Two new species of Hypodontolaiminae (Nematoda, Chromadorida, Chromadoridae) from the Yellow Sea with a phylogenetic analysis in the subfamily.

Two new species of Hypodontolaiminae, Dichromadoramediasp. nov. and Neochromadoraparabilineatasp. nov., were isolated and described from the Yellow Sea, China. Dichromadoramediasp. nov. is characterized by four long cephalic setae, the amphidial fovea transverse oval in the male and slit-shaped in the female, the pharynx with a single posterior bulb, spicules curved and distally bifurcated, gubernaculum jointed, four (1+3) precloacal supplements papilliform, and the tail conical elongated with a short spinneret. Neochromadoraparabilineatasp. nov. is characterized by the buccal cavity with one large hollow dorsal tooth and two small subventral teeth, the pharynx with an obvious posterior bulb, spicules L-shaped and widened medially, gubernaculum boat-shaped, seven cup-shaped and equidistant precloacal supplements, and a long and gradually tapering tail. The phylogenetic analysis of maximum likelihood and Bayesian inference based on rDNA sequences confirmed the taxonomic positions of Neochromadoraparabilineatasp. nov. and Dichromadoramediasp. nov. within Hypodontolaiminae. Tree topology in Hypodontolaiminae shows the genera Neochromadora, Dichromadora, Ptycholaimellus, and Spilophorella as polyphyletic groups, and the genus Chromadorita as a paraphyletic group.

PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders.

INTRODUCTION: Natural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. OBJECTIVES: Inspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. METHODS: Taking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. RESULTS: In this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10-hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo, leading to potent antitumor activities and reduced toxic side effects. CONCLUSION: In summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development.

Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation.

Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.

Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid ß-Oxidation.

Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid ß-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

Discovery of novel bis-evodiamine derivatives with potent antitumor activity.

Inspired by antitumor natural product evodiamine, a series of novel bis-evodiamine derivatives were designed and synthesized, which showed potent antitumor activity. In particular, compound 13b effectively inhibited the proliferation and migration of HCT116 cells. Further mechanism studies revealed that compound 13b acted by inducing HCT116 cell apoptosis and arresting the cell cycle at the G2/M phase. Thus, compound 13b represents a promising lead compound for the discovery of novel antitumor agents.

Design, Synthesis, and Structure-Activity relationships of Evodiamine-Based topoisomerase (Top)/Histone deacetylase (HDAC) dual inhibitors.

On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.

Robotic in situ 3D bio-printing technology for repairing large segmental bone defects.

Introduction: The traditional clinical treatment of long segmental bone defects usually requires multiple operations and depends on donor availability. The 3D bio-printing technology constitutes a great potential therapeutic tool for such an injury. However, in situ 3D bio-printing remains a major challenge. Objectives: In this study, we report the repair of long segmental bone defects by in situ 3D bio-printing using a robotic manipulator 3D printer in a swine model. Methods: We systematically optimized bio-ink gelation under physiological conditions to achieve desirable mechanical properties suitable for bone regeneration, and a D-H kinematic model was used to improve printing accuracy to 0.5 mm. Results: These technical improvements allowed the repair of long segmental defects generated on the right tibia of pigs using 3D bio-printing within 12 min. The 3D bio-printing group showed improved treatment effects after 3 months. Conclusion: These findings indicated that robotic in situ 3D bio-printing is promising for direct clinical application.

The Effects of Acarbose on Non-Diabetic Overweight and Obese Patients: A Meta-Analysis.

INTRODUCTION: This systematic review aims to verify the efficacy of acarbose monotherapy in treating obese or overweight patients without diabetes. METHODS: In the study, we conducted a systematic search of the Pub-Med, EMBASE, Cochrane and Science Citation Index Expanded databases in search of clinical trials on acarbose treatment, overweight and obesity. The crucial inclusion criteria were as follows: (1) patients were diagnosed as overweight or obese (BMI ≥ 25 kg/m2); (2) randomized controlled trials (RCTs); (3) patients had undergone acarbose monotherapy or placebo control; (4) acarbose treatment had been carried out for at least 3 months. Exclusion criteria were as follows: (1) patients diagnosed with diabetes mellitus (DM); (2) patients had received a weight loss medication or surgery in the past 3 months; (3) papers not published in English; (4) repeated research results of the same experiment or repeated published documents. RESULTS: A total of 7 studies involving 132 in the acarbose group and 137 in placebo group, 269 subjects in total, were included in this meta-analysis. From the selected seven papers, we extracted the following clinical parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP), body weight (BW), body mass index (BMI), triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), high density cholesterol (HDL) and fasting plasma glucose (FPG). An important finding of our research is that TG was the only significantly reduced parameter in the acarbose group. Weight mean difference (WMD) was - 0.21 (95% CI - 0.33, - 0.09) mmol/l between acarbose (P = 0.0006) and placebo patients. Reduction of BMI was also greater for acarbose than placebo subjects, although the discrepancy was not statistically significant (P = 0.56). Moreover, no hypoglycemia occurred in either the acarbose group or placebo group. A few subjects experienced gastrointestinal reactions, but these were mild and improved over time. Acarbose has no obvious influence on other metabolic indexes. CONCLUSION: Acarbose monotherapy is beneficial in reducing TG levels in obese or overweight patients and will not result in hypoglycemia during medication. The side effects of acarbose are mild.

