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The development of myeloid malignancies is influenced by a range of cell-intrinsic and cell-extrinsic factors, which can be conceptualized using the hallmarks of cancer. Although many facets of myeloid transformation are similar to those in solid tumors, there are also notable differences. Unlike solid tumors, hematologic malignancies typically exhibit fewer genetic mutations, which have been well characterized. However, understanding the cell-extrinsic factors contributing to myeloid malignancies can be challenging due to the complex interactions in the hematopoietic microenvironment. Researchers need to focus on these intricate factors to prevent the early onset of myeloid transformation and develop appropriate interventions. Significance: Myeloid malignancies are common in the elderly, and acute myeloid leukemia has an adverse prognosis in older patients. Investigating cell-extrinsic factors influencing myeloid malignancies is crucial to developing approaches for preventing or halting disease progression and predicting clinical outcomes in patients with advanced disease. Whereas successful intervention may require targeting various mechanisms, understanding the contribution of each cell-extrinsic factor will help prioritize clinical targets., (©2024 American Association for Cancer Research.)

Introduction: Aneurysmal subarachnoid hemorrhage (SAH) constitutes a life-threatening condition, and identifying the ruptured aneurysm is essential for further therapy. This study aimed to evaluate the diagnostic accuracy of hypo-attenuating berry sign (HBS) observed on computed tomography (CT) scan in distinguishing ruptured aneurysms., Methods: In this diagnostic accuracy study, patients who had SAH and underwent non-enhanced brain CT scan were recruited. The HBS was defined as a hypo-attenuating area with an identifiable border in the blood-filled hyper-dense subarachnoid space. The screening performance characteristics of HBS in identifying ruptured aneurysms were calculated considering the digital subtraction angiography (DSA) as the gold standard., Results: A total of 129 aneurysms in 131 patients were analyzed. The overall sensitivity and specificity of HBS in the diagnosis of aneurysms were determined to be 78.7% (95%CI: 73.1% - 83.4%) and 70.7% (95%CI: 54.3% - 83.4%), respectively. Notably, the sensitivity increased to 90.9% (95%CI: 84.3% - 95.0%) for aneurysms larger than 5mm. The level of inter-observer agreement for assessing the presence of HBS was found to be substantial (kappa=0.734). The diagnostic accuracy of HBS in individuals exhibited enhanced specificity, sensitivity, and reliability when evaluating patients with a solitary aneurysm or assessing ruptured aneurysms. The multivariate logistic regression analysis revealed a statistically significant relationship between aneurysm size and the presence of HBS (odds ratios of 1.667 (95%CI: 1.238 - 2.244; p < 0.001) and 1.696 (95%CI: 1.231 - 2.335; p = 0.001) for reader 1 and reader 2, respectively)., Conclusions: The HBS can serve as a simple and easy-to-use indicator for identifying a ruptured aneurysm and estimating its size in SAH patients.   ., Competing Interests: The authors declare that they have no conflicts of interest.

Abstract: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Measurable residual disease (MRD), defined as the population of cancer cells that persist following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones, and normal precursors remains a challenge with current MRD tools. Here, we developed a single-cell MRD (scMRD) assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated single-cell DNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture, and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/preleukemic and leukemic cells surviving acute myeloid leukemia therapy.

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis 1,2 . Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs 3-5 . In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6 ). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In this paper, based on high-throughput technology, polymer dispersed liquid crystals (PDLC) composed of pentaerythritol tetra (2-mercaptoacetic acid) (PETMP), trimethylolpropane triacrylate (TMPTA), and polyethylene glycol diacrylate (PEGD 600) were investigated in detail. A total of 125 PDLC samples with different ratios were quickly prepared using ink-jet printing. Based on the method of machine vision to identify the grayscale level of samples, as far as we know, it is the first time to realize high-throughput detection of the electro-optical performance of PDLC samples, which can quickly screen out the lowest saturation voltage of batch samples. Additionally, we compared the electro-optical test results of manual and high-throughput preparation PDLC samples and discovered that they had very similar electro-optical characteristics and morphologies. This demonstrated the viability of PDLC sample high-throughput preparation and detection, as well as promising application prospects, and significantly increased the efficiency of PDLC sample preparation and detection. The results of this study will contribute to the research and application of PDLC composites in the future.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered., (© 2022 Wiley Periodicals LLC.)

