bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021‒08‒08
fourteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment.
  2. Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells.
  3. Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.
  4. Immunogenomic pan-cancer landscape reveals immune escape mechanisms and immunoediting histories.
  5. MICA/B antibody induces macrophage-mediated immunity against acute myeloid leukemia.
  6. [Performing integrative transcriptomic and chemical screening to identify patient-specific vulnerabilities in poor-prognosis acute myeloid leukemia].
  7. Targeting leukemia-specific dependence on the de novo purine synthesis pathway.
  8. Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.
  9. Alterations in mitochondrial morphology as a key driver of immunity and host defence.
  10. Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase.
  11. A novel 4-mRNA signature predicts the overall survival in acute myeloid leukemia.
  12. The Basic Research of the Combinatorial Therapy of ABT-199 and Homoharringtonine on Acute Myeloid Leukemia.
  13. Drug treatment options for acute promyelocytic leukemia.
  14. A review on myeloid cell leukemia 1 (MCL-1): Structural characteristics and application in cancer therapy.
  1. Front Oncol. 2021 ;11 702642
    Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment.
    Miriam Gaggianesi, Simone Di Franco, Vincenzo Davide Pantina, Gaetana Porcelli, Caterina D'Accardo, Francesco Verona, Veronica Veschi, Lorenzo Colarossi, Naida Faldetta, Giuseppe Pistone, Maria Rita Bongiorno, Matilde Todaro, Giorgio Stassi.
      Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME.
    Keywords:  anticancer drugs; cancer stem cells; chemoresistance; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.702642
  2. Cells. 2021 Jul 13. pii: 1772. [Epub ahead of print]10(7):
    Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells.
    Yao-An Shen, Chang-Cyuan Chen, Bo-Jung Chen, Yu-Ting Wu, Jiun-Ru Juan, Liang-Yun Chen, Yueh-Chun Teng, Yau-Huei Wei.
      Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism. Because of metabolic plasticity, CSCs can switch between these metabolisms to acquire energy for tumor progression in different microenvironments compare to the rest of tumor bulk. Thus, we highlight the specific conditions and factors that promote or suppress CSCs properties to portray distinct metabolic phenotypes that attribute to CSCs in common cancers. Identification and characterization of the features in these metabolisms can offer new anticancer opportunities and improve the prognosis of cancer. However, the therapeutic window of metabolic inhibitors used alone or in combination may be rather narrow due to cytotoxicity to normal cells. In this review, we present current findings of potential targets in these four metabolic pathways for the development of more effective and alternative strategies to eradicate CSCs and treat cancer more effectively in the future.
    Keywords:  cancer stem cell; fatty acid metabolism; glutamninolysis; glycolysis; metabolic pathway; metabolic plasticity; mitochondrial respiration
    DOI:  https://doi.org/10.3390/cells10071772
  3. Stem Cell Rev Rep. 2021 Aug 05.
    Metabostemness in cancer: Linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.
    Prajna Paramita Naik, Swagatika Panigrahi, Ratnakar Parida, Prakash Priyadarshi Praharaj, Chandra Sekhar Bhol, Shankargouda Patil, Nml Manjunath, Dipanjan Ghosh, Samir Kumar Patra, Sujit Kumar Bhutia.
