Harnessing function of EMT in cancer drug resistance: a metastasis regulator determines chemotherapy response.

Epithelial-mesenchymal transition (EMT) is a complicated molecular process that governs cellular shape and function changes throughout tissue development and embryogenesis. In addition, EMT contributes to the development and spread of tumors. Expanding and degrading the surrounding microenvironment, cells undergoing EMT move away from the main location. On the basis of the expression of fibroblast-specific protein-1 (FSP1), fibroblast growth factor (FGF), collagen, and smooth muscle actin (-SMA), the mesenchymal phenotype exhibited in fibroblasts is crucial for promoting EMT. While EMT is not entirely reliant on its regulators like ZEB1/2, Twist, and Snail proteins, investigation of upstream signaling (like EGF, TGF-ß, Wnt) is required to get a more thorough understanding of tumor EMT. Throughout numerous cancers, connections between tumor epithelial and fibroblast cells that influence tumor growth have been found. The significance of cellular crosstalk stems from the fact that these events affect therapeutic response and disease prognosis. This study examines how classical EMT signals emanating from various cancer cells interfere to tumor metastasis, treatment resistance, and tumor recurrence.

MetaHMEI: meta-learning for prediction of few-shot histone modifying enzyme inhibitors.

MOTIVATION: Histones are the chief protein components of chromatin, and the chemical modifications on histones crucially influence the transcriptional state of related genes. Histone modifying enzyme (HME), responsible for adding or removing the chemical labels, has emerged as a very important class of drug target, with a few HME inhibitors launched as anti-cancerous drugs and tens of molecules under clinical trials. To accelerate the drug discovery process of HME inhibitors, machine learning-based predictive models have been developed to enrich the active molecules from vast chemical space. However, the number of compounds with known activity distributed largely unbalanced among different HMEs, particularly with many targets of less than a hundred active samples. In this case, it is difficult to build effective virtual screening models directly based on machine learning. RESULTS: To this end, we propose a new Meta-learning-based Histone Modifying Enzymes Inhibitor prediction method (MetaHMEI). Our proposed MetaHMEI first uses a self-supervised pre-training approach to obtain high-quality molecular substructure embeddings from a large unlabeled chemical dataset. Then, MetaHMEI exploits a Transformer-based encoder and meta-learning framework to build a prediction model. MetaHMEI allows the effective transfer of the prior knowledge learned from HMEs with sufficient samples to HMEs with a small number of samples, so the proposed model can produce accurate predictions for HMEs with limited data. Extensive experimental results on our collected and curated HMEs datasets show that MetaHMEI is better than other methods in the case of few-shot learning. Furthermore, we applied MetaHMEI in the virtual screening process of histone JMJD3 inhibitors and successfully obtained three small molecule inhibitors, further supporting the validity of our model.

The role of ABCC10/MRP7 in anti-cancer drug resistance and beyond.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 ß-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

Selective C-H Bond Activation in Propane with Molecular Oxygen over Cu(I)-ZSM-5 at Ambient Conditions.

Selective activation of C-H bonds in light alkanes under mild conditions is challenging but holds the promise of efficient upgrading of abundant hydrocarbons. In this work, we report the conversion of propane to propylene with ∼95% selectivity on Cu(I)-ZSM-5 with O2 at room temperature and pressure. The intraporous Cu(I) species was oxidized to Cu(II) during the reaction but could be regenerated with H2 at 220 °C. Diffuse reflectance ultraviolet spectroscopy indicated the presence of both Cu+-O2 and Cu2(µ-O2)2+ species in the zeolite pores during the reaction, and electron paramagnetic resonance results showed that propane activation occurred via a radical-mediated pathway distinct from that with H2O2 as the oxidant. Correlation between spectroscopic and reactivity results on Cu(I)-ZSM-5 with different Cu loadings suggests that the isolated intraporous Cu(I) species is the main active species in propane activation.

Unraveling Eumelanin Radical Formation by Nanodiamond Optical Relaxometry in a Living Cell.

