.6±1.0 with the 4.5-mm BFs (P<0.001). The 6.0-mm BFs provided a larger biopsy size and a less crushed specimen compared with the 4.5-mm BFs. The overall tissue scores were 5.2±0.8 with 6.0-mm BFs and 4.5±1.0 with 4.5-mm BFs (P=0.012). CONCLUSIONS: There was no statistically significant difference in the clinical results between the 2 BFs in the context of percutaneous transhepatic cholangiobiopsy. Superior samples were obtained using the 6.0-mm BFs, with a fewer number of passes. The complication rate did not increase compared with the 4.5-mm BFs.

Passively Q-switched Tm:YAP laser with a lead zirconate titanate saturable absorber.

In the paper, we prepare a lead zirconate titanate saturable absorber, which is used to demonstrate a passively Q-switched (PQS) Tm:YAP laser. In the PQS mode, an average output power of 0.81 W and pulse width of 1.69 µs at 175 kHz are obtained at 1991.9 nm with a pump power of 12.76 W, corresponding to an optical-optical conversion efficiency of 6.35%. In addition, the beam quality factors M2 of the PQS Tm:YAP laser in the x and y directions are 1.17 and 1.15, respectively.

Circular RNA hsa_circ_0000277 sequesters miR-4766-5p to upregulate LAMA1 and promote esophageal carcinoma progression.

Growing evidence has indicated that circular RNAs (circRNAs) play a pivotal role as functional RNAs in diverse cancers. However, most circRNAs involved in esophageal squamous cell carcinoma (ESCC) remain undefined, and the underlying molecular mechanisms mediated by circRNAs are largely unclear. Here, we screened human circRNA expression profiles in ESCC tissues and found significantly increased expression of hsa_circ_0000277 (termed circPDE3B) in ESCC tissues and cell lines compared to the normal controls. Moreover, higher circPDE3B expression in patients with ESCC was correlated with advanced tumor-node-metastasis (TNM) stage and dismal prognosis. Functional experiments demonstrated that circPDE3B promoted the tumorigenesis and metastasis of ESCC cells in vitro and in vivo. Mechanistically, bioinformatics analysis, a dual-luciferase reporter assay, and anti-AGO2 RNA immunoprecipitation showed that circPDE3B could act as a competing endogenous RNA (ceRNA) by harboring miR-4766-5p to eliminate the inhibitory effect on the target gene laminin α1 (LAMA1). In addition, LAMA1 was significantly upregulated in ESCC tissues and was positively associated with the aggressive oncogenic phenotype. More importantly, rescue experiments revealed that the oncogenic role of circPDE3B in ESCC is partly dependent on the miR-4766-5p/LAMA1 axis. Furthermore, bioinformatics analysis combined with validation experiments showed that epithelial-mesenchymal transition (EMT) activation was involved in the oncogenic functions of the circPDE3B-miR-4766-5p/LAMA1 axis in ESCC. Taken together, we demonstrate for the first time that the circPDE3B/miR-4766-5p/LAMA1 axis functions as an oncogenic factor in promoting ESCC cell proliferation, migration, and invasion by inducing EMT, implying its potential prognostic and therapeutic significance in ESCC.

Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer.

PARP inhibitors have achieved great success in cancers with BRCA mutations, but only a small portion of patients carry BRCA mutations, which results in their narrow indication spectrum. Recently, emerging evidence has demonstrated that combinations of PARP and PI3K inhibitors could evoke unanticipated synergistic effects in various cancers, even including BRCA-proficient ones. In this work, a series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities. It was found that compounds 9a and 23a exhibited excellent inhibitory activities against PARP-1 (9a: IC50 = 1.57 nM, 23a: IC50 = 0.91 nM) and PI3Kα (9a: IC50 = 2.0 nM, 23a: IC50 = 1.5 nM), and showed promising antiproliferative activities against both BRCA-deficient (HCT-116, HCC-1937) and BRCA-proficient (SW620, MDA-MB-231/468) tumor cells. 9a and 23a also exhibited considerable in vivo antitumor efficacy in an MDA-MB-468 xenograft mouse model, with TGI values of 56.39% and 48.77%, respectively. Additionally, 23a possessed promising profiles including high kinase selectivity and low cardiotoxicity. Overall, this work indicates 9a and 23a might be potential PARP/PI3K dual inhibitors for cancer therapy and deserve further research.

Three-tube method and covered metallic stent for the treatment of anastomotic leakage after esophagectomy.