      Cancer stem cells (CSCs) are rare populations of malignant cells with stem cell-like features of self-renewal, uninterrupted differentiation, tumorigenicity, and resistance to conventional therapeutic agents, and these cells have a decisive role in treatment failure and tumor relapse. The self-renewal potential of CSCs with atypical activation of developmental signaling pathways involves the maintenance of stemness to support cancer progression. The acquisition of stemness in CSCs has been accomplished through genetic and epigenetic rewiring following the metabolic switch. In this context, "metabostemness" denotes the metabolic parameters that essentially govern the epitranscriptional gene reprogramming mechanism to dedifferentiate tumor cells into CSCs. Several metabolites often referred to as oncometabolites can directly remodel chromatin structure and thereby influence the operation of epitranscriptional circuits. This integrated metaboloepigenetic dimension of CSCs favors the differentiated cells to move in dedifferentiated macrostates. Some metabolic events might perform as early drivers of epitranscriptional reprogramming; however, subsequent metabolic hits may govern the retention of stemness properties in the tumor mass. Interestingly, selective removal of mitochondria through autophagy can promote metabolic plasticity and alter metabolic states during differentiation and dedifferentiation. In this connection, novel metabostemness-specific drugs can be generated as potential cancer therapeutics to target the metaboloepigenetic circuitry to eliminate CSCs.
    Keywords:  Cancer Stem Cell; Metaboloepigenetics; Metabostemness; Mitophagy; Oncometabolism
    DOI:  https://doi.org/10.1007/s12015-021-10216-9
  4. Sci Rep. 2021 Aug 03. 11(1): 15713
    Immunogenomic pan-cancer landscape reveals immune escape mechanisms and immunoediting histories.
    Shinichi Mizuno, Rui Yamaguchi, Takanori Hasegawa, Shuto Hayashi, Masashi Fujita, Fan Zhang, Youngil Koh, Su-Yeon Lee, Sung-Soo Yoon, Eigo Shimizu, Mitsuhiro Komura, Akihiro Fujimoto, Momoko Nagai, Mamoru Kato, Han Liang, Satoru Miyano, Zemin Zhang, Hidewaki Nakagawa, Seiya Imoto.
      Immune reactions in the tumor microenvironment are an important hallmark of cancer, and emerging immune therapies have been proven effective against several types of cancers. To investigate cancer genome-immune interactions and the role of immunoediting or immune escape mechanisms in cancer development, we analyzed 2834 whole genome and RNA sequencing datasets across 31 distinct tumor types with respect to key immunogenomic aspects and provided comprehensive immunogenomic profiles of pan-cancers. We found that selective copy number changes in immune-related genes may contribute to immune escape. Furthermore, we developed an index of the immunoediting history of each tumor sample based on the information of mutations in exonic regions and pseudogenes and evaluated the immunoediting history of each tumor. Our immuno-genomic analyses of pan-cancers have the potential to identify a subset of tumors with immunogenicity and diverse backgrounds or intrinsic pathways associated with their immune status and immunoediting history.
    DOI:  https://doi.org/10.1038/s41598-021-95287-x
  5. Blood. 2021 Aug 06. pii: blood.2021011619. [Epub ahead of print]
    MICA/B antibody induces macrophage-mediated immunity against acute myeloid leukemia.
    Pedro Henrique Alves da Silva, Samantha Xing, Andriana G Kotini, Eirini P Papapetrou, Xiaoyu Song, Kai W Wucherpfennig, John Mascarenhas, Lucas Ferrari de Andrade.
      Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. MICA and MICB (MICA/B) are stress-proteins expressed by cancer cells, and antibody-mediated inhibition of MICA/B shedding represents a novel approach to stimulate immunity against cancers. We found that the MICA/B antibody 7C6 potently inhibits the outgrowth of AML in two models in immunocompetent mice. Macrophages were essential for therapeutic efficacy, and 7C6 triggered antibody-dependent phagocytosis of AML cells. Furthermore, we found that romidepsin, a selective histone deacetylase inhibitor, increased MICB mRNA in AML cells and enabled subsequent stabilization of the translated protein by 7C6. This drug combination substantially increased surface MICA/B expression in a human AML line, pluripotent stem cell-derived AML blasts and leukemia stem cells, as well as primary cells from three untreated AML patients. Human macrophages phagocytosed AML cells following treatment with 7C6 and romidepsin, and the combination therapy lowered leukemia burden in a humanized model of AML. Therefore, inhibition of MICA/B shedding promotes macrophage-driven immunity against AML via Fc receptor signaling and synergizes with an epigenetic regulator. These results provide the rationale for the clinical testing of this innovative immunotherapeutic approach for the treatment of AML.
