PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α.

Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.

TROP2 is highly expressed in triple-negative breast cancer CTCs and is a potential marker for epithelial mesenchymal CTCs.

Circulating tumor cells (CTCs) are the seeds of distant metastases of malignant tumors and are associated with malignancy and risk of metastasis. However, tumor cells undergo epithelial-mesenchymal transition (EMT) during metastasis, leading to the emergence of different types of CTCs. Real-time dynamic molecular and functional typing of CTCs is necessary to precisely guide personalized treatment. Most CTC detection systems are based on epithelial markers that may fail to detect EMT CTCs. Therefore, it is clinically important to identify new markers of different CTC types. In this study, bioinformatics analysis and experimental assays showed that trophoblast cell surface antigen 2 (TROP2), a target molecule for advanced palliative treatment of triple-negative breast cancer (TNBC), was highly expressed in TNBC tissues and tumor cells. Furthermore, TROP2 can promote the migration and invasion of TNBC cells by upregulating EMT markers. The specificity and potential of TROP2 as an EMT-associated marker of TNBC CTCs were evaluated by flow cytometry, immunofluorescence, spiking experiments, and a well-established CTC assay. The results indicated that TROP2 is a potential novel CTC marker associated with EMT, providing a basis for more efficacious markers that encompass CTC heterogeneity in patients with TNBC.

Efficacy and safety of tetrandrine in treatment of rheumatoid arthritis: a meta analysis. / æ±‰é˜²å·±ç”²ç´ æ²»ç–—ç±»é£Žæ¹¿å ³èŠ‚ç‚Žæœ‰æ•ˆæ€§å’Œå®‰å ¨æ€§çš„meta分析.

OBJECTIVES: To explore the efficacy and safety of tetrandrine in the treatment of rheumatoid arthritis. METHODS: Randomized controlled studies of tetrandrine in the treatment of rheumatoid arthritis were searched in China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), World Wide Web Database, SinoMed, PubMed, Springer, Web of Science, the Cochrane Central Register of Controlled Trails database. A meta-analysis was conducted using R software version 3.5.3 to evaluate the clinical outcomes, including the total effective rate, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), visual analog scale (VAS) for pain, disease activity score (DAS), tender joint count (TJC), swollen joint count (SJC), and morning stiffness duration, as well as adverse events of RA patients. RESULTS: A total of 10 articles were included in the study. The meta-analysis indicated that tetrandrine significantly improved the total effective rate (OR=3.27, 95%CI: 2.01-5.37, P<0.01), ESR (SMD=1.12, 95%CI: 0.06-2.19, P<0.05), CRP (SMD=0.75, 95%CI: 0.28-1.22, P<0.01), VAS (SMD=0.55, 95%CI: 0.21-0.89, P<0.01), SJC (SMD=0.85, 95%CI: 0.40-1.31, P<0.01), TJC (SMD=1.16, 95%CI: 0.58-1.74, P<0.01), and morning stiffness (SMD=1.09, 95%CI: 0.68-1.50, P<0.01). However, no statistical significance was found in RF (SMD=1.70, 95%CI: －1.10-4.51, P>0.05) and DAS (SMD=0.26, 95%CI: －0.59-1.11, P>0.05). The overall incidence of adverse events associated with tetrandrine treatment for rheumatoid arthritis was 20% (95%CI: 12%-27%, I2=60%, P<0.05), with mild severity and favorable outcomes. CONCLUSIONS: Tetrandrine is effective in the treatment of RA patients with a mild degree of adverse events.

Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells.

Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.

Anti-synthetase syndrome is associated with a higher risk of hospitalization among patients with idiopathic inflammatory myopathy and COVID-19.