Introduction: SCLC is a highly aggressive neuroendocrine tumor that is characterized by early acquired therapeutic resistance and modest benefit from immune checkpoint blockade (ICB). Repression of the major histocompatibility complex class I (MHC-I) represents a key mechanism driving resistance to T cell-based immunotherapies., Methods: We evaluated the role of the lysine-specific demethylase 1 (LSD1) as a determinant of MHC-I expression, functional antigen presentation, and immune activation in SCLC in vitro and in vivo through evaluation of both human SCLC cell lines and immunocompetent mouse models., Results: We found that targeted inhibition of LSD1 in SCLC restores MHC-I cell surface expression and transcriptionally activates genes encoding the antigen presentation pathway. LSD1 inhibition further activates interferon signaling, induces tumor-intrinsic immunogenicity, and sensitizes SCLC cells to MHC-I-restricted T cell cytolysis. Combination of LSD1 inhibitor with ICB augments the antitumor immune response in refractory SCLC models. Together, these data define a role for LSD1 as a potent regulator of MHC-I antigen presentation and provide rationale for combinatory use of LSD1 inhibitors with ICB to improve therapeutic response in SCLC., Conclusions: Epigenetic silencing of MHC-I in SCLC contributes to its poor response to ICB. Our study identifies a previously uncharacterized role for LSD1 as a regulator of MHC-I antigen presentation in SCLC. LSD1 inhibition enables MHC-I-restricted T cell cytolysis, induces immune activation, and augments the antitumor immune response to ICB in SCLC., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this analysis is to evaluate the current evidence with regard to the effectiveness and safety between coiling and clipping in patients with ruptured intracranial aneurysms (RIAs)., Methods: We performed a meta-analysis that compared clipping with coiling between July 2000 and September 2021. PubMed, EMBASE, and the Cochrane Library were searched for related articles systematically. And the treatment efficacy and postoperative complications were analyzed., Results: We identified three randomized controlled trials and thirty-seven observational studies involving 60,875 patients with ruptured cerebral aneurysms. The summary results showed that coiling was related a better quality of life (mRS0-2; OR=1.327; CI=1.093-1.612; p<0.05), a higher risk of mortality (OR=1.116; CI=1.054-1.180; p<0.05), higher rate of rebleeding (RR=1.410; CI=1.092-1.822; p<0.05), lower incidence of vasospasm (OR=0.787; CI=0.649-0.954; p<0.05), higher risk of hydrocephalous (RR=1.143; CI=1.043-1.252; p<0.05), lower risk of cerebral infarction (RR=0.669; CI=0.596-0.751; p<0.05), lower risk of neuro deficits (RR=0.720; CI=0.582-0.892; p<0.05), and a lower rate of complete occlusion (OR=0.495; CI=0.280-0.876; p<0.05)., Conclusion: Coiling was significantly associated with a better life quality (mRS0-2), a lower incidence of postoperative complications, and a higher rate of mortality, rebleeding, hydrocephalous, and a lower rate of complete occlusion than clipping., (© 2022. The Author(s).)

Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT; however, the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia [PEL]). This PEL arises from the megakaryocyte-erythroid progenitor population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic lethality strategy, by targeting active DNA repair pathways, we show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches., (© 2022 by The American Society of Hematology.)

