Generation and Application of Mouse-Rat Allodiploid Embryonic Stem Cells.

Mammalian interspecific hybrids provide unique advantages for mechanistic studies of speciation, gene expression regulation, and X chromosome inactivation (XCI) but are constrained by their limited natural resources. Previous artificially generated mammalian interspecific hybrid cells are usually tetraploids with unstable genomes and limited developmental abilities. Here, we report the generation of mouse-rat allodiploid embryonic stem cells (AdESCs) by fusing haploid ESCs of the two species. The AdESCs have a stable allodiploid genome and are capable of differentiating into all three germ layers and early-stage germ cells. Both the mouse and rat alleles have comparable contributions to the expression of most genes. We have proven AdESCs as a powerful tool to study the mechanisms regulating X chromosome inactivation and to identify X inactivation-escaping genes, as well as to efficiently identify genes regulating phenotypic differences between species. A similar method could be used to create hybrid AdESCs of other distantly related species.

Cold granular targets slow the bulk freezing of an impacting droplet.

When making contact with an undercooled target, a drop freezes. The colder the target is, the more rapid the freezing is supposed to be. In this research, we explore the impact of droplets on cold granular material. As the undercooling degree increases, the bulk freezing of the droplet is delayed by at least an order of magnitude. The postponement of the overall solidification is accompanied by substantial changes in dynamics, including the spreading-retraction process, satellite drop generation, and cratering in the target. The solidification of the wetted pores in the granular target primarily causes these effects. The freezing process over the pore dimension occurs rapidly enough to match the characteristic timescales of impact dynamics at moderate undercooling degrees. As a result, the hydrophilic impact appears "hydrophobic," and the dimension of the solidified droplet shrinks. A monolayer of cold grains on a surface can reproduce these consequences. Our research presents a potential approach to regulate solidified morphology for subfreezing drop impacts. It additionally sheds light on the impact scenario of strong coupling between the dynamics and solidification.

Themis: advancing precision oncology through comprehensive molecular subtyping and optimization.

Recent advances in tumor molecular subtyping have revolutionized precision oncology, offering novel avenues for patient-specific treatment strategies. However, a comprehensive and independent comparison of these subtyping methodologies remains unexplored. This study introduces 'Themis' (Tumor HEterogeneity analysis on Molecular subtypIng System), an evaluation platform that encapsulates a few representative tumor molecular subtyping methods, including Stemness, Anoikis, Metabolism, and pathway-based classifications, utilizing 38 test datasets curated from The Cancer Genome Atlas (TCGA) and significant studies. Our self-designed quantitative analysis uncovers the relative strengths, limitations, and applicability of each method in different clinical contexts. Crucially, Themis serves as a vital tool in identifying the most appropriate subtyping methods for specific clinical scenarios. It also guides fine-tuning existing subtyping methods to achieve more accurate phenotype-associated results. To demonstrate the practical utility, we apply Themis to a breast cancer dataset, showcasing its efficacy in selecting the most suitable subtyping methods for personalized medicine in various clinical scenarios. This study bridges a crucial gap in cancer research and lays a foundation for future advancements in individualized cancer therapy and patient management.

scSTAR reveals hidden heterogeneity with a real-virtual cell pair structure across conditions in single-cell RNA sequencing data.

Cell-state transition can reveal additional information from single-cell ribonucleic acid (RNA)-sequencing data in time-resolved biological phenomena. However, most of the current methods are based on the time derivative of the gene expression state, which restricts them to the short-term evolution of cell states. Here, we present single-cell State Transition Across-samples of RNA-seq data (scSTAR), which overcomes this limitation by constructing a paired-cell projection between biological conditions with an arbitrary time span by maximizing the covariance between two feature spaces using partial least square and minimum squared error methods. In mouse ageing data, the response to stress in CD4+ memory T cell subtypes was found to be associated with ageing. A novel Treg subtype characterized by mTORC activation was identified to be associated with antitumour immune suppression, which was confirmed by immunofluorescence microscopy and survival analysis in 11 cancers from The Cancer Genome Atlas Program. On melanoma data, scSTAR improved immunotherapy-response prediction accuracy from 0.8 to 0.96.

Exploration of poly (ADP-ribose) polymerase inhibitor resistance in the treatment of BRCA1/2-mutated cancer.

