Search

Morphology-based classification of cells in the bone marrow aspirate (BMA) is a key step in the diagnosis and management of hematologic malignancies. However, it is time-intensive and must be performed by expert hematopathologists and laboratory professionals. We curated a large, high-quality dataset of 41,595 hematopathologist consensus-annotated single-cell images extracted from BMA whole slide images (WSIs) containing 23 morphologic classes from the clinical archives of the University of California, San Francisco. We trained a convolutional neural network, DeepHeme, to classify images in this dataset, achieving a mean area under the curve (AUC) of 0.99. DeepHeme was then externally validated on WSIs from Memorial Sloan Kettering Cancer Center, with a similar AUC of 0.98, demonstrating robust generalization. When compared to individual hematopathologists from three different top academic medical centers, the algorithm outperformed all three. Finally, DeepHeme reliably identified cell states such as mitosis, paving the way for image-based quantification of mitotic index in a cell-specific manner, which may have important clinical applications.

Background/Aims: To investigate the clinical situation, treatment methods, and clinical predictors of surgical intervention in children with magnetic foreign bodies in the digestive tract. Materials and Methods: From January 2019 to June 2022, we retrospectively analyzed the clinical data of 72 children who ingested magnetic foreign bodies inadvertently in our hospital, including their general information, admissions, clinical manifestations, and treatment methods, as well as pertinent literature and statistical data. Following software processing, univariate and multivariate logistic regression analyses were conducted to determine the independent risk factors of this study, and the receiver operating characteristic curve (ROC) was used to evaluate their predictive performance. Results: Among the 72 children who accidentally ingested magnetic foreign bodies, 59 (86.8%) ingested foreign bodies, with an average of 3.42 days and 11.03 foreign bodies. The predominant symptoms were nausea and vomiting. 19 cases (31.2%), 33 cases (54.1%) with abdominal pain; 9 cases (14.8%) with peritoneal irritation; 13 cases (21.3%) within 24 hours with foreign body movement. Treatment: conservative in 16 cases (22.2%), gastroscope in 19 cases (26.4%), and surgery in 37 cases (51.4%), with gastrointestinal perforation occurring in 26 cases (70.3%). ROC (AUC = 0.808) for predicting surgical treatment plans for children with magnetic foreign body ingestion. Conclusion: We found that nausea、vomiting and intermittent abdominal pain significantly increased the likelihood of surgical treatment in children undergoing surgery.

The 2016 International Myeloma Working Group consensus recommendations emphasize high-sensitivity methods for minimal residual disease (MRD) detection, treatment response assessment, and prognostication. Next-generation sequencing (NGS) of IGH gene rearrangements is highly specific and sensitive, but its description in routine clinical practice and performance comparison with high-sensitivity flow cytometry (hsFC) remain limited. In this large, single-institution study including 438 samples from 251 patients, the use of NGS targeting the IGH and IGK genes for clonal characterization and monitoring, with comparison to hsFC, is described. The index clone characterization success rate was 93.6% (235/251), which depended on plasma cell (PC) cellularity, reaching 98% when PC ≥10% and below 80% when PC

Key Points Myeloid neoplasm (MPN) clones can evolve from acute myeloid leukemia to gain dominance with isocitrate dehydrogenase inhibition. Pro-differentiation agents such as ivosidenib can unmask MPN sequelae.

A ternary nanocomposite structure of TiO2–Cu2O–Au was successfully synthesized by the hydrothermal method to explore the light trapping mechanism of Au nanoparticles in photoelectrochemical water splitting. The photocurrent curve of TiO2–Cu2O–Au quickly arrived at saturation and increased to 1044 μA/cm2 at 1.23 V (vs RHE), which was 10.4 times higher than the TiO2 only. This attributed to the positive synergistic effect of Au plasmon and TiO2–Cu2O heterojunction, in which Au act as a light absorber extended the optical path while Cu2O promoted the separation of photogenerated electron–hole pairs in semiconductors. These intriguing results expanded the comprehensive understanding of the plasmon-assisted photocatalyic reactions and gave a better manipulation in the design of efficient artificial photosynthesis systems. TiO2–Cu2O–Au nanorod arrays were successfully synthesized by the hydrothermal method. TiO2–Cu2O–Au nanorod arrays photoanode were strategically designed to improve photoelectrocatalytic (PEC) performance by Au plasmon loading and building TiO2–Cu2O heterojunction. The Au in TiO2–Cu2O–Au nanorod array act as a light absorber extended the optical path, and the Cu2O promoted the separation of photogenerated electron–hole pairs. On the merits of such a synergistic effect, TiO2–Cu2O–Au nanorod array shows higher light-harvesting ability, lower carrier recombination rate, and resultant improved PEC performance than the contrast of TiO2, TiO2–Cu2O and TiO2–Au.