    DOI:  https://doi.org/10.1182/blood.2021011619
  6. Rinsho Ketsueki. 2021 ;62(7): 774-780
    [Performing integrative transcriptomic and chemical screening to identify patient-specific vulnerabilities in poor-prognosis acute myeloid leukemia].
    Mari Hashimoto, Fumihiko Ishikawa.
      Genetic complexity and heterogeneity have made drug discovery difficult in human malignancies. In the past few years, we aimed to find vulnerabilities in therapy-resistant and refractory acute myeloid leukemia (AML) through integrative analyses of genomic data, clinical information, and results from in vivo/in vitro cell biological assays. Through analyses, we found that the cells of patients with AML show distinct sensitivity/resistance to small inhibiting molecules for anti-apoptosis and cell cycle/division. In particular, AML cells harboring the IDH1/2 mutations were highly sensitive to BCL-2 inhibition, while inhibition of IAP proteins resulted in efficient elimination of AML cells with varied FLT3, NRAS, and CBL mutations. Linking AML-initiating events with appropriate therapeutic strategies through cellular and genomic analyses might be further translated into nonmyeloid malignancies and solid tumors in the future.
    Keywords:  Acute myeloid leukemia; Chemical screening; Transcriptomics; Xenograft
    DOI:  https://doi.org/10.11406/rinketsu.62.774
  7. Leukemia. 2021 Aug 03.
    Targeting leukemia-specific dependence on the de novo purine synthesis pathway.
    Takuji Yamauchi, Kohta Miyawaki, Yuichiro Semba, Masatomo Takahashi, Yoshihiro Izumi, Jumpei Nogami, Fumihiko Nakao, Takeshi Sugio, Kensuke Sasaki, Luca Pinello, Daniel E Bauer, Takeshi Bamba, Koichi Akashi, Takahiro Maeda.
      Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
    DOI:  https://doi.org/10.1038/s41375-021-01369-0
  8. Leukemia. 2021 Aug 02.
    Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.
    Yana Pikman, Nicole Ocasio-Martinez, Gabriela Alexe, Boris Dimitrov, Samuel Kitara, Frances F Diehl, Amanda L Robichaud, Amy Saur Conway, Linda Ross, Angela Su, Frank Ling, Jun Qi, Giovanni Roti, Caroline A Lewis, Alexandre Puissant, Matthew G Vander Heiden, Kimberly Stegmaier.
      Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.
    DOI:  https://doi.org/10.1038/s41375-021-01361-8
  9. EMBO Rep. 2021 Aug 02. e53086
    Alterations in mitochondrial morphology as a key driver of immunity and host defence.
    Mariana P Cervantes-Silva, Shannon L Cox, Annie M Curtis.
      Mitochondria are dynamic organelles whose architecture changes depending on the cell's energy requirements and other signalling events. These structural changes are collectively known as mitochondrial dynamics. Mitochondrial dynamics are crucial for cellular functions such as differentiation, energy production and cell death. Importantly, it has become clear in recent years that mitochondrial dynamics are a critical control point for immune cell function. Mitochondrial remodelling allows quiescent immune cells to rapidly change their metabolism and become activated, producing mediators, such as cytokines, chemokines and even metabolites to execute an effective immune response. The importance of mitochondrial dynamics in immunity is evident, as numerous pathogens have evolved mechanisms to manipulate host cell mitochondrial remodelling in order to promote their own survival. In this review, we comprehensively address the roles of mitochondrial dynamics in immune cell function, along with modulation of host cell mitochondrial morphology during viral and bacterial infections to facilitate either pathogen survival or host immunity. We also speculate on what the future may hold in terms of therapies targeting mitochondrial morphology for bacterial and viral control.
    Keywords:  bacteria; immune response; mitochondrial dynamics; therapy; virus
    DOI:  https://doi.org/10.15252/embr.202153086
  10. Int J Mol Sci. 2021 Jul 21. pii: 7779. [Epub ahead of print]22(15):
    Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase.
    Minu Chaudhuri, Anuj Tripathi, Fidel Soto Gonzalez.
      Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mitochondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei.
    Keywords:  HAD-phosphatase family; TIM; TIMM50; TOM; Tim50; Trypanosoma
    DOI:  https://doi.org/10.3390/ijms22157779
  11. Am J Hematol. 2021 Aug 02.
    A novel 4-mRNA signature predicts the overall survival in acute myeloid leukemia.
    Zizhen Chen, Junzhe Song, Wenjun Wang, Jiaojiao Bai, Yuhui Zhang, Jun Shi, Jie Bai, Yuan Zhou.
      Acute myeloid leukemia (AML) is an aggressive cancer of myeloid cells with high levels of heterogeneity and great variability in prognostic behaviors. Cytogenetic abnormalities and genetic mutations have been widely used in the prognostic stratification of AML to assign patients into different risk categories. Nevertheless, nearly half of intermediate-risk AML patients need more precise prognostic schemes. Here, 336 differentially expressed genes (DEGs) between AML and control samples and 206 genes representing the intratumor heterogeneity of AML were identified. By applying a LASSO Cox regression model, we generated a 4-mRNA prognostic signature comprising KLF9, ENPP4, TUBA4A and CD247. Higher risk scores were significantly associated with shorter overall survival, complex karyotype, and adverse mutations.We then validated the prognostic value of this 4-mRNA signature in two independent cohorts. We also proved that incorporation of the 4-mRNA-based signature in the 2017 European LeukemiaNet (ELN) risk classification could enhance the predictive accuracy of survival in patients with AML. Univariate and multivariate analyses showed that this signature was independent of traditional prognostic factors such as age, WBC count, and unfavorable cytogenetics. Finally, the molecular mechanisms underlying disparate outcomes in high- and low-risk AML patients were explored. Therefore, our findings suggest that the 4-mRNA signature refines the risk stratification and prognostic prediction of AML patients. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26309
  12. Front Oncol. 2021 ;11 692497
    The Basic Research of the Combinatorial Therapy of ABT-199 and Homoharringtonine on Acute Myeloid Leukemia.
    Yuanfei Shi, Jing Ye, Ying Yang, Yanchun Zhao, Huafei Shen, Xiujin Ye, Wanzhuo Xie.
      Background: Existing research shows that ABT-199, as a first-line drug, have been widely used in hematological malignancies, especially in leukemia, but the clinical efficacy of single drug therapy was limited part of the reason was that BCL-2 inhibitors failure to target other anti-apoptotic BCL-2 family proteins, such as MCL-1. In this case, combination therapy may be a promising way to overcome this obstacle. Here, we investigate the preclinical efficacy of a new strategy combining ABT-199 with homoharringtonine (HHT), a selective inhibitor of MCL-1 may be a promising approach for AML treatment as these two molecules are important in apoptosis.Methods: A Cell Counting Kit-8 (CCK8) assay and flow cytometry were used to determine the half-maximal inhibitory concentration (IC50) value and cell apoptosis rate, respectively. The flow cytometry results showed that combined treatment with HHT and ABT-199 caused apoptosis in AML patient samples (n=5) but had no effect on normal healthy donor samples (n=11). Furthermore, we used a Western blot assay to explore the mechanism underlying the efficacy of HHT combined with ABT-199. Finally, antileukemic activity was further evaluated in vivo xenograft model.
    Results: Our results indicated that ABT-199 combined with HHT significantly inhibited cell growth and promoted apoptosis in both AML cell lines and primary AML tumors in a dose- and time-dependent manner. Moreover, HHT combined with ABT-199 suppressed AML cell growth and progression in vivo xenograft model.
