المؤلفون: Kobayashi, Yasuaki, Kojima, Kensuke, Matsubara, Norihide, Sone, Taiga, Yamamoto, Akihiro

مصطلحات موضوعية: Computer Science - Data Structures and Algorithms, Mathematics - Combinatorics

الوصف: The Balanced Connected Subgraph problem (BCS) was recently introduced by Bhore et al. (CALDAM 2019). In this problem, we are given a graph $G$ whose vertices are colored by red or blue. The goal is to find a maximum connected subgraph of $G$ having the same number of blue vertices and red vertices. They showed that this problem is NP-hard even on planar graphs, bipartite graphs, and chordal graphs. They also gave some positive results: BCS can be solved in $O(n^3)$ time for trees and $O(n + m)$ time for split graphs and properly colored bipartite graphs, where $n$ is the number of vertices and $m$ is the number of edges. In this paper, we show that BCS can be solved in $O(n^2)$ time for trees and $O(n^3)$ time for interval graphs. The former result can be extended to bounded treewidth graphs. We also consider a weighted version of BCS (WBCS). We prove that this variant is weakly NP-hard even on star graphs and strongly NP-hard even on split graphs and properly colored bipartite graphs, whereas the unweighted counterpart is tractable on those graph classes. Finally, we consider an exact exponential-time algorithm for general graphs. We show that BCS can be solved in $2^{n/2}n^{O(1)}$ time. This algorithm is based on a variant of Dreyfus-Wagner algorithm for the Steiner tree problem.
Comment: accepted at COCOA 2019

الوصول الحر: http://arxiv.org/abs/1910.07305Test

المؤلفون: Kojima, Kensuke

مصطلحات موضوعية: Computer Science - Logic in Computer Science, Computer Science - Data Structures and Algorithms, Mathematics - Category Theory, F.2.0, E.1, F.3.1

الوصف: This paper studies a difference between Binary Decision Diagrams (BDDs) and Zero-suppressed BDDs (ZDDs) from a conceptual point of view. It is commonly understood that a BDD is a representation of a Boolean function, whereas a ZDD is a representation of a set of sets. However, there is a one-to-one correspondence between Boolean functions and sets of sets, and therefore we could also regard a BDD as a representation of a set of sets, and similarly for a ZDD and a Boolean function. The aim of this paper is to give an explanation why the distinction between BDDs and ZDDs mentioned above is made despite the existence of the one-to-one correspondence. To achieve this, we first observe that Boolean functions and sets of sets are equipped with non-isomorphic functor structures, and show that these functor structures are reflected in the definitions of BDDs and ZDDs. This result can be stated formally as naturality of certain maps. To the author's knowledge, this is the first formally stated theorem that justifies the commonly accepted distinction between BDDs and ZDDs. In addition, we show that this result extends to sentential decision diagrams and their zero-suppressed variant.
Comment: 13 pages, 1 figure

الوصول الحر: http://arxiv.org/abs/1806.10261Test

المؤلفون: Okudono, Takamasa, Nishida, Yuki, Kojima, Kensuke, Suenaga, Kohei, Kido, Kengo, Hasuo, Ichiro

مصطلحات موضوعية: Computer Science - Logic in Computer Science

الوصف: Interpolation of jointly infeasible predicates plays important roles in various program verification techniques such as invariant synthesis and CEGAR. Intrigued by the recent result by Dai et al.\ that combines real algebraic geometry and SDP optimization in synthesis of polynomial interpolants, the current paper contributes its enhancement that yields sharper and simpler interpolants. The enhancement is made possible by: theoretical observations in real algebraic geometry; and our continued fraction-based algorithm that rounds off (potentially erroneous) numerical solutions of SDP solvers. Experiment results support our tool's effectiveness; we also demonstrate the benefit of sharp and simple interpolants in program verification examples.

الوصول الحر: http://arxiv.org/abs/1709.00314Test

المؤلفون: Nishida, Yuki, Ishizawa, Jo, Ayoub, Edward, Montoya, Rafael Heinz, Ostermann, Lauren B, Muftuoglu, Muharrem, Ruvolo, Vivian R, Patsilevas, Tallie, Scruggs, Darah A, Khazaei, Shayaun, Mak, Po Yee, Tao, Wenjing, Carter, Bing Z, Boettcher, Steffen, Ebert, Benjamin L, Daver, Naval G, Konopleva, Marina, Seki, Takahiko, Kojima, Kensuke, Andreeff, Michael

المصدر: Nishida, Yuki; Ishizawa, Jo; Ayoub, Edward; Montoya, Rafael Heinz; Ostermann, Lauren B; Muftuoglu, Muharrem; Ruvolo, Vivian R; Patsilevas, Tallie; Scruggs, Darah A; Khazaei, Shayaun; Mak, Po Yee; Tao, Wenjing; Carter, Bing Z; Boettcher, Steffen; Ebert, Benjamin L; Daver, Naval G; Konopleva, Marina; Seki, Takahiko; Kojima, Kensuke; Andreeff, Michael (2023). Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias. Science Advances, 9(48):eadh1436.

