Gluconeogenesis in the extraembryonic yolk syncytial layer of the zebrafish embryo.

Yolk-consuming (lecithotrophic) embryos of oviparous animals, such as those of fish, need to make do with the maternally derived yolk. However, in many cases, yolk possesses little carbohydrates and sugars, including glucose, the essential monosaccharide. Interestingly, increases in the glucose content were found in embryos of some teleost fishes; however, the origin of this glucose has been unknown. Unveiling new metabolic strategies in fish embryos has a potential for better aquaculture technologies. In the present study, using zebrafish, we assessed how these embryos obtain the glucose. We employed stable isotope (13C)-labeled substrates and injected them to the zebrafish embryos. Our liquid chromatography-mass spectrometry-based isotope tracking revealed that among all tested substrate, glutamate was most actively metabolized to produce glucose in the zebrafish embryos. Expression analysis for gluconeogenic genes found that many of these were expressed in the yolk syncytial layer (YSL), an extraembryonic tissue found in teleost fishes. Generation 0 (G0) knockout of pck2, a gene encoding the key enzyme for gluconeogenesis from Krebs cycle intermediates, reduced gluconeogenesis from glutamate, suggesting that this gene is responsible for gluconeogenesis from glutamate in the zebrafish embryos. These results showed that teleost YSL undergoes gluconeogenesis, likely contributing to the glucose supplementation to the embryos with limited glucose source. Since many other animal lineages lack YSL, further comparative analysis will be interesting.

Prognostic relevance of tumor-infiltrating CD4+ cells and total metabolic tumor volume-based risk stratification in diffuse large B-cell lymphoma.

To elucidate the relationship between pre-treatment radiomic parameters and the proportions of various tumour-infiltrating (TI) cells, we retrospectively analysed the association of total metabolic tumour volume (TMTV) and TI cells on biopsied tumour lesions in 171 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The surface markers of TI cells were analysed by multicolour flow cytometry using a dissected single-cell suspension. In examining the correlation between TI cells and PET-derived parameters (SUVmax, TMTV, and total lesion glycolysis), intratumoural cell types minimally influenced the results, except for a weak negative correlation between CD4+ cells and SUVmax (R=-0.16, P=0.045). Even for the lesion fluorodeoxyglucose uptake at the biopsied site, CD19+ cells (indicative of malignant burden) showed only a weak correlation with the highest SUV (R=0.21, P=0.009), whereas CD3+ (R=-0.25, P=0.002) and CD4+ cells (R=-0.29, P.

Analysis of baseline circulating tumor cells integrated with PET/CT findings in transplant-ineligible multiple myeloma.

ABSTRACT: We aimed to improve prognostic predictors in patients with transplant-ineligible multiple myeloma (TIE-MM) by combining baseline circulating clonal tumor cells (CTCs) and positron emission tomography/computed tomography (PET/CT) findings. The factors associated with prognosis were retrospectively investigated in 126 patients with TIE-MM who underwent CTC quantification by multiparameter flow cytometry and PET/CT at the initial presentation. The total lesion glycolysis (TLG) level was calculated using the Metavol software. The median percentage of CTC was 0.06% (range, 0%-4.82%), and 54 patients (42.9%) demonstrated high CTC levels. High CTC levels were associated with significantly poorer progression-free survival (PFS, 2-year 43.4% vs 68.1%; P < .001) and overall survival (OS, 5-year 39.0% vs 68.3%; P < .001). Similarly, high TLG levels significantly worsened the PFS (2-year, 41.2% vs 67.6%; P = .038) and OS (5-year, 37.7% vs 63.1%; P = .019). The multivariate analyses showed that Revised International Staging System (R-ISS) III, high CTC and TLG levels, and complete response were significant prognostic factors for PFS and OS. A novel predictive model was constructed using CTCs, TLG, and R-ISS III. The patients were stratified into 3 groups according to the number of risk factors, revealing an extremely high-risk group with a 2-year PFS of 0% and a 5-year OS of 20%. Patients without any high-risk features had better prognosis, with a 2-year PFS of 78.6% and a 5-year OS of 79.5%. The combination of CTCs and volumetric assessment of PET/CT at diagnosis augments the existing stratification systems and may pave the way for a risk-adapted treatment approach.

Cold-induced muscle atrophy in zebrafish: Insights from swimming activity and gene expression analysis.