Owing to the capacity of efficiently harvesting and converting incident energy, localized surface-plasmon resonance of noble metals was introduced into a metal–semiconductor design for promoting hydrogen evolution. In this study, a plasmonic nanodumbbell structure was employed to strategically modulate the energy transfer in the water reduction reaction. A maximum H2 evolution rate of 80 μmol g−1 h−1 was obtained in the Au-TiO2 nanodumbbells, and further improvement was achieved through surface modification with Pt nanoparticles functioning as active sites, leading to ∼4.3 times enhanced photocatalytic activity. Compared with similar nanostructures reported previously, the present superior photoactivity response is ascribed to the injection process of the energetic hot electrons generated from the excitation and decay of the longitudinal surface-plasmon resonance (LSPR) and transverse surface-plasmon resonance (TSPR) in the Au nanorods, which corresponds to the electric field distribution of the finite-difference-time-domain simulation. These intriguing results, originating from the positive synergistic effect of the plasmon and co-catalyst, demonstrated the mechanism of the plasmon-assisted photochemistry and provided a promising strategy for the rational design of novel plasmonic photocatalysts.

The Z-scheme design was employed to strategically modulate the transfer process of photogenerated charges for hydrogen evolution reaction. The hydrothermally treated Au nanoparticles were introduced as the Z-scheme bridge, which was advantageous in the separation and transportation of active charges. Comparing with pristine samples, the TiO2-Au-CdS nanorods exhibited superior performance for solar water splitting. Keywords: Au nanoparticle, Z-scheme, Hydrogen generation

