bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023‒04‒09
eighteen papers selected by
Ayesh Seneviratne
Western University
  1. Mitochondrial dynamics as a pathobiological mediator of clonal myeloid disorders.
  2. Health for all requires commitment to healthy ageing.
  3. Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
  4. A mechanical niche promotes the rejuvenation of blood stem cells.
  5. Biomarkers of the ageing immune system and their association with frailty - A systematic review.
  6. Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation.
  7. Childhood Cancer Treatment and Clonal Hematopoiesis.
  8. Forging the microbiome to help us live long and prosper.
  9. Accelerated aging in people experiencing homelessness: A rapid review of frailty prevalence and determinants.
  10. The role of Sirtuin 1 and its activators in age-related lung disease.
  11. Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis.
  12. Malnutrition as a major related factor of frailty among older adults residing in long-term care facilities in Korea.
  13. Editorial: DNA methylation: The aging clock.
  14. Frailty and Cancer: Current Perspectives on Assessment and Monitoring.
  15. The transcription regulator ATF4 is a mediator of skeletal muscle aging.
  16. Epigenetic clocks and female fertility timeline: A new approach to an old issue?
  17. Human CD34+ hematopoietic stem cell hierarchy: how far are we with its delineation at the most primitive level?
  18. Why Diverse Clinical Trial Participation Matters.
  1. Cancer Sci. 2023 Apr 07.
    Mitochondrial dynamics as a pathobiological mediator of clonal myeloid disorders.
    Yoshihiro Hayashi, Hironori Harada.
      Myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia, are a group of clonal hematopoietic stem cell (HSC) diseases. The incidence increases with global population aging. Genome sequencing uncovered mutational profiles in patients with myeloid malignancies and healthy elderly individuals. However, the molecular and cellular basis of disease development remains unclear. Accumulating evidence shows mitochondrial involvement in the pathogenesis of myeloid malignancies, aging-related HSC phenotypes, and clonal hematopoiesis. Mitochondria are dynamic organelles that continuously undergo fission and fusion processes to maintain their function, integrity, and activity. Mitochondria could be a hub of various biological processes that underlie cellular and systemic homeostasis. Thus, mitochondrial dysfunction could directly lead to the disruption of cellular homeostasis and the development of various disorders, including cancer. Notably, emerging data have revealed that mitochondria dynamics also primarily affect not only mitochondrial function and activity but also cellular homeostasis, the aging process, and tumorigenesis. Here, by focusing on mitochondrial dynamics, we highlight the current understanding of mitochondrial roles as a pathobiological mediator of myeloid malignancies and aging-related clonal hematopoiesis.
    Keywords:  acute myeloid leukemia; aging; clonal hematopoiesis; mitochondrial dynamics; myelodysplastic syndromes
    DOI:  https://doi.org/10.1111/cas.15810
  2. Lancet. 2023 04 01. pii: S0140-6736(23)00516-0. [Epub ahead of print]401(10382): 1073
    Health for all requires commitment to healthy ageing.
    George Vradenburg.
      
    DOI:  https://doi.org/10.1016/S0140-6736(23)00516-0
  3. Free Radic Biol Med. 2023 Apr 01. pii: S0891-5849(23)00368-4. [Epub ahead of print]
    Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA.
    Mansoor Hussain, Xixia Chu, Burcin Duan Sahbaz, Samuel Gray, Komal Pekhale, Jae-Hyeon Park, Deborah L Croteau, Vilhelm A Bohr.
      Aging is accompanied by a decline in DNA repair efficiency, which leads to the accumulation of different types of DNA damage. Age-associated chronic inflammation and generation of reactive oxygen species exacerbate the aging process and age-related chronic disorders. These inflammatory processes establish conditions that favor accumulation of DNA base damage, especially 8-oxo-7,8 di-hydroguanine (8-oxoG), which in turn contributes to various age associated diseases. 8-oxoG is repaired by 8-oxoG glycosylase1 (OGG1) through the base excision repair (BER) pathway. OGG1 is present in both the cell nucleus and in mitochondria. Mitochondrial OGG1 has been implicated in mitochondrial DNA repair and increased mitochondrial function. Using transgenic mouse models and cell lines that have been engineered to have enhanced expression of mitochondria-targeted OGG1 (mtOGG1), we show that elevated levels of mtOGG1 in mitochondria can reverse aging-associated inflammation and improve functions. Old male mtOGG1Tg mice show decreased inflammation response, decreased TNFα levels and multiple pro-inflammatory cytokines. Moreover, we observe that male mtOGG1Tg mice show resistance to STING activation. Interestingly, female mtOGG1Tg mice did not respond to mtOGG1 overexpression. Further, HMC3 cells expressing mtOGG1 display decreased release of mtDNA into the cytoplasm after lipopolysacchride induction and regulate inflammation through the pSTING pathway. Also, increased mtOGG1 expression reduced LPS-induced loss of mitochondrial functions. These results suggest that mtOGG1 regulates age-associated inflammation by controlling release of mtDNA into the cytoplasm.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.03.262
  4. Cell Stem Cell. 2023 Apr 06. pii: S1934-5909(23)00086-3. [Epub ahead of print]30(4): 337-338
    A mechanical niche promotes the rejuvenation of blood stem cells.
    Mohammad Mahdi Hasani-Sadrabadi, Song Li.
      Zhang et al.1 show that the mechanical properties of a three-dimensional (3D) hydrogel can enhance the secretion of niche factors from bone marrow stromal cells, which in turn promotes the maintenance of hematopoietic stem cells (HSCs) and reverses aging hallmarks in HSCs.
    DOI:  https://doi.org/10.1016/j.stem.2023.03.015
  5. Exp Gerontol. 2023 Apr 05. pii: S0531-5565(23)00084-0. [Epub ahead of print] 112163
    Biomarkers of the ageing immune system and their association with frailty - A systematic review.
    E Tran Van Hoi, N A De Glas, J E A Portielje, D Van Heemst, F Van Den Bos, S P Jochems, S P Mooijaart.
      INTRODUCTION: Ageing is associated with several physiological changes, including changes in the immune system. Age-related changes in the innate and adaptive immune system are thought to contribute to frailty. Understanding the immunological determinants of frailty could help to develop and deliver more effective care to older people. This systematic review aims to study the association between biomarkers of the ageing immune system and frailty.METHODS: The search strategy was performed in PubMed and Embase, using the keywords "immunosenescence", "inflammation", "inflammaging" and "frailty". We included studies that investigated the association of biomarkers of the ageing immune system and frailty cross-sectionally in older adults, without an active disease that affects immune parameters. Three independent researchers selected the studies and performed data extraction. Study quality was assessed using the Newcastle-Ottawa scale adapted for cross-sectional studies.
    RESULTS: A total of 44 studies, with a median number of 184 participants, was included. Study quality was good in 16 (36 %), moderate in 25 (57 %) and poor in 3 (7 %) of studies. The most frequently studied inflammaging biomarkers were IL-6, CRP and TNF-α. Associations with frailty were observed for increased levels of (i) IL-6 in 12 of 24 studies, (ii) CRP in 7 of 19 studies, and (ii) TNF-α in 4 of 13 studies. In none of the other studies were associations observed of frailty with these biomarkers. Different types of T-lymphocyte subpopulations were studied but each subset was studied only once, and the study sample sizes were low.
    CONCLUSION: Our review of 44 studies on the relation between immune biomarkers and frailty identified IL-6 and CRP as the biomarkers that were most consistently associated with frailty. T-lymphocyte subpopulations were investigated but too infrequently to draw strong conclusions yet, although initial results are promising. Additional studies are required in order to further validate these immune biomarkers in larger cohorts. Furthermore, prospective studies in more uniform settings and larger cohorts are needed to further investigate the association with immune candidate biomarkers for which potential associations with ageing and frailty were previously observed, before these can be used in clinical practice to help assess frailty and improve the care treatments of older patients.