Spinal cord injury (SCI) is one kind of severe trauma for central nervous system. Myelin debris clearance and axon regeneration are essential for nerve regeneration after SCI. Metformin, a glucose-lowering drug, has been demonstrated to promote the locomotor functional recovery after SCI. In this study, we investigated the role and molecular mechanism of metformin on myelin preservation in a rat SCI model. SCI was induced in rats by compression at T9 level using a vascular clip. We showed that administration of metformin (50 mg·kg -1 ·d -1 , ip) for 28 days significantly improved locomotor function in SCI rats. Metformin also ameliorated SCI-induced neuronal apoptosis and promoted axon regeneration in the spinal cord. Using co-immunofluorescence of IBa-1 and MBP, and luxol fasting blue (LFB) staining, we demonstrated that metformin promoted the transformation of M1 to M2 phenotype polarization of microglial cells, then greatly facilitated myelin debris clearance and protected the myelin in SCI rats. Furthermore, metformin ameliorated SCI-induced blockade of autophagic flux in the spinal cord, and enhanced the fusion of autophagosome and lysosome by inhibiting the AMPK-mTOR signaling pathway. Moreover, metformin significantly attenuated inflammatory responses in the spinal cord. In LPS-treated BV2 cells, pretreatment with metformin (2 mM) significantly enhanced autophagy level, suppressed inflammation and cell apoptosis. The protective effects were blocked in the presence of an autophagy inhibitor 3-methyladenine (3-MA, 5 mM), suggesting that the effect of metformin on autophagy in microglial cells is essential for the myelin preservation during nerve recovery. This study reveals a novel therapeutic effect of metformin in SCI recovery by regulating the activation of microglial cells and enhancing its autophagy level., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

The current study aimed to investigate the efficacy and safety of carotid endarterectomy combined with endovascular therapy in hybrid operating room for patients with segmental atherosclerotic internal carotid artery occlusion, and share the experience of preoperative screening of patients suitable for vascular reconstruction. A total of 20 patients with internal carotid artery occlusion (ICAO) who were admitted to the Department of Neurosurgery, General Hospital of Tianjin Medical University from May 2018 to May 2020 were collected, and 15 patients met the inclusion criteria. All patients received hybrid surgery. The total success rate of recanalization was 14/15, and only 1 patient developed ICA re-occlusion at 1 year follow up.Therefore, carotid endarterectomy combined with endovascular treatment in hybrid operating room was an alternative treatment for patients with segmental atherosclerotic internal carotid artery occlusion.

Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in ∼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML., (© 2021 by The American Society of Hematology.)

Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted., (© 2021 by The American Society of Hematology.)

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; P =0.077) and 3.83 (95%CI: 1.51-9.74; P =0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% vs 2 of 18, 11%; P =0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML., (Copyright© 2019 Ferrata Storti Foundation.)

Free vitamin D is the biologically active form of vitamin D. Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. The goal of our current study was to investigate the relation between blood concentrations of free 25-hydroxyvitamin D with cardiovascular events in end-stage chronic kidney disease patients on hemodialysis, because this is unknown so far. We measured free vitamin D levels in 117 stable consecutive prevalent patients in September as a surrogate of vitamin D exposure during the past 6 months, and recorded the number of cardiovascular events during the previous 6 months defined as hospitalization due to heart failure, episodes of acute coronary syndrome, and stroke. Fourteen events occurred during the observation period. In patients without any cardiovascular events the free vitamin D levels were significantly higher as compared to those with cardiovascular events (patients without events: 5.68 [4.37-9.27] pg/mL; patients with events: 4.74 [3.46-5.37] pg/mL, p = 0.015). This finding remained stable after multiple regression analysis considering confounding factors such as age, time on dialysis, preexisting diabetes, hypertension, and coronary heart disease. In conclusion, our study shows that free vitamin D serum concentrations are independently associated with major cardiovascular events in chronic kidney disease patients on dialysis., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

The aim of the present study was to investigate the ultrasound features and classify the lesion types of congenital vaginal oblique septum syndrome (CVOS) in 21 patients prior to surgery. Grey-scale pelvic ultrasound was performed to evaluate the uterus, vagina and kidneys in 21 patients with suspected CVOS. Ultrasound features, including the presence of a double uterus, hematocolpos masses and renal absence, in CVOS types I, II and III were studied and compared with intra-operative results and the results of surgery. Ultrasound identified the presence of double uteruses and cervices with ipsilateral renal agenesis on the oblique septum side in all 21 patients. There were 14 hematocolpos lesions on the right and 7 on the left of the vagina. Type I CVOS was diagnosed in 15 patients with a large hematocolpos mass (volume, 64-268 ml) and these diagnoses were confirmed by surgery. Furthermore, there were 4 patients with type II and 2 patients with type III CVOS exhibiting small hematocolpos lesions (volume, 5-36 ml) identified by ultrasound, which were all confirmed by surgery. Therefore, ultrasound imaging is useful tool to evaluate the abnormal features of CVOS and determine the type of CVOS in patients prior to surgical intervention.

