Experiment-free exoskeleton assistance via learning in simulation.

Exoskeletons have enormous potential to improve human locomotive performance1-3. However, their development and broad dissemination are limited by the requirement for lengthy human tests and handcrafted control laws2. Here we show an experiment-free method to learn a versatile control policy in simulation. Our learning-in-simulation framework leverages dynamics-aware musculoskeletal and exoskeleton models and data-driven reinforcement learning to bridge the gap between simulation and reality without human experiments. The learned controller is deployed on a custom hip exoskeleton that automatically generates assistance across different activities with reduced metabolic rates by 24.3%, 13.1% and 15.4% for walking, running and stair climbing, respectively. Our framework may offer a generalizable and scalable strategy for the rapid development and widespread adoption of a variety of assistive robots for both able-bodied and mobility-impaired individuals.

Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic ß-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-ß1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

Phase transition of tensin-1 during the focal adhesion disassembly and cell division.

Biomolecular condensates are nonmembranous structures that are mainly formed through liquid-liquid phase separation. Tensins are focal adhesion (FA) proteins linking the actin cytoskeleton to integrin receptors. Here, we report that GFP-tagged tensin-1 (TNS1) proteins phase-separate to form biomolecular condensates in cells. Live-cell imaging showed that new TNS1 condensates are budding from the disassembling ends of FAs, and the presence of these condensates is cell cycle dependent. TNS1 condensates dissolve immediately prior to mitosis and rapidly reappear while postmitotic daughter cells establish new FAs. TNS1 condensates contain selected FA proteins and signaling molecules such as pT308Akt but not pS473Akt, suggesting previously unknown roles of TNS1 condensates in disassembling FAs, as the storage of core FA components and the signaling intermediates.

Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma.

The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic "don't eat me" signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.

Supramolecular Polymerization as a Tool to Reveal the Magnetic Transition Dipole Moment of Heptazines.

Heptazine derivatives have attracted significant interest due to their small S1-T1 gap, which contributes to their unique electronic and optical properties. However, the nature of the lowest excited state remains ambiguous. In the present study, we characterize the lowest optical transition of heptazine by its magnetic transition dipole moment. To measure the magnetic transition dipole moment, the flat heptazine must be chiroptically active, which is difficult to achieve for single heptazine molecules. Therefore, we used supramolecular polymerization as an approach to make homochiral stacks of heptazine derivatives. Upon formation of the supramolecular polymers, the preferred helical stacking of heptazine introduces circular polarization of absorption and fluorescence. The magnetic transition dipole moments for the S1 ← S0 and S1 → S0 are determined to be 0.35 and 0.36 Bohr magneton, respectively. These high values of magnetic transition dipole moments support the intramolecular charge transfer nature of the lowest excited state from nitrogen to carbon in heptazine and further confirm the degeneracy of S1 and T1.

Two Cytochrome P450 Enzymes Form the Tricyclic Nested Skeleton of Meroterpenoids by Sequential Oxidative Reactions.

Meroterpenoid clavilactones feature a unique benzo-fused ten-membered carbocyclic ring unit with an α,ß-epoxy-γ-lactone moiety, forming an intriguing 10/5/3 tricyclic nested skeleton. These compounds are good inhibitors of the tyrosine kinase, attracting a lot of chemical synthesis studies. However, the natural enzymes involved in the formation of the 10/5/3 tricyclic nested skeleton remain unexplored. Here, we identified a gene cluster responsible for the biosynthesis of clavilactone A in the basidiomycetous fungus Clitocybe clavipes. We showed that a key cytochrome P450 monooxygenase ClaR catalyzes the diradical coupling reaction between the intramolecular hydroquinone and allyl moieties to form the benzo-fused ten-membered carbocyclic ring unit, followed by the P450 ClaT that exquisitely and stereoselectively assembles the α,ß-epoxy-γ-lactone moiety in clavilactone biosynthesis. ClaR unprecedentedly acts as a macrocyclase to catalyze the oxidative cyclization of the isopentenyl to the nonterpenoid moieties to form the benzo-fused macrocycle, and a multifunctional P450 ClaT catalyzes a ten-electron oxidation to accomplish the biosynthesis of the 10/5/3 tricyclic nested skeleton in clavilactones. Our findings establish the foundation for the efficient production of clavilactones using synthetic biology approaches and provide the mechanistic insights into the macrocycle formation in the biosynthesis of fungal meroterpenoids.