BACKGROUND: Anastomotic leakage is common and life-threatening complication after esophagectomy. The management of esophageal anastomotic leakage remains challenging. We aimed to determine the safety, feasibility and efficacy of three-tube method and covered metallic stent placement for the management of anastomotic leakage. METHODS: Twenty-six consecutive patients with anastomotic leakage were treated using three-tube method and covered metallic stent and the medical records were retrospectively assessed. All patients received placement of abscess drainage tube, jejunal feeding tube and gastrointestinal decompression tube as well as esophageal covered stent, followed by continue abscess drainage, nutritional support and anti-inflammatory treatment. Tubes and esophageal stents will be removed once anastomotic leakage heals. RESULTS: The procedure was technically successful in 23 patients (95.8%). A total of 31 covered stents were used. Esophageal stents and abscess drainage tubes were successfully removed from 14 patients. The median retention duration was 2.3 months and 2.6 months for stent and abscess drainage tubes, respectively. No perioperative death, esophageal rupture, massive hemorrhage, or other severe complications were observed during procedures. The abscess cavity had markedly decreased in 8 patients or disappeared in 16 cases. During follow-up, 8 patients died of cancer recurrence and 2 patients died of severe pulmonary infection. The 1-, 3-, 5-year survival rates were 60.1, 51.5 and 51.5%, respectively. CONCLUSION: Three-tube method and covered metallic stent placement is safe, feasible and efficacious for treatment of anastomotic leakage after esophagectomy.

Effects of eigen and actual frequencies of soft elastic surfaces on droplet rebound from stationary flexible feather vanes.

The aim of this paper is to investigate the effect of eigenfrequency and the actual frequency of the elastic surface for droplet rebound. The elastic surface used in this study is the stationary flexible feather vanes. A fluid-structure interaction (FSI) numerical model is proposed to predict the phenomenon, and later it is validated by an experiment where droplets impact the stationary flexible feather vanes. The effect of mass and stiffness of the surface is analysed. First, a suitable combination of mass and stiffness of the surface will enhance the drop rebound. Second, a small mass system with a higher eigenfrequency will decrease the minimum contact time. Finally, the actual frequencies of the elastic surface, approximately 75 Hz, can accelerate the drop rebound for all cases.

Role of fundoplication in treatment of patients with symptoms of hiatal hernia.

Gastroesophageal reflux disease (GERD) is often associated with hiatal hernia (HH). However, the need for fundoplication during hiatal hernia repair (HHR) remains controversial. The objective of this study was to evaluate the effect of HHR with concomitant laparoscopic Nissen fundoplication (HHR-LNF) in HH patients. A total of 122 patients with symptomatic HH were randomized to receive either HHR (n = 61) or HHR-LNF (n = 61). The measures of evaluating outcomes included DeMeester scores (DMS), complications, Reflux Diagnostic Questionnaire and patients' satisfaction 24 months following surgery. Despite comparable values in both groups at randomization, the DMS, total numbers of reflux episodes and percentage of time with pH < 4 were significantly higher in HHR group than in HHR-LNF group (P = 0.017, P = 0.002 and P = 0.019, respectively) at 6 months after surgery. One months postoperatively, complications were higher in the HHR-LNF group than in the HHR group (all P < 0.001), and there was no difference between the two groups at 6 months. By the end of the 2-year follow-up, HHR-LNF group showed a significantly lower reflux syndrome frequency-intensity score and greater percentage of satisfaction compared with HHR group (all P < 0.001). Laparoscopic HHR should be combined with a fundoplication in GERD patients with HH. HHR-LNF is safe and effective, not only improve reflux-related symptom, but also reduce the incidence of complications.

Perilipin 5 deficiency promotes atherosclerosis progression through accelerating inflammation, apoptosis, and oxidative stress.

Excessive plasma triglyceride (TG) and cholesterol levels promote the progression of several prevalent cardiovascular risk factors, including atherosclerosis, which is a leading death cause. Perilipin 5 (Plin5), an important perilipin protein, is abundant in tissues with very active lipid catabolism and is involved in the regulation of oxidative stress. Although inflammation and oxidative stress play a critical role in atherosclerosis development, the underlying mechanisms are complex and not completely understood. In the present study, we demonstrated the role of Plin5 in high-fat-diet-induced atherosclerosis in apolipoprotein E null (ApoE-/- ) mice. Our results suggested that Plin5 expressions increased in the artery tissues of ApoE-/- mice. ApoE/Plin5 double knockout (ApoE-/- Plin5-/- ) exacerbated severer atherogenesis, accompanied with significantly disturbed plasma metabolic profiles, such as elevated TG, total cholesterol, and low-density lipoprotein cholesterol levels and reduced high-density lipoprotein cholesterol contents. ApoE-/- Plin5-/- exhibited a higher number of inflammatory monocytes and neutrophils, as well as overexpression of cytokines and chemokines linked with an inflammatory response. Consistently, the IκBα/nuclear factor kappa B pathway was strongly activated in ApoE-/- Plin5-/- . Notably, apoptosis was dramatically induced by ApoE-/- Plin5-/- , as evidenced by increased cleavage of Caspase-3 and Poly (ADP-ribose) polymerase-2. In addition, ApoE-/- Plin5-/- contributed to oxidative stress generation in the aortic tissues, which was linked with the activation of phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinases pathways. In vitro, oxidized low-density lipoprotein (ox-LDL) increased Plin5 expression in RAW264.7 cells. Its knockdown enhanced inflammation, apoptosis, oxidative stress, and lipid accumulation, while promotion of Plin5 markedly reduced all the effects induced by ox-LDL in cells. These studies strongly supported that Plin5 could be a new regulator against atherosclerosis, providing new insights on therapeutic solutions.