Objective: This study aimed to illustrate the magnetic resonance venography (MRV) manifestations of obstructed hepatic veins (HVs), the inferior vena cava (IVC), and accessory hepatic veins (AHVs) in patients with Budd-Chiari syndrome (BCS) and to evaluate the visualization capacity of MRV in the diagnosis of BCS., Materials and Methods: Fifty-two patients with chronic BCS were included in this study. All patients were examined via MRV performed with a 3T system following injections of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) or Gd-ethoxibenzyl-DTPA. HV and IVC lesions were classified, and their characteristics were described. HV cord-like occlusions detected via MRV were compared using ultrasonography (US). Digital subtraction angiography (DSA) was performed as a contrast in the MRV detection of IVC lesions. The HVs draining collaterals, mainly AHVs, were carefully observed. HV lesions were classified as segmental stenosis, segmental occlusion, membranous stenosis, membranous occlusion, cord-like occlusion, or non-visualized. Except for patent IVCs, IVC lesions were classified as segmental occlusion, segmental stenosis, membranous occlusion, membranous stenosis, and hepatomegaly-induced stenosis., Results: All patients (52/52, 100%) showed HV lesions of different degrees. MRV was inferior to US in detecting cord-like occlusions (6 vs. 19, χ 2 = 11.077, p < 0.001). Dilated AHVs, including 50 (50/52, 96.2%) caudate lobe veins and 37 (37/52, 71.2%) inferior HV and AHV lesions, were well-detected. There were no significant differences in detecting segmental lesions and thrombosis between MRV and DSA (χ 2 = 0.000, p 1 = 1.000, p 2 = 1.000). The capacity of MRV to detect membranous lesions was inferior to that of DSA (7 vs. 15, χ 2 = 6.125, p = 0.013)., Conclusion: In patients with BCS, MRV can clearly display the lesions in HVs and the IVC, as well as in AHVs, and it has diagnostic and therapeutic value.

Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine-specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML. We performed a comparative assessment of chromatin dynamics during the treatment of mixed lineage leukemia (MLL)-AF9-driven murine leukemias and MLL-rearranged patient-derived xenografts using 2 distinct but effective differentiation-inducing targeted epigenetic therapies, the LSD1 inhibitor GSK-LSD1 and the DOT1L inhibitor EPZ4777. Intriguingly, GSK-LSD1 treatment caused global gains in chromatin accessibility, whereas treatment with EPZ4777 caused global losses in accessibility. We captured PU.1 and C/EBPα motif signatures at LSD1 inhibitor-induced dynamic sites and chromatin immunoprecipitation coupled with high-throughput sequencing revealed co-occupancy of these myeloid transcription factors at these sites. Functionally, we confirmed that diminished expression of PU.1 or genetic deletion of C/EBPα in MLL-AF9 cells generates resistance of these leukemias to LSD1 inhibition. These findings reveal that pharmacologic inhibition of LSD1 represents a unique path to overcome the differentiation block in AML for therapeutic benefit., (© 2018 by The American Society of Hematology.)