    Keywords:  Ageing; Biomarkers; Elderly; Frailty; Immunosenescence; Inflammaging
    DOI:  https://doi.org/10.1016/j.exger.2023.112163
  6. Cell Stem Cell. 2023 Apr 06. pii: S1934-5909(23)00076-0. [Epub ahead of print]30(4): 378-395.e8
    Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation.
    Xiaoying Zhang, Dandan Cao, Liting Xu, Yanhua Xu, Zehua Gao, Yuanzhong Pan, Ming Jiang, Yuhui Wei, Lihua Wang, Yue Liao, Qigang Wang, Lei Yang, Xiaocui Xu, Yawei Gao, Shaorong Gao, Jing Wang, Rui Yue.
      Hematopoietic stem cell (HSC) self-renewal and aging are tightly regulated by paracrine factors from the bone marrow niche. However, whether HSC rejuvenation could be achieved by engineering a bone marrow niche ex vivo remains unknown. Here, we show that matrix stiffness fine-tunes HSC niche factor expression by bone marrow stromal cells (BMSCs). Increased stiffness activates Yap/Taz signaling to promote BMSC expansion upon 2D culture, which is largely reversed by 3D culture in soft gelatin methacrylate hydrogels. Notably, 3D co-culture with BMSCs promotes HSC maintenance and lymphopoiesis, reverses aging hallmarks of HSCs, and restores their long-term multilineage reconstitution capacity. In situ atomic force microscopy analysis reveals that mouse bone marrow stiffens with age, which correlates with a compromised HSC niche. Taken together, this study highlights the biomechanical regulation of the HSC niche by BMSCs, which could be harnessed to engineer a soft bone marrow niche for HSC rejuvenation.
    Keywords:  aging; bone marrow stromal cell; hematopoietic stem cell; matrix; niche; rejuvenation
    DOI:  https://doi.org/10.1016/j.stem.2023.03.005
  7. Cancer Discov. 2023 Apr 03. 13(4): 811-813
    Childhood Cancer Treatment and Clonal Hematopoiesis.
    Grace Collord, Sam Behjati.
      SUMMARY: Hagiwara and colleagues investigated the effects of childhood cancer treatment on the clonal composition of blood. Their findings provide strong evidence that treatment promotes clonal outgrowths (clonal hematopoiesis) in childhood cancer survivors. See related article by Hagiwara et al., p. 844 (4).
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0090
  8. PLoS Biol. 2023 Apr 05. 21(4): e3002087
    Forging the microbiome to help us live long and prosper.
    Rachel R Rock, Peter J Turnbaugh.
      Aging is often accompanied by an increased risk of an array of diseases spanning the cardiovascular, nervous, and immune systems, among others. Despite remarkable progress in understanding the cellular and molecular mechanisms involved in aging, the role of the microbiome remains understudied. In this Essay, we highlight recent progress towards understanding if and how the microbiome contributes to aging and age-associated diseases. Furthermore, we discuss the need to consider sexually dimorphic phenotypes in the context of aging and the microbiome. We also highlight the broad implications for this emerging area of interdisciplinary research to address long-standing questions about host-microbiome interactions across the life span.
    DOI:  https://doi.org/10.1371/journal.pbio.3002087
  9. Front Public Health. 2023 ;11 1086215
    Accelerated aging in people experiencing homelessness: A rapid review of frailty prevalence and determinants.
    Rhys Mantell, Ye In Jane Hwang, Kylie Radford, Silvija Perkovic, Patricia Cullen, Adrienne Withall.
      Introduction: Older people experiencing homelessness (PEH) are a rapidly growing population at risk of accelerated aging and the early onset of geriatric conditions. One construct that shows promise in predicting age-related decline is frailty. Better understanding the rates and causes of frailty in PEH may improve understanding of its antecedents, thereby facilitating more targeted health and aged care service interventions. The aim of this study was to conduct a rapid review on the prevalence and determinants of frailty in adult PEH.Methods: We conducted a rapid review of primary research papers studying PEH and frailty or frailty-related concepts.