Background: Data with fine granularity about COVID-19-related outcomes and risk factors were still limited in the idiopathic inflammatory myopathies (IIMs) population. This study aimed to investigate clinical factors associated with hospitalized and severe COVID-19 in patients with IIMs, particularly those gauged by myositis-specific antibodies. Methods: This retrospective cohort study was conducted in the Renji IIM cohort in Shanghai, China, under an upsurge of SARS-CoV-2 omicron variant infections from December 2022 to January 2023. Clinical data were collected and analyzed by multivariable logistic regression to determine risk factors. High-dimensional flow cytometry analysis was performed to outline the immunological features. Results: Among 463 infected patients in the eligible cohort (n=613), 65 (14.0%) were hospitalized, 19 (4.1%) suffered severe COVID-19, and 10 (2.2%) died. Older age (OR=1.59/decade, 95% CI 1.18 to 2.16, p=0.003), requiring family oxygen supplement (2.62, 1.11 to 6.19, 0.028), patients with anti-synthetase syndrome (ASyS) (2.88, 1.12 to 7.34, 0.027, vs. other dermatomyositis), higher IIM disease activity, and prednisone intake >10mg/day (5.59, 2.70 to 11.57, <0.001) were associated with a higher risk of hospitalization. Conversely, 3-dose inactivated vaccination reduced the risk of hospitalization (0.10, 0.02 to 0.40, 0.001, vs. incomplete vaccination). Janus kinase inhibitor (JAKi) pre-exposure significantly reduced the risk of severe COVID-19 in hospitalized patients (0.16, 0.04 to 0.74, 0.019, vs. csDMARDs). ASyS patients with severe COVID-19 had significantly reduced peripheral CD4+ T cells, lower CD4/CD8 ratio, and fewer naive B cells but more class-switched memory B cells compared with controls. Conclusion: ASyS and family oxygen supplement were first identified as risk factors for COVID-19-related hospitalization in patients with IIMs. JAKi pre-exposure might protect IIM patients against severe COVID-19 complications.

The prognosis, chemotherapy and immunotherapy efficacy of the SUMOylation pathway signature and the role of UBA2 in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors worldwide. Small Ubiquitin-like Modifier (SUMO)-ylation plays a crucial role in tumorigenesis. However, the SUMOylation pathway landscape and its clinical implications in LUAD remain unclear. Here, we analyzed genes involved in the SUMOylation pathway in LUAD and constructed a SUMOylation pathway signature (SUMOPS) using the LASSO-Cox regression model, validated in independent cohorts. Our analysis revealed significant dysregulation of SUMOylation-related genes in LUAD, comprising of favorable or unfavorable prognostic factors. The SUMOPS model was associated with established molecular and histological subtypes of LUAD, highlighting its clinical relevance. The SUMOPS stratified LUAD patients into SUMOPS-high and SUMOPS-low subtypes with distinct survival outcomes and adjuvant chemotherapy responses. The SUMOPS-low subtype showed favorable responses to adjuvant chemotherapy. The correlations between SUMOPS scores and immune cell infiltration suggested that patients with the SUMOPS-high subtype exhibited favorable immune profiles for immune checkpoint inhibitor (ICI) treatment. Additionally, we identified UBA2 as a key SUMOylation-related gene with an increased expression and a poor prognosis in LUAD. Cell function experiment confirmed the role of UBA2 in promoting LUAD cell proliferation, invasion, and migration. These findings provide valuable insights into the SUMOylation pathway and its prognostic implications in LUAD, paving the way for personalized treatment strategies and the development of novel therapeutic targets.

Camrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial.

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

Prognostic and chemotherapeutic response prediction by proliferation essential gene signature: Investigating POLE2 in bladder cancer progression and cisplatin resistance.