Background: Patients treated with cytotoxic chemotherapies and/or autologous stem-cell transplantation (ASCT) are at risk for therapy-related myeloid neoplasms (tMN). As these agents yield increased mutation burden in relapsed malignancies and leave evidence of exposure via mutational signatures, we studied the genomic and temporal relationship between chemo exposure and progression of clonal hematopoiesis (CH) to tMN. Methods: We analyzed 32 tMN whole genomes (WG) from 31 patients [27 acute myeloid leukemias (AML), 4 myelodysplastic syndromes]. For 7 patients with tMN post-high-dose melphalan/ASCT, we investigated the presence of antecedent CH using targeted sequencing (MSK-IMPACT; Bolton et al. Nat Gen 2020) on pre-melphalan blood mononuclear cells, granulocytes, or CD34+ apheresis samples. Results: TMN was diagnosed a median of 4.2 years (IQR, 2.6-6.6) following primary treatment. When compared to data from 200 de novo AML from TCGA (NEJM, 2013), tMNs had fewer mutations in FLT3 (9.7% v 28.0%; p = 0.028) and NPM1 (3.2% v 27.0%; p = 0.003). TP53 loss was enriched in tMNs (25.8% v 10.5%; p = 0.035 ). Mutational signature analysis revealed 5 known single base substitution (SBS) signatures in tMN: the hematopoietic stem-cell (SBS-HSC), aging (SBS1), melphalan (SBS-MM1), and platinum signatures (E-SBS1, E-SBS20) (Rustad et al. Nat Comm 2020, Pich et al. Nat Gen 2019). Complex structural variants (SV), defined as ≥3 breakpoint pairs involved in simultaneous copy number changes (Rustad et al. Blood Can Disc 2020), were observed in 7 tMNs; including chromothripsis in 6 tumors (19.4%), chromoplexy in 2 (6.5%), templated insertion in 1 (3.2%), and unspecified complex SV in 2 (6.5%). Chromothripsis has not been previously reported in de novo AML and, in 4 cases, involved chromosome 19 with hyper-amplification of the SMARCA4 locus (≥5 copies). CH variants that became clonal in tumor were seen in 5/7 pre-melphalan/ASCT samples and included mutations in TP53, RUNX1, NCOR1, NF1, CREBBP, DNMT3A, and PPM1D. Chemotherapy introduces hundreds of mutations, leaving each exposed cell with a unique catalogue (i.e., barcode). In fact, TMNs with evidence of chemo signatures had a higher mutation burden (median 1574 single nucleotide variants) than those without (median 938; p = 0.004). Detection of chemo signatures in bulk genome sequencing relies on one cell, with its catalogue of mutations, to expand to clonal dominance (Fig 1a, Landau et al. Nat Comm 2020). Given the long latency between exposure and tMN diagnosis, this single-cell expansion model was expected for all samples exposed to melphalan or platinum-based regimens (i.e., agents with a measurable signature). Strikingly, all patients with pre-tMN platinum exposure (n=7) had evidence of platinum SBS signatures whereas only 2 of 7 patients with prior melphalan/ASCT had a melphalan signature (SBS-MM1). As all platinum-exposed tMN had mutational evidence of exposure, a CH clone must have existed prior to exposure, supporting a single-cell expansion model. Absence of a chemo signature for 5/7 post-melphalan/ASCT tumors despite exposure implies tumor progression driven either by multiple clones in parallel (Fig 1b) or by an unexposed clone. As latency largely excludes the former, this suggests pre-tMN CH clones were re-infused during SCT, thus avoiding chemo exposure (Fig 1c). This is supported by two lines of evidence: 1) tMNs from 2 patients exposed to sequential platinum and melphalan/ASCT had platinum but not melphalan signatures confirming single-cell expansion of the pre-tMN CH clone post-platinum but with escape from exposure to melphalan in the ASCT (Fig 1d); 2) targeted sequencing of pre-tMN samples from melphalan/ASCT patients identified tMN genomic mutations at the CH level in 5/7 cases, including in all 3 tested apheresis samples - one of which (TP53) expanded to dominance without a melphalan signature. Conclusion: WG sequencing identified novel features of tMN revealing the key driver role of complex SV. Mutational signature analyses and targeted sequencing of pre-tMN samples can increase our understanding of tMN pathogenesis and demonstrate that tMNs arising post-ASCT are often driven by CH clones that re-engraft after escaping melphalan exposure. This mode of expansion suggests that a permissive, immunosuppressed, post-transplant environment might play a more important role than chemotherapy-induced mutagenesis in tMN pathogenesis. Figure 1 Figure 1. Disclosures Diamond: Sanofi: Honoraria; Medscape: Honoraria. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley: AbbVie: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bolli: Amgen: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Scordo: Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Lahoud: MorphoSys: Membership on an entity's Board of Directors or advisory committees. Stein: Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy. Sauter: Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Bristol Myers Squibb/Juno: Research Funding; Physician Education Resource: Honoraria; Plexus Communications: Honoraria; Takeda Oncology: Research Funding; Jansen Oncology: Research Funding; Fate Therapeutics: Research Funding; Allogene Therapeutics: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy. Korde: Medimmune: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Hultcrantz: Daiichi Sankyo: Research Funding; Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding. Shah: Bristol Myers Squibb: Research Funding; Janssen: Research Funding. Shah: Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Park: Servier: Consultancy; Affyimmune: Consultancy; Autolus: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Novartis: Consultancy; Kura Oncology: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Kite Pharma: Consultancy. Landau: Genzyme: Honoraria; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Sekeres: BMS: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ho: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Lesokhin: pfizer: Consultancy, Research Funding; Janssen: Honoraria, Research Funding; Iteos: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Behringer Ingelheim: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Landgren: Janssen: Other: IDMC; Janssen: Research Funding; Amgen: Honoraria; Celgene: Research Funding; Janssen: Honoraria; Amgen: Research Funding; Takeda: Other: IDMC; GSK: Honoraria. Maura: OncLive: Honoraria; Medscape: Consultancy, Honoraria.

