Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

<p>Abstract</p> <p>Background</p> <p>The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed.</p> <p>Methods</p> <p>To address questions related to the <it>in vivo </it>interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I ⁺lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8⁺CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer.</p> <p>Results</p> <p>The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner <it>in vitro</it>. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors <it>in vivo</it>, and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors <it>in vivo </it>without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface.</p> <p>Conclusion</p> <p>These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the <it>in vivo </it>model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular immunotherapy as effector cells seek and destroy areas of tumor growth and for testing strategies to improve clinical effectiveness.</p

Mushakoji Saneatsu and Showa 9 (1934) : On the "Buddhism reconstruction" period in which "Yuima-gyo" (Vimalakirti Sutra) was written

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長野県西部地震における松越地区の崩壊と地質

金沢大学先端科学・社会共創推進機構昭和59年9 月14 日，長野県木曾郡王滝村を震源とするマグニチュード6．8 の「長野県西部地震」が発生した。この地震により，御岳山南東斜面，松越地区および滝越地区において大規模な斜面崩壊が発生するとともに，多数の小規模な崩壊が発生した。　筆者らは，地震直後より松越地区の崩壊地を中心とする地域において， 被害状況， 地質分布などの調査を行って，崩壊地一帯の被害の現況と地質構造を明らかにした。　その結果， 崩壊地には基盤をなす古生層の上面に埋没した谷地形が発達していることと，この古生層上に堆積した御岳火山噴出物の下部層準である火山円礫岩に大量の地下水が賦存していたことが明らかになった。さらに，地震により生じた崩壌のすべD 面を形成する軟質な御岳火山噴出物の軽石凝灰岩に対して，前述の火山円礫岩から地下水が供給され， 過剰問隙水圧の発生などの影響が生じやすい地質構造をなしていたことが判明した。　本報告においては，以上の調査結果の事実関係とその特徴について報告するとともに，松越地区の崩壊の発生に関係する素因について述べる

RUNX inhibitor suppresses graft‐versus‐host disease through targeting RUNX‐NFATC2 axis

Patients with refractory graft-versus-host disease (GVHD) have a dismal prognosis. Therefore, novel therapeutic targets are still needed to be identified. Runt-related transcriptional factor (RUNX) family transcription factors are essential transcription factors that mediate the essential roles in effector T cells. However, whether RUNX targeting can suppress, and GVHD is yet unknown. Here, we showed that RUNX family members have a redundant role in directly transactivating NFATC2 expression in T cells. We also found that our novel RUNX inhibitor, Chb-M’, which is the inhibitor that switches off the entire RUNX family by alkylating agent–conjugated pyrrole-imidazole (PI) polyamides, inhibited T-cell receptor mediated T cell proliferation and allogenic T cell response. These were designed to specifically bind to consensus RUNX-binding sequences (TGTGGT). Chb-M’ also suppressed the expression of NFATC2 and pro-inflammatory cytokine genes in vitro. Using xenogeneic GVHD model, mice injected by Chb-M’ showed almost no sign of GVHD. Especially, the CD4 T cell was decreased and GVHD-associated cytokines including tissue necrosis factor-α and granulocyte-macrophage colony-stimulating factor were reduced in the peripheral blood of Chb-M’ injected mice. Taken together, our data demonstrates that RUNX family transcriptionally upregulates NFATC2 in T cells, and RUNX-NFATC2 axis can be a novel therapeutic target against GVHD

Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation

CDC42-C末端異常症に於ける炎症病態を解明 --ゴルジ体への異常蓄積がパイリンインフラマソーム形成を過剰促進--. 京都大学プレスリリース. 2022-05-02.Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42[R186C], we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42[R186C] protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42[*192C*24] that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation

RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL

Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody

Introduction: Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. Methods: Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. Results: Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein &#x3c; 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8+ cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8+ tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (p &#x3c; 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. Discussion/Conclusion: The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8+ TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI

Age, gender, will, and use of home-visit nursing care are critical factors in home care for malignant diseases; a retrospective study involving 346 patients in Japan

<p>Abstract</p> <p>Background</p> <p>We aimed to clarify the factors affecting outcomes of home care for patients with malignant diseases.</p> <p>Methods</p> <p>Of 607 patients who were treated in 10 clinics specialized in home care between January and December 2007 at Chiba, Fukuoka, Iwate, Kagoshima, Tochigi and Tokyo prefectures across Japan, 346 (57%; 145 men and 201 women) had malignant diseases. We collected information on medical and social backgrounds, details of home care, and its outcomes based on their medical records.</p> <p>Results</p> <p>Median age of the patients was 77 years (range, 11-102), and 335 patients were economically self-sufficient. Their general condition was poor; advanced cancer (n = 308), performance status of 3-4 (n = 261), and dementia (n = 121). At the beginning of home care, 143 patients and 174 family members expressed their wish to die at home. All the patients received supportive treatments including fluid replacement and oxygenation. Median duration of home care was 47 days (range, 0-2,712). 224 patients died at home. For the remaining 122, home care was terminated due to complications (n = 109), change of attending physicians (n = 8), and others (n = 5). The factors which inhibited the continuity of home care were the non-use of home-visit nursing care (hazard ratio [HR] = 1.78, 95% confidence interval [CI]: 1.05-3.00, <it>p </it>= 0.03), the fact that the patients themselves do not wish to die at home (HR = 1.83, CI: 1.09-3.07, <it>p </it>= 0.02), women (HR = 1.81, CI: 1.11-2.94, <it>p </it>= 0.02), and age (HR = 0.98, CI: 0.97-1.00, <it>p </it>= 0.02).</p> <p>Conclusions</p> <p>Continuation of home care is influenced by patients' age, gender, will, and use of home-visit nursing.</p

Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child–Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1), (2) Child–Pugh score 5 and ALBI grade 2 (group 2), (3) Child–Pugh score 6 (group 3), and (4) Child–Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p &lt; 0.05 and p &lt; 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level &lt;200 ng/mL as the significant predictors of a high objective response rate (p &lt; 0.05 and p &lt; 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p &lt; 0.01). Conclusions: Patients with Child–Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment