Clonal origin of Epstein-Barr virus-infected T/NK-cell subpopulations in chronic active Epstein-Barr virus infection

Clonal expansion of Epstein-Barr virus (EBV) infected B-cells occasionally occurs in immunocompromized subjects. EBV-infected T/natural killer (NK)-cells proliferate in patients with chronic active EBV infection (CAEBV) that is a rare mononucleosis syndrome. It is classified into either T-cell type or NK-cell type according to the primary target of infection, while the pathogenesis remains unclear. To search the clonal origin of EBV-infected T/NK-cells, virus distribution and clonotype were assessed by using highly purified cell fractions obtained from 6 patients. Patient 1 had a monoclonal proliferation of EBV-infected T-cell receptor Vδ2/Vγ9-expressing cells, and carried lower copy number of EBV in αβT-cells. Patients 2 and 3 had a clonal expansion of EBV-infected CD4+T-cells, and lower EBV load in CD56+cells. Patients 4, 5 and 6 had an expansion of CD56+cells with higher EBV load than CD3+cells. EBV-terminal repeats were determined as clonal bands in the minor targeted populations of 5 patients. The size of terminal repeats indicated the same clonotype in minor subsets as in major subsets of 4 patients. However, EBV was not detected in bone marrow-derived lineage negative CD34+cells of patients. These results suggested that EBV could infect T/NK-cells at differentiation stage, but spared bone marrow CD34+hematopoietic stem cells in CAEBV patients

ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells

<p>Abstract</p> <p>Background</p> <p>Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4⁺T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The <it>HTLV-1 bZIP factor </it>(<it>HBZ</it>) gene, which is encoded by the minus strand of the viral genome, is expressed as an antisense transcript in all ATL cases. By using yeast two-hybrid screening, we identified activating transcription factor 3 (ATF3) as an HBZ-interacting protein. ATF3 has been reported to be expressed in ATL cells, but its biological significance is not known.</p> <p>Results</p> <p>Immunoprecipitation analysis confirmed that ATF3 interacts with HBZ. Expression of ATF3 was upregulated in ATL cell lines and fresh ATL cases. Reporter assay revealed that ATF3 could interfere with the HTLV-1 Tax's transactivation of the 5' proviral long terminal repeat (LTR), doing so by affecting the ATF/CRE site, as well as HBZ. Suppressing ATF3 expression inhibited proliferation and strongly reduced the viability of ATL cells. As mechanisms of growth-promoting activity of ATF3, comparative expression profiling of ATF3 knockdown cells identified candidate genes that are critical for the cell cycle and cell death, including cell division cycle 2 (CDC2) and cyclin E2. ATF3 also enhanced p53 transcriptional activity, but this activity was suppressed by HBZ.</p> <p>Conclusions</p> <p>Thus, ATF3 expression has positive and negative effects on the proliferation and survival of ATL cells. HBZ impedes its negative effects, leaving ATF3 to promote proliferation of ATL cells via mechanisms including upregulation of CDC2 and cyclin E2. Both HBZ and ATF3 suppress Tax expression, which enables infected cells to escape the host immune system.</p

Mixing Histopathology Prototypes into Robust Slide-Level Representations for Cancer Subtyping

Whole-slide image analysis via the means of computational pathology often relies on processing tessellated gigapixel images with only slide-level labels available. Applying multiple instance learning-based methods or transformer models is computationally expensive as, for each image, all instances have to be processed simultaneously. The MLP-Mixer is an under-explored alternative model to common vision transformers, especially for large-scale datasets. Due to the lack of a self-attention mechanism, they have linear computational complexity to the number of input patches but achieve comparable performance on natural image datasets. We propose a combination of feature embedding and clustering to preprocess the full whole-slide image into a reduced prototype representation which can then serve as input to a suitable MLP-Mixer architecture. Our experiments on two public benchmarks and one inhouse malignant lymphoma dataset show comparable performance to current state-of-the-art methods, while achieving lower training costs in terms of computational time and memory load. Code is publicly available at https://github.com/butkej/ProtoMixer.Comment: The final authenticated publication is available online at https://doi.org/10.1007/978-3-031-45676-3_1

Candida dubliniensis in Japanese Oral Microbiota: A Cross-Sectional Study of Six Geographic Regions in Japan