INTRODUCTION Lymphoma cells are dependent on the tumor microenvironment (TME) for their survival and proliferation. Dissection of TME composition provides insight into lymphomagenesis, better prognostication, and enhancement of therapeutic options. Flow cytometry provides a robust approach for single-cell analysis. Nonetheless lack of well-defined comparator groups and/or a robust, reproducible approaches for analyzing the multidimensional data often limited such studies. In the current study, we analyzed the T cell background on a large reference set of follicular hyperplasia (FH) lymph node samples utilizing a robust standardized high dimensionality flow cytometry and a novel reproducible analytical pipeline. We then compared this baseline reference set with tumor infiltrating T cell subsets in follicular lymphoma (FL; in treatment naïve FL-NA and relapsed/refractory FL-RR sets). METHODS On behalf of the imCORE Network we analyzed 44 FH and 81 FL (35 FL-NA and 44 FL-RR) with 2 standardized flow cytometry panels (23 antigen/18-color) (Table 1). We evaluated the T cell subset distribution as well as immune checkpoint expression (TIGIT, TIM3, PD-1, CD96, LAG3, CTLA4, CD73) within analytically defined T cell clusters. Analysis was performed using semiautomated multi-step analytical pipeline as outlined in Figure 1. Using standardized instrument settings and an R-based algorithms (gaussNorm) to minimize technical variations in sample acquisition we analyzed the T-cells subpopulations using a dimensionality reduction technique (UMAP), combined with an unsupervised clustering algorithm (FlowSOM). Statistical analysis was performed using non-parametric Wilcoxon test. RESULTS In the 3 cohorts, several marked differences in the composition T cells subsets were observed. Compared to FH the FL lymph nodes were depleted for CD4 & CD8 naïve subsets (Table 2) and were characterized by an immune suppressive microenvironment enriched in specific subsets of activated T regulatory cells and exhausted memory effector cells. The pool of CD8 naïve cells was restored in FL-RR cases (Table 2). FL-NA nodes showed enrichment of T follicular regulatory cells (Tfr; Table 2) (0.9% vs 2.7%, p In association with the increase of Tfr cells, the concentration of CTLA4+, TIGIT+, PD1bright T follicular helper cells (Tfh) was reduced in FL-RR compared to FL-NA (Fig. 2C). The Tfr/Treg expansion was also associated with a marked increase in exhausted memory T cells in both CD4 and CD8 compartments (CD4 EM TP and CD8 EM DP, Table 2). In FL isolates the CD4 compartment was characterized by the expression of triple positive (CTLA4, TIGIT, PD1) phenotype in EM cells while the memory CD8 cells overexpressed TIGIT and PD1 (Fig. 2D). A smaller subpopulation of memory CD8 cells, almost undetectable in FH samples, characterized by the expression of CTLA4, PD1, TIGIT and TIM3 is expanded in FL isolates (Fig. 2D). CONCLUSION Our data suggest that change in balance between TFH and Tfr may lead to more aggressive therapy resistant disease in FL. The interplay between TFH and Tfr, has been postulated to shape the immune response in FL with TFH promoting germinal center formation and Tfr inhibiting TFH and follicular effector T cells. While both TFH and Tfr compartments are expanded in FL, in the relapsed/ refractory FL cases, the Tfr compartment is further expanded at the expense of TFH leading to more immunosuppressive background. Furthermore our study suggests a rational way of designing immune checkpoint inhibitor studies in FL. Effector memory T-cells in FL isolates show an exhausted phenotype characterized by the expression of the inhibitory receptors CTLA4, TIGIT, PD1 in the CD4 compartment, and TIGIT, PD1 in the CD8. In addition, the noteworthy expansion of TIM3+ memory CD8 cells in FL. Targeting these most highly expressed checkpoints in FL alone or in combination may provide an avenue for rational trial design. Figure 1 Figure 1. Disclosures Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Dogan: Physicians' Education Resource: Honoraria; Peer View: Honoraria; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy.