Traditional Medicine Pien Tze Huang Suppresses Colorectal Tumorigenesis Through Restoring Gut Microbiota and Metabolites.

BACKGROUND & AIMS: Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota. METHODS: CRC mouse models were established by azoxymethane plus dextran sulfate sodium treatment or in Apcmin/+ mice treated with or without PZH (270 mg/kg and 540 mg/kg). Gut barrier function was determined by means of intestinal permeability assays and transmission electron microscopy. Fecal microbiota and metabolites were analyzed by means of metagenomic sequencing and liquid chromatography mass spectrometry, respectively. Germ-free mice or antibiotic-treated mice were used as models of microbiota depletion. RESULTS: PZH inhibited colorectal tumorigenesis in azoxymethane plus dextran sulfate sodium-treated mice and in Apcmin/+ mice in a dose-dependent manner. PZH treatment altered the gut microbiota profile, with an increased abundance of probiotics Pseudobutyrivibrio xylanivorans and Eubacterium limosum, while pathogenic bacteria Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, and Peptoniphilus harei were depleted. In addition, PZH increased beneficial metabolites taurine and hypotaurine, bile acids, and unsaturated fatty acids, and significantly restored gut barrier function. Transcriptomic profiling revealed that PZH inhibited PI3K-Akt, interleukin-17, tumor necrosis factor, and cytokine-chemokine signaling. Notably, the chemopreventive effect of PZH involved both microbiota-dependent and -independent mechanisms. Fecal microbiota transplantation from PZH-treated mice to germ-free mice partly recapitulated the chemopreventive effects of PZH. PZH components ginsenoside-F2 and ginsenoside-Re demonstrated inhibitory effects on CRC cells and primary organoids, and PZH also inhibited tumorigenesis in azoxymethane plus dextran sulfate sodium-treated germ-free mice. CONCLUSIONS: PZH manipulated gut microbiota and metabolites toward a more favorable profile, improved gut barrier function, and suppressed oncogenic and pro-inflammatory pathways, thereby suppressing colorectal carcinogenesis.

Exploration of the prognostic effect of costimulatory genes in bladder cancer.

BACKGROUND: A prognostic model of bladder cancer was constructed based on costimulatory molecules, and its stability and accuracy were verified in different datasets. METHOD: The expression profile of bladder cancer RNA and the corresponding clinical data in The Cancer Genome Atlas (TCGA) database were analyzed employing computational biology, and a prognostic model was constructed for costimulating molecule-related genes. The model was applied in GSE160693, GSE176307, Xiangya_Cohort, GSE13507, GSE19423, GSE31684, GSE32894, GSE48075, GSE69795 and GSE70691 in TCGA dataset and Gene Expression Omnibus database. The role of costimulating molecules in bladder cancer tumor subtypes was also explored. By consistent cluster analysis, bladder cancer in the TCGA dataset was categorized into two subtypes: C1 and C2. The C1 subtype exhibited a poor prognosis, high levels of immune cell infiltration and significant enrichment of natural killer cells, T cells and dendritic cells in the C1 subtype. In addition, the ImmuneScore calculated by the ESTIMATE algorithm differed greatly between the two subtypes, and the ImmuneScore of the C1 subtype was greater than the C2 subtype in a significant manner. RESULTS: This study also assessed the relationship between costimulating molecules and immunotherapy response. The high-risk group responded poorly to immunotherapy, with significant differences in the amount of most immune cells between the two groups. Further, three indices of the ESTIMATE algorithm and 22 immune cells of the CIBERSORT algorithm were significantly correlated with risk values. These findings suggest the potential value of costimulating molecules in predicting immunotherapy response. CONCLUSION: A costimulatory molecule-based prognostic model for bladder cancer was established and validated across multiple datasets. This model introduces a novel mode for tailoring treatments to each individual with bladder cancer, and offers valuable insights for informed clinical choices. Simultaneously, this research also delved into the significance of costimulating molecules within distinct bladder cancer subtypes, shedding novel insights into improving immunotherapy strategies for the treatment of bladder cancer.

Safety and efficacy of sirolimus in recurrent intravenous leiomyomatosis, pulmonary benign metastatic leiomyomatosis, and leiomyomatosis peritonealis disseminata: a pilot study.

BACKGROUND: Intravenous leiomyomatosis (IVL), pulmonary benign metastatic leiomyomatosis (PBML), and leiomyomatosis peritonealis disseminata (LPD) are leiomyomas with special growth patterns and high postoperative recurrence rates. We report the safety and efficacy of a pilot study of sirolimus in the treatment of recurrent IVL, PBML, and recurrent LPD. METHODS: This was a pilot study to evaluate the safety and efficacy of sirolimus in the treatment of leiomyomatosis (ClinicalTrials.gov identifier NCT03500367) conducted in China. Patients received oral sirolimus 2 mg once a day for a maximum of 60 months or until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision to stop. The primary end point of this study was the objective response rate. Secondary end points included safety and tolerability, disease control rate, and progression-free survival. RESULTS: A total of 15 patients with leiomyomatosis were included in the study, including five with recurrent IVL, eight with PBML and two with recurrent LPD. The median follow-up time was 15 months (range 6-54 months), nine patients (60%) had treatment-related adverse events (including all levels), and two patients had treatment-related grade 3 or 4 adverse events. The objective response rate was 20.0% (95% CI, 7.1-45.2%), and the disease control rate was 86.7% (95% CI, 62.1-96.3%). Partial response was achieved in three patients. The median response time in the three partial response patients was 33 months (range 29-36 months), and the sustained remission time of these three patients reached 0, 18, and 25 months, respectively. CONCLUSIONS: Sirolimus was safe and effective in the treatment of recurrent IVL, PBML, and recurrent LPD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03500367. Registered on 18 April 2018.

Broad-spectrum resistance gene RPW8.1 balances immunity and growth via feedback regulation of WRKYs.

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.1 (RPW8.1) is an important tool for engineering broad-spectrum disease resistance against multiple pathogens. Ectopic expression of RPW8.1 leads to enhanced disease resistance with cell death at leaves and compromised plant growth, implying a regulatory mechanism balancing RPW8.1-mediated resistance and growth. Here, we show that RPW8.1 constitutively enhances the expression of transcription factor WRKY51 and activates salicylic acid and ethylene signalling pathways; WRKY51 in turn suppresses RPW8.1 expression, forming a feedback regulation loop. RPW8.1 and WRKY51 are both induced by pathogen infection and pathogen-/microbe-associated molecular patterns. In ectopic expression of RPW8.1 background (R1Y4), overexpression of WRKY51 not only rescues the growth suppression and cell death caused by RPW8.1, but also suppresses RPW8.1-mediated broad-spectrum disease resistance and pattern-triggered immunity. Mechanistically, WRKY51 directly binds to and represses RPW8.1 promoter, thus limiting the expression amplitude of RPW8.1. Moreover, WRKY6, WRKY28 and WRKY41 play a role redundant to WRKY51 in the suppression of RPW8.1 expression and are constitutively upregulated in R1Y4 plants with WRKY51 being knocked out (wrky51 R1Y4) plants. Notably, WRKY51 has no significant effects on disease resistance or plant growth in wild type without RPW8.1, indicating a specific role in RPW8.1-mediated disease resistance. Altogether, our results reveal a regulatory circuit controlling the accumulation of RPW8.1 to an appropriate level to precisely balance growth and disease resistance during pathogen invasion.

Prevalence of urolithiasis in China: a systematic review and meta-analysis.

