Polymeric artificial heart valves derived from modified diol-based polycarbonate polyurethanes.

A series of polycarbonate silicone polyurethanes (SiPCUs) have been synthesized to develop elastomers with the mechanical properties, biostability, and biocompatibility required for artificial heart valve manufacturing. In these SiPCUs, the polar functional group 4,4'-dicyclohexylmethane diisocyanate (HMDI) was incorporated into the soft segment 1,6-poly (hexamethylene carbonate) diol (PCDL) to form the modified macromolecular diol, PCDL-HMDI-PCDL. The hard segment consisted of HMDI and the chain extenders 1,4-butanediol and 1,3-bis(4-hydroxybutyl)-1,1,3,3-tetramethyl disiloxane (BHTD). The synthesized PHC-PCUB improves the excessive microphase separation caused by the introduction of PDMS. This material possesses good physicochemical properties, long-term oxidative degradation stability, and comparatively low mechanical performance loss after degradation. Compared to the commercially available bioprosthetic heart valve (BHV) material Glut-PP, PHC-PCUB demonstrated enhanced biocompatibility, good thromboresistant properties, less calcification, and higher endothelial cell adhesion. Furthermore, valve prototypes fabricated with PHC-PCUB showed improved hemodynamic performance under various simulated conditions, highlighting the potential of PHC-PCUB as an advanced material for valve leaflets. STATEMENT OF SIGNIFICANCE: Artificial heart valves are crucial for treating valve diseases, and polyurethane-based valves present a promising alternative due to their durability, strong biocompatibility, and customizable properties. This study improves the biostability and post-degradation mechanical properties of siloxane polyurethanes by reducing the content of polydimethylsiloxane (PDMS) and adding modified diol (PCDL-HMDI-PCDL). By integrating hexamethylene diisocyanate (HMDI) and chain extenders, we developed polycarbonate siloxane polyurethanes (SiPCUs) that improve phase mixing, mechanical strength, and oxidative stability. These SiPCUs also exhibit good thromboresistance and calcification resistance, low cytotoxicity, and promote cell adhesion, positioning them as highly promising materials for heart valve leaflets, effectively addressing the limitations of current mechanical and bioprosthetic valves.

Suyin Detoxification Granule alleviates trimethylamine N-oxide-induced tubular ferroptosis and renal fibrosis to prevent chronic kidney disease progression.

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, is a risk factor for chronic kidney disease (CKD) progression. Suyin Detoxification Granule (SDG) is a traditional Chinese medicine preparation that has been proven to significantly reduce renal function damage and serum TMAO levels in patients with CKD. However, its specific mechanism remains unclear. PURPOSE: This study investigated the role of TMAO-induced ferroptosis in CKD, and further explored the mechanism of SDG in improving TMAO-induced kidney injury. METHODS: A TMAO renal tubular epithelial cell injury model was constructed in vitro. After using freeze-dried powder of Suyin Detoxification Prescription (SDP), proteomic analysis, Western blotting, ferroptosis phenotype-related detection, and ELISA were performed to explore its mechanism. In vivo, a adenine-induced CKD model was established, with or without a high-choline diet to observe the impact of TMAO on CKD, and SDG or 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) was used for intervention. The composition of gut microbiota was analyzed using 16SrRNA sequencing, and the effect of SDG on gut-derived TMAO-induced kidney injury under the background of CKD was evaluated by pathological staining, immunoblotting, immunohistochemistry, and fluorescence staining. RESULTS: In vitro, TMAO could induce ferroptosis and secrete profibrotic factors in NRK-52E cells. SDP could inhibit TMAO-induced ferroptosis and reduce the secretion of profibrotic factors. The amelioration of ferroptosis by SDP was also verified in RSL3-induced cells. In vivo, our results demonstrated that gut-derived TMAO could promote CKD progression by inducing tubular ferroptosis, profibrotic factors expression and renal fibrosis. In addition, we illustrated that SDG might reduce circulating TMAO levels by down-regulating the gut microbiota related to TMAO (including Muribaculaceae, Bacteroides and Ruminococcaceae_UCG-010). Furthermore, SDG could prevent CKD progression by reducing TMAO-induced renal damage. CONCLUSION: SDG reduced circulating TMAO levels by regulating gut microbiota and inhibited TMAO-induced renal tubular ferroptosis, profibrotic factors secretion, and renal fibrosis to prevent CKD progression.

Development and validation of an ultrasound-based estimated fetal weight reference for Chinese twin pregnancy: a retrospective cohort study.

BACKGROUND: Fetal growth monitoring is important for twin pregnancies. However, there has been no clinically validated tool for monitoring fetal growth of twin pregnancies in China. This study aims to develop and validate a chorionicity-specific growth chart of ultrasound estimated fetal weight (EFW) for Chinese twin pregnancies. METHODS: This retrospective cohort study included all twin pregnancies who delivered two live fetuses with gestational age ≥ 34 weeks without severe obstetric complications at a tertiary hospital from January 2007 to March 2021. The participants were divided into a development set (delivered in or before December 2017) and a validation set (delivered in or after January 2018). Chorionicity-specific growth charts were created using the generalized additive models for location, scale, and shape (GAMLSS) based on the development set. The fetuses from the validation set were classified into three groups based on the last EFW: small-for-gestational-age (SGA) indicated by both the newly established twin charts and the Hadlock singleton chart currently used for twin pregnancies in China, suspected SGA indicated by only the singleton chart, and no SGA indicated by either chart. The incidence of neonatal outcomes among the three groups was then compared accordingly, including intensive care unit (NICU) stay length, respiratory diseases, and neurological disorders. RESULTS: The development set included 883 twin pregnancies and a total of 6374 EFW measurements between 16 and 38 weeks of gestation, and the validation set included 801 twin pregnancies and 7630 EFW measurements. In the development set, monochorionic diamniotic (MCDA) twins had a significantly lower EFW compared to dichorionic diamniotic (DCDA) twins beginning at 26 weeks, with the difference gradually increasing thereafter, supporting the establishment of chorionicity-specific growth charts. Of the 1,602 twin neonates in the validation set, 103 (6.4%) were classified into the SGA group, 164 (10.2%) into the suspected SGA group, and 1335 (83.3%) into the no SGA group. The incidence of respiratory diseases and neurological disorders was comparable between the suspected SGA group and the no SGA group, but apparently higher in the SGA group. Meanwhile, NICU stay lengths were consistently longer for twins in the SGA group compared to the no SGA group (difference: 0.57, 95% CI: 0.31-0.83), with no significant differences observed between the suspected SGA and no SGA groups. CONCLUSIONS: The fetal growth trajectories differed by chorionicity, with a lower EFW for MCDA twins beginning at 26 weeks. The establishment of chorionicity-specific growth chart could reduce overdiagnosis of SGA and improve fetal growth monitoring of twin pregnancies.

Mining and characterization of a novel cytochrome P450 MaCYP71BG22 involved in the C4-stereoselective hydroxylation of 1-deoxynojirimycin biosynthesis in mulberry leaves.

1-Deoxynojirimycin (DNJ), a primary active component in mulberry leaves, has garnered significant attention due to its unique structure and notable pharmacological properties. Our previous investigations have elucidated the biosynthetic pathways of DNJ from lysine to 2-methylpiperidine. However, the hydroxylation process and its underlying mechanisms remain elusive. In this study, five CYP450s hydroxylase genes significantly correlated (P < 0.05) with DNJ content in mulberry leaves at various time were screened through transcriptome profile. MaCYP71BG22 was first cloned and functionally characterized. This gene was shown to specifically catalyze the stereoselective hydroxylation of (R)-2-methylpiperidine at the C4-position to produce (2R, 4R)-2-methylpiperidin-4-ol. In hairy roots of mulberry, overexpression of MaCYP71BG22 increased DNJ accumulation, while virus-induced gene silencing (VIGS) decreased its production. Furthermore, structural-function analysis pinpointed a critical residue, G460, in MaCYP71BG22, mutation of this residue to G460E enhanced the enzyme's catalytic efficiency. This study represents the first report of a CYP450 hydroxylase involved in the biosynthesis of piperidine alkaloids in mulberry leaves, and demonstrates that MaCYP71BG22 selectively catalyzes the C4-stereoselective hydroxylation of (R)-2-methylpiperidine in DNJ biosynthesis. These findings further elucidate the DNJ biosynthetic pathway and provide new insights into the stereo- and regio-selective hydroxylation abilities of CYP450s hydroxylase in DNJ biosynthesis.

Erratum: Improved Measurement of the Differential Polarizability Using Co-trapped Ions [Phys. Rev. Lett. 133, 033001 (2024)].

This corrects the article DOI: 10.1103/PhysRevLett.133.033001.

Spin waves and orbital contribution to ferromagnetism in a topological metal.

Honeycomb and kagome lattices can host propagating excitations with non-trivial topology as defined by their evolution along closed paths in momentum space. Excitations on such lattices can also be momentum-independent, and the associated flat bands are of interest due to strong interactions between heavy quasiparticles. Here, we report the discovery - using circularly polarized X-rays for the unambiguous isolation of magnetic signals - of a nearly flat spin-wave band and large (compared to elemental iron) orbital moment in the metallic ferromagnet Fe3Sn2 with compact AB-stacked kagome bilayers. As a function of out-of-plane momentum, the nearly flat optical mode and the global rotation symmetry-restoring acoustic mode are out of phase, consistent with a bilayer exchange coupling that is larger than the already large in-plane couplings. The defining units of this topological metal are therefore triangular lattices of octahedral iron clusters rather than weakly coupled kagome planes. The spin waves are strongly damped when compared to elemental iron, opening the topic of topological boson-fermion interactions for deeper exploration within this material platform.

The association between maternal anemia and neonatal anemia: a systematic review and meta-analysis.

IMPORTANCE: Neonatal anemia has a long-term effect on children's growth and development. Anemia during pregnancy is also the most widespread nutritional deficiency among pregnant women in the world; If it leads to anemia in newborns, it will affect a wide range of people and be a public health problem worthy of attention. OBJECTIVE: To study the relationship between maternal anemia during pregnancy and neonatal hemoglobin levels. DATA SOURCES: PubMed, Web of science, Scopus, MEDLINE, Embase, ProQuest, Dissertations & Theses Global, The Cochrane Library, China Biology Medicine Database, Chinese CNKI Database, and Chinese Wanfang Database were systematically searched from inception to August 31, 2022. STUDY SELECTION: The meta-analysis included all original studies which pertain to   cohort studies, case-control studies or cross-sectional studies that investigated the relationship between maternal anemia during pregnancy and neonatal hemoglobin levels. DATA EXTRACTION AND SYNTHESIS: Hemoglobin level of both anemic and non-anemic  pregnant mothers and their paired newborns were pooled from the selected studies. The random-effects model was used to assess the risk of getting a lower neonatal hemoglobin level between mothers with and without pregnant anemia. Data analyses were performed from September 5, 2022, to March 10, 2023. MAIN OUTCOMES AND MEASURES: Maternal anemia during pregnancy is a risk factor of lower neonatal hemoglobin levels. RESULTS: The initial search yielded 4267 records of which 116 articles underwent full-text evaluation, which identified 18 articles and a total of 1873 patients that were included. The findings of the meta-analysis showed a significant difference between the two groups(MD=-1.38; 95%CI:[-1.96,-0.80]. p<0.01), while the co-effect showed that the neonatal hemoglobin value of anemic mothers was 1.38g/dL lower than that of non-anemic mothers(-1.96,-0.80), suggesting a correlation between maternal anemia lower neonatal hemoglobin levels. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis demonstrated that maternal anemia during pregnancy were associated with a lower level of newborn hemoglobin levels. This may enable a better understanding of neonatal anemia and provide guidance towards future development of nutritional supplementation during pregnancy and the prediction of postpartum outcomes. TRIAL REGISTRATION: PROSPERO Identifier: CRD42022352759.

Improving completion rate of advance care planning at a tertiary rheumatological centre in Singapore: a quality improvement project.

Advanced care planning (ACP) is a series of ongoing voluntary discussions between patients, families and healthcare professionals to plan for their future healthcare needs. Despite patients with rheumatic diseases having high symptom burden and disease complications, the ACP completion rates in patients with rheumatic diseases remain low. In this quality improvement project, we aimed to increase the number of completed ACP in a tertiary referral rheumatology centre in Singapore from 0 to 1 per month. We showed a statistically significant increase in ACP completion across 1 year with two Plan-Do-Study-Act cycles. Further studies are needed to explore further interventions for ACP completion in patients with rheumatic diseases.