Background: Bladder cancer (BLCA) is the most common genitourinary malignancy. Proliferation essential genes (PEGs) are crucial to the survival of cancer cells. This study aimed to build a PEG signature to predict BLCA prognosis and treatment efficacy. Methods: BLCA PEGs and differentially expressed PEGs were identified using DepMap and TCGA-BLCA datasets, respectively. Based on the prognostic analysis of the differentially expressed PEGs, a PEG model was constructed. Subsequently, we analyzed the relationship between the PEG signature and prognosis of BLCA patients as well as their response to chemotherapy. Finally, we performed random forest analysis to target and functional experiments to validate the most significant PEG which is associated with BLCA progression. CCK-8, invasion, migration, and chemosensitivity assays were performed to assess effects of gene knockdown on BLCA cell proliferation, invasion and migration abilities, and cisplatin chemosensitivity. Results: We screened 10 prognostic PEGs from 201 differentially expressed PEGs and used them to construct a PEG signature model. Patients with high PEG signature score (PEGs-high) exhibited worse OS and lower sensitivity to chemotherapy than those with PEGs-low. We also found significant correlations between the PEG score and previously defined BLCA molecular subtypes. This suggests that the PEG score may effectively predict the molecular subtypes which have distinct clinical outcomes. Random forest analysis revealed that POLE2 (DNA polymerase epsilon subunit 2) was the most significant PEG differentiating BLCA tissue and normal tissue. Bioinformatic analysis and an immunohistochemistry staining assay confirmed that POLE2 was significantly up-regulated in tumor tissues and was associated with poor survival in BLCA patients. Moreover, POLE2 knockdown inhibited the ability of cell clone formation, proliferation, invasion, immigration and IC50 of cisplatin. Conclusion: The PEG signature acts as a potential predictor for prognosis and chemotherapy response in BLCA patients. POLE2 is a key PEG and plays a remarkable role in promoting the malignant progression and cisplatin resistance of BLCA.

Discovery and Bioinspired Synthesis of Salpratone A.

Salpratone A (1), a novel abietane diterpenoid containing a unique cis-fused A/B ring, was isolated from Salvia prattii. Bioactivity studies showed that 1 has potent activity in inhibiting platelet aggregation induced by multiple agonists as well as antithrombotic efficacy in the FeCl3-induced rat in vivo thrombosis model. Furthermore, a bioinspired synthesis of 1 from the abundant natural product ferruginol was achieved in 6 steps with a 22% overall yield. The key steps include a stereoselective allyl oxidation and a subsequent regioselective Meinwald rearrangement.

Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis.

BACKGROUND: The complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs. METHODS: By exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and ß-glycerophosphate disodium salt (ß-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel). RESULTS: Cellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity. CONCLUSION: This triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.

PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer.

BACKGROUND: Prohibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC). METHODS: PHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan-Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272). The biological role of PHB2 and its subsequent regulatory mechanisms were elucidated in vitro and in vivo. GC cell viability and proliferation were assessed using MTT cell viability analysis, clonogenic assays, and BrdU incorporation assays, while the growth of GC xenografted tumours was measured via IHC staining of Ki67. The interaction among PHB2 and SHIP2, as well as between SHIP2 and NEDD4, was identified through co-immunoprecipitation, GST pull-down assays, and deletion-mapping experiments. SHIP2 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis. RESULTS: Our analysis revealed a substantial increase in PHB2 expression in GC tissues compared to adjacent normal tissues. Notably, higher PHB2 levels correlated with poorer patient outcomes, suggesting its clinical relevance. Functionally, silencing PHB2 in GC cells significantly reduced cell proliferation and retarded GC tumour growth, whereas overexpression of PHB2 further enhanced GC cell proliferation. Mechanistically, PHB2 physically interacted with Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in the cytoplasm of GC cells, thus leading to SHIP2 degradation via its novel E3 ligase NEDD4. It subsequently activated the PI3K/Akt signaling pathway and thus promoted GC cell proliferation. CONCLUSIONS: Our findings highlight the importance of PHB2 upregulation in driving GC progression and its association with adverse patient outcomes. Understanding the functional impact of PHB2 on GC growth contributes valuable insights into the molecular underpinnings of GC and may pave the way for the development of targeted therapies to improve patient outcomes.

Mechanism exploration of Osteoking in the treatment of lumbar disc herniation based on network pharmacology and molecular docking.

