Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration.

Mammalian retrotransposons constitute 40% of the genome. During tissue regeneration, adult stem cells coordinately repress retrotransposons and activate lineage genes, but how this coordination is controlled is poorly understood. Here, we observed that dynamic expression of histone methyltransferase SETDB1 (a retrotransposon repressor) closely mirrors stem cell activities in murine skin. SETDB1 ablation leads to the reactivation of endogenous retroviruses (ERVs, a type of retrotransposon) and the assembly of viral-like particles, resulting in hair loss and stem cell exhaustion that is reversible by antiviral drugs. Mechanistically, at least two molecularly and spatially distinct pathways are responsible: antiviral defense mediated by hair follicle stem cells and progenitors and antiviral-independent response due to replication stress in transient amplifying cells. ERV reactivation is promoted by DNA demethylase ten-eleven translocation (TET)-mediated hydroxymethylation and recapitulated by ablating cell fate transcription factors. Together, we demonstrated ERV silencing is coupled with stem cell activity and essential for adult hair regeneration.

Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer.

Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, binds Toll-like receptor 4 (TLR4)-MD2 complex and activates innate immune responses. LPS transfer to TLR4-MD2 is catalyzed by both LPS binding protein (LBP) and CD14. To define the sequential molecular interactions underlying this transfer, we reconstituted in vitro the entire LPS transfer process from LPS micelles to TLR4-MD2. Using electron microscopy and single-molecule approaches, we characterized the dynamic intermediate complexes for LPS transfer: LBP-LPS micelles, CD14-LBP-LPS micelle, and CD14-LPS-TLR4-MD2 complex. A single LBP molecule bound longitudinally to LPS micelles catalyzed multi-rounds of LPS transfer to CD14s that rapidly dissociated from LPB-LPS complex upon LPS transfer via electrostatic interactions. Subsequently, the single LPS molecule bound to CD14 was transferred to TLR4-MD2 in a TLR4-dependent manner. The definition of the structural determinants of the LPS transfer cascade to TLR4 may enable the development of targeted therapeutics for intervention in LPS-induced sepsis.

The Circadian Clock of Müller Glia Is Necessary for Retinal Homeostasis and Neuronal Survival.

Biological processes throughout the body are orchestrated in time through the regulation of local circadian clocks. The retina is among the most metabolically active tissues, with demands depending greatly on the light/dark cycle. Most cell types within the rodent retina are known to express the circadian clock; however, retinal clock expression in humans has not previously been localized. Moreover, the effect of local circadian clock dysfunction on retinal homeostasis is incompletely understood. The current study indicated an age-dependent decline in circadian clock gene and protein expression in the human retina. An animal model of targeted Bmal1 deficiency was used to identify the circadian clock of the retinal Müller glia as essential for neuronal survival, vascular integrity, and retinal function. These results suggest a potential role for the local retinal circadian clock within the Müller glia in age-related retinal disease and retinal degeneration.

From Homogeneity to Turing Pattern: Kinetically Controlled Self-Organization of Transmembrane Protein.

Understanding the spatial organization of membrane proteins is crucial for unraveling key principles in cell biology. The reaction-diffusion model is commonly used to understand biochemical patterning; however, applying reaction-diffusion models to subcellular phenomena is challenging because of the difficulty in measuring protein diffusivity and interaction kinetics in the living cell. In this work, we investigated the self-organization of the plasmalemma vesicle-associated protein (PLVAP), which creates regular arrangements of fenestrated ultrastructures, using single-molecule tracking. We demonstrated that the spatial organization of the ultrastructures is associated with a decrease in the association rate by actin destabilization. We also constructed a reaction-diffusion model that accurately generates a hexagonal array with the same 130 nm spacing as the actual scale and informs the stoichiometry of the ultrastructure, which can be discerned only through electron microscopy. Through this study, we integrated single-molecule experiments and reaction-diffusion modeling to surpass the limitations of static imaging tools and proposed emergent properties of the PLVAP ultrastructure.

Proteomics Profiling of Bilirubin Nanoparticle Treatment against Myocardial Ischemia-Reperfusion Injury.

In myocardial infarction, ischemia-reperfusion injury (IRI) poses a significant challenge due to a lack of effective treatments. Bilirubin, a natural compound known for its anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic agent for IRI. Currently, there are no reports about proteomic studies related to IRI and bilirubin treatment. In this study, we explored the effects of bilirubin nanoparticles in a rat model of myocardial IRI. A total of 3616 protein groups comprising 76,681 distinct peptides were identified using LC-MS/MS, where we distinguished two kinds of protein groups: those showing increased expression in IRI and decreased expression in IRI with bilirubin treatment, and vice versa, accounting for 202 and 35 proteins, respectively. Our proteomic analysis identified significant upregulation in the Wnt and insulin signaling pathways and increased Golgi markers, indicating their role in mediating bilirubin nanoparticle's protective effects. This research contributes to the proteomic understanding of myocardial IRI and suggests bilirubin nanoparticles as a promising strategy for cardiac protection, warranting further investigation in human models.

Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon.

Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2V617F or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2V617F and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2R715T in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2R715T mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2R715T kinase. Similar to PV, the JAK2R715T native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2V617F PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2R715T gain-of-function mutation with many but not all comparable molecular features to JAK2V617F PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.

Effect of rock bream iridovirus (RBIV) contained tissue intake on rock bream (Oplegnathus fasciatus) mortality and blood cell distribution.

Rock bream (Oplegnathus fasciatus) is one of the highly priced cultured marine fish in Korea. Rock bream iridovirus (RBIV) outbreaks in aquaculture farms may involve environmental factors, co-infection with other pathogenic microorganisms and grounded (raw) fish feed. This study evaluated the effects of RBIV-containing tissue intake on mortality and oral transmission in rock bream. Virus-containing tissues administered to rock bream [50 mg (1.53 × 108/major capsid protein, MCP gene copies) to 2400 mg (7.34 × 109)] held at 23 °C lead to 100 % mortality by 27 days post administration. Interestingly, the mortality rates were not viral dose- or concentration dependent. Further, high MCP gene copy numbers were observed in the gill, liver, intestine, stomach, spleen, heart, kidney, brain and muscle tissues (viral load range of 3.03 × 106 to 4.01 × 107/mg, average viral load 1.70 × 107/mg) of dead rock bream. Moreover, a high viral load was detected in the intestine and stomach, where the virus was directly administered. This indicated that the intake of RBIV-containing tissue feed weakens the intestinal mucosal immunity and increases viral load in the intestine. Moreover, the levels of complete blood cell count (CBC) indicators, such as red blood cell (RBC), hemoglobin (HGB) and hematocrit (HCT) significantly decreased from 15 dpi with red blood cell distribution width (RDW), and white blood cells (lymphocyte, monocyte and granulocyte) significantly increased from the initial to later stage of infection. These results highlight the significance of blood-mediated indicators against RBIV infection in rock bream. We demonstrate the existence of an oral transmission route for RBIV in rock bream. Our findings indicate that pathogen-containing feed is an important risk factor for disease outbreaks in rock bream.

Near-flat top bandpass filter based on non-local resonance in a dielectric metasurface.

Localized light matter interaction at a resonant nanostructure facilitates spectrally selective transmission of light, which has led to demonstrations of ultrathin metasurface based optical filters. Unfortunately, due to the nature of Lorentzian spectral line shape in such resonances, it is inevitable to suffer significant spectral crosstalk. In this work, we demonstrate a conceptually new type of spectral filter which exhibits near flat-top bandpass with minimized spectral overlaps. To realize this, we leverage the recent development of non-local resonance in dielectric nanostructure to design a double-layered optical filter with performance comparable to the ideal spectral filters. The designed metasurface shows averaged transmission of more than 90% across the target spectral band and suppressed transmission of less than 10% out of the spectral band.

Molecular basis for SMC rod formation and its dissolution upon DNA binding.

SMC condensin complexes are central modulators of chromosome superstructure in all branches of life. Their SMC subunits form a long intramolecular coiled coil, which connects a constitutive "hinge" dimerization domain with an ATP-regulated "head" dimerization module. Here, we address the structural arrangement of the long coiled coils in SMC complexes. We unequivocally show that prokaryotic Smc-ScpAB, eukaryotic condensin, and possibly also cohesin form rod-like structures, with their coiled coils being closely juxtaposed and accurately anchored to the hinge. Upon ATP-induced binding of DNA to the hinge, however, Smc switches to a more open configuration. Our data suggest that a long-distance structural transition is transmitted from the Smc head domains to regulate Smc-ScpAB's association with DNA. These findings uncover a conserved architectural theme in SMC complexes, provide a mechanistic basis for Smc's dynamic engagement with chromosomes, and offer a molecular explanation for defects in Cornelia de Lange syndrome.