How the extra X chromosome impairs the development of male fetal germ cells.

The dosage of X-linked genes is accurately regulated with the development of fetal germ cells (FGCs)1,2. How aberrant dosage of X-linked genes impairs FGC development in humans remains poorly understood. FGCs of patients with Klinefelter syndrome (KS), who have an extra X chromosome, provide natural models for addressing this issue3. Here we demonstrate that most human FGCs in KS are arrested at an early stage, characterized by the upregulation of genes related to pluripotency, the WNT pathway and the TGF-ß pathway, along with the downregulation of genes involved in FGC differentiation. The limited KS FGCs that are capable of reaching the late stage remain relatively naive. X chromosomes are not inactivated and the dosage of X-linked genes is excessive in KS FGCs. X-linked genes dominate the differentially expressed genes and are enriched in critical biological processes associated with the developmental delay of KS FGCs. Moreover, aberrant interactions between Sertoli cells and FGCs disrupt the migration of late FGCs to the basement membrane in KS. Notably, inhibition of the TGF-ß pathway improves the differentiation of KS FGCs. Our findings elucidate how the extra X chromosome impairs the development of male FGCs and reveal the initial molecular events preceding germ cell loss in KS.

Influence of rhizospheric symbiotic microorganisms on the behavioural effects of antimony in soil-plant system: Insights from a proteomic perspective.

Antimony (Sb) pollution in soil-rice systems can affect human health by enriching of food chains. Currently, the mechanism of the negative role underlying microorganisms in plant responses to Sb stress remains clear. The results of this study showed that the presence of arbuscular mycorrhizal (AM) fungi, a common symbiotic microorganism in rhizosphere soil, significantly enhanced Sb uptake by upland rice and inhibited its growth. Furthermore, we explained the reasons for the adverse effects of AM fungi mediation on upland rice growth under Sb stress from a molecular perspective. The results also showed that AM fungi affect the biological processes of the response of upland rice to oxidative stress and the functions of its antioxidant active molecules throughout the vegetative growth phase of upland rice, and that the phenylpropanoid biosynthesis pathway is significantly downregulated. At the same time, phenylalanine/tyrosine ammonia-lyase (PTAL) in the pathway was significantly expressed in the middle and late stages of vegetative growth of upland rice. Therefore, PTAL can act as a potential reference protein to investigate the response of upland rice to Sb stress mediated by AM fungi. These findings enrich our understanding of the impact of Sb pollution on soil-plant systems in real soil environments.

Molecular characterization of PANoptosis-related genes in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by fibrosis and inflammation in renal tissues. Several types of cell death have been implicated in CKD onset and progression. Unlike traditional forms of cell death, PANoptosis is characterized by the crosstalk among programmed cell death pathways. However, the interaction between PANoptosis and CKD remains unclear. Here, we used bioinformatics methods to identify differentially expressed genes and differentially expressed PANoptosis-related genes (DE-PRGs) using data from the GSE37171 dataset. Following this, we further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and gene set enrichment analysis using the data. We adopted a combined approach to select hub genes, using the STRING database and CytoHubba plug-in, and we used the GSE66494 as a validation dataset. In addition, we constructed ceRNA, transcription factor (TF)-gene, and drug-gene networks using Cytoscape. Lastly, we conducted immunohistochemical analysis and western blotting to validate the hub genes. We identified 57 PANoptosis-associated genes as DE-PRGs. We screened nine hub genes from the 57 DE-PRGs. We identified two hub genes (FOS and PTGS2) using the GSE66494 database, Nephroseq, immunohistochemistry, and western blotting. A common miRNA (Hsa-miR-101-3p) and three TFs (CREB1, E2F1, and RELA) may play a crucial role in the onset and progression of PANoptosis-related CKD. In our analysis of the drug-gene network, we identified eight drugs targeting FOS and 52 drugs targeting PTGS2.

S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells suppress ferroptosis and alleviate radiation-induced lung injury and long-term pulmonary fibrosis.