OBJECTIVE: Lumbar disc herniation (LDH) is a common spinal surgical disease. Low back and leg pain caused by LDH is the main factor leading to functional disability, which has caused a serious burden to patients and society. Osteoking can delay the progression of osteoporosis and osteoarthritis, and even has a significant effect on the prevention of deep vein thrombosis after fracture surgery. In recent years, it has been gradually used in the treatment of LDH and has received significant results. However, the underlying mechanism remains unclear. The aim of this study was to predict the mechanism of Osteoking in the treatment of LDH through network pharmacology and verify it by molecular docking method. METHODS: The TCMSP database was used to collect the relevant active components and targets of Osteoking, while the GeneCards, OMIM and DisGeNET databases were utilized to collect the relevant disease targets of LDH. The Venny 2.1.0 software was employed to obtain the intersecting gene targets of Osteoking and LDH. PPI network construction and core target selection were performed using Cytoscape 3.9.0 software. The Metascape database was used for GO and KEGG enrichment analysis of the relevant targets. Finally, molecular docking was conducted using AutoDock software. RESULTS: The study identified 116 potential targets and 26 core targets for the treatment of LDH with Osteoking. Pathways in cancer, Alzheimer's disease, microRNAs in cancer and the IL-17 signalling pathway were among the main involved signalling pathways. Molecular docking results demonstrated that the key targets AKT1, IL-6, ALB, TNF and IL-1ß exhibited relatively stable binding activities with the main active components of Osteoking. CONCLUSIONS: Osteoking can alleviate the symptoms of lumbar disc herniation through the modulation of multiple targets and signalling pathways.

Prevalence of hypertension among type 2 diabetes mellitus patients in China: a systematic review and meta-analysis.

This study aimed to estimate the prevalence of hypertension in Chinese patients with type 2 diabetes mellitus (T2DM) using the results of a regional study. The studies were reviewed using PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, Wan Fang Data and Chinese Science Citation Database. After screening articles and data extraction, Stata V.16 was used for statistical analysis. This study was registered in the Prospective Register Systematic Reviews (CRD42020170649). A total of 2126 articles were identified, and nine papers were finally included. Random-effects modelling showed that the pooled prevalence of hypertension among Chinese patients with T2DM was 54% (95% CI 47 to 61%). Subgroup analysis showed that the prevalence in men (59.8%; 95% CI 49.0 to 70.7%) was higher than that in women (40.2%; 95% CI 29.3 to 59.2%). The prevalence in North China was higher than that in East China. The prevalence in institution-based settings (56%; 95% CI 48 to 64%) was higher than that in community-based settings (51%; 95% CI 34 to 69%). Appropriate preventive measures should be undertaken, such as health education, to control and reduce the risk of hypertension in diabetic patients and reduce the burden of cardiovascular disease.

A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer.

OBJECTIVE: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m²) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. METHODS: In this phase I trial, a time-to-event Bayesian optimal interval design was used. Docetaxel was given at a starting dose of 60 mg/m² and was increased in 5 mg/m² increments until the MTD was determined or the maximum dose level of 75 mg/m² was reached. The dose-limiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. RESULTS: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m², no DLT was reported. DLTs were observed in one patient who received 70 mg/m² docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m² docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m² in combination with cisplatin 75 mg/m² had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. CONCLUSION: Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m²), can be used safely at intraperitoneal doses of 75 mg/m² in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05410483.

ß-1,3-d-glucan particles-based "nest" protected co-loaded Rhein and Emodin regulates microbiota and intestinal immunity for ulcerative colitis treatment.