OBJECTIVE: To estimate the pooled prevalence, as well as the spatial and temporal distribution, of urolithiasis among subjects in China. MATERIALS AND METHODS: We conducted a comprehensive search of both Chinese and English databases to retrieve literature pertaining to the prevalence of urolithiasis in the indigenous Chinese population. A random-effects meta-analysis model was employed to calculate the pooled prevalence of urolithiasis. Subgroup analyses were conducted based on factors such as time, region, gender, and sample size. Prevalence and spatial distribution maps were created based on provinces and latitude/longitude coordinates. RESULTS: A total of 46 studies conducted in 22 provinces across China were included in this meta-analysis and the pooled prevalence of urolithiasis, kidney stones, ureteric calculi, urethral and bladder stones were 8.1% (95% confidence interval [CI] 5.6-11.1%), 7.8% (95% CI 5.8-10.0%), 3.2% (95% CI 0.6-5.7%), 0.5% (95% CI 0.1-0.9%). Most of the urolithiasis prevalence screening in China was concentrated between 100° E and 120° E, with higher rates observed in low latitude areas. Subgroup analysis of kidney stones revealed that Guangdong (12.7%) and Guangxi (10.3%) had the highest prevalence, with the eastern developed area exhibiting higher rates compared to the west. The prevalence in males was higher than in females (odds ratio 1.67, 95% CI 1.46-1.92), although the gender gap has significantly reduced since 2006. Moreover, a greater sample size is associated with a decreased prevalence of urolithiasis. CONCLUSIONS: The prevalence of urolithiasis is increasing in China, and there are noteworthy regional or provincial disparities in occurrence. It is worth noting that the current number of screening studies in some areas is insufficient. Additional investigations with appropriate sample sizes should be supplemented in time.

Design and Applications of Supramolecular Peptide Hydrogel as Artificial Extracellular Matrix.

Supramolecular peptide hydrogels (SPHs) consist of peptides containing hydrogelators and functional epitopes, which can first self-assemble into nanofibers and then physically entangle together to form dynamic three-dimensional networks. Their porous structures, excellent bioactivity, and high dynamicity, similar to an extracellular matrix (ECM), have great potential in artificial ECM. The properties of the hydrogel are largely dependent on peptides. The noncovalent interactions among hydrogelators drive the formation of assemblies and further transition into hydrogels, while bioactive epitopes modulate cell-cell and cell-ECM interactions. Therefore, SPHs can support cell growth, making them ideal biomaterials for ECM mimics. This Review outlines the classical molecular design of SPHs from hydrogelators to functional epitopes and summarizes the recent advancements of SPHs as artificial ECMs in nervous system repair, wound healing, bone and cartilage regeneration, and organoid culture. This emerging SPH platform could provide an alternative strategy for developing more effective biomaterials for tissue engineering.

The therapeutic effects of saikosaponins on depression through the modulation of neuroplasticity: From molecular mechanisms to potential clinical applications.

Depression is a major global health issue that urgently requires innovative and precise treatment options. In this context, saikosaponin has emerged as a promising candidate, offering a variety of therapeutic benefits that may be effective in combating depression. This review delves into the multifaceted potential of saikosaponins in alleviating depressive symptoms. We summarized the effects of saikosaponins on structural and functional neuroplasticity, elaborated the regulatory mechanism of saikosaponins in modulating key factors that affect neuroplasticity, such as inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, and the brain-gut axis. Moreover, this paper highlights existing gaps in current researches and outlines directions for future studies. A detailed plan is provided for the future clinical application of saikosaponins, advocating for more targeted researches to speed up its transition from preclinical trials to clinical practice.

Optical trapping-induced crystallization promoted by gold and silicon nanoparticles.

This study investigates the promotion of sodium chlorate (NaClO3) crystallization through optical trapping, enhanced by the addition of gold nanoparticles (AuNPs) and silicon nanoparticles (SiNPs). Using a focused laser beam at the air-solution interface of a saturated NaClO3 solution with AuNPs or SiNPs, the aggregates of these particles were formed at the laser focus, the nucleation and growth of metastable NaClO3 (m-NaClO3) crystals were induced. Continued laser irradiation caused these m-NaClO3 crystals to undergo repeated cycles of growth and dissolution, eventually transitioning to a stable crystal form. Our comparative analysis showed that AuNPs, due to their significant heating due to higher photon absorption efficiency, caused more pronounced size fluctuations in m-NaClO3 crystals compared to the stable behavior observed with SiNPs. Interestingly, the maximum diameter of the m-NaClO3 crystals that appeared during the size fluctuation step was consistent, regardless of nanoparticle type, concentration, or size. The crystallization process was also promoted by using polystyrene nanoparticles, which have minimal heating and electric field enhancement, suggesting that the reduction in activation energy for nucleation at the particle surface is a key factor. These findings provide critical insights into the mechanisms of laser-induced crystallization, emphasizing the roles of plasmonic heating, particle surfaces, and optical forces.