مصطلحات موضوعية: Clinic for Oncology and Hematology, 610 Medicine & health

الوصف: The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.

وصف الملف: application/pdf

العلاقة: https://www.zora.uzh.ch/id/eprint/251944/1/sciadv.adh1436.pdfTest; info:pmid/38019903; urn:issn:2375-2548

الإتاحة: https://doi.org/10.5167/uzh-25194410.1126/sciadv.adh1436Test
https://www.zora.uzh.ch/id/eprint/251944Test/
https://www.zora.uzh.ch/id/eprint/251944/1/sciadv.adh1436.pdfTest

المؤلفون: Hosono, Naoko, Chi, SungGi, Yamauchi, Takahiro, Fukushima, Kentaro, Shibayama, Hirohiko, Katagiri, Seiichiro, Gotoh, Akihiko, Eguchi, Motoki, Morishita, Takanobu, Ogasawara, Reiki, Kondo, Takeshi, Yanada, Masamitsu, Yamamoto, Kazuhito, Kobayashi, Tsutomu, Kuroda, Junya, Usuki, Kensuke, Utsu, Yoshikazu, Yoshimitsu, Makoto, Ishitsuka, Kenji, Ono, Takaaki, Takahashi, Naoto, Iyama, Satoshi, Kojima, Kensuke, Nakamura, Yukinori, Fukuhara, Suguru, Izutsu, Koji, Abutani, Hikaru, Yamauchi, Nobuhiko, Yuda, Junichiro, Minami, Yosuke

المصدر: Cancer Science ; volume 114, issue 5, page 2098-2108 ; ISSN 1347-9032 1349-7006

الوصف: Next‐generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)‐SCREEN‐Japan 01 is a multicenter study to detect actionable mutations using paraffin‐embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R‐AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High‐quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1 ‐ RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R‐AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP5 3 mutations had a poor prognosis. As for the detection of actionable mutations, 38% ( n = 69) of patients had useful genetic mutation ( FLT3 ‐ ITD / TKD , IDH1 / 2 , and DNMT3A R822 ) for treatment selection. Comprehensive genomic profiling using paraffin‐embedded BM clot specimens successfully identified leukemic‐associated genes that can be used as therapeutic targets.

الإتاحة: https://doi.org/10.1111/cas.15746Test

المؤلفون: Samejima, Hironobu, Kojima, Kensuke, Fujiwara, Ayako, Tokunaga, Toshiteru, Okishio, Kyoichi, Yoon, Hyungeun

المصدر: BMC Cancer ; volume 23, issue 1 ; ISSN 1471-2407

مصطلحات موضوعية: Cancer Research, Genetics, Oncology

الوصف: Background While PD-L1 expression and neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers for lung cancer, few studies have considered their interaction. We hypothesized that the product of PD-L1 expression (tumor proportion score) and the NLR (PD-L1 × NLR) might be a postoperative prognostic marker reflecting the immune microenvironment of lung cancer. Methods We analyzed the association between PD-L1 × NLR and postoperative recurrence-free survival in 647 patients with NSCLC using multivariable Cox proportional hazards models. Results In the analysis of PD-L1 × NLR as a categorical variable, the group with PD-L1 × NLR ≥ 25.8 had a significantly higher hazard ratio (HR) than the group with < 25.8 (adjusted HR 1.78, 95% confidence interval [CI] 1.23–2.60). The adjusted HR for PD-L1 × NLR, considered a continuous variable, was 1.004 (95% CI, 1.002–1.006). The risk of postoperative recurrence increased by 1.004-fold for each unit increase in PD-L1 × NLR, and a more than 2-fold increase in risk was observed for values ≥ 170. Conclusions PD-L1 × NLR may be used in real-world clinical practice as a novel factor for predicting the risk of postoperative recurrence after lung cancer surgery.