Chromatin regulatory mechanisms play a major role in the control of gene expression programs during normal development and are disrupted in specific disease states, particularly in cancer. Important mediators of chromatin regulatory processes can broadly be classified into writers, erasers, and readers of covalent chromatin modifications that modulate eukaryotic gene transcription and maintain the integrity of the genome. The reversibility and disease-specific nature of these chromatin states make these regulators attractive therapeutic targets. As such, there is an ever-increasing number of candidate therapies aimed at targeting cancer-associated chromatin states that are in various stages of preclinical and clinical development. In this review, we discuss recent advances that have been made in the rational therapeutic targeting of chromatin regulatory mechanisms and highlight certain cancers where there is a specific rationale to assess these therapeutic approaches., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of this study was to assess the computed tomography angiography (CTA) manifestations of collateral circulations in patients with Budd-Chiari syndrome (BCS). Eighty patients with BCS were examined by CT scan. Using the CTA images of the relevant blood vessels, including the affected hepatic veins (HVs) and inferior venae cavae (IVCs), the collateral circulations were reconstructed. In addition to obstructed HVs and IVCs, collateral circulations were found in each of the patients. The collateral circulations were classified as intrahepatic, extrahepatic and portosystemic pathways. Intrahepatic collateral pathways were further classified as the following six types: HV-accessory HV (n=51, 63.8%), HV-HV (n=6, 7.5%), HV-accessory HV plus HV (n=6, 7.5%), IVC-HV/accessory HV-HV-right atrium (n=5, 6.3%), HV-umbilical vein (n=4, 5.0%) and HV-inferior phrenic vein (n=8, 10.0%). Extrahepatic collateral pathways included IVC-lumbar-ascending lumbar-hemiazygos/azygos vein (n=80, 100.0%), IVC-left renal-ascending lumbar-hemiazygos vein (n=75, 93.8%), IVC-left renal-inferior phrenic vein (n=49, 61.3%), IVC-renal -peri-renal -superficial epigastric vein (n=26, 32.5%) and superficial epigastric vein (n=12, 15.0%) types. The CTA characteristics of each type of collateral circulation were demonstrated. In conclusion, the present study revealed that CTA is able to show the intra- and extrahepatic collateral circulations of patients with BCS, which may be useful for therapeutic planning.

The aim of this study was to investigate the ultrasonic features of the cavo-hepato-atrial pathway in Budd-Chiari syndrome (BCS), by which blood is drained from the occluded inferior vena cava (IVC) to the right atrium via hepatic veins. Ultrasonograms from 11 patients with BCS with cavo-hepato-atrial pathways were retrospectively studied. Doppler ultrasound was used to observe the direction of the flow and measure the velocity of the blood-draining vessels. Blood flow in the draining vessels and the collaterals was shown as blue, red or bicolored depending on whether the flow direction was away from the transducer, towards the transducer or both. For measurement, the Doppler angle between the axis of the Doppler beam and that of the vein examined was always <60°. Ultrasonography was performed 1-2 weeks prior to digital subtraction angiography (DSA). All patients were confirmed by DSA. Membranous and segmental occlusions of IVCs were observed in seven and four cases, respectively. Blood flow from the IVC reversed to the hepatic/accessory hepatic vein, continued through the dilated intrahepatic collaterals, onward to the other hepatic vein and finally to the right atrium. The majority of the inlets (8/11) of hepatic veins above the occlusion were narrow compared with the dilated distant parts of the lumens. Accelerated blood flow in the inlets was detected in all patients regardless of the luminal diameter. In conclusion, the results from the present study suggest that the unusual cavo-hepato-atrial pathway can be diagnosed reliably by ultrasonography, which may be useful for clinical management.

Background: This study was conducted to investigate whether apparent diffusion coefficient (ADC) measurements by dividing the liver into left and right hepatic lobes may be utilized to improve the accuracy of differential diagnosis of benign and malignant focal liver lesions., Materials and Methods: A total of 269 consecutive patients with 429 focal liver lesions were examined by 3-T magnetic resonance imaging that included diffusion-weighted imaging. For 58 patients with focal liver lesions of the same etiology in left and right hepatic lobes, ADCs of normal liver parenchyma and focal liver lesions were calculated and compared using the paired t-test. For all 269 patients, ADC cutoffs for focal liver lesions and diagnostic accuracy in the left hepatic lobe, right hepatic lobe and whole liver were evaluated by receiver operating characteristic curve analysis., Results: For the group of 58 patients, mean ADCs of normal liver parenchyma and focal liver lesions in the left hepatic lobe were significantly higher than those in the right hepatic lobe. For differentiating malignant lesions from benign lesions in all patients, the sensitivity and specificity were 92.6% and 92.0% in the left hepatic lobe, 94.4% and 94.4% in the right hepatic lobe, and 90.4% and 94.7% in the whole liver, respectively. The area under the curve of the right hepatic lobe, but not the left hepatic lobe, was higher than that of the whole liver., Conclusions: ADCs of normal liver parenchyma and focal liver lesions in the left hepatic lobe were significantly higher than those in the right hepatic lobe. Optimal ADC cutoff for focal liver lesions in the right hepatic lobe, but not in the left hepatic lobe, had higher diagnostic accuracy compared with that in the whole liver.

