Single-crystalline metal-oxide dielectrics for top-gate 2D transistors.

Two-dimensional (2D) structures composed of atomically thin materials with high carrier mobility have been studied as candidates for future transistors1-4. However, owing to the unavailability of suitable high-quality dielectrics, 2D field-effect transistors (FETs) cannot attain the full theoretical potential and advantages despite their superior physical and electrical properties3,5,6. Here we demonstrate the fabrication of atomically thin single-crystalline Al2O3 (c-Al2O3) as a high-quality top-gate dielectric in 2D FETs. By using intercalative oxidation techniques, a stable, stoichiometric and atomically thin c-Al2O3 layer with a thickness of 1.25 nm is formed on the single-crystalline Al surface at room temperature. Owing to the favourable crystalline structure and well-defined interfaces, the gate leakage current, interface state density and dielectric strength of c-Al2O3 meet the International Roadmap for Devices and Systems requirements3,5,7. Through a one-step transfer process consisting of the source, drain, dielectric materials and gate, we achieve top-gate MoS2 FETs characterized by a steep subthreshold swing of 61 mV dec-1, high on/off current ratio of 108 and very small hysteresis of 10 mV. This technique and material demonstrate the possibility of producing high-quality single-crystalline oxides suitable for integration into fully scalable advanced 2D FETs, including negative capacitance transistors and spin transistors.

Structural evidence for intermediates during O2 formation in photosystem II.

In natural photosynthesis, the light-driven splitting of water into electrons, protons and molecular oxygen forms the first step of the solar-to-chemical energy conversion process. The reaction takes place in photosystem II, where the Mn4CaO5 cluster first stores four oxidizing equivalents, the S0 to S4 intermediate states in the Kok cycle, sequentially generated by photochemical charge separations in the reaction center and then catalyzes the O-O bond formation chemistry1-3. Here, we report room temperature snapshots by serial femtosecond X-ray crystallography to provide structural insights into the final reaction step of Kok's photosynthetic water oxidation cycle, the S3→[S4]→S0 transition where O2 is formed and Kok's water oxidation clock is reset. Our data reveal a complex sequence of events, which occur over micro- to milliseconds, comprising changes at the Mn4CaO5 cluster, its ligands and water pathways as well as controlled proton release through the hydrogen-bonding network of the Cl1 channel. Importantly, the extra O atom Ox, which was introduced as a bridging ligand between Ca and Mn1 during the S2→S3 transition4-6, disappears or relocates in parallel with Yz reduction starting at approximately 700 µs after the third flash. The onset of O2 evolution, as indicated by the shortening of the Mn1-Mn4 distance, occurs at around 1,200 µs, signifying the presence of a reduced intermediate, possibly a bound peroxide.

A non-canonical role of the inner kinetochore in regulating sister-chromatid cohesion at centromeres.

The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.

Utilizing big data without domain knowledge impacts public health decision-making.

New data sources and AI methods for extracting information are increasingly abundant and relevant to decision-making across societal applications. A notable example is street view imagery, available in over 100 countries, and purported to inform built environment interventions (e.g., adding sidewalks) for community health outcomes. However, biases can arise when decision-making does not account for data robustness or relies on spurious correlations. To investigate this risk, we analyzed 2.02 million Google Street View (GSV) images alongside health, demographic, and socioeconomic data from New York City. Findings demonstrate robustness challenges; built environment characteristics inferred from GSV labels at the intracity level often do not align with ground truth. Moreover, as average individual-level behavior of physical inactivity significantly mediates the impact of built environment features by census tract, intervention on features measured by GSV would be misestimated without proper model specification and consideration of this mediation mechanism. Using a causal framework accounting for these mediators, we determined that intervening by improving 10% of samples in the two lowest tertiles of physical inactivity would lead to a 4.17 (95% CI 3.84-4.55) or 17.2 (95% CI 14.4-21.3) times greater decrease in the prevalence of obesity or diabetes, respectively, compared to the same proportional intervention on the number of crosswalks by census tract. This study highlights critical issues of robustness and model specification in using emergent data sources, showing the data may not measure what is intended, and ignoring mediators can result in biased intervention effect estimates.

Prostate cancer-induced endothelial-cell-to-osteoblast transition drives immunosuppression in the bone-tumor microenvironment through Wnt pathway-induced M2 macrophage polarization.

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC.

The CsAP2-09-CsWRKY25-CsRBOH2 cascade confers resistance against citrus bacterial canker by regulating ROS homeostasis.

Citrus bacterial canker (CBC) is a serious bacterial disease caused by Xanthomonas citri subsp. citri (Xcc) that adversely impacts the global citrus industry. In a previous study, we demonstrated that overexpression of an Xcc-inducible apetala 2/ethylene response factor encoded by Citrus sinensis, CsAP2-09, enhances CBC resistance. The mechanism responsible for this effect, however, is not known. In the present study, we showed that CsAP2-09 targeted the promoter of the Xcc-inducible WRKY transcription factor coding gene CsWRKY25 directly, activating its transcription. CsWRKY25 was found to localize to the nucleus and to activate transcriptional activity. Plants overexpressing CsWRKY25 were more resistant to CBC and showed higher expression of the respiratory burst oxidase homolog (RBOH) CsRBOH2, in addition to exhibiting increased RBOH activity. Transient overexpression assays in citrus confirmed that CsWRKY25 and CsRBOH2 participated in the generation of reactive oxygen species (ROS) bursts, which were able to restore the ROS degradation caused by CsAP2-09 knockdown. Moreover, CsWRKY25 was found to bind directly to W-box elements within the CsRBOH2 promoter. Notably, CsRBOH2 knockdown had been reported previously to reduce the CBC resistance, while demonstrated in this study, CsRBOH2 transient overexpression can enhance the CBC resistance. Overall, our results outline a pathway through which CsAP2-09-CsWRKY25 transcriptionally reprograms CsRBOH2-mediated ROS homeostasis in a manner conducive to CBC resistance. These data offer new insight into the mechanisms and regulatory pathways through which CsAP2-09 regulates CBC resistance, highlighting its potential utility as a target for the breeding of CBC-resistant citrus varieties.

TransGEM: a molecule generation model based on Transformer with gene expression data.

MOTIVATION: It is difficult to generate new molecules with desirable bioactivity through ligand-based de novo drug design, and receptor-based de novo drug design is constrained by disease target information availability. The combination of artificial intelligence and phenotype-based de novo drug design can generate new bioactive molecules, independent from disease target information. Gene expression profiles can be used to characterize biological phenotypes. The Transformer model can be utilized to capture the associations between gene expression profiles and molecular structures due to its remarkable ability in processing contextual information. RESULTS: We propose TransGEM (Transformer-based model from gene expression to molecules), which is a phenotype-based de novo drug design model. A specialized gene expression encoder is used to embed gene expression difference values between diseased cell lines and their corresponding normal tissue cells into TransGEM model. The results demonstrate that the TransGEM model can generate molecules with desirable evaluation metrics and property distributions. Case studies illustrate that TransGEM model can generate structurally novel molecules with good binding affinity to disease target proteins. The majority of genes with high attention scores obtained from TransGEM model are associated with the onset of the disease, indicating the potential of these genes as disease targets. Therefore, this study provides a new paradigm for de novo drug design, and it will promote phenotype-based drug discovery. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/hzauzqy/TransGEM.

m5C and m6A modifications regulate the mobility of pumpkin CHOLINE KINASE 1 mRNA under chilling stress.

Mobile mRNAs serve as crucial long-distance signaling molecules, responding to environmental stimuli in plants. Although many mobile transcripts have been identified, only a limited subset has been characterized as functional long-distance signals within specific plant species, raising an intriguing question about whether the prevalence of species specificity in mobile transcripts implies a divergence in the mechanisms governing mRNA mobility across distinct plant species. Our study delved into the notable case of CHOLINE KINASE 1 (CK1), an extensively studied instance of mobile mRNAs regulated by a tRNA-like sequence (TLS) in Arabidopsis (Arabidopsis thaliana). We established an association between mRNA mobility and length, independent of TLS numbers. Notably, neither the mobile mRNAs nor the mechanisms underpinning their mobility proved to be conserved across different plant species. The exclusive mobility of pumpkin CK1 mRNA under chilling stress was pivotal in enhancing the chilling tolerance of cucumber/pumpkin heterografts. Distinct from the TLS-mediated mobility of AtCK1 mRNA, the mobility of CmoCK1 mRNA is orchestrated by both m5C and m6A modifications, adding dimensions to our understanding of mRNA transport mechanisms.

Quantum Griffiths Singularity in Ordered Artificial Superconducting-Islands-Array on Graphene.

Quantum Griffiths phase (QGP) is a novel quantum phenomenon of quantum phase transition in two-dimensional (2D) superconductors, and the emergence of inhomogeneous superconducting rare regions immersed in a metallic matrix is theoretically related to the quantum Griffiths singularity (QGS). However, the theoretical proposal of superconducting rare regions still lacks intuitive experimental verification. Here, we construct an artificial ordered superconducting-islands-array on monolayer graphene with the aid of an anodic aluminum oxide (AAO) membrane. The QGS under both in-plane and out-of-plane magnetic fields is evidenced by the divergent dynamical critical exponent and is in compliance with the direct activated scaling behavior. The phase diagram clearly shows that the QGP is indeed bred in the rare superconducting regions within isolated superconducting islands with a vanished quantum coherence. Our results reveal the universal features of QGP in artificial heterostructured systems and provide a visualized platform for the theoretical proposal of QGS.

Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. FINDINGS: Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. INTERPRETATION: Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. FUNDING: Exelixis.

Modulating endothelial cell dynamics in fat grafting: the impact of DLL4 siRNA via adipose stem cell extracellular vesicles.

In the context of improving the efficacy of autologous fat grafts (AFGs) in reconstructive surgery, this study delineates the novel use of adipose-derived mesenchymal stem cells (ADSCs) and their extracellular vesicles (EVs) as vehicles for delivering delta-like ligand 4 (DLL4) siRNA. The aim was to inhibit DLL4, a gene identified through transcriptome analysis as a critical player in the vascular endothelial cells of AFG tissues, thereby negatively affecting endothelial cell functions and graft survival through the Notch signaling pathway. By engineering ADSC EVs to carry DLL4 siRNA (ADSC EVs-siDLL4), the research demonstrated a marked improvement in endothelial cell proliferation, migration, and lumen formation, and enhanced angiogenesis in vivo, leading to a significant increase in the survival rate of AFGs. This approach presents a significant advancement in the field of tissue engineering and regenerative medicine, offering a potential method to overcome the limitations of current fat grafting techniques.NEW & NOTEWORTHY This study introduces a groundbreaking method for enhancing autologous fat graft survival using adipose-derived stem cell extracellular vesicles (ADSC EVs) to deliver DLL4 siRNA. By targeting the delta-like ligand 4 (DLL4) gene, crucial in endothelial cell dynamics, this innovative approach significantly improves endothelial cell functions and angiogenesis, marking a substantial advancement in tissue engineering and regenerative medicine.

Mechanical strain regulates osteogenesis via Antxr1/LncRNA H19/Wnt/ß-catenin axis.

Alleviating bone loss is an essential way to prevent osteoporotic fractures. Proper exercise improves bone density without the side effects of long-term medications, but the mechanism is unclear. Our study explored the role of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of exercise-mediated alleviation of bone loss. Here we discovered that moderate-intensity treadmill exercise alleviates bone loss caused by ovariectomy and ameliorates bone strength accompanied by an increased lncRNA H19 expression. Concomitantly, Antxr1, a mechanosensitive protein was found downregulated by exercise but upregulated by ovariectomy. Interestingly, knockdown expression of Antxr1 increased lncRNA H19 expression and Wnt/ß-catenin signaling pathway in bone marrow mesenchymal stem cells, whereas overexpression of Antxr1 decreased lncRNA H19 expression and Wnt/ß-catenin signaling pathway. Hence, our study demonstrates the regulation of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of mechanical strain-induced osteogenic differentiation, which provides further mechanistic insight into the role of mechanical regulation in bone metabolism.

Comparative mitochondrial genomics of Terniopsis yongtaiensis in Malpighiales: structural, sequential, and phylogenetic perspectives.

BACKGROUND: Terniopsis yongtaiensis, a member of the Podostemaceae family, is an aquatic flowering plant displaying remarkable adaptive traits that enable survival in submerged, turbulent habitats. Despite the progressive expansion of chloroplast genomic information within this family, mitochondrial genome sequences have yet to be reported. RESULTS: In current study, the mitochondrial genome of the T. yongtaiensis was characterized by a circular genome of 426,928 bp encoding 31 protein-coding genes (PCGs), 18 tRNAs, and 3 rRNA genes. Our comprehensive analysis focused on gene content, repeat sequences, RNA editing processes, intracellular gene transfer, phylogeny, and codon usage bias. Numerous repeat sequences were identified, including 130 simple sequence repeats, 22 tandem repeats, and 220 dispersed repeats. Phylogenetic analysis positioned T. yongtaiensis (Podostemaceae) within the Malpighiales order, showing a close relationship with the Calophyllaceae family, which was consistent with the APG IV classification. A comparative analysis with nine other Malpighiales species revealed both variable and conserved regions, providing insights into the genomic evolution within this order. Notably, the GC content of T. yongtaiensis was distinctively lower compared to other Malpighilales, primarily due to variations in non-coding regions and specific protein-coding genes, particularly the nad genes. Remarkably, the number of RNA editing sites was low (276), distributed unevenly across 27 PCGs. The dN/dS analysis showed only the ccmB gene of T. yongtaiensis was positively selected, which plays a crucial role in cytochrome c biosynthesis. Additionally, there were 13 gene-containing homologous regions between the mitochondrial and chloroplast genomes of T. yongtaiensis, suggesting the gene transfer events between these organellar genomes. CONCLUSIONS: This study assembled and annotated the first mitochondrial genome of the Podostemaceae family. The comparison results of mitochondrial gene composition, GC content, and RNA editing sites provided novel insights into the adaptive traits and genetic reprogramming of this aquatic eudicot group and offered a foundation for future research on the genomic evolution and adaptive mechanisms of Podostemaceae and related plant families in the Malpighiales order.

Visualizing the Heterogeneity in Homogeneous Supramolecular Polymers.

The dynamic properties of supramolecular polymers enable new functionality beyond the limitations of conventional polymers. The mechanism of the monomer exchange between different supramolecular polymers is proposed to be closely associated with local disordered domains within the supramolecular polymers. However, a direct detection of such heterogeneity has never been experimentally probed. Here, we present the direct visualization of the local disordered domains in the backbone of supramolecular polymers by a super-resolution microscopy technique: Nile Red-based spectrally resolved point accumulation for imaging in nanoscale topography (NR-sPAINT). We investigate the local disordered domains in trisamide-based supramolecular polymers comprising a (co)assembly of benzene-1,3,5-tricarboxamide (BTA) and a variant with one of the amide bonds inverted (iBTA). The NR-sPAINT allows us to simultaneously map the spatial distribution and polarity of the local disordered domains along the polymers with a spatial precision down to ∼20 nm. Quantitative autocorrelation and cross-correlation analysis show subtle differences in the spatial distribution of the disordered domains between polymers composed of different variants of BTA monomers. Further, statistical analysis unraveled high heterogeneity in monomer packing at both intra- and interpolymer levels. The results reported here demonstrate the necessity of investigating the structures in soft materials at nanoscale to fully understand their intricacy.

Host defense peptides mitigate the spread of antibiotic resistance in physiologically relevant condition.

Antibiotic resistance represents a significant challenge to public health and human safety. The primary driver behind the dissemination of antibiotic resistance is the horizontal transfer of plasmids. Current conjugative transfer assay is generally performed in a standardized manner, ignoring the effect of the host environment. Host defense peptides (HDPs) possess a wide range of biological targets and play an essential role in the innate immune system. Herein, we reveal that sub-minimum inhibitory concentrations of HDPs facilitate the conjugative transfer of RP4-7 plasmid in the Luria Broth medium, and this observation is reversed in the RPMI medium, designed to simulate the host environment. Out of these HDPs, indolicidin (Ind), a cationic tridecapeptide from bovine neutrophils, significantly inhibits the conjugation of multidrug resistance plasmids in a dose-dependent manner, including blaNDM- and tet(X4)-bearing plasmids. We demonstrate that the addition of Ind to RPMI medium as the incubation substrate downregulates the expression of conjugation-related genes. In addition, Ind weakens the tricarboxylic acid cycle, impedes the electron transport chain, and disrupts the proton motive force, consequently diminishing the synthesis of adenosine triphosphate and limiting the energy supply. Our findings highlight the importance of the host-like environments for the development of horizontal transfer inhibitors and demonstrate the potential of HDPs in preventing the spread of resistance plasmids.

Histone H2A phosphorylation recruits topoisomerase IIα to centromeres to safeguard genomic stability.

Chromosome segregation in mitosis requires the removal of catenation between sister chromatids. Timely decatenation of sister DNAs at mitotic centromeres by topoisomerase IIα (TOP2A) is crucial to maintain genomic stability. The chromatin factors that recruit TOP2A to centromeres during mitosis remain unknown. Here, we show that histone H2A Thr-120 phosphorylation (H2ApT120), a modification generated by the mitotic kinase Bub1, is necessary and sufficient for the centromeric localization of TOP2A. Phosphorylation at residue-120 enhances histone H2A binding to TOP2A in vitro. The C-gate and the extreme C-terminal region are important for H2ApT120-dependent localization of TOP2A at centromeres. Preventing H2ApT120-mediated accumulation of TOP2A at mitotic centromeres interferes with sister chromatid disjunction, as evidenced by increased frequency of anaphase ultra-fine bridges (UFBs) that contain catenated DNA. Tethering TOP2A to centromeres bypasses the requirement for H2ApT120 in suppressing anaphase UFBs. These results demonstrate that H2ApT120 acts as a landmark that recruits TOP2A to mitotic centromeres to decatenate sister DNAs. Our study reveals a fundamental role for histone phosphorylation in resolving centromere DNA entanglements and safeguarding genomic stability during mitosis.

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.