Breast cancer susceptibility 1/2 (BRCA1/2) genes play a crucial role in DNA damage repair, yet mutations in these genes increase the susceptibility to tumorigenesis. Exploiting the synthetic lethality mechanism between BRCA1/2 mutations and poly(ADP-ribose) polymerase (PARP) inhibition has led to the development and clinical approval of PARP inhibitor (PARPi), representing a milestone in targeted therapy for BRCA1/2 mutant tumors. This approach has paved the way for leveraging synthetic lethality in tumor treatment strategies. Despite the initial success of PARPis, resistance to these agents diminishes their efficacy in BRCA1/2-mutant tumors. Investigations into PARPi resistance have identified replication fork stability and homologous recombination repair as key factors sensitive to PARPis. Additionally, studies suggest that replication gaps may also confer sensitivity to PARPis. Moreover, emerging evidence indicates a correlation between PARPi resistance and cisplatin resistance, suggesting a potential overlap in the mechanisms underlying resistance to both agents. Given these findings, it is imperative to explore the interplay between replication gaps and PARPi resistance, particularly in the context of platinum resistance. Understanding the impact of replication gaps on PARPi resistance may offer insights into novel therapeutic strategies to overcome resistance mechanisms and enhance the efficacy of targeted therapies in BRCA1/2-mutant tumors.

In Situ Detection of Interfacial Ions at the Single-Bond Level.

Detecting the ionic state at the solid-liquid interface is essential to reveal the various chemical and physical processes that occur at the interface. In this study, the adsorption states of the highly electronegative ions F- and OH- at the solid-liquid interface are detected by using the scanning tunneling microscopy break junction technique. With the active hydrogen atom of the amino group as a probe, the formed ionic hydrogen bonds are successfully detected, thereby enabling in situ monitoring of the ionic state at the solid-liquid interface. Through noise power spectral density analysis and theoretical simulations, we reveal the mechanism by which ionic hydrogen bonds at the interface affect the charge transport properties. In addition, we discover that the ionic state at the solid-liquid interface can be effectively manipulated by electric fields. Under high electric fields, the concentration of the anion near the electrode is higher, and the proportion of hydrogen bonds formed is greater than that under low electric fields. This study of the interfacial ionic state at the single-bond level provides guidance for the design of high-performance materials for energy conversion and environmental purification.

Tracking Noncovalent Interactions of π, π-Hole, and Ion in Molecular Complexes at the Single-Molecule Level.

Noncovalent interactions involving aromatic rings, such as π-stacking and π-ion interactions, play an essential role in molecular recognition, assembly, catalysis, and electronics. However, the inherently weak and complex nature of these interactions has made it challenging to study them experimentally, especially with regard to elucidating their properties in solution. Herein, the noncovalent interactions between π and π-hole, π and cation, and π-hole and anion in molecular complexes in nonpolar solution are investigated in situ through single-molecule electrical measurements in combination with theoretical calculations. Specifically, phenyl and pentafluorobenzyl groups serve as π and π-hole sites, respectively, while Li+ and Cl- are employed as the cation and anion. Our findings reveal that, in comparison with homogeneous π···π interactions, heterogeneous π···π-hole and π···cation interactions exhibit greater binding energies, resulting in a longer binding lifetime of the molecular junctions. Meanwhile, π···Li+ and π-hole···Cl- interactions present significantly distinct binding characteristics, with the former being stronger but more flexible than the latter. Furthermore, by changing the molecular components, similar conductivity can be achieved in both molecular dimers or sandwich complexes. These results provide new insights into π- and π-hole-involved noncovalent interactions, offering novel strategies for precise manipulation of molecular assembly, recognition, and molecular device.

Electrolyte Chemistry toward Ultrawide-Temperature (-25 to 75 °C) Sodium-Ion Batteries Achieved by Phosphorus/Silicon-Synergistic Interphase Manipulation.

All-weather operation is considered an ultimate pursuit of the practical development of sodium-ion batteries (SIBs), however, blocked by a lack of suitable electrolytes at present. Herein, by introducing synergistic manipulation mechanisms driven by phosphorus/silicon involvement, the compact electrode/electrolyte interphases are endowed with improved interfacial Na-ion transport kinetics and desirable structural/thermal stability. Therefore, the modified carbonate-based electrolyte successfully enables all-weather adaptability for long-term operation over a wide temperature range. As a verification, the half-cells using the designed electrolyte operate stably over a temperature range of -25 to 75 °C, accompanied by a capacity retention rate exceeding 70% even after 1700 cycles at 60 °C. More importantly, the full cells assembled with Na3V2(PO4)2O2F cathode and hard carbon anode also have excellent cycling stability, exceeding 500 and 1000 cycles at -25 to 50 °C and superb temperature adaptability during all-weather dynamic testing with continuous temperature change. In short, this work proposes an advanced interfacial regulation strategy targeted at the all-climate SIB operation, which is of good practicability and reference significance.

Hybrid Binder Chemistry with Hydrogen-Bond Helix for High-Voltage Cathode of Sodium-Ion Batteries.

Since sodium-ion batteries (SIBs) have become increasingly commercialized in recent years, Na3V2(PO4)2O2F (NVPOF) offers promising economic potential as a cathode for SIBs because of its high operating voltage and energy density. According to reports, NVPOF performs poorly in normal commercial poly(vinylidene fluoride) (PVDF) binder systems and performs best in combination with aqueous binder. Although in line with the concept of green and sustainable development for future electrode preparation, aqueous binders are challenging to achieve high active material loadings at the electrode level, and their relatively high surface tension tends to cause the active material on the electrode sheet to crack or even peel off from the collector. Herein, a cross-linkable and easily commercial hybrid binder constructed by intermolecular hydrogen bonding (named HPP) has been developed and utilized in an NVPOF system, which enables the generation of a stable cathode electrolyte interphase on the surface of active materials. According to theoretical simulations, the HPP binder enhances electronic/ionic conductivity, which greatly lowers the energy barrier for Na+ migration. Additionally, the strong hydrogen-bond interactions between the HPP binder and NVPOF effectively prevent electrolyte corrosion and transition-metal dissolution, lessen the lattice volume effect, and ensure structural stability during cycling. The HPP-based NVPOF offers considerably improved rate capability and cycling performance, benefiting from these benefits. This comprehensive binder can be extended to the development of next-generation energy storage technologies with superior performance.

Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Efficacy and safety of olverembatinib in adult BCR::ABL1-positive ALL with T315I mutation or relapsed/refractory disease.

Third-generation tyrosine kinase inhibitors (TKIs) have much potential for the treatment of BCR::ABL1-positive leukaemia, particularly that harbouring the ABL1 T315I mutation. Olverembatinib (HQP1351), a novel third-generation TKI, has favourable efficacy and safety profiles in chronic myeloid leukaemia. Here, we present the clinical findings from 31 BCR::ABL1-positive acute lymphoblastic leukaemia (ALL) patients who received olverembatinib. Among the 14 patients with overt relapsed/refractory (R/R) disease (including 10 with the T315I mutation), 71.4% achieved an overall response. Of the other 17 patients with minimal residual disease (MRD)-positive ALL (including 14 with the T315I mutation), 60.0% and 47.1% achieved MRD flow negativity and complete molecular remission, respectively. With a median follow-up time of 16.3 months, the median event-free survival and overall survival were 3.9 and 8.3 months respectively, in overt R/R patients, and 11.5 and 18.4 months in MRD-positive patients. Allogeneic haematopoietic stem cell transplantation further improved outcomes among responders. The safety profile was generally manageable. This study suggests that olverembatinib-based therapy is another promising option for BCR::ABL1-positive ALL in addition to ponatinib, especially for patients with MRD-positive disease and a single T315I mutation.

ZmPHR1 contributes to drought resistance by modulating phosphate homeostasis in maize.

As an essential macronutrient, phosphorus (P) is often a limiting nutrient because of its low availability and mobility in soils. Drought is a major environmental stress that reduces crop yield. How plants balance and combine P-starvation responses (PSRs) and drought resistance is unclear. In this study, we identified the transcription factor ZmPHR1 as a major regulator of PSRs that modulates phosphate (Pi) signaling and homeostasis. We found that maize zmphr1 mutants had reduced P concentration and were sensitive to Pi starvation, whereas ZmPHR1-OE lines displayed elevated Pi concentration and yields. In addition, 57% of PSR genes and nearly 70% of ZmPHR1-regulated PSR genes in leaves were transcriptionally responsive to drought. Under moderate and early drought conditions, the Pi concentration of maize decreased, and PSR genes were up-regulated before drought-responsive genes. The ZmPHR1-OE lines exhibited drought-resistant phenotypes and reduced stomatal apertures, whereas the opposite was true of the zmphr1 mutants. ZmPT7-OE lines and zmspx3 mutants, which had elevated Pi concentration, also exhibited drought resistance, but zmpt7 mutants were sensitive to drought. Our results suggest that ZmPHR1 plays a central role in integrating Pi and drought signals and that Pi homeostasis improves the ability of maize to combat drought.

scCODE: an R package for data-specific differentially expressed gene detection on single-cell RNA-sequencing data.