Due to the capacity of efficiently harvesting and converting light energy, the property of localized surface plasmon resonance (LSPR) in the noble metal is employed as an efficient assistant in photoelectrochemical water splitting. In this study, the Au nanoparticles (NPs) were modified on the 1D ordered structure as the active sites of the SPR effect for the plasmon-enhanced photocatalytic performance. A maximum current density of 4.45 mA cm−2 at 1.2 V (versus RHE) was obtained in alkaline solution without a sacrificial agent for the ZnO–CdS–Au photoelectrode, which was 1.48 times higher than that of the ZnO–CdS nanorods without Au decoration, as well as the ~235% enhancement of the photoconversion efficiency. Compared to similar nanostructures previously reported, the present superior photoactivity response was ascribed to the injection process of the energetic hot electrons generated through the excitation and decay of surface plasmons in the Au NPs, resulting in the efficient separation and migration of photogenerated electron–hole pairs in ternary nanorod arrays. These excellent results have expanded the comprehensive understanding of hot electron migration in plasmonic NP-semiconductor nanocomposite, and provided a promising strategy for the rational design of the plasmonic-enhanced photocatalyst.

C9 arenes consist of a series of isomeric compounds with very close boiling points. Although hard to separate by distillation, e.g. the separation of 1,2,4-trimethylbenzene and 1,3,5-trimethylbenzene, it was possible to perform flow sheet and equipment analyses of the actual operating data by computer simulation and produce a successful flow sheet revamp. That is, with new separation technology and structured packing technology, the original flow sheet was rearranged and columns were reconstructed. The conclusion of the retrofit demonstrated increased throughput, purity and productivity of 1,2,4-trimethylbenzene (the main product). In addition, 1,3,5-trimethylbenzene, a very important by-product, was obtained at higher purity. This reconstruction brings significant economic benefit and advanced technology for the separation and utilization of C9 arenes in worldwide operations. Copyright © 2007 Curtin University of Technology and John Wiley & Sons, Ltd.

Neuroendocrine differentiation (NED) has been recognized in prostatic adenocarcinomas. NED prostate adenocarcinoma represent a subset of aggressive tumor phenotypes which may be associated with therapeutic resistance and dismal outcome. Genomic and transcriptomic studies have suggested that there is marked intra-tumor heterogeneity of neuroendocrine differentiation in prostatic adenocarcinoma. NED tumors surges with increase in tumor grade and/or stage prostate cancers particularly in hormone-treated and hormone-refractory tumors. However, the prognostic value of NED in prostate adenocarcinoma is not well understood due to conflicting results in reported studies. We hypothesize that the heterogeneous nature of NED in prostate cancer may contribute to the difficulty in predicting outcomes in morphologically similar tumor specimens. In this study, 36 radical prostatectomy cases with a diagnosis of prostatic adenocarcinoma were procured from the archive of the Department of Pathology at the University Hospitals Cleveland Medical Center, including 18 patients who developed recurrent cancer after curative surgery with PSA level >0.1 ng/mL, and 18 patients whose cancers did not recur during matched follow up times. NED was subjectively evaluated by performing immunohistochemistry (IHC) for Chromogranin A (CgA), a neuroendocrine differentiation marker, and the scores were evaluated independently by two pathologist. Ten areas were randomly selected from areas of cancer present on each whole mount section, and the CgA IHC staining intensity in these areas was graded from 0-5, wherein 0 represents no staining and 4 represents strong staining. CgA staining intensity was positively associated with rise in serum PSA level. A significant intratumoral heterogeneity of CgA staining intensity was observed. The cumulative CgA scores from 10 areas were higher in specimens from patients whose cancers relapsed, as compared with specimens from patients whose cancers did not recur. Average cumulative CgA score was noted to be 18.72 ± 2.78 in the relapsed group and 8.28 ± 1.44 in the remission group. Taken together, the study revealed that intra-tumor heterogeneity of NED exists in prostate adenocarcinoma and influences the precise evaluation of NED in clinical specimens. Though the data is not conclusive, we do observe a lower level of NED in patients with remission compared to patients with a clinical failure in treatment by thorough evaluation of NED in prostate whole mount sections. This study potentially provides guidance to clinical usage of NED markers in prostate adenocarcinoma. Citation Format: Menglei Zhu, Wei Chen, Michael Glover, Eswar Shankar, Gregory T. MacLennan, Sanjay Gupta. Prognostic role of neuroendocrine differentiation marker in prostate adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-255. doi:10.1158/1538-7445.AM2017-LB-255