The investigation into the effects of cold acclimation on fish skeletal muscle function and its potential implications for muscle atrophy is of great interest to us. This study examines how rearing zebrafish at low temperatures affects their locomotor activity and the expression of genes associated with muscle atrophy. Zebrafish were exposed to temperatures ranging from 10 °C to 25 °C, and their swimming distance was measured. The expression levels of important muscle atrophy genes, Atrogin-1 and MuRF1, were also evaluated. Our findings show that swimming activity significantly decreases when the water temperature ranges from 10 °C to 15 °C, indicating a decrease in voluntary movement. Additionally, gene expression analysis shows a significant increase in the expression of Atrogin-1 and MuRF1 at 10 °C. This up-regulation could lead to muscle atrophy caused by decreased activity in cold temperatures. To investigate the effects of exercise on reducing muscle atrophy, we subjected zebrafish to forced swimming at a temperature of 8 °C for ten days. This treatment significantly reduced the expression of Atrogin-1 and MuRF1, emphasizing the importance of muscle stimulation in preventing muscle atrophy in zebrafish. These findings suggest that zebrafish can serve as a valuable model organism for studying muscle atrophy and can be utilized in drug screening for muscle atrophy-related disorders. Cold-reared zebrafish provide a practical and ethical approach to inducing disuse muscle atrophy, providing valuable insights into potential therapeutic strategies for addressing skeletal muscle atrophy.

Use of the Second Revision of the International Staging System for prognostic stratification of multiple myeloma patients in real-world clinical practice and the importance of sub-groups, including age.

Not available.

Concordance between HokUS-10 Scoring and Transjugular Liver Biopsy for the Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Allogeneic Stem Cell Transplantation.

The aim of this study was to evaluate the concordance between clinical diagnosis and pathologic findings of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in post-hematopoietic stem cell transplantation recipients and to investigate the accuracy of the HOKUS-10 score in diagnosing VOD/SOS. We included 13 patients who underwent transjugular liver biopsy for clinical suspicion of VOD/SOS and collected their clinical, laboratory, imaging, and pathologic data. Eleven patients were confirmed to have VOD/SOS by pathologic examination. The median HokUS-10 score and hepatic venous pressure gradient were 6 points (range, 0 to 10 points) and 13 mmHg (range, 7 to 24 mmHg), respectively. There was no significant difference between these scores in VOD/SOS and non-VOD/SOS cases; however, patients with lower HokUS-10 scores tended to have milder histologic features of VOD/SOS compared with severe cases. This study highlights the potential discordance between clinical diagnosis and pathologic diagnosis of VOD/SOS and emphasizes the importance of liver biopsy to optimize treatment.

Safety and efficacy of venetoclax for acute myeloid leukaemia in real-world clinical practice.

Venetoclax combined with low-intensity chemotherapy has led to longer survival and higher remission rates in patients with untreated acute myeloid leukaemia who are ineligible for intensive chemotherapy. We reviewed 41 newly diagnosed and relapse/refractory acute myeloid leukaemia patients who received venetoclax at our institute. Complete remission or complete remission with incomplete recovery was achieved in 73.1% of patients. A total of 95.1% of patients discontinued venetoclax, mainly because of severe cytopenia, disease progression and haematopoietic stem cell transplantation. The median number of courses of venetoclax was 2. In all, 92.6% of the patients experienced grade ≥ 3 neutropenia. The median overall survival was 287 days. Venetoclax dose reduction resulted in better continuity of treatment with fewer complications. In conclusion, venetoclax and low-intensity chemotherapy led to high remission rates, but survival was restrained because of the large number of venetoclax discontinuations. Dose reduction of venetoclax may mitigate cytopenia while maintaining efficacy.

Clinical Characteristics and Outcomes of Cyclin D1-Positive AL Amyloidosis.