Regulatory T (T(reg)) cells can suppress a wide variety of immune responses, including antitumor and alloimmune responses. The mechanisms by which T(reg) cells mediate their suppressive effects depend on the context of their activation. We previously reported that granzyme B is important for T(reg) cell-mediated suppression of antitumor immune responses. We therefore hypothesized that granzyme B may likewise be important for suppression of graft-versus-host disease (GVHD). We found that allogeneic mismatch induces the expression of granzyme B in mixed lymphocyte reactions and in a model of graft-versus-host disease (GVHD). However, wild-type and granzyme B-deficient T(reg) cells were equally able to suppress effector T (T(eff)) cell proliferation driven by multiple stimuli, including allogeneicantigen-presenting cells. Surprisingly, adoptive transfer of granzyme B-deficient T(reg) cells prevented GVHD lethality, suppressed serum cytokine production in vivo, and prevented target organ damage. These data contrast strikingly with our previous study, which demonstrated that granzyme B plays a nonredundant role in T(reg) cell-mediated suppression of antitumor responses. Taken together, these findings suggest that targeting specific T(reg) cell-suppressive mechanisms, such as granzyme B, may be therapeutically beneficial for segregating GVHD and graft-versus-tumor immune responses.

To define the factors that modulate regulatory T (Treg) cells in the tumor setting, we cocultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumor-induced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumor-induced Treg expansion. We inadvertently discovered that interleukin (IL)-12 treatment blocked Treg expansion in an IL-12 receptor-dependent fashion. Additional studies showed that IL-12 acts by stimulating IFN-gamma mediated inhibition of Treg cell proliferation, which may partially account for the antitumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to IFN-gamma-independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that IFN-gamma signaling directly causes cell cycle arrest in Treg cells. This study shows that an IL-12-IFN-gamma axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo.

The oxo-diperoxo molybdenum(VI) complex MoO(O(2))(2).2QOH (QOH = 8-quinilinol) was prepared and characterized by elemental analysis, IR and UV-Vis spectra. The ionic liquids (ILs) [bmim][BF(4)], [hydemim][BF(4)], and [bmim][PF(6)] were characterized by (1)H-NMR and UV-Vis spectra. The epoxidation of a technical mixture of methyl oleate and methyl linoleate with H(2)O(2), in [bmim][BF(4)], [hydemim][BF(4)] and [bmim][PF(6)], catalyzed by MoO(O(2))(2).2QOH (QOH = 8-quinilinol) and with NaHCO(3) as co-catalyst has been studied for the first time. It was found that high conversions of methyl oleate and methyl linoleate to their respective oxidation products, as well as the total selectivity of their oxidation products to oxirane in [hydemim][BF(4)] were obtained. Also, the IL phases containing the Mo(VI) catalyst can be readily recycled by washing with diethyl ether and drying, and the Mo(VI) catalyst can be reused at least five times.

Granzyme B is important for the ability of NK cells and CD8(+) T cells to kill their targets. However, we showed here that granzyme B-deficient mice clear both allogeneic and syngeneic tumor cell lines more efficiently than do wild-type (WT) mice. To determine whether regulatory T (Treg) cells utilize granzyme B to suppress immune responses against these tumors, we examined the expression and function of granzyme B in Treg cells. Granzyme B was not expressed in naive Treg cells but was highly expressed in 5%-30% of CD4(+)Foxp3(+) Treg cells in the tumor environment. Adoptive transfer of WT Treg cells, but not granzyme B- or perforin-deficient Treg cells, into granzyme B-deficient mice partially restored susceptibility to tumor growth; Treg cells derived from the tumor environment could induce NK and CD8(+) T cell death in a granzyme B- and perforin-dependent fashion. Granzyme B and perforin are therefore relevant for Treg cell-mediated suppression of tumor clearance in vivo.