Differential expression (DE) gene detection in single-cell ribonucleic acid (RNA)-sequencing (scRNA-seq) data is a key step to understand the biological question investigated. Filtering genes is suggested to improve the performance of DE methods, but the influence of filtering genes has not been demonstrated. Furthermore, the optimal methods for different scRNA-seq datasets are divergent, and different datasets should benefit from data-specific DE gene detection strategies. However, existing tools did not take gene filtering into consideration. There is a lack of metrics for evaluating the optimal method on experimental datasets. Based on two new metrics, we propose single-cell Consensus Optimization of Differentially Expressed gene detection, an R package to automatically optimize DE gene detection for each experimental scRNA-seq dataset.

eccDB: a comprehensive repository for eccDNA-mediated chromatin contacts in multi-species.

SUMMARY: We developed the eccDB database to integrate available resources for extrachromosomal circular DNA (eccDNA) data. eccDB is a comprehensive repository for storing, browsing, searching, and analyzing eccDNAs from multispecies. The database provides regulatory and epigenetic information on eccDNAs, with a focus on analyzing intrachromosomal and interchromosomal interactions to predict their transcriptional regulatory functions. Moreover, eccDB identifies eccDNAs from unknown DNA sequences and analyzes the functional and evolutionary relationships of eccDNAs among different species. Overall, eccDB offers web-based analytical tools and a comprehensive resource for biologists and clinicians to decipher the molecular regulatory mechanisms of eccDNAs. AVAILABILITY AND IMPLEMENTATION: eccDB is freely available at http://www.xiejjlab.bio/eccDB.

ZmCRK1 negatively regulates maize's response to drought stress by phosphorylating plasma membrane H+-ATPase ZmMHA2.

Drought severely affects crop growth and yields. Stomatal regulation plays an important role in plant response to drought stress. Light-activated plasma membrane-localized proton ATPase (PM H+-ATPase) mainly promoted the stomatal opening. Abscisic acid (ABA) plays a dominant role in the stomatal closure during drought stress. It is not clear how PM H+-ATPase is involved in the regulation of ABA-induced stomatal closure. We found that a CALCIUM-DEPENDENT PROTEIN KINASE RELATED KINASE 1 (ZmCRK1), and its mutant zmcrk1 exhibited slow water loss in detached leaves, high-survival rate after drought stress, and sensitivity to stomatal closure induced by ABA. The ZmCRK1 overexpression lines are opposite. ZmCRK1 interacted with the maize PM H+-ATPase ZmMHA2. ZmCRK1 phosphorylated ZmMHA2 at the Ser-901 and inhibited its proton pump activity. ZmCRK1 overexpression lines and zmmha2 mutants had low H+-ATPase activity, resulting in impaired ABA-induced H+ efflux. Taken together, our study indicates that ZmCRK1 negatively regulates maize drought stress response by inhibiting the activity of ZmMHA2. Reducing the expression level of ZmCRK1 has the potential to reduce yield losses under water deficiency.

Metal Polyphenol Nanoparticle-Based Chemo/Ferroptosis Synergistic Therapy for the Treatment of Oral Squamous Cell Carcinoma.