Defect centers in a nanodiamond (ND) allow the detection of tiny magnetic fields in their direct surroundings, rendering them as an emerging tool for nanoscale sensing applications. Eumelanin, an abundant pigment, plays an important role in biology and material science. Here, for the first time, we evaluate the comproportionation reaction in eumelanin by detecting and quantifying semiquinone radicals through the nitrogen-vacancy color center. A thin layer of eumelanin is polymerized on the surface of nanodiamonds (NDs), and depending on the environmental conditions, such as the local pH value, near-infrared, and ultraviolet light irradiation, the radicals form and react in situ. By combining experiments and theoretical simulations, we quantify the local number and kinetics of free radicals in the eumelanin layer. Next, the ND sensor enters the cells via endosomal vesicles. We quantify the number of radicals formed within the eumelanin layer in these acidic compartments by applying optical relaxometry measurements. In the future, we believe that the ND quantum sensor could provide valuable insights into the chemistry of eumelanin, which could contribute to the understanding and treatment of eumelanin- and melanin-related diseases.

Targeting PNPO to suppress tumor growth via inhibiting autophagic flux and to reverse paclitaxel resistance in ovarian cancer.

Our previous study showed that pyridoxine 5'-phosphate oxidase (PNPO) is a tissue biomarker of ovarian cancer (OC) and has a prognostic implication but detailed mechanisms remain unclear. The current study focused on PNPO-regulated lysosome/autophagy-mediated cellular processes and the potential role of PNPO in chemoresistance. We found that PNPO was overexpressed in OC cells and was a prognostic factor in OC patients. PNPO significantly promoted cell proliferation via the regulation of cyclin B1 and phosphorylated CDK1 and shortened the G2M phase in a cell cycle. Overexpressed PNPO enhanced the biogenesis and perinuclear distribution of lysosomes, promoting the degradation of autophagosomes and boosting the autophagic flux. Further, an autolysosome marker LAMP2 was upregulated in OC cells. Silencing LAMP2 suppressed cell growth and induced cell apoptosis. LAMP2-siRNA blocked PNPO action in OC cells, indicating that the function of PNPO on cellular processes was mediated by LAMP2. These data suggest the existence of the PNPO-LAMP2 axis. Moreover, silencing PNPO suppressed xenographic tumor formation. Chloroquine counteracted the promotion effect of PNPO on autophagic flux and inhibited OC cell survival, facilitating the inhibitory effect of PNPO-shRNA on tumor growth in vivo. Finally, PNPO was overexpressed in paclitaxel-resistant OC cells. PNPO-siRNA enhanced paclitaxel sensitivity in vitro and in vivo. In conclusion, PNPO has a regulatory effect on lysosomal biogenesis that in turn promotes autophagic flux, leading to OC cell proliferation, and tumor formation, and is a paclitaxel-resistant factor. These data imply a potential application by targeting PNPO to suppress tumor growth and reverse PTX resistance in OC.

PCDHGB7 hypermethylation-based Cervical cancer Methylation (CerMe) detection for the triage of high-risk human papillomavirus-positive women: a prospective cohort study.

BACKGROUND: Implementation of high-risk human papillomavirus (hrHPV) screening has greatly reduced the incidence and mortality of cervical cancer. However, a triage strategy that is effective, noninvasive, and independent from the subjective interpretation of pathologists is urgently required to decrease unnecessary colposcopy referrals in hrHPV-positive women. METHODS: A total of 3251 hrHPV-positive women aged 30-82 years (median = 41 years) from International Peace Maternity and Child Health Hospital were included in the training set (n = 2116) and the validation set (n = 1135) to establish Cervical cancer Methylation (CerMe) detection. The performance of CerMe as a triage for hrHPV-positive women was evaluated. RESULTS: CerMe detection efficiently distinguished cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) from cervical intraepithelial neoplasia grade 1 or normal (CIN1 -) women with excellent sensitivity of 82.4% (95% CI = 72.6 ~ 89.8%) and specificity of 91.1% (95% CI = 89.2 ~ 92.7%). Importantly, CerMe showed improved specificity (92.1% vs. 74.9%) in other 12 hrHPV type-positive women as well as superior sensitivity (80.8% vs. 61.5%) and specificity (88.9% vs. 75.3%) in HPV16/18 type-positive women compared with cytology testing. CerMe performed well in the triage of hrHPV-positive women with ASC-US (sensitivity = 74.4%, specificity = 87.5%) or LSIL cytology (sensitivity = 84.4%, specificity = 83.9%). CONCLUSIONS: PCDHGB7 hypermethylation-based CerMe detection can be used as a triage strategy for hrHPV-positive women to reduce unnecessary over-referrals. TRIAL REGISTRATION: ChiCTR2100048972. Registered on 19 July 2021.