The biomechanical changes of load distribution with longitudinal tears of meniscal horns on knee joint: a finite element analysis.

BACKGROUND: Meniscal horns are important structures of meniscus, and longitudinal tears of these places could significantly change the load distribution among the knee joint. Few studies concerned the stress concentrated on bones, which may induce the osteonecrosis of subchondral bone. The goal of this study was to construct a finite element (FE) model with high fidelity of the knee joint and evaluate the biomechanical changes of load distribution of components after longitudinal tears of the horns of meniscus. METHODS: Computed tomography and magnetic resonance images were used to develop the FE model, and two different kinds of simulations, the vertical and the anterior load, mimicking the static stance and slight flexion simulations, were applied after longitudinal tears of the horns of meniscus. RESULTS: Significantly elevated peak compressive and shear stress was observed on the menisci, cartilages, and subchondral bones, and enlarged meniscus extrusion was noticed. Between all the four types of longitudinal tears investigated in this study, longitudinal tears at the posterior horn of the medial meniscus were found to be the most significant. CONCLUSIONS: These findings showed that longitudinal tears of the meniscal horns lead to increased magnitude and changed distribution of stress and indicated the important role of posterior horn of medial meniscus. This may contribute to the mechanism between meniscal tears and spontaneous subchondral bone osteonecrosis.

SENP2 exerts an anti­tumor effect on chronic lymphocytic leukemia cells through the inhibition of the Notch and NF­κB signaling pathways.

Chronic lymphocytic leukemia (CLL) is one of the most often diagnosed hematological malignant tumors in the Western world and a type of inert B­cell lymphoma that commonly attacks the elderly. Small ubiquitin related modifier (SUMO)­specific protease 2 (SENP2) can act as a suppressor in various types of cancer by regulating the stability of ß­catenin to affect the Notch signaling pathway; however, it has a low expression level in CLL cells. In this study, we firstly used western blot analysis and RT­qPCR to detect the protein and mRNA expression levels of SENP2 in the peripheral blood of patients with CLL and healthy volunteers. Secondly, we overexpressed or knocked down the expression of SENP2 in CLL cells and then determined the cell invasive and chemotactic ability in a Transwell assay and chemotaxis assay. We examined the sensitivity of the cells to cytarabine and dexamethasone via a CCK­8 assay and determined the cell apoptotic condition and the expression of the Notch signaling pathway using flow cytometry and western blot analysis. The results demonstrated that the patients with CLL had relatively low expression levels of SENP2. The overexpression of SENP2 in the CLL cells decreased their invasive and proliferative ability, as well as their chemotactic response and enhanced their sensitivity to cytarabine and dexamethasone, while it promoted cell apoptosis. The silencing of SENP2 in the CLL cells generally produced the opposite results. We thus hypothesized that the overexpression of SENP2 downregulated ß­catenin expression, thus inhibiting the Notch signaling pathway in CLL cells. Moreover, the nuclear factor (NF)­κB signaling pathway was also regulated by the overexpression of SENP2. On the whole, the findings of this study indicate tha SENP2 can act as a tumor suppressor in CLL cells, and may thus prove to be a novel target for CLL treatment in clinical practice.

Ultrasensitive electrochemical immunoassay for squamous cell carcinoma antigen using dumbbell-like Pt-Fe3O4 nanoparticles as signal amplification.

Dumbbell-like Pt-Fe3O4 nanoparticles (NPs) were synthesized and used as a novel kind of label for the preparation of electrochemical immunosensor, which is applied to the detection of cancer biomarker squamous cell carcinoma antigen (SCC-Ag). The signal amplification strategy, using the synergetic effect present in Pt-Fe3O4 to increase the reduction ability of the NPs toward H2O2, improved the sensitivity of the immunosensor. Nitrogen-doped graphene sheets (N-GS) were synthesized from graphite oxides through thermal annealing of graphite oxides in ammonia, which was used to immobilize primary anti-SCC antibody (Ab1). Secondary anti-SCC antibody (Ab2) was adsorbed onto the Pt-Fe3O4 NPs. The immunosensor was prepared through a sandwich structure and displayed a wide linear range (0.05-18 ng/mL), low detection limit (15.3 pg/mL), good reproducibility and stability. The method has been applied to the analysis of clinical serum samples with satisfactory results. These labels for immunosensors can provide many potential applications for the detection of different biomolecules.