الإتاحة: https://doi.org/10.1186/s12885-023-11604-9Test

المؤلفون: Kurayoshi, Kenta, Takase, Yusuke, Ueno, Masaya, Ohta, Kumiko, Fuse, Kyoko, Ikeda, Shuji, Watanabe, Takayoshi, Nishida, Yuki, Horike, Shin-ichi, Hosomichi, Kazuyoshi, Ishikawa, Yuichi, Tadokoro, Yuko, Kobayashi, Masahiko, Kasahara, Atsuko, Jing, Yongwei, Shoulkamy, Mahmoud I., Meguro-Horike, Makiko, Kojima, Kensuke, Kiyoi, Hitoshi, Sugiyama, Hiroshi, Nagase, Hiroki, Tajima, Atsushi, Hirao, Atsushi

المصدر: Cell Death & Disease ; volume 14, issue 9 ; ISSN 2041-4889

مصطلحات موضوعية: Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology

الوصف: Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1 , a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1 , causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.

الإتاحة: https://doi.org/10.1038/s41419-023-06168-2Test
https://www.nature.com/articles/s41419-023-06168-2.pdfTest
https://www.nature.com/articles/s41419-023-06168-2Test

المؤلفون: Kojima, Kensuke, Yoon, Hyungeun, Okishio, Kyoichi, Tsuyuguchi, Kazunari

المصدر: Scientific Reports ; volume 13, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Chest computed tomography (CT) is effective for assessing the severity of coronavirus disease 2019 (COVID-19). However, the clinical factors reflecting the disease progression of COVID-19 pneumonia on chest CT and predicting a subsequent exacerbation remain controversial. We conducted a retrospective cohort study of 450 COVID-19 patients. We used an automated image processing tool to quantify the COVID-19 pneumonia lesion extent on chest CT at admission. The factors associated with the lesion extent were estimated by a multiple regression analysis. After adjusting for background factors by propensity score matching, we conducted a multivariate Cox proportional hazards analysis to identify factors associated with severe disease after admission. The multiple regression analysis identified, body-mass index (BMI), lactate dehydrogenase (LDH), C-reactive protein (CRP), and albumin as continuous variables associated with the lesion extent on chest CT. The standardized partial regression coefficients for them were 1.76, 2.42, 1.54, and 0.71. The multivariate Cox proportional hazards analysis identified LDH (hazard ratio, 1.003; 95% confidence interval, 1.001–1.005) as a factor independently associated with the development of severe COVID-19 pneumonia. Increased serum LDH at admission may be useful in real-world clinical practice for the simple screening of COVID-19 patients at high risk of developing subsequent severe disease.

الإتاحة: https://doi.org/10.1038/s41598-023-28201-2Test
https://www.nature.com/articles/s41598-023-28201-2.pdfTest
https://www.nature.com/articles/s41598-023-28201-2Test

المؤلفون: Egawa, Yuki, Higuchi, Tomonori, Hashida, Yumiko, Ueno, Kazuyuki, Kojima, Kensuke, Daibata, Masanori

المصدر: Scientific Reports; 5/31/2024, Vol. 14 Issue 1, p1-13, 13p

مصطلحات موضوعية: REGULATORY T cells, T cells, HTLV, ADULT T-cell leukemia, CELL physiology, CELL growth

مستخلص: Adult T-cell leukemia/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4⁺CD25⁺ phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13⁺ Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13⁻ (designated as MT-50.1) and CD13⁺ (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-β, expressed higher levels of Foxp3, and showed stronger suppression of CD4⁺CD25⁻ T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13⁺Foxp3⁺ HTLV-1-infected cells. [ABSTRACT FROM AUTHOR]

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المؤلفون: Golob-Schwarzi, Nicole, Bettermann, Kira, Mehta, Anita Kuldeep, Kessler, Sonja M., Unterluggauer, Julia, Krassnig, Stefanie, Kojima, Kensuke, Chen, Xintong, Hoshida, Yujin, Bardeesy, Nabeel M., Mueller, Heimo, Svendova, Vendula, Schimek, Michael G., Diwoky, Clemens, Lipfert, Alexandra, Mahajan, Vineet, Stumptner, Cornelia, Thueringer, Andrea, Froehlich, Leopold F., Stojakovic, Tatjana, Nilsson, Peter, Kolbe, Thomas, Ruelicke, Thomas, Magin, Thomas M., Strnad, Pavel, Kiemer, Alexandra K., Moriggl, Richard, Haybaeck, Johannes

المصدر: Translational Oncology. 12(2):256-268

الوصف: BACKGROUND amp; AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termedMallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: Weanalyzed livers of aged Krt18(-/-) mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18(-/-) mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18(-/-) mice with 26 human hepatoma cell lines and with data sets of amp;gt;300 patients with HCC, where Krt18(-/-) gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-154092Test
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-164174Test
https://liu.diva-portal.org/smash/get/diva2:1283669/FULLTEXT01.pdfTest