Introduction: Candida dubliniensis was reclassified from the C. albicans genotype D, and reports show its frequent detection in HIV-positive individuals and easy acquisition of antifungal drug resistance. However, the oral carriage rate in healthy people and contribution to candidiasis in Japan is unclear. Methods: We conducted a cross-sectional survey of the C. dubliniensis carriage rate, performed genotyping and tested antifungal drug susceptibility and protease productivity. Specimens from 2432 Japanese subjects in six regions (1902 healthy individuals, 423 with candidiasis individuals, 107 HIV-positive individuals) were cultured using CHROMagarTMCandida, and the species was confirmed via 25S rDNA amplification and ITS sequences analyzed for genotyping. Results: The C. dubliniensis carriage rate in healthy Japanese was low in the central mainland (0–15%) but high in the most northerly and southerly areas (30–40%). The distribution of these frequencies did not differ depending on age or disease (HIV-infection, candidiasis). Genotype I, previously identified in other countries, was most frequent in Japan, but novel genotypes were also observed. Six antifungal drugs showed higher susceptibility against C. albicans, but protease productivity was low. Conclusions: Oral C. dubliniensis has low pathogenicity with distribution properties attributed to geography and not dependent on age or disease status

Case-based similar image retrieval for weakly annotated large histopathological images of malignant lymphoma using deep metric learning

In the present study, we propose a novel case-based similar image retrieval (SIR) method for hematoxylin and eosin (H&E)-stained histopathological images of malignant lymphoma. When a whole slide image (WSI) is used as an input query, it is desirable to be able to retrieve similar cases by focusing on image patches in pathologically important regions such as tumor cells. To address this problem, we employ attention-based multiple instance learning, which enables us to focus on tumor-specific regions when the similarity between cases is computed. Moreover, we employ contrastive distance metric learning to incorporate immunohistochemical (IHC) staining patterns as useful supervised information for defining appropriate similarity between heterogeneous malignant lymphoma cases. In the experiment with 249 malignant lymphoma patients, we confirmed that the proposed method exhibited higher evaluation measures than the baseline case-based SIR methods. Furthermore, the subjective evaluation by pathologists revealed that our similarity measure using IHC staining patterns is appropriate for representing the similarity of H&E-stained tissue images for malignant lymphoma

Central nervous system post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: The Nagasaki transplant group experience

A 17-year-old male received allogeneic transplantation for acute lymphoblastic leukemia, and presented with generalized seizures due to a solitary brain lesion with massive necrosis on day +621. Epstein?Barr virus (EBV) DNA copies were below the cut-off value in plasma. Stereotactic biopsy of the cerebral lesion confirmed the diagnosis of post-transplant lymphoproliferative disorder (PTLD) with large atypical cells positive for CD20 and EBER.In order to diagnose primary central nervous system PTLD, the biopsy should be applied as early as possible when brain lesion with necrosis develops in post-transplant patients regardless of EBV-DNA in plasma

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma

成人T細胞白血病リンパ腫（ATL）におけるゲノム情報と臨床情報を統合したリスクモデルを確立 --ATLの個別化医療を推進--. 京都大学プレスリリース. 2023-04-10.The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment. To identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] 5.46, p < 0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR 2.33, p = 0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATL-PI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3)

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae

We systematically surveyed period variations of superhumps in SU UMa-type dwarf novae based on newly obtained data and past publications. In many systems, the evolution of superhump period are found to be composed of three distinct stages: early evolutionary stage with a longer superhump period, middle stage with systematically varying periods, final stage with a shorter, stable superhump period. During the middle stage, many systems with superhump periods less than 0.08 d show positive period derivatives. Contrary to the earlier claim, we found no clear evidence for variation of period derivatives between superoutburst of the same object. We present an interpretation that the lengthening of the superhump period is a result of outward propagation of the eccentricity wave and is limited by the radius near the tidal truncation. We interpret that late stage superhumps are rejuvenized excitation of 3:1 resonance when the superhumps in the outer disk is effectively quenched. Many of WZ Sge-type dwarf novae showed long-enduring superhumps during the post-superoutburst stage having periods longer than those during the main superoutburst. The period derivatives in WZ Sge-type dwarf novae are found to be strongly correlated with the fractional superhump excess, or consequently, mass ratio. WZ Sge-type dwarf novae with a long-lasting rebrightening or with multiple rebrightenings tend to have smaller period derivatives and are excellent candidate for the systems around or after the period minimum of evolution of cataclysmic variables (abridged).Comment: 239 pages, 225 figures, PASJ accepte