Quantum chemical studies of the reaction mechanisms of enzymatic CO2 conversion.

Enzymatic capture and conversion of carbon dioxide (CO2) into value-added chemicals are of great interest in the field of biocatalysis and have a positive impact on climate change. The quantum chemical methods, recognized as valuable tools for studying reaction mechanisms, have been widely employed in investigating the reaction mechanisms of the enzymes involved in CO2 utilization. In this perspective, we review the mechanistic studies of representative enzymes that are either currently used or have the potential for converting CO2, utilizing the quantum chemical cluster approach and the quantum mechanical/molecular mechanical (QM/MM) method. We begin by summarizing current trends in enzymatic CO2 conversion, followed by a brief description of the computational details of quantum chemical methods. Then, a series of representative examples of the computational modeling of biocatalytic CO2 conversion are presented, including the reduction of CO2 to C1 species (carbon monoxide and formate), and the fixation of CO2 to form aliphatic and aromatic carboxylic acids. The microscopic views of reaction mechanisms obtained from these studies are helpful in guiding the rational design of current enzymes and the discovery of novel enzymes with enhanced performance in converting CO2. Additionally, they provide key information for the de novo design of new-to-nature enzymes. To conclude, we present a perspective on the potential combination of machine learning with quantum description in the study of enzymatic conversion of CO2.

Quantum chemical modeling of enantioselective sulfoxidation and epoxidation reactions by indole monooxygenase VpIndA1.

Indole monooxygenases (IMOs) are enzymes from the family of Group E monooxygenases, requiring flavin adenine dinucleotide (FAD) for their activities. IMOs play important roles in both sulfoxidation and epoxidation reactions. The broad substrate range and high selectivity of IMOs make them promising biocatalytic tools for synthesizing chiral compounds. In the present study, quantum chemical calculations using the cluster approach were performed to investigate the reaction mechanism and the enantioselectivity of the IMO from Variovorax paradoxus EPS (VpIndA1). The sulfoxidation of methyl phenyl sulfide (MPS) and the epoxidation of indene were chosen as the representative reactions. The calculations confirmed that the FADOOH intermediate is the catalytic species in the VpIndA1 reactions. The oxidation of MPS adopts a one-step mechanism involving the direct oxygen-transfer from FADOOH to the substrate and the proton transfer from the -OH group back to FAD, while the oxidation of indene follows a stepwise mechanism involving a carbocation intermediate. It was computationally predicted that VpIndA1 prefers the formation of (S)-product for the MPS sulfoxidation and (1S,2R)-product for the indene epoxidation, consistent with the experimental observations. Importantly, the factors controlling the stereo-preference of the two reactions are identified. The findings in the present study provide valuable insights into the VpIndA1-catalyzed reactions, which are essential for the rational design of this enzyme and other IMOs for industrial applications. It is also worth emphasizing that the quantum chemical cluster approach is again demonstrated to be powerful in studying the enantioselectivity of enzymatic reactions.

Enhancing reductive dechlorination of trichloroethylene in bioelectrochemical systems with conductive materials.

The incorporation of conductive materials to enhance electron transfer in bioelectrochemical systems (BES) is considered a promising approach. However, the specific effects and mechanisms of these materials on trichloroethylene (TCE) reductive dechlorination in BES remains are not fully understood. This study investigated the use of magnetite nanoparticles (MNP) and biochars (BC) as coatings on biocathodes for TCE reduction. Results demonstrated that the average dechlorination rates of MNP-Biocathode (122.89 µM Cl·d-1) and BC-Biocathode (102.88 µM Cl·d-1) were greatly higher than that of Biocathode (78.17 µM Cl·d-1). Based on MATLAB calculation, the dechlorination rate exhibited a more significantly increase in TCE-to-DCE step than the other dechlorination steps. Microbial community analyses revealed an increase in the relative abundance of electroactive and dechlorinating populations (e.g., Pseudomonas, Geobacter, and Desulfovibrio) in MNP-Biocathode and BC-Biocathode. Functional gene analysis via RT-qPCR showed the expression of dehalogenase (RDase) and direct electron transfer (DET) related genes was upregulated with the addition of MNP and BC. These findings suggest that conductive materials might accelerate reductive dechlorination by enhancing DET. The difference of physicochemical characteristics (e.g. particle size and specific surface area), electron transfer enhancement mechanism between MNP and BC as well as the reduction of Fe(III) by hydrogen may explain the superior dechlorination rate observed with MNP-Biocathode.