BACKGROUND: Radiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis. RESULTS: Adenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p < 0.05), thereby constructing miR-486-5p engineered MSC exosomes (miR-486-MSC-Exo). MiR-486-MSC-Exo promoted the proliferation and migration of irradiated mouse lung epithelial (MLE-12) cells in vitro and inhibited RILI in vivo (all p < 0.05). MiR-486-MSC-Exo suppressed ferroptosis in MLE-12 cells, and an in vitro assay revealed that the expression of fibrosis-related genes is up-regulated following ferroptosis (both p < 0.05). MiR-486-MSC-Exo reversed the up-regulated expression of fibrosis-related genes induced by TGF-ß1 in vitro and improved pathological fibrosis in RIPF mice in vivo (all p < 0.05). SARS-CoV-2-S-RBD-modified and miR-486-5p-engineered MSC exosomes (miR-486-RBD-MSC-Exo) were also constructed, and the distribution of DiR dye-labeled miR-486-RBD-MSC-Exo in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated long-term retention in the lung (p < 0.05). MiR-486-RBD-MSC-Exo significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice (all p < 0.05). Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects via targeted SMAD2 inhibition and Akt phosphorylation activation (p < 0.05). CONCLUSIONS: Engineered MSC exosomes with SARS-CoV-2-S-RBD- and miR-486-5p-modification were developed. MiR-486-RBD-MSC-Exo suppressed ferroptosis and fibrosis of MLE-12 cells in vitro, and alleviated RILI and long-term RIPF in ACE2 humanized mice in vivo. MiR-486-MSC-Exo exerted anti-fibrotic effects via SMAD2 inhibition and Akt activation. This study provides a potential approach for RIPF intervention.

A Liquid Band-Aid with Mesenchymal Stem Cell-Derived Exosomes for Wound Healing in Mice.

INTRODUCTION/OBJECTIVE: This study aimed to examine the effect of a human umbilical cord mesenchymal stem cell-derived exosome (hUC-MSC-Exo) liquid band-aid on wound healing in mice. METHODS: hUC-MSC-Exos were prepared from the supernatant via ion exchange chromatography. The composition ratio of the chitosan liquid band-aid was optimized to form a film and encapsulate hUC-MSC-Exo. The biological effects of chitosan exosome liquid band-aid on human umbilical vein endothelial cells (HUVECs) were observed, and its anti-bacterial properties were tested. BALB/c mice with back skin injury were randomly divided into chitosan exosome liquid band-aid group (CS-Exo), chitosan liquid band-aid group (CS), and normal saline control group (Con), and wound healing was evaluated post-treatment. Skin tissue samples posttreatment were collected for H&E staining. RESULTS: The hUC-MSC-Exo was prepared and characterized. The optimum conditions for film formation were 1% chitosan solution and 15% poloxamer 407/poloxamer 188 (pH 5.0 ~ 7.0). The chitosan exosome liquid band-aid promoted HUVEC proliferation and migration and markedly inhibited Escherichia coli and Staphylococcus aureus growth in vitro. In vivo, the wound healing rate in the CS-Exo group was higher than that in the Con and CS groups. Fourteen days post-treatment, the wounds completely healed, and hair grew normally, which was consistent with H&E results. Mouse weights in each group did not change significantly after administration, indicating that the chitosan exosome liquid band-aid had no obvious toxic side effects. CONCLUSION: Local chitosan exosome liquid band-aid application can promote wound healing in mice, and the mechanism could be related to hUC-MSC-Exo-induced vascular endothelial cell proliferation and migration.

Dynamic Jahn-Teller effect in the strong spin-orbit coupling regime.

Exotic quantum phases, arising from a complex interplay of charge, spin, lattice and orbital degrees of freedom, are of immense interest to a wide research community. A well-known example of such an entangled behavior is the Jahn-Teller effect, where the lifting of orbital degeneracy proceeds through lattice distortions. Here we demonstrate that a highly-symmetrical 5d1 double perovskite Ba2MgReO6, comprising a 3D array of isolated ReO6 octahedra, represents a rare example of a dynamic Jahn-Teller system in the strong spin-orbit coupling regime. Thermodynamic and resonant inelastic x-ray scattering experiments, supported by quantum chemistry calculations, undoubtedly show that the Jahn-Teller instability leads to a ground-state doublet, resolving a long-standing puzzle in this family of compounds. The dynamic state of ReO6 octahedra persists down to the lowest temperatures, where a multipolar order sets in, allowing for investigations of the interplay between a dynamic JT effect and strongly correlated electron behavior.

Inhalation of Microplastics Induces Inflammatory Injuries in Multiple Murine Organs via the Toll-like Receptor Pathway.

Previous studies have detected microplastics (MPs) in human biological samples, such as lungs, alveolar lavage fluid, and thrombus. However, whether MPs induce health effects after inhalation are unclear. In this study, fluorescent polystyrene microplastics (PS-MPs) were found in the thymus, spleen, testes, liver, kidneys, and brain on day 1 or day 3 after one intratracheal instillation. Furthermore, mice showed inflammation in multiple organs, manifested as obvious infiltration of neutrophils and macrophages, increased Toll-like receptors (TLRs), myeloid differentiation primary response protein 88 (MyD88) and nuclear factor-κB (NF-κB), as well as proinflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1ß) in the lungs, thymus, spleen, liver, and kidneys after four intratracheal instillations of PS-MPs at once every 2 weeks. Hepatic and renal function indexes were also increased. Subsequently, the inflammatory response in multiple murine organs was significantly alleviated by TLR2 and TLR4 inhibitors. Unexpectedly, we did not find any elevated secretion of monocyte chemotactic protein (MCP)-1 or TNF-α by RAW264.7 macrophages in vitro. Thus, PS-MPs induced inflammatory injuries in multiple murine organs via the TLRs/MyD88/NF-κB pathway in vivo, but not macrophages in vitro. These results may provide theoretical support for healthy protection against PS-MPs and their environmental risk assessment.

Impact of Time Period and Birth Cohort on the Trend of Advanced Neoplasm Prevalence in the 40-49 Average-Risk Screening Population.

BACKGROUND AND AIMS: Early-onset colorectal cancer (CRC) is increasing globally. While the United States have lowered the age of initiation of screening to 45 years, other countries still start screening at 50 years of age. In Taiwan, the incidence of CRC has declined in 55- to 74-year-olds after the initiation of screening, but still increased in those 50-54 years of age, potentially due to rising precancerous lesion incidence in 40- to 49-year-olds. This study aimed to explore the chronological trend of the prevalence of colorectal advanced neoplasms (AN) in the screening population 40-54 years of age. METHODS: We retrospectively analyzed a screening colonoscopy cohort for prevalence of AN in average-risk subjects 40-54 years of age from 2003 to 2019. Logistic regression was used to distinguish cohort effect from time-period effect on the prevalence of AN. RESULTS: In total, 27,805 subjects (52.1% male) men were enrolled. There were notable increases in prevalence of AN in all 3 age groups during the 17-year span, but these were more rapid in those 40-44 years of age (0.99% to 3.22%) and 45-49 years of age (2.50% to 4.19%). Those 50-54 years of age had a higher risk of AN (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.19-2.19) in 2003-2008 but not in later periods (2009-2014: aOR, 1.08; 95% CI, 0.83-1.41; 2015-2019: aOR, 0.76; 95% CI, 0.56-1.03) when compared with those 45-49 years of age. CONCLUSION: The prevalence of AN in those 40-54 years of age increased in the Taiwanese population, with a later birth cohort having a higher prevalence of AN. However, the prevalence of AN in those 45-49 years of age increased more remarkably and approximated that in those 50-54 years of age, which may justify earlier initiation of CRC screening in those 45 years of age.

Effect of a novel artificial intelligence-based cecum recognition system on adenoma detection metrics in a screening colonoscopy setting.