Although activated murine NK cells can use the granule exocytosis pathway to kill target cells immediately upon recognition, resting murine NK cells are minimally cytotoxic for unknown reasons. Here, we showed that resting NK cells contained abundant granzyme A, but little granzyme B or perforin; in contrast, the mRNAs for all three genes were abundant. Cytokine-induced in vitro activation of NK cells resulted in potent cytotoxicity associated with a dramatic increase in granzyme B and perforin, but only minimal changes in mRNA abundance for these genes. The same pattern of regulation was found in vivo with murine cytomegalovirus infection as a physiologic model of NK cell activation. These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation.

Accumulating evidence indicates that the beta-arrestins act as scaffold molecules that couple G-protein-coupled receptors to mitogen-activated protein (MAP) kinase signaling pathways. Recently, we identified the c-Jun N-terminal kinase 3 (JNK3) as a beta-arrestin2-interacting protein in yeast-two hybrid and co-immunoprecipitation studies. Beta-arrestin2 acts as a scaffold to enhance signaling to JNK3 stimulated by overexpression of the MAP3 kinase ASK1 or by agonist activation of the angiotensin 1A receptor. Whereas beta-arrestin2 is a very strong activator of JNK3 signaling, beta-arrestin1 is very weak in this regard. The data also indicate that the specific step enhanced by beta-arrestin2 involves phosphorylation of JNK3 by the MAP2 kinase MKK4. We reasoned that defining the region (or domain) in beta-arrestin2 responsible for high level JNK3 activation would provide insight into the mechanism by which beta-arrestin2 enhances the activity of this signaling pathway. Using chimeric beta-arrestins, we have determined that sequences in the carboxyl-terminal region of beta-arrestin2 are important for the enhancement of JNK3 phosphorylation. More detailed analysis of the carboxyl-terminal domains of the beta-arrestins indicated that beta-arrestin2, but not beta-arrestin1, contains a sequence (RRSLHL) highly homologous to the conserved docking motif present in many MAP kinase-binding proteins. Replacement of the beta-arrestin2 RRS residues with the corresponding KP residues present in beta-arrestin1 dramatically reduced both JNK3 interaction and enhancement of JNK3 phosphorylation. Conversely, replacement of the KP residues in beta-arrestin1 with RRS significantly increased both JNK3 binding and enhancement of JNK3 phosphorylation. These results delineate a mechanism by which beta-arrestin2 functions as a scaffold protein in the JNK3 signaling pathway and implicate the conserved docking site in beta-arrestin2 as an important factor in binding JNK3 and stimulating the phosphorylation of JNK3 by MKK4.

The current study used the human Caco-2 cell line and mouse intestine to explore the topology of expression of the class B type I scavenger receptor (SR-BI) in intestinal cells. Results showed that intestinal cells expressed only the SR-BI isoform with little or no expression of the SR-BII variant. The expression of SR-BI in Caco-2 cells is differentiation dependent, with little or no expression in preconfluent undifferentiated cells. Analysis of Caco-2 cells cultured in Transwell porous membranes revealed the presence of SR-BI on both the apical and basolateral cell surface. Immunoblot analysis of mouse intestinal cell extracts demonstrated a gradation of SR-BI expression along the gastrocolic axis of the intestine, with the highest level of expression in the proximal intestine and decreasing to minimal expression levels in the distal intestine. Immunofluorescence studies with SR-BI-specific antibodies also confirmed this expression pattern. Importantly, the immunofluorescence studies also revealed that SR-BI immunoreactivity was most intense in the apical membrane of the brush border in the duodenum. The crypt cells did not show any reactivity with SR-BI antibodies. The localization of SR-BI in the jejunum was found to be different from that observed in the duodenum. SR-BI was present on both apical and basolateral surfaces of the jejunum villus. Localization of SR-BI in the ileum was also different, with little SR-BI detectable on either apical or basolateral membranes. Taken together, these results suggest that SR-BI has the potential to serve several functions in the intestine. The localization of SR-BI on the apical surface of the proximal intestine is consistent with the hypothesis of its possible role in dietary cholesterol absorption, whereas SR-BI present on the basolateral surface of the distal intestine suggests its possible involvement in intestinal lipoprotein uptake.