Low-dose lenvatinib and anti-programmed cell death protein-1 combination therapy in patients with heavily pre-treated recurrent ovarian and endometrial cancer: a pilot study.

OBJECTIVE: Treatment options for heavily pre-treated recurrent ovarian and endometrial cancer are limited. Lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has been efficacious in advanced endometrial cancer, but at the recommended dose level, high-grade adverse events occur and lead to drug discontinuation. This study evaluated the feasibility of low-dose lenvatinib plus anti-PD-1 therapy in patients with recurrent ovarian and endometrial cancer. METHODS: This is a single-arm, protocol-based pilot study. Patients with recurrent ovarian cancer or endometrial cancer who had at least one line of previous therapy were included and given lenvatinib 8 or 12 mg daily (based on the patient's weight) and anti-PD-1 therapy. The primary endpoint was the objective response rate. RESULTS: Twenty-one patients were enrolled, including 15 with ovarian cancer and six with endometrial cancer. All patients were pre-treated, and the median number of lines of previous treatment of the ovarian and endometrial cancer cohorts was three and two, respectively. After a median follow-up of 11.0 months (range 6.8-23.9), the objective response rate for the ovarian cancer and endometrial cancer cohorts was 46.7% (95% CI 21.3% to 73.4%) and 66.7% (95% CI 22.3% to 95.7%), respectively. The median duration of response for the ovarian cancer and endometrial cancer cohorts was 5.3 (95% CI 0 to 11.7) and 6.1 (95% CI 2.4 to 9.8) months, respectively. The median progression-free survival for the ovarian cancer and endometrial cancer cohorts was 4.1 (95% CI 2.6 to 5.6) and 6.6 (95% CI 1.7 to 11.5) months, respectively. No grade 4 or 5 adverse events occurred. Eight (38.1%) patients had a lenvatinib dose reduction. There was no discontinuation of lenvatinib alone, and only one patient discontinued both drugs due to adverse events. CONCLUSION: Low-dose lenvatinib in combination with anti-PD-1 therapy showed promising efficacy and favorable tolerability in patients with heavily pre-treated ovarian and endometrial cancer.

Enantioselective control in chiral crystallization of ethylenediamine sulfate using optical trapping with circularly polarized laser beams.

In this study, we conducted successful experiments on ethylenediamine sulfate (EDS), an organic compound, to investigate its enantioselectivity in chiral crystallization. We employed optical trapping with circularly polarized laser beams, using a continuous wave laser at 1064 nm. By focusing the laser at the air-solution interface of a heavy water-saturated EDS solution, the formation of sub-micrometer-sized chiral EDS crystals was verified. Two generated enantiomorphs (d-crystal and l-crystal) were identified by the rotating analyzer method. The enantioselectivity in the chiral crystallization of EDS was assessed through 30 to 60 times experiments conducted under various conditions of laser powers and polarization modes, utilizing the count of generated crystals for each enantiomorph in the evaluation. Circularly polarized lasers at a specific power created an imbalance in the generation probability of the enantiomorphs, resulting in crystal enantiomeric excess values of 23% and -30%. The enantioselectivity mechanism was explored from two perspectives: refractive index differences of two enantiomorphs and 3D helical optical forces. Study of the thermodynamic mechanism was insufficient to explain the outcomes. Conversely, the 3D helical optical force mechanism revealed that the forces acting on EDS clusters in solution induced helical fluid motion, driving EDS nucleation, with the helicity of fluid motion determining the crystal's chirality. This approach will present new insights into chirality in industrial and research fields, with potential applications in regard to improving optical resolution and addressing the origin of homochirality.

PGE2 binding to EP2 promotes ureteral stone expulsion by relaxing ureter via the cAMP-PKA pathway.

BACKGROUND: This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development. METHODS: By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes. RESULTS: The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA. CONCLUSIONS: PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones.