Developmental characteristics of aggregated lymphoid nodules area in the abomasum of fetal Bactrian camels (Camelus bactrianus).

BACKGROUND: Bactrian camel is one of the important economic animals in northwest China. They live in arid desert, and their gestation period is about 13 months, which is longer than other ruminants (such as cattle and sheep). The harsh living conditions have made its unique histological characteristics a research focus. Aggregated lymphoid nodules area (ALNA) in the abomasum of Bactrian camels, as one of the most important sites for the induction of the immune response, provide a comprehensive and effective protective role for the organism, and their lack of information will affect the feeding management, reproduction and epidemic prevention of Bactrian camels. In this study, the histological characteristics of the fetal ALNA in the abomasum of Bactrian camels at different developmental gestation have been described by using light microscopy and histology . RESULTS: The ALNA in the abomasum of the Chinese Alashan Bactrian camel is a special immune structure that was first discovered and reported by Wen-hui Wang. To further establish the developmental characteristics of this special structure in the embryonic stage, the abomasum ALNA of 8 fetuses of Alashan Bactrian camels with different gestational ages (5~13 months) were observed and studied by anatomy and histology. The results showed that the aggregation of reticular epithelial cells (RECs) surrounded by a very small number of lymphoid cells was detected for the first time in the abomasum of fetal camel at 5 months gestation, which was presumed to be primitive ALNA. At 7 months gestation, the reticular mucosal folds region (RMFR) appeared, but the longitudinal mucosal folds region (LMFR) was not significant, and histological observations showed that there were diffusely distributed lymphocytes around the RECs. At 10months gestation, RMFR and LMFR were clearly visible, lymphoid follicles appeared in histological observation, lymphocytes proliferated vigorously. By 13 months, the volume of lymphoid follicles increased, forming the subepithelial dome (SED), and there was a primitive interfollicular area between the lymphoid follicles, which contained high endothelial vein (HEV), but no germinal center (GC) was found. In summary, ALNA of Bactrian camels is not fully mature before birth. CONCLUSIONS: Generally, the small intestine PPs of ruminants (such as cattle and sheep) is already mature before birth, while the ALNA in the abomasum of Bactrian camels is not yet mature in the fetal period. During the development of ALNA in Bactrian camel, the development of lymphoid follicles extends from submucosa to Lamina propria. Interestingly, the deformation of FAE changes with age from simple columnar epithelium at the beginning of pregnancy to Simple cuboidal epithelium, which is opposite to the FAE deformation characteristics of PPs in the small intestine of fetal cattle and sheep. These results are the basis of further research on the specificity of ALNA in the abomasum of Bactrian camels.

Amplifying dual-visible-light photoswitching in aqueous media via confinement promoted triplet-triplet energy transfer.

Achieving visible-light photochromism is a long-term goal of chemists keen to exploit the opportunities of molecular photoswitches in multi-disciplinary research studies. Triplet-sensitization offers a flexible approach to building diverse visible-light photoswitches using existing photochromic scaffolds, circumventing the need for sophisticated molecular design and synthesis. Unfortunately, distance-dependence and environment-sensitivity of triplet-excited species remain as key challenges that severely impair sensitization efficiency and limit their practical availability. We present herein a nature-inspired nanoconfinement strategy in which a triplet-sensitized visible-light photoswitch/sensitizer system is assembled into nanoconfined micelles (d ∼ 40 nm). A ca. 10-fold efficiency increase of triplet-triplet energy transfer for photochromism as well as an amplified fluorescence on/off contrast upon bi-directional visible-light excitation (470/560 nm) was achieved in full aqueous media. By virtue of this, the hybrid photoswitchable system is successfully applied for both flash information encryption and multiple dynamic cell imaging assays, further proving its versatility in materials and life science.

Effects of Argatroban on Hcy, hs-CRP and FIB levels in patients with acute cerebral infarction.

Objective To evaluate the effects of argatroban on the levels of Hcy, hs-CRP and FIB in patients with acute cerebral infarction (ACI). Methods A retrospective analysis was performed on 382 patients with ACI who were hospitalized in the Department of Neurology of our hospital from January 2017 to December 2019. Among them, 158 patients received conventional treatment as the control group and 224 patients received combined treatment with argatroban as the study group. NHISS score, mRS score, Hcy, hs-CRP, FIB level, quality of life, adverse reactions were compared between the two groups after treatment. The levels of Hcy and hs-CRP in patients with different mRS scores were compared. Results A superior clinical efficacy of the study group was observed than the control group (P < 0.05). The study group witnessed a remarkably lower NHISS score, Hcy, hs-CRP and FIB level as compare to the control group (P < 0.05). The ADL and FMA scores in the study group were higher than those in the control group (P < 0.05). The levels of Hcy and hs-CRP in mRS 0-2 patients were lower than those in mRS 3-6 patients (P < 0.05). Conclusion Argatroban in ACI patients can significantly enhance the clinical efficacy and improve the quality of life. It is closely related to the reduction of Hcy and hs-CRP levels, but the mechanism needs to be further studied.

Efficient Electrochemical Microsensor for the Simultaneous Measurement of Hydrogen Peroxide and Ascorbic Acid in Living Brains.

Hydrogen peroxide (H2O2) and ascorbic acid (AA), acting as two significant indicative species, correlate with the oxidative stress status in living brains, which have historically been considered to be involved mainly in neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and Parkinson's disease (PD). The development of efficient biosensors for the simultaneous measurement of their levels in living brains is vital to understand their roles played in the brain and their interactive relationship in the progress of these diseases. Herein, a robust ratiometric electrochemical microsensor was rationally designed to realize the determination of H2O2 and AA simultaneously. Therefore, a specific probe was designed and synthesized with both recognition units responsible for reacting with H2O2 to produce a detectable signal on the microsensor and linkage units helping the probe modify onto the carbon substrate. A topping ingredient, single-walled carbon nanotubes (SWCNTs) was added on the surface of the electrode, with the purpose of not only facilitating the oxidation of AA but also absorbing methylene blue (MB), prompting to read out the inner reference signal. This proposed electrochemical microsensor exhibited a robust ability to real-time track H2O2 and AA in linear ranges of 0.5-900 and 10-1000 µM with high selectivity and accuracy, respectively. Eventually, the efficient electrochemical microsensor was successfully applied to the simultaneous measurement of H2O2 and AA in the rat brain, followed by microinjection, and in the PD mouse brain.

Corrigendum: Optimizing window size and directional parameters of GLCM texture features for estimating rice AGB based on UAVs multispectral imagery.

[This corrects the article DOI: 10.3389/fpls.2023.1284235.].

Microfluidic Impedance Cytometry Enabled One-Step Sample Preparation for Efficient Single-Cell Mass Spectrometry.

Single-cell mass spectrometry (MS) is significant in biochemical analysis and holds great potential in biomedical applications. Efficient sample preparation like sorting (i.e., separating target cells from the mixed population) and desalting (i.e., moving the cells off non-volatile salt solution) is urgently required in single-cell MS. However, traditional sample preparation methods suffer from complicated operation with various apparatus, or insufficient performance. Herein, a one-step sample preparation strategy by leveraging label-free impedance flow cytometry (IFC) based microfluidics is proposed. Specifically, the IFC framework to characterize and sort single-cells is adopted. Simultaneously with sorting, the target cell is transferred from the local high-salinity buffer to the MS-compatible solution. In this way, one-step sorting and desalting are achieved and the collected cells can be directly fed for MS analysis. A high sorting efficiency (>99%), cancer cell purity (≈87%), and desalting efficiency (>99%), and the whole workflow of impedance-based separation and MS analysis of normal cells (MCF-10A) and cancer cells (MDA-MB-468) are verified. As a standalone sample preparation module, the microfluidic chip is compatible with a variety of MS analysis methods, and envisioned to provide a new paradigm in efficient MS sample preparation, and further in multi-modal (i.e., electrical and metabolic) characterization of single-cells.

Research progress of mechanism of acupuncture for migraine. / é’ˆåˆºæ²»ç–—åå¤´ç—›çš„æœºåˆ¶ç ”ç©¶è¿›å±•.

The literature regarding the action mechanism of acupuncture for migraine published from 2013 to 2023 was searched in China National Knowledge Infrastructure (CNKI), Wanfang, VIP, Chinese Science and Technology Periodical Database, PubMed, Medline, and Cochrane Library. The pathogenesis of migraine and potential mechanisms of acupuncture treatment were summarized from the aspects of trigeminovascular system (TGVS), metabolic-related mechanisms, genetic factors, and alterations in brain structure and function. The results revealed that current research on the mechanisms of acupuncture for migraine predominantly centered around the TGVS, with studies confirming the specific regulatory effects of acupuncture on trigeminal system-related components, such as cortical spreading depression (CSD), astrocytes, and neurogenic kinin. While metabolic-related mechanisms and genetic factors are gaining attention, further in-depth exploration is needed to fully understand their roles in the mechanism of acupuncture for migraine. The study of brain structure and function in migraine has advanced, albeit with some controversies. Future research should prioritize larger sample sizes and standardized study designs to delve deeper into the mechanisms of acupuncture in treating migraine.

TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

Mesh-less laparoscopic extraperitoneal linear suspension treatment of vaginal vault prolapse.

OBJECTIVES: To report the results of a mesh-less laparoscopic extraperitoneal linear suspension technique for the treatment of post-hysterectomy vaginal vault prolapse (PHVP). STUDY DESIGN: A retrospective observational study was conducted collecting medical records of 41 patients with symptomatic PHVP treated between November 2017 to November 2019 in Gynecologic department of China-Japan Friendship Hospital. All patients had Pelvic Organ Prolapse Quantification (POP-Q) scores indicating stage 3-4 PHVP and underwent mesh-less laparoscopic extraperitoneal linear suspension.The primary outcome was the subjective satisfaction rate based on responses to validated questionnaires. The secondary outcomes were the objective anatomical cure rate based on POP-Q scores and complication rates. All listed parameters were determined before the surgery and at control examinations in 1 year and 3 years after the treatment. RESULTS: The operation was completed successfully without serious complications in all patients. Mean operation time was 53.8 mins. Comparison of the scores by the questionnaires revealed a significant improvement in the quality of life in the postoperative period.The subjective satisfaction rates were 100 % (41/41) and 95 % (38/40) at 1 year and 3 years after surgery. The objective cure rates were 100 % (41/41) and 97.5 % (39/40) at 1 year and 3 years after surgery, respectively. During the follow-up, none of the patients experienced suture exposure, infection, chronic pelvic pain, or other related complications. CONCLUSION: The mesh-less laparoscopic extraperitoneal linear suspension technique avoids the use of implantable synthetic mesh. It has been shown to lead to favorable postoperative outcomes, considerable patient contentment, and low complication rates. It offers a new, cost-effective treatment option for PHVP patients.

Insecticidal Effects of Transgenic Maize Bt-Cry1Ab, Bt-Vip3Aa, and Bt-Cry1Ab+Vip3Aa against the Oriental Armyworm, Mythimna separata (Walker) in Southwest China.

The oriental armyworm, Mythimna separata (Walker), an important migratory pest of maize and wheat, is posing a severe threat to maize production in Asian countries. As source areas of spring-summer emigratory populations, the control of M. separata in southwestern China is of great significance for East Asian maize production. To assess the toxicity of Bt maize against the pest, bioassays of Bt-(Cry1Ab+Vip3Aa) maize (event DBN3601T), Bt-Cry1Ab maize (event DBN9936), and Bt-Vip3Aa maize (event DBN9501) were conducted in Yunnan province of southwest China. There were significant differences in insecticidal activity between the three Bt maize events, and DBN3601T presented the highest insecticidal role. The results also indicated that the insecticidal effect of various Bt maize tissues took an order in leaf > kernel > silk, which is highly consistent with the expression amounts of Bt insecticidal protein in leaf (69.69 ± 1.18 µg/g), kernel (11.69 ± 0.75 µg/g), and silk (7.32 ± 0.31 µg/g). In field trials, all larval population densities, plant damage rates, and leaf damage levels of DBN3601T maize were significantly lower than the conventional maize. This research indicated that the DBN3601T event had a high control efficiency against M. separata and could be deployed in southwest China for the management of M. separata.

Bubble Turbulent Gas-Permeable Membrane for Ammonia Recovery from Swine Wastewater: Mass Transfer Enhancement and Antifouling Mechanisms.

Recovering ammonium from swine wastewater employing a gas-permeable membrane (GM) has potential but suffers from the limitations of unattractive mass transfer and poor-tolerance antifouling properties. Turbulence is an effective approach to enhancing the release of volatile ammonia from wastewater while relying on interfacial disturbance to interfere with contaminant adhesion. Herein, we design an innovative gas-permeable membrane coupled with bubble turbulence (BT-GM) that enhances mass transfer while mitigating membrane fouling. Bubbles act as turbulence carriers to accelerate the release and migration of ammonia from the liquid phase, increasing the ammonia concentration gradient at the membrane-liquid interface. In comparison, the ammonium mass transfer rate of the BT-GM process applied to real swine wastewater is 38% higher than that of conventional GM (12 h). Through a computational fluid dynamics simulation, the turbulence kinetic energy of BT-GM system is 3 orders of magnitude higher than that of GM, and the effective mass transfer area is nearly 3 times that of GM. Seven batches of tests confirmed that the BT-GM system exhibits remarkable antifouling ability, broadens its adaptability to complex water quality, and practically promotes the development of sustainable resource recycling.

PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion.

Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity. CCDs from mice fed a high-K+ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca2+]i than CCDs from mice fed a control K+ diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC-Piezo1-KO) exhibited a blunted [Ca2+]i response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC-Piezo1-KO mice selectively exhibited an increased blood [K+] in response to an oral K+ bolus and blunted urinary K+ excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC-Piezo1-KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca2+ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.

Moniezia benedeni infection increases IgE+ cells in sheep (Ovis aries) small intestine.

The concentration of immunoglobulin (Ig) E is the lowest among serum Igs, but it can induces type I hypersensitivity and plays an important role in anti-parasitic infection. The present study aimed to explore the residence characteristics of IgE+ cells in the sheep small intestine and the impact of Moniezia benedeni infection on them. The recombinant plasmids pET-28a-IgE were constructed and induced and expressed in Escherichia coli. BL21 (DE3). The rabbit anti-sheep IgE polyclonal antibody was prepared using the obtained recombinant protein as antigen. Finally, the levels of IgE+ cells in the small intestine of healthy (Control group) and naturally M. benedeni-infected (Infected group) sheep were detected analyzed. The results showed that the rabbit anti-sheep IgE polyclonal antibody with good immunogenicity (titer = 1: 128000) could specifically bind to the heavy chain of natural sheep IgE. In the Control group, the IgE+ cells were mainly distributed in lamina propria of the small intestine, and the densities were significantly decreased from duodenum to ileum (P<0.05), with respective values of (4.28 cells / 104 µm2, 1.80 cells / 104 µm2, and 1.44 cells / 104 µm2 in duodenum, jejunum, and ileum. In the Infected group, IgE+ cells density were 6.26 cells / 104 µm2, 3.01 cells / 104 µm2, and 2.09 cells / 104 µm2 in duodenum, jejunum and ileum respectively, which were significantly higher in all segments compared to the Control group (P<0.05), increasing by 46.26%, 67.22% and 45.14%, respectively. In addition, compared with the Control group, the IgE protein levels were significantly increased in all intestinal segments of the Infected group (P<0.01), however, there was no significant differences among the different intestinal segments within the same group (P>0.05). The results demonstrated that M. benedeni infection could significantly increase the content of IgE and the distribution density of its secreting cells in sheep small intestine. The intestinal mucosal immune system of sheep presented obvious specificity against M. benedeni infection. This lays a good foundation for further exploring molecular mechanisms of the intestinal mucosal immune system monitoring and responding to M. benedeni infection.

ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Current trends and emerging patterns in the application of nanomaterials for ovarian cancer research: a bibliometric analysis.

Introduction: Ovarian cancer remains to be a significant cause of global cancer-related mortality. In recent years, there has been a surge of studies in investigating the application of nanomaterials in the diagnosis and treatment of ovarian cancer. This study aims to conduct a comprehensive bibliometric analysis regarding nanomaterial-based researches on ovarian cancer to evaluate the current state and emerging patterns in this field. Methods: A thorough literature search on the Web of Science Core Collection database was conducted to identify articles focused on nanomaterial-based ovarian cancer researches. The studies that met the inclusion criteria were selected for further analysis. VOSviewer and CiteSpace were applied for the bibliometric and visual analyses of the selected publications. Results: A total of 2,426 studies were included in this study. The number of annual publications showed a consistent upward trend from 2003 to 2023. Notably, China, the United States, and India have emerged as the leading contributors in this field, accounting for 37.39%, 34.04%, and 5.69% of the publications, respectively. The Chinese Academy of Sciences and Anil K. Sood were identified as the most influential institution and author, respectively. Furthermore, the International Journal of Nanomedicine was the most frequently cited journal. In terms of the research focus, significant attention has been directed towards nanomaterial-related drug delivery, while the exploration of immunogenic cell death and metal-organic frameworks represented recent areas of interest. Conclusion: Through comprehensive analyses, an overview of current research trends and emerging areas of interest regarding the application of nanomaterials in ovarian cancer was illustrated. These findings offered valuable insights into the status and future directions of this dynamic field.

Compounds from Agathis dammara exert hypoglycaemic activity by enhancing glucose uptake: lignans, terpenes and others.

In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1-12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathis dammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.

The adaptor protein ECAP, the co-repressor LEUNIG, and the transcription factor BEH3 interact and regulate microsporocyte generation in Arabidopsis.

Histo-specification and morphogenesis of anthers during development in Arabidopsis (Arabidopsis thaliana) are well understood. However, the regulatory mechanism of microsporocyte generation at the pre-meiotic stage remains unclear, especially how archesporial cells are specified and differentiate into two cell lineages with distinct developmental fates. SPOROCYTELESS (SPL) is a key reproductive gene that is activated during early anther development and remains active. In this study, we demonstrated that the EAR motif-containing adaptor protein (ECAP) interacts with the Gro/Tup1 family co-repressor LEUNIG (LUG) and the BES1/BZR1 HOMOLOG3 (BEH3) transcription factor to form a transcription activator complex, epigenetically regulating SPL transcription. SPL participates in microsporocyte generation by modulating the specification of archesporial cells and the archesporial cell-derived differentiation of somatic and reproductive cell layers. This study illustrates the regulation of SPL expression by the ECAP-LUG-BEH3 complex, which is essential for the generation of microsporocytes. Moreover, our findings identified ECAP as a key transcription regulator that can combine with different partners to regulate gene expression in distinct ways, thereby facilitating diverse processes in various aspects of plant development.

Alkali-Ion Intercalation Chemistry and Phase Evolution of Sn4P3.

Despite its high theoretical capacities, Sn4P3 anodes in alkali-ion batteries (AIBs) have been plagued by electrode damage and capacity decay during cycling, mainly rooted in the huge volume changes and irreversible phase segregation. However, few reports endeavor to ascertain whether these causes bear relevance to phase evolution upon cycling. Moreover, the phase evolution mechanism for alkali-ion intercalation remains imprecise. Herein, the structural transformations and detailed mechanisms upon various alkali-ion intercalation processes are systematically revealed, utilizing both experimental techniques and theoretical simulations. The results reveal that the energy storage of Sn4P3 occurs in a two-stage process, starting from an insertion process, followed by a transition process. As the cycle proceeds, the final delithiated/desodiated/depotassiated components gradually trap alkali ions (Li+, Na+, and K+), which is attributed to the incomplete electrochemical transition and difficulty in Sn4P3 regeneration due to the kinetic limitations in removing M (M = Li, Na, and K). Furthermore, Sn4P3 anode obeys the "shrinking core mechanism" in potassium-ion batteries (KIBs), wherein a minor fraction of Sn4P3 in the outer layer of the particles is initially involved in the potassiation/depotassiation processes, followed by a gradual participation of the inner parts until the entire particle is involved. It is worth mentioning that K-Sn alloys are not found to exist during the transition process of KIBs; instead, K-Sn-P phases are found, which makes it differ from that in lithium-ion batteries (LIBs) and sodium-ion batteries (NIBs). These findings are expected to deepen the understanding of the reaction mechanism of Sn4P3 and enlighten the material designs for improved performance.

Metabolism pathway-based subtyping in endometrial cancer: An integrated study by multi-omics analysis and machine learning algorithms.

Endometrial cancer (EC), the second most common malignancy in the female reproductive system, has garnered increasing attention for its genomic heterogeneity, but understanding of its metabolic characteristics is still poor. We explored metabolic dysfunctions in EC through a comprehensive multi-omics analysis (RNA-seq datasets from The Cancer Genome Atlas [TCGA], Cancer Cell Line Encyclopedia [CCLE], and GEO datasets; the Clinical Proteomic Tumor Analysis Consortium [CPTAC] proteomics; CCLE metabolomics) to develop useful molecular targets for precision therapy. Unsupervised consensus clustering was performed to categorize EC patients into three metabolism-pathway-based subgroups (MPSs). These MPS subgroups had distinct clinical prognoses, transcriptomic and genomic alterations, immune microenvironment landscape, and unique patterns of chemotherapy sensitivity. Moreover, the MPS2 subgroup had a better response to immunotherapy. Finally, three machine learning algorithms (LASSO, random forest, and stepwise multivariate Cox regression) were used for developing a prognostic metagene signature based on metabolic molecules. Thus, a 13-hub gene-based classifier was constructed to predict patients' MPS subtypes, offering a more accessible and practical approach. This metabolism-based classification system can enhance prognostic predictions and guide clinical strategies for immunotherapy and metabolism-targeted therapy in EC.

A physiologically-based pharmacokinetic/pharmacodynamic modeling approach for drug-drug-gene interaction evaluation of S-warfarin with fluconazole.

Warfarin is a widely used anticoagulant, and its S-enantiomer has higher potency compared to the R-enantiomer. S-warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug-drug interactions (DDIs). This study provides a whole-body physiologically-based pharmacokinetic/PD (PBPK/PD) model of S-warfarin for predicting the effects of drug-drug-gene interactions on S-warfarin PKs and PDs. The PBPK/PD model of S-warfarin was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Of the 34 S-warfarin plasma concentration-time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S-warfarin plasma concentration-time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration-time curve to the last measurable timepoint (AUClast ) ratio within twofold of the observed values. The anticoagulant effect of S-warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose-adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.