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Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis. Our study suggests that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis. We present evidence that signaling through the S100a8/S100a9‐Emmprin‐Vegfa axis is essential for progression of a lung cancer model established in a microenvironment of Tet2‐deficient immune cells. Furthermore, we provide a novel target for lung cancer patients with accompanying TET2‐mutated clonal hematopoiesis.

Recent progress in next-generation sequencing technologies has shown that tumor cells in many solid cancers undergo dynamic clonal evolution. 1 Notably, diverse clones have been observed in biopsy samples acquired from primary or metastatic legions in solid cancers. 2-4 In contrast, intratumor heterogeneity (ITH) in lymphomas is less characterized: samples are taken only for diagnosis and multiregional sample collection is rarely performed in living patients, because chemotherapy rather than surgery is the standard treatment for most lymphoma subtypes. Black dots indicate a tumor mass; organs with red diagonal lines represent intravascular tumor invasions. kid, kidney; ll, left lung; lym, lymph node; rl1, right lung; spl, spleen. [...]this analysis shows a clear phylogenic tree of aggressive lymphoma, confirming that dynamic time-dependent and spatial ITH occurs even in systemic disease.

Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is a rare peripheral T‐cell lymphoma characterized by cutaneous lesions and immunologic manifestations. The five‐year survival rate of SPTCL has been reported to be over 80%, indicating a favorable prognosis. Recent studies have uncovered recurrent germline variants in HAVCR2, encoding an immunomodulator. In this study, we integrated whole‐exome sequencing data from 60 samples collected from 36 SPTCL patients, encompassing six patients of our cohort and 30 patients of publicly available data. We identified 138 somatic mutations in skin tumors of 24 patients and HAVCR2 germline mutations in 23 of 29 patients. HAVCR2 p.Tyr82Cys mutations were identified in four of six Japanese patients. During the clinical courses of four patients, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone were administered to all patients, but it resulted in incomplete responses in all four patients. However, disease conditions of all patients remained stable with additional treatment, including autologous peripheral blood stem cell transplantation. Over a 7.5‐year median follow‐up, one patient developed autoimmune‐related diseases, while one developed other hematological malignancy, resulting in death. To our knowledge, this is the first report of recurrent HAVCR2 germline mutations in Japanese patients, suggesting the necessity for long‐term follow‐up. This article is the first report of HAVCR2 germline mutations of subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) Japanese patients.

Background/Aim: Glioblastoma multiforme (GBM) is an intractable tumor that has a very poor prognosis despite intensive treatment with temozolomide plus radiotherapy. Patients and Methods: Sixteen newly diagnosed patients with high-grade gliomas were enrolled in a phase II study of the α-type-1 DC vaccine. Briefly, DCs obtained from the culture of enriched monocytes in the presence of a cytokine cocktail, were pulsed with a cocktail of 5 synthetic peptides and cryopreserved until injection into patients. Results: The amount of IL-12 produced by activated DCs was higher than that previously reported. Among 15 evaluable patients, 10 showed positive CTL responses to any peptides in an ELISPOT assay. After 6 years of observation, five patients were still alive, and two of these patients were relapse-free. Moreover, a significant survival-prolonging effect was verified in DC-treated glioma patients. Conclusion: Peptide-cocktail-pulsed α-type-1 DC vaccines have a potential therapeutic effect on survival when used in combination with the standard regimen, which is partly based on IL-12-IFN-γ-mediated T-cell activation.

This study numerically investigated the mechanisms of separation control using a synthetic jet (SJ) and plasma actuator (PA) around an NACA0015 airfoil at the chord Reynolds number of 63,000. Both SJ and PA were installed on the leading edge with the same order of input momentum (Cμ=O(10−3–10−5)) and the same actuation frequencies in F+=1.0–30. The momentum coefficient Cμ is defined as the normalized momentum introduced from the SJ or the PA, and F+ stands for the actuation frequency normalized by the chord length and uniform velocity. A number of large-eddy simulations (LES) were conducted for the SJ and the PA, and the mechanisms were clarified in terms of the exchange of chordwise momentum with Reynolds shear stress and coherent vortex structures. First, four main differences in the induced flows of the SJ and the PA were clarified as follows: (A) wall-tangential velocity; (B) three-dimensional flow structures; (C) spatial locality; and (D) temporal fluctuation. Then, a common feature of flow control by the SJ and the PA was revealed: a lift-to-drag ratio was found to be better recovered in F+=6.0–20 than in other frequencies. Although there were differences in the induced flows, the phase decomposition of the flow fields identified common mechanisms that the turbulent component of the Reynolds shear stress mainly contributes to the exchange of the chordwise (streamwise) momentum; and the turbulent vortices are convected over the airfoil surface by the coherent spanwise vortices in the frequency of F+.