Synergistic Inclusion Effects of Hard Magnetic Nanorods on the Magnetomechanical Actuation of Soft Magnetic Microsphere-Based Polymer Composites.

The magnetomechanical actuation of micropillars is developed for the contactless manipulation of miniaturized actuators and microtextured surfaces. Anisotropic geometry of micropillars can significantly enhance the magnetic actuation compared with their isotropic counterparts by directional stress distributions. However, this strategy is not viable for triangular micropillars owing to insufficient anisotropy. In this study, a significant improvement in the magnetic actuation of triangular micropillars using composite magnetic particles is reported. A minute and optimal amount of hard magnetic gamma-ferrite nanorods are hybridized with soft magnetic iron microspheres to generate synergistic effects of magnetic coupling and percolation phenomenon on the magnetic actuation of polymer composites. The addition of 1 wt% face-centered cubic-phased gamma-ferrite nanorods suppresses the magnetic coupling interference of body-centered cubic-phased iron microspheres. Furthermore, the nanorods reduce the percolation threshold by participating in the percolation of the microspheres. A systematic compositional study on the magnetization and magnetorheological properties reveals that the coupling effect dominates the percolation effect at a low magnetic field, whereas the percolation effect governs the magnetic actuation at a high magnetic field. This hybrid approach can help in designing material constituents for effective magnetic actuators and robotic systems that can sensitively respond to an external magnetic field.

Nuclear Magnetic Resonance-Based Metabolomics and Risk of CKD.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) leads to lipid and metabolic abnormalities, but a comprehensive investigation of lipids, lipoprotein particles, and circulating metabolites associated with the risk of CKD has been lacking. We examined the associations of nuclear magnetic resonance (NMR)-based metabolomics data with CKD risk in the UK Biobank study. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A total of 91,532 participants in the UK Biobank Study without CKD and not receiving lipid-lowering therapy. EXPOSURE: Levels of metabolites including lipid concentration and composition within 14 lipoprotein subclasses, as well as other metabolic biomarkers were quantified via NMR spectroscopy. OUTCOME: Incident CKD identified using ICD codes in any primary care data, hospital admission records, or death register records. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: We identified 2,269 CKD cases over a median follow-up period of 13.1 years via linkage with the electronic health records. After adjusting for covariates and correcting for multiple testing, 90 of 142 biomarkers were significantly associated with incident CKD. In general, higher concentrations of very-low-density lipoprotein (VLDL) particles were associated with a higher risk of CKD whereas higher concentrations of high-density lipoprotein (HDL) particles were associated with a lower risk of CKD. Higher concentrations of cholesterol, phospholipids, and total lipids within VLDL were associated with a higher risk of CKD, whereas within HDL they were associated with a lower risk of CKD. Further, higher triglyceride levels within all lipoprotein subclasses, including all HDL particles, were associated with greater risk of CKD. We also identified that several amino acids, fatty acids, and inflammatory biomarkers were associated with risk of CKD. LIMITATIONS: Potential underreporting of CKD cases because of case identification via electronic health records. CONCLUSIONS: Our findings highlight multiple known and novel pathways linking circulating metabolites to the risk of CKD. PLAIN-LANGUAGE SUMMARY: The relationship between individual lipoprotein particle subclasses and lipid-related traits and risk of chronic kidney disease (CKD) in general population is unclear. Using data from 91,532 participants in the UK Biobank, we evaluated the associations of metabolites measured using nuclear magnetic resonance testing with the risk of CKD. We identified that 90 out of 142 lipid biomarkers were significantly associated with incident CKD. We found that very-low-density lipoproteins, high-density lipoproteins, the lipid concentration and composition within these lipoproteins, triglycerides within all the lipoprotein subclasses, fatty acids, amino acids, and inflammation biomarkers were associated with CKD risk. These findings advance our knowledge about mechanistic pathways that may contribute to the development of CKD.

Fast, intelligent and high-precision adaptive null interferometry for optical freeform surfaces by backpropagation.