Exosomal miR-184 in the aqueous humor of patients with central serous chorioretinopathy: a potential diagnostic and prognostic biomarker.

BACKGROUND: Central serous chorioretinopathy (CSC) is the fourth most prevalent retinal disease leading to age-related macular degeneration (AMD) and retinal atrophy. However, CSC's pathogenesis and therapeutic target need to be better understood. RESULTS: We investigated exosomal microRNA in the aqueous humor of CSC patients using next-generation sequencing (NGS) to identify potential biomarkers associated with CSC pathogenesis. Bioinformatic evaluations and NGS were performed on exosomal miRNAs obtained from AH samples of 62 eyes (42 CSC and 20 controls). For subgroup analysis, patients were divided into treatment responders (CSC-R, 17 eyes) and non-responders (CSC-NR, 25 eyes). To validate the functions of miRNA in CECs, primary cultured-human choroidal endothelial cells (hCEC) of the donor eyes were utilized for in vitro assays. NGS detected 376 miRNAs. Our results showed that patients with CSC had 12 significantly upregulated and 17 downregulated miRNAs compared to controls. miR-184 was significantly upregulated in CSC-R and CSC-NR patients compared to controls and higher in CSC-NR than CSC-R. In vitro assays using primary cultured-human choroidal endothelial cells (hCEC) demonstrated that miR-184 suppressed the proliferation and migration of hCECs. STC2 was identified as a strong candidate for the posttranscriptional down-regulated target gene of miR-184. CONCLUSION: Our findings suggest that exosomal miR-184 may serve as a biomarker reflecting the angiostatic capacity of CEC in patients with CSC.

Blockade of mTORC1-NOX signaling pathway inhibits TGF-ß1-mediated senescence-like structural alterations of the retinal pigment epithelium.

The retinal pigment epithelium (RPE) undergoes characteristic structural changes and epithelial-mesenchymal transition (EMT) during normal aging, which are exacerbated in age-related macular degeneration (AMD). Although the pathogenic mechanisms of aging and AMD remain unclear, transforming growth factor-ß1 (TGF-ß1) is known to induce oxidative stress, morphometric changes, and EMT as a senescence-promoting factor. In this study, we examined whether intravitreal injection of TGF-ß1 into the mouse eye elicits senescence-like morphological alterations in the RPE and if this can be prevented by suppressing mammalian target of rapamycin complex 1 (mTORC1) or NADPH oxidase (NOX) signaling. We verified that intravitreal TGF-ß1-induced stress fiber formation and EMT in RPE cells, along with age-associated morphometric changes, including increased variation in cell size and reduced cell density. In RPE cells, exogenous TGF-ß1 increased endogenous expression of TGF-ß1 and upregulated Smad3-ERK1/2-mTORC1 signaling, increasing reactive oxygen species (ROS) production and EMT. We demonstrated that inhibition of the mTORC1-NOX4 pathway by pretreatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-dependent protein kinase, or GKT137831, a NOX1/4 inhibitor, decreased ROS generation, prevented stress fiber formation, attenuated EMT, and improved the regularity of the RPE structure in vitro and in vivo. These results suggest that intravitreal TGF-ß1 injection could be used as a screening model to investigate the aging-related structural and functional changes to the RPE. Furthermore, the regulation of TGF-ß-mTORC1-NOX signaling could be a potential therapeutic target for reducing pathogenic alterations in aged RPE and AMD.

Chryseobacterium oryzae sp. nov. and Chryseobacterium suipulveris sp. nov., isolated from Andong sikhye and pigpen dust, respectively.

Two Gram-stain-negative, aerobic, mesophilic, rod-shaped bacteria, ADR-1T and SC2-2T, were isolated from Andong sikhye and dust in a pigpen, respectively. The phylogenetic tree on the basis of 16S rRNA gene sequences showed that strains ADR-1T and SC2-2T were members of the genus Chryseobacterium and revealed the highest sequence similarities to Chryseobacterium binzhouense LM2T (97.6 %) and Chryseobacterium koreense Chj707T (94.9 %), respectively. Phylogenomic treeing using 92 core genes clearly indicated that strain ADR-1T clustered with Chryseobacterium echinoideorum CC-CZW010T, Chryseobacterium binzhouense LM2T and Chryseobacterium taihuense CGMCC 1.10941T, and strain SC2-2T formed a compact cluster with Chryseobacterium koreense CCUG 49689T. The digital DNA-DNA hybridization (dDDH) and orthologous average nucleotide identity (ANI) values of strain ADR-1T with the closely related species of the genus Chryseobacterium were ≤24.4 % and ≤80.7 %, and those of strain SC2-2T were ≤24.0 % and ≤77.8 %, respectively, which are well below the cut-off values of species discrimination (>70 % dDDH and >95-96 % ANI). The only respiratory quinone in both strains was menaquinone 6. The polar lipid profile of strain ADR-1T comprised phosphatidylethanolamine, four unidentified aminolipids and three unidentified lipids, while strain SC2-2T contained phosphatidylethanolamine, two unidentified aminolipids, one unidentified aminophospholipid and five unidentified polar lipids. The major fatty acids (>10 %) of strain ADR-1T were iso-C15 : 0, summed feature 9 (iso-C17 : 1 ω9c and/or C16 : 0 10-methyl), iso-C17 : 0 3-OH and summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), and those of strain SC2-2T were iso-C15 : 0 and anteiso-C15 : 0. On the basis of the results of phenotypic and phylogenetic analyses, strains ADR-1T and SC2-2T represent two distinct novel species in the genus Chryseobacterium, for which the names Chryseobacterium oryzae sp. nov. (type strain ADR-1T=KACC 19311T=NBRC 113104T) and Chryseobacterium suipulveris sp. nov. (type strain SC2-2T=KACC 19313T=NBRC 113106T) are proposed.

Efficacy of a recombinant M-like protein, SimA as a subunit vaccine candidate against Streptococcus parauberis infection in olive flounder, Paralichthys olivaceus.

Streptococcus parauberis, a gram-positive cocci, causes bacterial disease in farmed fish. The recent increase in S. parauberis infection in aquatic farms in South Korea has justified the importance of vaccine development for the prevention of this disease. In this study, we evaluated the effect of subunit vaccines prepared from recombinant M-like protein (SimA) and fibrinogen-binding protein (FBP) candidates with an aluminum hydroxide adjuvant against S. parauberis infection in olive flounder Paralichthys olivaceus. For the in vivo experiment, fish (average length, 7.18 cm; average weight, 3.5 g) were injected intraperitoneally with: phosphate buffer saline (PBS, group 1), PBS/aluminum hydroxide (group 2), FBP/aluminum hydroxide (group 3), SimA/aluminum hydroxide (group 4), and SimA/FBP/aluminum hydroxide (group 5). After 3 weeks, the fish in each group were boosted using PBS (group 1 and 2), FBP (group 3), SimA (group 4), and SimA/FBP (group 5) without adjuvant. We found that the relative percent survival of fish after S. parauberis exposure in group 2, 3, 4, and 5 was 6.25%, 18.75%, 50%, and 12.5%, respectively, whereas the mortality in groups 1 was 80%, respectively. We performed Western blot, ELISA, and quantitative real time RT-PCR (qRT-PCR) after vaccination to investigate the further efficacy of the vaccine. Western blot and ELISA of vaccinated fish serum confirmed the production of specific antibodies against SimA and FBP. Furthermore, results of qRT-PCR showed that recombinant protein SimA induced a remarkably specific-antibody response compared with that in FBP or control and increased the expression of various immune response-related genes including interleukin-8 (IL-8), toll-like receptor 2 (TLR2), tumor necrosis factor-α (TNF-α), CD4-1, and MHC II. Thus, these results indicate that SimA is a potent vaccine candidate for protection against S. parauberis infection.

Efficacy of endoscopic management for anastomotic leakage after gastrectomy in patients with gastric cancer.

BACKGROUND: Anastomotic leakage (AL) after gastrectomy in gastric cancer patients is associated with high mortality rates. Various endoscopic procedures are available to manage this postoperative complication. The aim of study was to evaluate the outcome of two endoscopic modalities, clippings and stents, for the treatment of AL. PATIENTS AND METHODS: There were 4916 gastric cancer patients who underwent gastrectomy between December 2007 and January 2016 at the National Cancer Center, Korea. A total of 115 patients (2.3%) developed AL. Of these, 85 patients (1.7%) received endoscopic therapy for AL and were included in this retrospective study. The endpoints were the complete leakage closure rates and risk factors associated with failure of endoscopic therapy. RESULTS: Of the 85 patients, 62 received endoscopic clippings (with or without detachable snares), and 23 received a stent insertion. Overall, the complete leakage closure rate was 80%, and no significant difference was found between the clipping and stent groups (79.0% vs. 82.6%, respectively; P = 0.89). The complete leakage closure rate was significantly lower in the duodenal and jejunal stump sites (60%) than esophageal sites (86.1%) and gastric sites (94.1%; P = 0.026). The multivariate analysis showed that stump leakage sites (adjusted odds ratio [aOR], 4.51; P = 0.031) and the presence of intra-abdominal abscess (aOR, 4.92; P = -0.025) were associated with unsuccessful leakage closures. CONCLUSIONS: Endoscopic therapy using clippings or stents is an effective method for the postoperative management of AL in gastric cancer patients. This therapy can be considered a primary treatment option due to its demonstrated efficacy, safety, and minimally invasive nature.

The Efficacy of Atelocollagen to Inhibit Fibrotic Proliferation in Tenon Tissue: in vitro study.

INTRODUCTION: To evaluate the safety and efficacy of atelocollagen in preventing the fibrotic change of human tenon tissue induced by transforming growth factor ß1 (TGFß1) Methods: Primary cultured human Tenon's fibroblasts (HTFs) were incubated with TGFß1 alone, and with a various concentrations of atelocollagen respectively. Cell viability was measured by cell counting kit-8 (CCK8). The mRNA levels of α-smooth muscle actin (α-SMA), vimentin, fibronectin, zonular occludens scaffolding protein (ZO-1), cellular communication network factor 2 (CCN2) and interleukin-6 (IL-6) were measured by quantitative reverse transcription polymerase chain reaction (RT-PCR), western blot and immunofluorescence analysis. Wound healing assay and collagen contraction assay were additionally evaluated for identifying the inhibitory effect of atelocollagen in HTFs. To elucidate the mechanism by which atelocollagen affects HTFs proliferation, the phospho-extracellular-signal-regulated kinases (pERK)/total-extracellular-signal-regulated kinases (tERK), phospho-focal adhesion kinase (pFAK)/total-focal adhesion kinase (tFAK), and pSmad3/tSmad3 protein expression ratios were measured by Western blot. RESULTS: The safety of atelocollagen in HTF was identified by CCK8 analysis. The expression of α-SMA and vimentin in HTFs treated with 0.023% and 0.046% atelocollagen significantly decreased at both mRNA and protein levels, while that of ZO-1 in 0.046% atelocollagen increased compared with TGFß1-treated cells. The protein expression of fibronectin, CCN2, and IL-6 in HTFs treated with 0.023% and 0.046% atelocollagen significantly decreased. Immunofluorescence microscopy of α-SMA and ZO-1 showed results similar to those of the western blot. In the wound scratch assays, cell migration was significantly attenuated in HTFs treated with 0.005% atelocollagen. Atelocollagen at 0.005, 0.011, and 0.023% significantly inhibited the gel contraction induced by TGFß1 at both 24 h and 48 h. The increase in pERK/tERK and pSmad3/tSmad3 protein expression ratios in TGFß1-treated HTFs significantly decreased after treatment with 0.023 and 0.046% atelocollagen. CONCLUSION: Since atelocollagen gel effectively suppresses the proliferation of HTFs in TGFß1 - induced transdifferentiation, it may be a potential therapeutic agent in glaucoma surgery.

Application of Lactic Acid Bacteria (LAB) in Sustainable Agriculture: Advantages and Limitations.

Lactic acid bacteria (LAB) are significant groups of probiotic organisms in fermented food and are generally considered safe. LAB regulate soil organic matter and the biochemical cycle, detoxify hazardous chemicals, and enhance plant health. They are found in decomposing plants, traditional fermented milk products, and normal human gastrointestinal and vaginal flora. Exploring LAB identified in unknown niches may lead to isolating unique species. However, their classification is quite complex, and they are adapted to high sugar concentrations and acidic environments. LAB strains are considered promising candidates for sustainable agriculture, and they promote soil health and fertility. Therefore, they have received much attention regarding sustainable agriculture. LAB metabolites promote plant growth and stimulate shoot and root growth. As fertilizers, LAB can promote biodegradation, accelerate the soil organic content, and produce organic acid and bacteriocin metabolites. However, LAB show an antagonistic effect against phytopathogens, inhibiting fungal and bacterial populations in the rhizosphere and phyllosphere. Several studies have proposed the LAB bioremediation efficiency and detoxification of heavy metals and mycotoxins. However, LAB genetic manipulation and metabolic engineered tools provide efficient cell factories tailor-made to produce beneficial industrial and agro-products. This review discusses lactic acid bacteria advantages and limitations in sustainable agricultural development.

JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera.

The V617F mutation in the JH2 domain of Janus kinase 2 (JAK2) is an oncogenic driver in several myeloproliferative neoplasms (MPNs), including essential thrombocythemia, myelofibrosis, and polycythemia vera (PV). Other mutations in JAK2 have been identified in MPNs, most notably exon 12 mutations in PV. Here, we describe a novel recurrent mutation characterized by a common 4-amino-acid deletion and variable 1-amino-acid insertion (Leu583-Ala586DelInsSer/Gln/Pro) within the JH2 domain of JAK2. All 4 affected patients had eosinophilia, and both patients with Leu583-Ala586DelInsSer fulfilled diagnostic criteria of both PV and chronic eosinophilic leukemia (CEL). Computational and functional studies revealed that Leu583-Ala586DelInsSer (herein referred to as JAK2ex13InDel) deregulates JAK2 through a mechanism similar to JAK2V617F, activates signal transducer and activator of transcription 5 and extracellular signal-regulated kinase, and transforms parental Ba/F3 cells to growth factor independence. In contrast to JAK2V617F, JAK2ex13InDel does not require an exogenous homodimeric type 1 cytokine receptor to transform Ba/F3 cells and is capable of activating ß common chain family cytokine receptor (interleukin-3 receptor [IL-3R], IL-5R, and granulocyte-macrophage colony stimulating factor receptor) signaling in the absence of ligand, with the maximum effect observed for IL-5R, consistent with the clinical phenotype of eosinophilia. Recognizing this new PV/CEL-overlap MPN has significant clinical implications, as both PV and CEL patients are at high risk for thrombosis, and concomitant cytoreduction of red cells, neutrophils, and eosinophils may be required for prevention of thromboembolic events. Targeted next-generation sequencing for genes recurrently mutated in myeloid malignancies in patients with unexplained eosinophilia may reveal additional cases of Leu583-Ala586DelInsSer/Gln/Pro, allowing for complete characterization of this unique MPN.

Diagnostic performance of core needle biopsy as a first-line diagnostic tool for thyroid nodules according to ultrasound patterns: Comparison with fine needle aspiration using propensity score matching analysis.

OBJECTIVE: This study aimed to compare the diagnostic performance of core-needle biopsy (CNB) to fine-needle aspiration (FNA) as a first-line diagnostic tool in initially detected thyroid nodules, according to ultrasound (US) patterns. MATERIALS AND METHODS: This study included 778 consecutive nodules from 705 patients who underwent CNB from one institution and 627 nodules from 583 patients who underwent FNA from two institutions. Adjustments for significant differences in patients' characteristics were facilitated via propensity score matching. We compared the diagnostic performance of CNB and FNA for thyroid malignancy according to three diagnostic criteria for all nodules and the US patterns. RESULTS: A 1:1 matching of 469 patients yielded no significant differences between CNB and FNA for any covariates. CNB showed a significantly higher sensitivity for malignancy than FNA with any criterion (criterion 1: category VI, criterion 2: category V and VI, criterion 3: category IV, V and VI) in overall and high suspicion nodules (90.1-99.5% vs 69.7%-88.3%, all P-values < 0.001) and low/intermediate suspicion nodules, except criterion 1 (61.9%-100% vs 36.4%-45.5%, all P ≤ .016). In ROC curve analysis, the areas under the ROC curve of CNB were significantly higher than those for FNA with any criterion in overall and high suspicion nodules (P < .001) and in low/intermediate suspicion nodules, except criterion 1 (P ≤ .008). CNB had a slightly higher minor complication rate than FNA (0.7% vs 0%, P ≥ .069). CONCLUSION: Our study suggests that CNB has a complementary role as an alternative first-line diagnostic tool to FNA for the initial diagnosis of thyroid nodules when performed by an experienced operator.

Multi-arterial phase MRI depicts inconsistent arterial phase hyperenhancement (APHE) subtypes in liver observations of patients at risk for hepatocellular carcinoma.

OBJECTIVES: According to LI-RADS, a major discriminating feature between hepatocellular carcinoma (HCC) and non-HCC malignancies is the subtype of arterial phase hyperenhancement (APHE). The aim of this study was to investigate whether APHE subtypes are consistent across multi-arterial phase (mHAP) MRI acquisitions while evaluating reader agreement. Secondarily, we investigated factors that may affect reader agreement for APHE subtype. METHODS: In this retrospective study, consecutive patients with liver cirrhosis and focal observations who underwent mHAP were included. Five radiologists reviewed MR images in 2 reading sessions. In reading session 1, individual AP series were reviewed and scored for presence of APHE and subtype. In reading session 2, readers scored observations' major and ancillary features and LI-RADS category in the complete MRI examination. Reader agreement was calculated using Fleiss' kappa for binary outcomes and Kendall's coefficient of concordance for LI-RADS categories. Univariate mixed effects logistic regressions were performed to investigate factors affecting agreement. RESULTS: In total, 61 patients with 77 focal observations were analyzed. Of observations unanimously scored as having APHE, 27.7% showed both rim and nonrim subtypes on mHAP. Inter-reader agreement for APHE subtype ranged from 0.49 (95% CI: 0.33, 0.64) to 0.57 (95% CI: 0.40, 0.74) between reading sessions. Observation size had a trend level effect on rim APHE agreement (p = 0.052). CONCLUSION: Approximately 1/3 of observations demonstrated inconsistent APHE subtype during mHAP acquisition. Small lesions were particularly challenging. Further guidance on APHE subtype classification, especially when applied to mHAP, could be a focus of LI-RADS refinement. KEY POINTS: • In a cohort of patients at risk for HCC, 28% of the observations showed inconsistent arterial phase hyperenhancement (APHE) subtypes (rim and nonrim) on multi-arterial phase imaging according to the majority score of 5 independent readers. • Inconsistent APHE subtypes may challenge reliable imaging diagnosis, i.e., LI-RADS categorization, of focal liver observations in patients at risk for HCC.

CNN color-coded difference maps accurately display longitudinal changes in liver MRI-PDFF.

OBJECTIVES: To assess the feasibility of a CNN-based liver registration algorithm to generate difference maps for visual display of spatiotemporal changes in liver PDFF, without needing manual annotations. METHODS: This retrospective exploratory study included 25 patients with suspected or confirmed NAFLD, who underwent PDFF-MRI at two time points at our institution. PDFF difference maps were generated by applying a CNN-based liver registration algorithm, then subtracting follow-up from baseline PDFF maps. The difference maps were post-processed by smoothing (5 cm2 round kernel) and applying a categorical color scale. Two fellowship-trained abdominal radiologists and one radiology resident independently reviewed difference maps to visually determine segmental PDFF change. Their visual assessment was compared with manual ROI-based measurements of each Couinaud segment and whole liver PDFF using intraclass correlation (ICC) and Bland-Altman analysis. Inter-reader agreement for visual assessment was calculated (ICC). RESULTS: The mean patient age was 49 years (12 males). Baseline and follow-up PDFF ranged from 2.0 to 35.3% and 3.5 to 32.0%, respectively. PDFF changes ranged from - 20.4 to 14.1%. ICCs against the manual reference exceeded 0.95 for each reader, except for segment 2 (2 readers ICC = 0.86-0.91) and segment 4a (reader 3 ICC = 0.94). Bland-Altman limits of agreement were within 5% across all three readers. Inter-reader agreement for visually assessed PDFF change (whole liver and segmental) was excellent (ICCs > 0.96), except for segment 2 (ICC = 0.93). CONCLUSIONS: Visual assessment of liver segmental PDFF changes using a CNN-generated difference map strongly agreed with manual estimates performed by an expert reader and yielded high inter-reader agreement. KEY POINTS: • Visual assessment of longitudinal changes in quantitative liver MRI can be performed using a CNN-generated difference map and yields strong agreement with manual estimates performed by expert readers.