Daratumumab-based therapy has been shown to have significant clinical efficacy in phase 3 trials of patients with relapse or refractory multiple myeloma. Outside of clinical trials, however, clinical data on daratumumab remain limited. We reviewed medical records of patients who received daratumumab combination therapy at our institute (median age 74 years; median lines of prior therapy 4). The overall response rate was 69.4%, and 36.7% of patients achieved complete response (CR) or better. The proportion of patients who attained CR or better was significantly higher among patients with < 4 prior therapies than those with ≥ 4 (56.5% vs 19.2%, P = 0.009). Estimated median progression-free survival (PFS) was 12.4 months (95% confidence interval 8.6—not reached). The median PFS was significantly worse in patients who were refractory to bortezomib and lenalidomide and had received ≥ 4 lines of prior therapy. Twelve of 49 patients attained negative minimal residual disease. Common adverse events included hematological toxicities including neutropenia and lymphopenia; however, the rate of febrile neutropenia was low (3.8%). Infusion-related reactions occurred in 32.1% of patients, but were grade 1 or 2. Daratumumab combination therapies therefore appear to be effective and safe as salvage regimens in clinical practice, especially when used in the early phase.

We describe a patient who presented with large cardiac diffuse large B-cell lymphoma (DLBCL) and adrenal masses. The patient also had subcutaneous intravascular lymphoma lesions which were detected by random skin biopsy. Although ambiguous, minimal extravascular location of lymphoma cells is permitted for the diagnosis of intravascular large B-cell lymphoma (IVLBCL) in the WHO definition, a number of rare cases have been reported as having concomitant tumours in other organs, such as the adrenal gland, brain, and penis. We assume that IVLBCL might be a peculiar feature of DLBCL characterised by preferential localisation of lymphoma cells within the capillaries rather than a distinct disease entity of DLBCL.

The flow control over the blades of a small horizontal-axis wind turbine (HAWT) model using a dielectric barrier discharge plasma actuator (DBD-PA) was studied based on large-eddy simulations. The numerical simulations were performed with a high-resolution computational method, and the effects of the DBD-PA on the flow fields around the blades were modeled as a spatial body force distribution. The DBD-PA was installed at the leading edge of the blades, and its impacts on the flow fields and axial torque generation were discussed. The increase in the ratios of the computed, cycle-averaged axial torque reasonably agreed with that of the available experimental data. In addition, the computed results presented a maximum of 19% increase in the cycle-averaged axial torque generation by modulating the operating parameters of the DBD-PA because of the suppression of the leading edge separation when the blade’s effective angles of attack were relatively high. Thus, the suppression of the leading edge separation by flow control can lead to a delay in the breakdown of the tip vortex as a secondary effect.

Background/Aim: The enzyme-linked immunospot (ELISPOT) assay is a well-established method used to evaluate the strength of T cell-mediated immune activity, and accepted as a standard functional immunological assay. Cytokine activity is a novel parameter reflecting spot size and intensity, which has not been used in ELISPOT assay before. Materials and Methods: In the present study, from 113 ELISPOT assay data derived from previous clinical trials with dendritic cell vaccines, both spot number count and cytokine activity data for IFN-γ secretion were obtained using an ELISPOT reader. Comparing the new parameter cytokine activity with the existing parameter spot number, the feasibility of cytokine activity was investigated. Results: There were no significant differences in sensitivity and specificity between spot number and cytokine activity among ELISPOT assay data from CMVpp65 and other antigen peptide-stimulated cytotoxic T lymphocytes. Conclusion: Although cytokine activity is a novel parameter unreported so far, it did not show any advantages in the evaluation T cell immune responses compared to the existing spot number parameter.

Neurolymphomatosis (NL) is a rare manifestation of non-Hodgkin lymphoma, in which malignant cells infiltrate the peripheral nerves. Most patients are treated with high-dose methotrexate (HD-MTX)-based systemic chemotherapy regimens similar to patients with central nervous system lymphoma. However, because NL is rare, the efficacy of HD-MTX is largely unknown. We reviewed medical records of patients diagnosed with NL over the past 10 years and identified 18 patients. The underlying hematological malignancy was diffuse large B-cell lymphoma (DLBCL) in 10 patients (55.6%), intravascular large B-cell lymphoma in six (33.3%), and other types in two patients. Ten patients were treated with HD-MTX-based systemic chemotherapy; the response rates with and without HD-MTX-based chemotherapy were 100% (n = 10) and 85.7% (n = 6), respectively (P = 0.41). The median progression-free and overall survival rates of patients with versus without HD-MTX treatment were 6.4 vs. 8.5 months (P = 0.97) and 13.5 vs. 8.5 months (P = 0.63), respectively. Despite the initial favorable responses, rapid disease recurrence was observed in most patients administered HD-MTX-based chemotherapy. Our observations suggest that HD-MTX-based chemotherapy may have insufficient efficacy against NL, and that other therapeutic approaches are required to improve the outcomes of patients with this rare disease.