Herein, a ß-1,3-D-glucan based yeast cell wall loaded with co-loaded nanoparticles of Rhein (RH) and Emodin (EMO), was developed for the combined treatment of ulcerative colitis (UC) by modulating gut microbiota and the Th17/Treg cell balance. This was achieved through an oral "nano-in-micro" advanced drug delivery system. Specifically, RH was grafted onto the HA chain via disulfide bonds to synthesize a reduction-sensitive carrier material and then used to encapsulate EMO to form nanoparticles with a specific drug ratio (denoted as HA-RH/EMO NPs). As anticipated, HA-RH/EMO NPs were encased within the "nests"-yeast cell wall microparticles (YPs), efficiently reach the colon and then released gradually, this occurs mainly due to the degradation of ß-1,3-D-glucan by ß-glucanase. Additionally, HA-RH/EMO NPs demonstrated a significant reduction-sensitive effect in GSH stimulation evaluations and a remarkable ability to target macrophages in in vitro cell uptake studies. Notably, HA-RH/EMO NYPs reduced inflammatory responses by inhibiting the PI3K/Akt signaling pathway. Even more crucially, the oral delivery and drug combination methods significantly enhanced the regulatory effects of HA-RH/EMO NYPs on gut microbiota and the Th17/Treg balance. Overall, this research marks the first use of YPs to encapsulate two components, RH and EMO, presenting a promising therapeutic strategy for UC.

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Rearranged Homoadamantane-Type Polycyclic Polyprenylated Acylphloroglucinols from Hypericum pseudohenryi.

Hypseudohenones A-C (1-3), the first rearranged homoadamantane-type polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum pseudohenryi. Their structures with an unprecedented tricyclo[4.3.1.13,8]undecane-2,4,10-trione core were determined by spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A method for determining the relative configuration at C-3 was established by the peak shape of H-28 or J-value of H-3/H-28. Moreover, 2-3 exhibited significant AChE inhibitory activity, and the interactions of 2-3 with AChE were evaluated by molecular docking.

Blockchain-based Electronic Medical Record Security Sharing Scheme.

To solve the difficulty of medical data sharing in traditional medical information systems, we proposed an electronic medical record secure-sharing scheme based on the Blockchain technique. The encrypted text of the patient's electronic medical record is stored in the cloud server while the metadata of the medical record and access strategy is stored in the blockchain system. We employed smart contracts in the blockchain system to achieve user rights management. We used the decentralized, tamper-proof, and traceable features of the blockchain to realize the safe sharing of electronic medical records. The experimental results of security analysis show that the method can defend against potential network attacks while satisfying patient privacy protection and confidentiality. This study verifies the feasibility and great operating efficiency of the blockchain-based electronic medical record security sharing scheme.Clinical relevance- Our proposed blockchain-based electronic medical record-sharing scheme has great potential for the safe access of third-party users to patient data.

Discovery and Engineering of a Novel Bacterial L-Aspartate α-Decarboxylase for Efficient Bioconversion.

L-aspartate α-decarboxylase (ADC) is a pyruvoyl-dependent decarboxylase that catalyzes the conversion of L-aspartate to ß-alanine in the pantothenate pathway. The enzyme has been extensively used in the biosynthesis of ß-alanine and D-pantothenic acid. However, the broad application of ADCs is hindered by low specific activity. To address this issue, we explored 412 sequences and discovered a novel ADC from Corynebacterium jeikeium (CjADC). CjADC exhibited specific activity of 10.7 U/mg and Km of 3.6 mM, which were better than the commonly used ADC from Bacillus subtilis. CjADC was then engineered leveraging structure-guided evolution and generated a mutant, C26V/I88M/Y90F/R3V. The specific activity of the mutant is 28.8 U/mg, which is the highest among the unknown ADCs. Furthermore, the mutant displayed lower Km than the wild-type enzyme. Moreover, we revealed that the introduced mutations increased the structural stability of the mutant by promoting the frequency of hydrogen-bond formation and creating a more hydrophobic region around the active center, thereby facilitating the binding of L-aspartate to the active center and stabilizing the substrate orientation. Finally, the whole-cell bioconversion showed that C26V/I88M/Y90F/R3V completely transformed 1-molar L-aspartate in 12 h and produced 88.6 g/L ß-alanine. Our study not only identified a high-performance ADC but also established a research framework for rapidly screening novel enzymes using a protein database.