    Conclusions: Our research found that HHT combined with ABT-199 exerted its anti-leukemia effect by inducing apoptosis through the treatment of AML in vitro and in vivo.
    Keywords:  ABT-199; acute myeloid leukemia; basic research; cancer; combinatorial therapy; homoharringtonine; molecular mechanisms
    DOI:  https://doi.org/10.3389/fonc.2021.692497
  13. Expert Opin Pharmacother. 2021 Aug 05. 1-11
    Drug treatment options for acute promyelocytic leukemia.
    Felicetto Ferrara, Massimo Bernardi, Matteo Molica.
      INTRODUCTION: Until the late 1980s, acute promyelocytic leukemia (APL) was the most rapidly fatal leukemia; however, nowadays, it is a curable disease with survival rates exceeding 90-95%. The improvement of APL outcome is mainly due to two agents, which target the typical translocation t(15;17) and its fusion transcript PML-RARα responsible for initiating and maintaining the disease: all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The story of APL represents a pioneering model for the development of precision medicine and curative chemotherapy-free approaches for acute leukemia.AREA COVERED: The authors examine the major advances in the treatment of patients with APL focusing on three different eras: 1) the pre-ATRA era; 2) the ATRA era; 3) the ATO era.
    EXPERT OPINION: The combination of ATRA and ATO is effective and curative for the majority of APL patients. It has been approved for low/intermediate risk cases while an experimental trial with a minimal addition of chemotherapy for high-risk ones is ongoing. Disease relapse is infrequent and can be cured with ATRA-ATO rechallenging, with or without subsequent transplantation depending on the interval between complete remission and relapse. New therapeutic landscapes contemplate the use of an oral chemo-free ATRA-ATO combination, implementing treatment as outpatient care, thus increasing quality of life and decreasing medical costs.
    Keywords:  Acute promyelocytic leukemia; arsenic trioxide; chemo-free approach; oral arsenic derivatives; risk-adapted strategies
    DOI:  https://doi.org/10.1080/14656566.2021.1961744
  14. Int J Biol Macromol. 2021 Jul 30. pii: S0141-8130(21)01615-9. [Epub ahead of print]
    A review on myeloid cell leukemia 1 (MCL-1): Structural characteristics and application in cancer therapy.
    Pooja Mittal, Sujata Singh, Rajesh Sinha, Anju Shrivastava, Archana Singh, Indrakant Kumar Singh.
      Apoptosis, a major hallmark of cancer cells, regulates cellular fate and homeostasis. BCL-2 (B-cell CLL/Lymphoma 2) protein family is popularly known to mediate the intrinsic mode of apoptosis, of which MCL-1 is a crucial member. Myeloid cell leukemia 1 (MCL-1) is an anti-apoptotic oncoprotein and one of the most investigated members of the BCL-2 family. It is commonly known to be genetically altered, aberrantly overexpressed, and primarily associated with drug resistance in various human cancers. Recent advancements in the development of selective MCL-1 inhibitors and evaluating their effectiveness in cancer treatment establish its popularity as a molecular target. The overall aim is the selective induction of apoptosis in cancer cells by using a single or combination of BCL-2 family inhibitors. Delineating the precise molecular mechanisms associated with MCL-1-mediated cancer progression will certainly improve the efficacy of clinical interventions aimed at MCL-1 and hence patient survival. This review is structured to highlight the structural characteristics of MCL-1, its specific interactions with NOXA, MCL-1-regulatory microRNAs, and at the same time focus on the emerging therapeutic strategies targeting our protein of interest (MCL-1), alone or in combination with other treatments.
    Keywords:  Apoptosis; BCL-2; BH3 groove; BH3 mimetics; Cancer; Inhibitors; MCL-1; microRNA
    DOI:  https://doi.org/10.1016/j.ijbiomac.2021.07.166
This page is being maintained by Thomas Krichel. It was last updated on 2021‒08‒10 at 13:44:01.