OBJECTIVES: To demonstrate the clinical features and prognostic impact of cyclin D1 positivity in patients with amyloid light chain amyloidosis (AL). METHODS: We consecutively included 71 patients diagnosed with AL with cyclin D1 positivity between February 2008 and January 2022. t(11;14) was examined through interphase fluorescence in situ hybridization using bone marrow cells. RESULTS: The median age of the patients was 73 years, and 53.5% were male. The underlying diseases included symptomatic multiple myeloma, smoldering multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy of undetermined significance, representing 33.8%, 26.8%, 2.8%, and 36.6%, respectively. The prevalence of cyclin D1 and t(11;14) was 38.0% and 34.7%, respectively. Higher frequency of light chain paraprotein type was seen in cyclin D1-positive patients with AL than in cyclin D1-negative patients (70.4% vs 18.2%). The median overall survival (OS) of patients with AL with and without cyclin D1 expression was 18.9 months and 73.1 months, respectively (P = .019). Early death occurred in 44.4% of cyclin D1-positive patients and 31.8% of cyclin D1-negative patients. Moreover, 83.3% of cyclin D1-positive patients and 21.4% of cyclin D1-negative patients died of cardiac causes. CONCLUSIONS: Cyclin D1 immunohistochemistry accurately identified patients with t(11;14). Cyclin D1-positive patients had significantly inferior OS compared with cyclin D1-negative patients.

Longitudinal changes in cell-mediated immunity after varicella-zoster virus skin test in the general population; Shozu Herpes Zoster Study: SHEZ study.

Varicella-zoster virus-specific cell-mediated immunity has been associated with the onset and severity of herpes zoster (HZ), and the administration of the HZ vaccine enhanced the immunity. However, limited data is available on the duration of cell-mediated immunity enhancement by soluble antigen of varicella-zoster virus (VZV) skin test. A prospective, community-based cohort study was conducted in Shozu County, Kagawa Prefecture, Japan. Repeated VZV skin tests containing inactivated VZV antigen and blood tests were performed on 365 subjects aged 60 years and older at baseline, 1, 2, and 3 years later. The differential immunity indices of VZV over time for cell-mediated and humoral immunity were evaluated. VZV skin test reaction and ELISpot counts increased significantly at 1, 2, and 3 years later compared to the baseline. However, humoral immunity indices did not change materially over time. Soluble antigen by VZV skin test enhanced VZV-specific cell-mediated immunity, and it persisted for at least 1 year. In addition, the inoculation with inactivated antigens every year by VZV skin test continued to enhance VZV-specific cell-mediated immunity after 2 and 3 years.

Antibody status following booster vaccination against SARS-CoV-2 virus in patients with haematologic malignancies.

Antibody titres in 462 patients with haematological malignancies after the second (D2) and third (D3) SARS-CoV-2 vaccine were compared with those of healthy controls (HCs). Significant decay of antibody titre was observed pre D3, but titre surged post D3. The number of seronegative patients decreased from 79 (17.1%) to 44 (9.5%) from post D2 to post D3, and patients with adequate antibody titre increased from 204 (44.2%) to 358 (77.5%). Of the patients who received B-cell-targeted therapy, 80% were seronegative and 71% remained seronegative after D3. CD19+, CD4+, CD8+ cell counts, and immunoglobulin G (IgG) levels were identified as independent predictors for adequate serologic response.

A dataset of pairs of an image and tags for cataloging image-based archives.

The dataset described in this paper contains pairs of images collected from the Web and their tags of keywords, which are linked to appropriate entity pages of Wikipedia, and programs to reproduce experiments. It is assumed for evaluating the disambiguation task, in which given an image and its tags to be disambiguated, an appropriate Wikipedia page is selected for each of the given tag. We collected images tagged keywords of animal names for that ambiguity and their tags since animal names may refer to not only names of animal but names of other types of objects, e.g., nicknames of sports teams from the photo sharing site Flickr. The tags are linked to the correspondence Wikipedia page judged by annotators. The dataset includes 420 images and 2,464 tags. It is useful for developing a system to link a keyword of an image to an entry of a knowledgebase as well as an image classification system, which include fine-grained classes, e.g. proper nouns of objects, as their classification targets.

Limited efficacy of high-dose methotrexate to prevent the central nervous system relapse in patients with IVLBCL.