Despite the use of surgical resection and chemotherapy in the clinical treatment of oral squamous cell carcinoma (OSCC), the 5-year survival rates of advanced patients are low. Therefore, more efficient strategies are urgently needed. Herein, a chemo/ferroptosis synergistic therapeutic system-DMEFe nanoparticles (NPs) is established for the treatment of OSCC. To create this system, the chemotherapeutic agent doxorubicin (DOX) was loaded into mesoporous silica nanoparticles and further coated with a pH-sensitive metal polyphenol (iron ion and epigallocatechin gallate). These nanoparticles displayed excellent pH-sensitive drug-control release properties, and the release ratio of DOX at pH 5.5 was twice as high than that at pH 7.4. Additionally, DMEF NPs were effectively taken up by the OSCC cell line SSC-25, which greatly impeded the proliferation of these cells. Notably, these nanoparticles increased the intracellular level of reactive oxygen species and effectively exhibited cytotoxity effects. The mechanistic results proved that DMEFe NPs regulated the expression of ferroptosis-related genes to induce ferroptosis of SSC-25 cells. Eventually, this chemo/ferroptosis therapeutic system exhibited remarkable antitumor effects and provided a novel strategy for the treatment of OSCC.

Is Kidney Function Associated with Age-Related Macular Degeneration?: Findings from the Asian Eye Epidemiology Consortium.

PURPOSE: Chronic kidney disease (CKD) may elevate susceptibility to age-related macular degeneration (AMD) because of shared risk factors, pathogenic mechanisms, and genetic polymorphisms. Given the inconclusive findings in prior studies, we investigated this association using extensive datasets in the Asian Eye Epidemiology Consortium. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty-one thousand two hundred fifty-three participants from 10 distinct population-based Asian studies. METHODS: Age-related macular degeneration was defined using the Wisconsin Age-Related Maculopathy Grading System, the International Age-Related Maculopathy Epidemiological Study Group Classification, or the Beckman Clinical Classification. Chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) of less than 60 ml/min per 1.73 m2. A pooled analysis using individual-level participant data was performed to examine the associations between CKD and eGFR with AMD (early and late), adjusting for age, sex, hypertension, diabetes, body mass index, smoking status, total cholesterol, and study groups. MAIN OUTCOME MEASURES: Odds ratio (OR) of early and late AMD. RESULTS: Among 51 253 participants (mean age, 54.1 ± 14.5 years), 5079 had CKD (9.9%). The prevalence of early AMD was 9.0%, and that of late AMD was 0.71%. After adjusting for confounders, individuals with CKD were associated with higher odds of late AMD (OR, 1.46; 95% confidence interval [CI], 1.11-1.93; P = 0.008). Similarly, poorer kidney function (per 10-unit eGFR decrease) was associated with late AMD (OR, 1.12; 95% CI, 1.05-1.19; P = 0.001). Nevertheless, CKD and eGFR were not associated significantly with early AMD (all P ≥ 0.149). CONCLUSIONS: Pooled analysis from 10 distinct Asian population-based studies revealed that CKD and compromised kidney function are associated significantly with late AMD. This finding further underscores the importance of ocular examinations in patients with CKD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Regulation of Human Hydrolases and Its Implications in Pharmacokinetics and Pharmacodynamics.

Hydrolases represent an essential class of enzymes indispensable for the metabolism of various clinically essential medications. Individuals exhibit marked differences in the expression and activation of hydrolases, resulting in significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by these enzymes. The regulation of hydrolase expression and activity involves both genetic polymorphisms and nongenetic factors. This review examines the current understanding of genetic and nongenetic regulators of six clinically significant hydrolases, including carboxylesterase (CES)-1 CES2, arylacetamide deacetylase (AADAC), paraoxonase (PON)-1 PON3, and cathepsin A (CTSA). We explore genetic variants linked to the expression and activity of the hydrolases and their effects on the PK and PD of their substrate drugs. Regarding nongenetic regulators, we focus on the inhibitors and inducers of these enzymes. Additionally, we examine the developmental expression patterns and gender differences in the hydrolases when pertinent information was available. Many genetic and nongenetic regulators were found to be associated with the expression and activity of the hydrolases and PK and PD. However, hydrolases remain generally understudied compared with other drug-metabolizing enzymes, such as cytochrome P450s. The clinical significance of genetic and nongenetic regulators has not yet been firmly established for the majority of hydrolases. Comprehending the mechanisms that underpin the regulation of these enzymes holds the potential to refine therapeutic regimens, thereby enhancing the efficacy and safety of drugs metabolized by the hydrolases. SIGNIFICANCE STATEMENT: Hydrolases play a crucial role in the metabolism of numerous clinically important medications. Genetic polymorphisms and nongenetic regulators can affect hydrolases' expression and activity, consequently influencing the exposure and clinical outcomes of hydrolase substrate drugs. A comprehensive understanding of hydrolase regulation can refine therapeutic regimens, ultimately enhancing the efficacy and safety of drugs metabolized by the enzymes.