In the past 10 years, adaptive wavefront interferometry (AWI) has been employed for measuring freeform surface profiles. However, existing AWI techniques relying on stepwise and model-free stochastic optimizations have resulted in inefficient tests. To address these issues, deterministic adaptive wavefront interferometry (DAWI) is firstly introduced in this paper based on backpropagation (BP), which employs a loss function to simultaneously reconstruct and sparsify initial incomplete interferometric fringes until they are nulled. Each iteration of BP requires two phase shifts. Through simulations, we have verified that freeform wavefront error with a peak-to-valley (PV) of up to 168 λ can be fully compensated in tens of iterations using a 1024 × 1024 pixel area of a liquid-crystal spatial light modulator. In experiments, we accomplished a null test of a freeform surface with 80% missing interference fringes in 39 iterations, resulting in a surface profile error PV of 66.22 λ and measurement error better than λ/4. The DAWI has at least 20 times fewer iterations in fringe reconstruction than the 3-step AWI methods, and nearly an order of magnitude fewer iterations in the whole process, paving the way for significantly enhanced efficiency, generality and precision in freeform surface adaptive interferometry.

Comparative study of the multiple wavelength lasing of nitrogen ions: the role of vibrational level-dependent photoionization.

We report on an optical amplification and energy threshold of the two most prominent emission lines, 391.4 and 427.8 nm, of the cavity-less lasing of nitrogen ions pumped by femtosecond laser pulses. It was found that the two transitions both show optical amplification under a low gas pressure condition, while the 391.4 nm emission is barely amplified under high gas pressure. Moreover, the 427.8 nm emission presents a significant lower pump laser energy threshold and a larger gain factor than the 391.4 nm emission. Numerical simulations based on a three-state coupling model suggest that the smaller ionization Franck-Condon factor from the ground state of N2 to the vibrational level ν = 1 in X 2 Σ g+ state of N2 + favors the formation of population inversion corresponding to the 427.8 nm emission. Meanwhile, the competition between the strong field ionization and excitation induced by the pumping laser requires higher laser intensity to acquire the population inversion for the 391.4 nm radiation, leading to a corresponding larger energy threshold.

HPV16-miRNAs exert oncogenic effects through enhancers in human cervical cancer.

BACKGROUND: Cervical cancer is a human papillomavirus (HPV)-related disease. HPV type 16 (HPV16), which is the predominant cause of cervical cancer, can encode miRNAs (HPV16-miRNAs). However, the role of HPV16-miRNAs in the pathogenesis of cervical cancer remains unclear. METHODS: Human cervical cancer cell lines SiHa (HPV16-positive) and C33A (HPV-negative), and cervical cancer tissues were collected to investigate the expression levels of two HPV16-miRNAs (HPV16-miR-H1 and HPV16-miR-H6). The overexpression and knockdown of HPV16-miR-H1 and HPV16-miR-H6 were performed using the lentiviral vector system and miRNA inhibitors, respectively. RNA-sequencing (RNA-seq) analysis and H3K27ac chromatin immunoprecipitation and sequencing (CHIP-seq) experiments were utilized to explore the roles of HPV16-miR-H1 and HPV16-miR-H6 facilitated by enhancers. CCK8, EdU, transwell, and wound healing assays were performed to verify the effects of HPV16-miR-H1 and HPV16-miR-H6 on cell proliferation and migration. RESULTS: HPV16-miR-H1 and HPV16-miR-H6 were highly expressed in both SiHa cells and tissue samples from HPV16-positive cervical cancer patients. RNA-seq analysis showed that HPV16-miR-H1 and HPV16-miR-H6 induced the upregulation of numerous tumor progression-associated genes. H3K27ac CHIP-seq experiments further revealed that HPV16-miR-H1 and HPV16-miR-H6 modulated the expression of critical genes by regulating their enhancer activity. The functional study demonstrated that HPV16-miR-H1 and HPV16-miR-H6 increased the migratory capacity of SiHa cells. CONCLUSIONS: Our data shed light on the role of HPV16-encoded miRNAs in cervical cancer, particularly emphasizing their involvement in the miRNA-enhancer-target gene system. This novel regulatory mechanism of HPV16-miRNAs provides new insights and approaches for the development of therapeutic strategies by targeting HPV16-positive cervical cancer.

A Facile Preparation of N-Heterocyclic Olefins: Ring-Opening Polymerization of ß-Butyrolactone and Frustrated Lewis Pair Reactivity.

A direct synthesis of N-heterocyclic olefins (NHOs) and their mesoionic congeners (mNHOs) from N-heterocyclic carbenes and N-aziridinylimines is reported. The reaction provided diverse functionalized (m)NHOs and π-extended analogues. The prepared NHOs initiated the ring-opening polymerization of ß-butyrolactone, and insertion of aldehyde and nitrile into an NHO-B(C6 F5 )3 adduct was demonstrated.

Effect of novel anti-tumor and anti-angiogenesis drug taurolactone on angiogenic factor AGGF1 and angiogenesis mimicry in patients with hepatocellular carcinoma.

OBJECTIVE: Our study was to investigate the impact of taurolactone, a novel anti-tumor and anti-angiogenic drug, on AGGF1, an angiogenic factor, and angiogenesis mimicry in patients diagnosed with hepatocellular carcinoma (HCC). METHODS: A total of 120 HCC patients were enrolled from the Department of Oncology and Hepatobiliary Surgery at our hospital between May 2021 and December 2022. HCC diagnoses were confirmed through imaging or tissue biopsy for all patients. The age of patients ranged from 37 to 72 years, with an average age of 64.29 ± 4.58 years. These participants were divided equally into two groups: the control group and the observation group, each consisting of 60 individuals. While the control group received standard drug treatment, the observation group was administered taurolactone treatment. Before being included in the study, all participants or their legal representatives provided signed informed consent. Patient demographic information was collected through a questionnaire survey. ELISA was used to measure the levels of VEGF and AGGF1 in patients following treatment. Western blot was applied to assess the protein expression of PDGF, Angiopoietin, and AGGF1. MRI imaging technology was utilized to assess the perfusion characteristics of tumor blood vessels in patients. Tumor vessel density was compared between patients using ultrasonography. We also conducted a comparison between the two groups in terms of progression-free survival and overall survival. RESULTS: General patient information between the two groups showed no significant differences (P > 0.05). Of note, the observation group exhibited greatly lower levels of VEGF and AGGF1 compared to the control group (P < 0.05). Moreover, the levels of PDGF, Angiopoietin, and AGGF1 protein expression were significantly reduced in the observation group compared to the control group (P < 0.05). In terms of tumor perfusion, the observation group displayed lower average and maximum perfusion volumes in tumor blood vessels compared to the control group (P < 0.05). Additionally, the observation group demonstrated delayed peak times and arrival times of tumor blood vessels in comparison to the control group (P < 0.05). Furthermore, the density of tumor blood vessels was notably lower in the observation group compared to the control group (P < 0.05). Patients in the observation group had longer progression-free survival and overall survival than the control group (P < 0.05). CONCLUSION: In HCC patients, our study highlighted the potential efficacy of taurolactone treatment as it effectively inhibited angiogenic factors and angiogenesis mimicry, ultimately leading to an improved prognosis for these patients.

Associations of Lower-Carbohydrate and Lower-Fat Diets with Mortality among People with Cardiovascular Disease.

BACKGROUND: Although low-carbohydrate and low-fat diets have been shown to have short-term metabolic benefits, the associations of these dietary patterns, particularly different food sources and macronutrient quality, with mortality in people with cardiovascular disease (CVD) remain unclear. OBJECTIVES: To examine the associations of different types of lower-carbohydrate diets (LCDs) and lower-fat diets (LFDs) with mortality in individuals with CVD. METHODS: This study included 3971 adults with CVD from the NHANES 1999-2014. Mortality status was linked to National Death Index mortality data through 31 December 2019. Overall, unhealthy and healthy LCD and LFD scores were determined based on the percentages of energy from total and subtypes of carbohydrate, fat, and protein. Cox proportional hazards regression models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Higher healthy LCD score was associated with favorable blood lipids and higher homeostasis model assessment of insulin resistance, whereas higher unhealthy LFD score was associated with lower high-density lipoprotein and higher C-reactive protein at baseline (all P-trend < 0.05). During 35,150 person-years of follow-up, 2163 deaths occurred. For per 20-percentile increment in dietary scores, the multivariate-adjusted HRs of all-cause mortality were 0.91 (95% CI: 0.86, 0.96) for healthy LCD score (P < 0.001), 0.94 (95% CI: 0.89, 1.00) for healthy LFD score (P = 0.04), and 1.07 (95% CI: 1.00, 1.14) for unhealthy LFD score (P = 0.04). CONCLUSIONS: Overall LCD and LFD scores are not associated with total mortality. Unhealthy LFD scores are associated with higher total mortality, whereas healthy LCD and LFD scores are associated with lower mortality in people with CVD.