To evaluate the efficacy of high-dose methotrexate (HD-MTX, ≥1 g/m2) for the prevention of central nervous system (CNS) recurrence in patients with intravascular large B-cell lymphoma (IVLBCL), we reviewed 51 patients with pathologically diagnosed untreated IVLBCL. In total, there were five cases of CNS relapse (9.8%), and the 12-month CNS relapse rate was 9.2%. No statistical difference in CNS relapse rate (p = 0.86) was observed between patients with and without HD-MTX (n = 20 and 31, respectively). Furthermore, the composite endpoint defined as either CNS and/or neurolymphomatosis relapse was not significant in terms of the administration of HD-MTX (p = 0.25). No significant predictor of CNS relapse was found. In conclusion, patients with IVLBCL are at high risk of CNS recurrence; however, HD-MTX administration may not be effective for CNS recurrence prophylaxis. Key pointsThe administration of HD-MTX for patients with untreated IVLBCL may not be effective for preventing CNS relapse.

Management of lymphoma-associated chylothorax by interventional radiology and chemotherapy: a report of five cases.

Chylous effusion is associated with lymphatic obstruction or leakage in mediastinal or abdominal lymph nodes, and is a rare but troublesome complication in patients with malignant lymphomas. Although there is no standard of care, it is often treated with simultaneous chemotherapeutic and non-chemotherapeutic interventions. Here, we describe the cases of five patients with lymphoma-associated chylothorax with the aim of clarifying an effective treatment strategy. All patients achieved a partial response or better for lymphoma. All patients underwent interventional radiology (IVR) procedures, including lymphangiography (LAG) and thoracic duct embolization (TDE). Complete resolution of chylothorax was eventually achieved by IVR procedures or pleurodesis in all patients. No patients experienced serious adverse events related to LAG/TDE. Treatment of chylous effusion required months for most patients (range: 0.2-4.8 months). Our data suggest that a combination of chemotherapy and LAG/TDE is effective for refractory lymphoma-related chylous effusion.

Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.

The European LeukemiaNet (ELN) criteria define the adverse genetic factors of acute myeloid leukemia (AML). AML with adverse genetic factors uniformly shows resistance to standard chemotherapy and is associated with poor prognosis. Here, we focus on the biological background and real-world etiology of these adverse genetic factors and then describe a strategy to overcome the clinical disadvantages in terms of targeting pivotal molecular mechanisms. Different adverse genetic factors often rely on common pathways. KMT2A rearrangement, DEK-NUP214 fusion, and NPM1 mutation are associated with the upregulation of HOX genes. The dominant tyrosine kinase activity of the mutant FLT3 or BCR-ABL1 fusion proteins is transduced by the AKT-mTOR, MAPK-ERK, and STAT5 pathways. Concurrent mutations of ASXL1 and RUNX1 are associated with activated AKT. Both TP53 mutation and mis-expressed MECOM are related to impaired apoptosis. Clinical data suggest that adverse genetic factors can be found in at least one in eight AML patients and appear to accumulate in relapsed/refractory cases. TP53 mutation is associated with particularly poor prognosis. Molecular-targeted therapies focusing on specific genomic abnormalities, such as FLT3, KMT2A, and TP53, have been developed and have demonstrated promising results.

Antibody response to COVID-19 vaccine in 130 recipients of hematopoietic stem cell transplantation.

We evaluated anti-spike protein antibody (anti-S) production in 130 hematopoietic stem cell transplant (HSCT) recipients who received the coronavirus disease-2019 vaccine. Sixty-five received allo-HSCT and 65 received auto-HSCT. Disease-specific treatments were being administered to 43.1% of allo-HSCT and 69.2% of auto-HSCT patients. Seropositivity was observed in 87.7% of allo-HSCT and 89.2% in auto-HSCT patients. Anti-S antibody production was significantly impaired in auto-HSCT patients compared with controls (178U/mL [0.4-4990.0] vs. 669 U/mL [40.3-4377.0], p < 0.001), but not in allo-HSCT patients (900 U/mL [0.4-12,893.0] vs. 860 U/mL [40.3-8988.0], P = 0.659). Clinically relevant anti-S antibody levels (> 264 U/mL) were achieved in 59.2% of patients (76.9% in allo-HSCT and 41.5% in auto-HSCT). The main factors influencing the protective level of the antibody response were the CD19 + cell count and serum immunoglobulin G levels, and these were significant in both allo-HSCT and auto-HSCT patients. Other factors included time since HSCT, complete remission status, use of immunosuppressive drugs, and levels of lymphocyte subsets including CD4, CD8 and CD56 positive cells, but these were only significant in allo-HSCT patients. Allo-HSCT patients had a relatively favorable antibody response, while auto-HSCT patients had poorer results.