Novel Independent Trans- and Cis-Genetic Variants Associated with CYP2D6 Expression and Activity in Human Livers.

Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%-25% of commonly used medications such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes of its substrate drugs. Although many functional CYP2D6 variants have been discovered and validated, a significant portion of the variability in the expression and activity of CYP2D6 remains unexplained. In this study, we performed a genome-wide association study (GWAS) to identify novel variants associated with CYP2D6 protein expression in individual human livers, followed by a conditional analysis to control for the effect of functional CYP2D6 star alleles. We also examined their impact on hepatic CYP2D6 activity. Genotyping on a genome-wide scale was achieved using the Illumina Multi-Ethnic Genotyping Array (MEGA). A data-independent acquisition (DIA)-based proteomics method was used to quantify CYP2D6 protein concentrations. CYP2D6 activity was determined by measuring the dextromethorphan O-demethylation in individual human liver s9 fractions. The GWAS identified 44 single nuclear polymorphisms (SNPs) that are significantly associated with CYP2D6 protein expressions with a P value threshold of 5.0 × 10-7 After the conditional analysis, five SNPs, including the cis-variants rs1807493 and rs1062753 and the trans-variants rs4073010, rs729559, and rs80274432, emerged as independent variants significantly correlated with hepatic CYP2D6 protein expressions. Notably, four of these SNPs, except for rs80274432, also exhibited a significant association with CYP2D6 activities in human livers, suggesting their potential as novel and independent cis- and trans-variants regulating CYP2D6. SIGNIFICANT STATEMENT: Using individual human livers, we identified four novel cis- and trans-pQTLs/aQTLs (protein quantitative trait loci/activity quantitative trait loci) of Cytochrome P450 2D6 (CYP2D6) that are independent from known functional CYP2D6 star alleles. This study connects the CYP2D6 gene expression and activity, enhancing our understanding of the genetic variants associated with CYP2D6 protein expression and activity, potentially advancing our insight into the interindividual variability in CYP2D6 substrate medication response.

Application Value of Iodine-131 Combined with Levothyroxine Sodium in Patients with Differentiated Thyroid Cancer after Surgery.

INTRODUCTION: This study aimed to evaluate the clinical value of iodine-131 combined with levothyroxine sodium in the treatment of patients with differentiated thyroid cancer (DTC) after surgery. METHODS: Prospective randomized controlled studies were conducted. A total of 374 DTC patients who underwent total or near-total thyroidectomy in the Department of Thyroid Surgery, Tianjin Union Medical Center and Tianjin Medical University General Hospital, from January 2019 to February 2022 were selected and divided into control group (187 cases) and observation group (187 cases) according to random number table method. The control group was treated with levothyroxine sodium after surgery, and the observation group was treated with iodine-131 on the basis of the control group. Gender, age, course of disease, tumor diameter, pathological type, TNM classification, treatment effect, thyroglobulin (Tg) levels before and after treatment, SF-36 health status questionnaires (SF-36), occurrence of adverse reactions after treatment, and recurrence rate of 1-year follow-up were compared and analyzed between the two groups. RESULTS: There was no significant difference in baseline data between the two groups. After treatment, the effective rate of the observation group increased by 11.23% compared to the control group, with a statistically significant difference (91.98% vs. 80.75%, p < 0.05). There was no significant difference in Tg level and scores of SF-36 evaluation including physical functioning, physical problems, vitality, pain, mental health, emotional problems, social functioning, and general health perception between the two groups before surgery (p > 0.05), Tg levels and scores of SF-36 evaluation in all dimensions were significantly improved in both groups after treatment (p < 0.05), and the levels of Tg and scores of SF-36 in all dimensions in observation group were significantly better than those in control group after treatment (p < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). The recurrence rate in the observation group was 5.89% lower than that in the control group 1 year after treatment, with a statistically significant difference (2.67% vs. 8.56%, p < 0.05). CONCLUSIONS: The combination of iodine-131 and levothyroxine sodium in the postoperative treatment of DTC can improve the therapeutic effect and reduce the postoperative recurrence rate without increasing adverse reactions, which is worthy of clinical reference and promotion.