Improved efficacy of FKRP AAV gene therapy by combination with ribitol treatment for LGMD2I.

Mutations in the fukutin-related protein (FKRP) gene cause dystroglycanopathy, with disease severity ranging from mild LGMD2I to severe congenital muscular dystrophy. Recently, considerable progress has been made in developing experimental therapies, with adeno-associated virus (AAV) gene therapy and ribitol treatment demonstrating significant therapeutic effect. However, each treatment has its strengths and weaknesses. AAV gene therapy can achieve normal levels of transgene expression, but it requires high doses, with toxicity concerns and variable distribution. Ribitol relies on residual FKRP function and restores limited levels of matriglycan. We hypothesized that these two treatments can work synergistically to offer an optimized therapy with efficacy and safety unmatched by each treatment alone. The most effective treatment is the combination of high-dose (5e-13 vg/kg) AAV-FKRP with ribitol, whereas low dose (1e-13 vg/kg) AAV-FKRP combined with ribitol showed a 22.6% increase in positive matriglycan fibers and the greater improvement in pathology when compared to low-dose AAV-FKRP alone. Together, our results support the potential benefits of combining ribitol with AAV gene therapy for treating FKRP-related muscular dystrophy. The fact that ribitol is a metabolite in nature and has already been tested in animal models and clinical trials in humans without severe side effects provides a safety profile for it to be trialed in combination with AAV gene therapy.

Circulating concentrations of bile acids and prevalent chronic kidney disease among newly diagnosed type 2 diabetes: a cross-sectional study.

BACKGROUND: The relationship between circulating bile acids (BAs) and kidney function among patients with type 2 diabetes is unclear. We aimed to investigate the associations of circulating concentrations of BAs, particularly individual BA subtypes, with chronic kidney disease (CKD) in patients of newly diagnosed type 2 diabetes. METHODS: In this cross-sectional study, we included 1234 newly diagnosed type 2 diabetes who participated in an ongoing prospective study, the Dongfeng-Tongji cohort. Circulating primary and secondary unconjugated BAs and their taurine- or glycine-conjugates were measured using ultraperformance liquid chromatography-tandem mass spectrometry. CKD was defined as eGFR < 60 ml/min per 1.73 m2. Logistic regression model was used to compute odds ratio (OR) and 95% confidence interval (CI). RESULTS: After adjusting for multiple testing, higher levels of total primary BAs (OR per standard deviation [SD] increment: 0.78; 95% CI: 0.65-0.92), cholate (OR per SD: 0.78; 95% CI: 0.66-0.92), chenodeoxycholate (OR per SD: 0.81; 95% CI: 0.69-0.96), glycocholate (OR per SD: 0.81; 95% CI: 0.68-0.96), and glycochenodeoxycholate (OR per SD: 0.82; 95% CI: 0.69-0.97) were associated with a lower likelihood of having CKD in patients with newly diagnosed type 2 diabetes. No significant relationships between secondary BAs and odds of CKD were observed. CONCLUSIONS: Our findings showed that higher concentrations of circulating unconjugated primary BAs and their glycine-conjugates, but not taurine-conjugates or secondary BAs, were associated with lower odds of having CKD in patients with type 2 diabetes.

Ultrasound-guided caudal anaesthesia combined with epidural anaesthesia for caesarean section: a randomized controlled clinical trial.

BACKGROUND: Although epidural anaesthesia and spinal anaesthesia are currently the general choices for patients undergoing caesarean section, these two neuraxial anaesthesia methods still have drawbacks. Caudal anaesthesia has been considered to be more appropriate for gynaecological surgery. The purpose of this study was to compare epidural anaesthesia combined with caudal anaesthesia, spinal anaesthesia and single-space epidural anaesthesia for caesarean section with respect to postoperative comfort and intraoperative anaesthesia quality. METHODS: In this clinical trial, 150 patients undergoing elective caesarean section were recruited and randomized into three groups according to a ratio of 1:1:1to receive epidural anaesthesia only, spinal anaesthesia only or epidural anaesthesia combined with caudal anaesthesia. The primary outcome was postoperative comfort in the three groups. Secondary outcomes included intraoperative anaesthesia quality and the incidences of nausea, vomiting, postdural puncture headache, maternal bradycardia, or hypotension. RESULTS: More patients were satisfied with the intraoperative anaesthesia quality in the EAC group than in the EA group (P = 0.001). The obstetrician was more significantly satisfied with the intraoperative anaesthesia quality in the SA and EAC groups than in the EA group (P = 0.004 and 0.020, respectively). The parturients felt more comfortable after surgery in the EA and EAC groups (P = 0.007). The incidence of maternal hypotension during caesarean section was higher in the SA group than in the EA and EAC groups (P = 0.001 and 0.019, respectively). CONCLUSIONS: Epidural anaesthesia combined with caudal anaesthesia may be a better choice for elective caesarean section. Compared with epidural anaesthesia and spinal anaesthesia, it has a higher quality of postoperative comfort and intraoperative anaesthesia.

Octamer-binding transcription factor 4-positive circulating tumor cell predicts worse treatment response and survival in advanced cholangiocarcinoma patients who receive immune checkpoint inhibitors treatment.

BACKGROUND: Octamer-binding transcription factor 4-positive circulating tumor cell (OCT4+CTC) exhibits high stemness and invasive potential, which may influence the efficacy of immune checkpoint inhibitors (ICI). This study aimed to assess the prognostic role of OCT4+CTC in advanced cholangiocarcinoma (CCA) patients who received ICI treatment. METHODS: In total, 40 advanced CCA patients who received ICI treatment were included, and CTC and OCT4 counts were detected via a Canpatrol system and an RNA in situ hybridization method before ICI treatment. Patients were subsequently divided into none CTC, OCT4-CTC, and OCT4+CTC groups. Patients were followed up for a median of 10.4 months. RESULTS: The percentages of patients in none CTC, OCT4-CTC, and OCT4+CTC groups were 25.0%, 30.0%, and 45.0%, respectively. The proportion of patients with lymph node metastasis was highest in OCT4+CTC group, followed by none CTC group, and lowest in OCT4-CTC group (P = 0.025). The objective response rate (ORR) was lowest in OCT4+CTC group, moderate in OCT4-CTC group, and highest in none CTC group (P = 0.009), while disease control rate was not different among three groups (P = 0.293). In addition, progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) were shorter in the OCT4+CTC group than in none CTC & OCT4-CTC group. Moreover, OCT4+CTC (versus none CTC) was independently linked with poorer PFS [hazard ratio (HR) = 6.752, P = 0.001] and OS (HR = 6.674, P = 0.003) in advanced CCA patients. CONCLUSION: OCT4+CTC relates to lymph node metastasis and shows a good predictive value for poor treatment response and survival in advanced CCA patients who receive ICI treatment.

Development and validation of an LC-MS/MS method for the determination of AZD7648 in rat plasma: Application to a pharmacokinetic study.

AZD7648 is a potent DNA-PK inhibitor that is being developed for the treatment of ovarian cancer. The study aimed to develop a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of AZD7648 in rat. AZD7648 was extracted from plasma by acetonitrile-mediated protein precipitation. The quantification was performed on a Thermo Vantage TSQ mass spectrometer with ibrutinib as an internal standard. A Waters Acquity UPLC BEH C18 column combined with 0.1% aqueous formic acid and acetonitrile was employed for chromatographic separation. The precursor-to-product ion transitions were m/z 421.2 > 337.2 and m/z 441.2 > 138.1 for AZD7648 and internal standard, respectively. This method was successfully validated according to the US Food and Drug Administration guidance. The calibration curve was linear over the concentration range of 0.5-1,000 ng/ml with correlation coefficient >0.999. The precision expressed as the coefficient of variation was <8.09%, while the accuracy expressed as relative error ranged from -10.00 to 9.08%. The mean recovery was >94.49%. AZD7648 was stable in rat plasma after storage under certain conditions. The validated method was demonstrated to be selective, sensitive and reliable, and has been successfully applied to the pharmacokinetic study of AZD7648 in rat plasma after oral and intravenous administration (1 mg/kg).