BACKGROUND AND AIMS: Cecal intubation in colonoscopy relies on self-reporting. We developed an artificial intelligence-based cecum recognition system (AI-CRS) for post-hoc verification of cecal intubation and explored its impact on adenoma metrics. METHODS: Quality metrics, including cecal intubation rate (CIR), adenoma detection rate (ADR), and other ADR-related metrics, were compared both before (2015-2018) and after (2019-2022) the implementation of the AI-CRS. RESULTS: Although the CIR did not change significantly after the implementation of the AI-CRS, the ADR and advanced ADR significantly increased. Although the ADR significantly increased in all segments, the most significant increase in advanced ADR was observed in the proximal colon. Implementation of the AI-CRS was associated with a higher likelihood of detecting adenoma (adjusted odds ratio, 1.35; 95% confidence interval, 1.26-1.45) and advanced adenoma (adjusted odds ratio, 1.23; 95% confidence interval, 1.07-1.41), respectively. CONCLUSIONS: Implementation of a post-hoc verification of cecal intubation using an AI-CRS significantly improved various adenoma metrics in screening colonoscopy.

Synergistic Effect of Ubiquitin-Specific Protease 14 and Poly(ADP-Ribose) Glycohydrolase Co-Inhibition in BRCA1-Mutant, Poly(ADP-Ribose) Polymerase Inhibitor-Resistant Triple-Negative Breast Cancer Cells.

Purpose: The clinical benefits of poly(ADP-ribose) polymerase (PARP) inhibitors are limited to triple-negative breast cancer (TNBC) with BRCA deficiency due to primary and acquired resistance. Thus, there is a pressing need to develop alternative treatment regimens to target BRCA-mutated TNBC tumors that are resistant to PARP inhibition. Similar to PARP, poly(ADP-ribose) glycohydrolase (PARG) plays a role in DNA replication and repair. However, there are conflicting reports on the vulnerability of BRCA1-deficient tumor cells to PARG inhibition. This study aims to investigate the synergistically lethal effect of the PARG inhibitor COH34 and the ubiquitin-specific protease (USP) 14 inhibitor IU1-248 and the underlying mechanisms in BRCA1-mutant, PARP inhibitor-resistant TNBC cells. Methods: The cytotoxicity of PARG inhibition alone or in combination with USP14 inhibition in the BRCA-mutant, PARP inhibitor-resistant TNBC cell lines, HCC1937 and SUM149PT, was analyzed using cell viability and proliferation assays and flow cytometry. The molecular mechanisms underlying the synergistic effects of IU1-248 and COH34 were evaluated by immunofluorescence staining, DNA repair reporter assays and Western blot analysis. Results: It was found that HCC1937 and SUM149PT cells exhibited moderate responsiveness to PARG inhibition alone. To the best of our knowledge, this research is the first to demonstrate that the combination of IU1-248 and COH34 produces synergistic effects against TNBC cells in the same setting. Mechanistically, the blockade of USP14 by IU1-248 was shown to increase DNA damage and promote error-prone non-homologous end joining (NHEJ), as evidenced by the accumulation of γH2AX and 53BP1 in the nucleus and the activation of a reporter assay. Additionally, it was demonstrated that the inhibition of NHEJ repair activity attenuates the synergistic effects of concomitant PARG and USP14 inhibition. IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. Conclusion: USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.

Synthesis of a Palladium Dimer Supported by a C-Bound Trifluoroacetonate Bridge Formed by Cleavage of a Hexafluoroacetylacetonate Ligand.

Palladium(II) hexafluoroacetylacetonate (Pd(Hfacac)2) is known to form adducts of bases, such as lutidine (2,6-dimethylpyridine). When treated with approximately 3 equiv of lutidine, Pd(Hfacac)2 yields a 1:1 complex as reported in the literature, Pd(O,O-Hfacac)(C-Hfacac)(lutidine), 1. However, when the amount of excess lutidine is increased, a new complex, 2, is formed. A single-crystal X-ray structure of 2 proves it is a rare example of a dimeric palladium complex containing two Pd(Hfacac)(lutidine) fragments bridged by a dianionic trifluoroacetonate ligand, µ-CHC(O)CF3. The formation of 2 is accompanied by a white precipitate determined to be a mixture of trans-Pd(O2CCF3)2(lutidine)2 (3), confirming the fate of the missing trifluoroacetate fragment from the cleavage of the Hfacac ligand, and [lutidinium][Hfacac] (4). Subsequent experiments revealed the determinative role that water played in this reaction. The mechanism of cleavage of the Hfacac ligand was explored by DFT methods.