    Results: Fourteen studies were included, which indicate that frailty presents earlier and at higher rates in PEH than community-dwelling cohorts. A notable difficulty for many aging PEH was early-onset cognitive impairment which was associated with a range of negative functional outcomes. Another recurrent theme was the negative impact that drug and alcohol use and dependence can have on the health of PEH. Further, psychosocial and structural determinants such as loneliness, living in an impoverished neighborhood and being female had statistically significant associations with frailty and functional decline in PEH.
    Discussion and implications: PEH in their 40s and 50s can be frail and experience geriatric conditions, including cognitive impairment. Factors that have important relationships to frailty and functional decline in PEH include cognitive deficits, drug and alcohol dependence and loneliness, as well as upstream determinants such as gender and ethnicity. More targeted data and research on these factors, including cohort studies to better investigate their potentially causal effects, is important for researchers and practitioners assessing and treating frailty in PEH, particularly those interested in early intervention and prevention.
    Prospero registration ID: CRD42022292549.
    Keywords:  accelerated aging; cognitive impairment; frailty; homelessness; marginalized and vulnerable groups; social determinants of health
    DOI:  https://doi.org/10.3389/fpubh.2023.1086215
  10. Biomed Pharmacother. 2023 Apr 03. pii: S0753-3322(23)00361-X. [Epub ahead of print]162 114573
    The role of Sirtuin 1 and its activators in age-related lung disease.
    Chaoqun Sun, Shuyou Bai, Yanmei Liang, Dewei Liu, Jinyu Liao, Yujuan Chen, Xuanna Zhao, Bin Wu, Dan Huang, Min Chen, Dong Wu.
      Aging is a major driving factor in lung diseases. Age-related lung disease is associated with downregulated expression of SIRT1, an NAD+-dependent deacetylase that regulates inflammation and stress resistance. SIRT1 acts by inducing the deacetylation of various substrates and regulates several mechanisms that relate to lung aging, such as genomic instability, lung stem cell exhaustion, mitochondrial dysfunction, telomere shortening, and immune senescence. Chinese herbal medicines have many biological activities, exerting anti-inflammatory, anti-oxidation, anti-tumor, and immune regulatory effects. Recent studies have confirmed that many Chinese herbs have the effect of activating SIRT1. Therefore, we reviewed the mechanism of SIRT1 in age-related lung disease and explored the potential roles of Chinese herbs as SIRT1 activators in the treatment of age-related lung disease.
    Keywords:  Age-related Lung Disease; Anti-aging; Chinese Herbal Medicine; Lung Aging; SIRT1
    DOI:  https://doi.org/10.1016/j.biopha.2023.114573
  11. Trends Cancer. 2023 Apr 05. pii: S2405-8033(23)00032-8. [Epub ahead of print]
    Stearoyl coenzyme A desaturase-1: multitasker in cancer, metabolism, and ferroptosis.
    Utsav Sen, Charles Coleman, Triparna Sen.
      Cancer progression is a highly balanced process and is maintained by a sequence of finely tuned metabolic pathways. Stearoyl coenzyme A desaturase-1 (SCD1), the fatty enzyme that converts saturated fatty acids into monounsaturated fatty acids, is a critical modulator of the fatty acid metabolic pathway. SCD1 expression is associated with poor prognosis in several cancer types. SCD1 triggers an iron-dependent cell death called ferroptosis and elevated levels of SCD1 protect cancer cells against ferroptosis. Pharmacological inhibition of SCD1 as monotherapy and in combination with chemotherapeutic agents shows promising antitumor potential in preclinical models. In this review, we summarize the role of SCD in cancer cell progression, survival, and ferroptosis and discuss potential strategies to exploit SCD1 inhibition in future clinical trials.
    Keywords:  NSCLC; SCD1; cancer therapy; fatty acid metabolism; ferroptosis; immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2023.03.003
  12. PLoS One. 2023 ;18(4): e0283596
    Malnutrition as a major related factor of frailty among older adults residing in long-term care facilities in Korea.
    SeolHwa Moon, Eunmi Oh, Daum Chung, Rina Choi, Gwi-Ryung Son Hong.
      OBJECTIVES: The objectives of this study were 1) to investigate the prevalence and co-existence of frailty and malnutrition and 2) to identify factors related to frailty (including malnutrition) according to the level of frailty.METHODS: Data collection was conducted from July 11, 2021, to January 23, 2022, in 558 older adults residing in 16 long-term care facilities (LTCFs) in Korea. The FRAIL-NH and Mini-Nutritional Assessment short form were used to measure frailty and nutrition, respectively. The data analysis included descriptive statistics and a multivariate logistic regression.
    RESULTS: The mean age of the participants was 83.68 (± 7.39) years. Among 558 participants, 37 (6.6%), 274 (49.1%), and 247 (44.3%) were robust, prefrail, and frail, respectively. At the same time, 75.8% were categorized as having malnutrition status (malnourished: 18.1%; risk of malnutrition: 57.7%), and 40.9% had co-existing malnutrition and frailty. In the multivariate analysis, malnutrition was identified as the major frailty-related factor. Compared with a normal nutritional status, the incidence of frailty in the malnutrition group was 10.35 times (95% CI: 3.78-28.36) higher than the incidence of robustness and 4.80 times (95% CI: 2.69-8.59) higher than the incidence of prefrail.
    CONCLUSION: The prevalence of frailty and malnutrition, and their co-existence, among older adults residing in LTCFs was high. Malnutrition is a major factor that increases the incidence of frailty. Therefore, active interventions are needed to improve the nutritional status of this population.
    DOI:  https://doi.org/10.1371/journal.pone.0283596
  13. Front Cell Dev Biol. 2023 ;11 1164429
    Editorial: DNA methylation: The aging clock.
    Barbara Ghinassi, Maria R Matarazzo, Annalisa Di Ruscio.
      
    Keywords:  DNA methylation; aging; alzheimer disease; breast cancer; epigenetic clock; metabolic disorders
    DOI:  https://doi.org/10.3389/fcell.2023.1164429
  14. Clin Interv Aging. 2023 ;18 505-521
    Frailty and Cancer: Current Perspectives on Assessment and Monitoring.
    Valentin Goede.
      Frailty, an age-related condition of increased vulnerability to acute endogenous or exogenous stressors, is a key barrier to successful treatment of cancer in older people. In this group of patients, assessment of frailty is required before starting a new treatment. According to guidelines, the gold standard to assess frailty in older adults with cancer is geriatric screening followed by geriatric assessment (GA) across essential GA-domains (social status, physical function, nutrition, cognition, emotion, co-morbidity, polypharmacy). GA enables tailoring of both oncological therapy and non-oncological interventions to the patient's vulnerabilities. Large clinical trials recently have demonstrated that the feasibility and tolerability of systemic cancer treatment in older patients are significantly improved by such GA-guided management. Indications and optimal tools for frailty monitoring during the course of cancer treatment have not yet been defined in greater detail. New technologies such as wearable sensors or apps offer promising new opportunities to further develop frailty monitoring. This review describes the current standards and perspectives for the assessment and monitoring of frailty in elderly patients with cancer.
    Keywords:  cancer; frailty; geriatric assessment; geriatric screening
    DOI:  https://doi.org/10.2147/CIA.S365494
  15. Geroscience. 2023 Apr 04.
    The transcription regulator ATF4 is a mediator of skeletal muscle aging.
    Matthew J Miller, George R Marcotte, Nathan Basisty, Cameron Wehrfritz, Zachary C Ryan, Matthew D Strub, Andrew T McKeen, Jennifer I Stern, Karl A Nath, Blake B Rasmussen, Andrew R Judge, Birgit Schilling, Scott M Ebert, Christopher M Adams.
      Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.
    Keywords:  ATF4; Aging; Protein turnover; Sarcopenia; Skeletal muscle; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1007/s11357-023-00772-y
  16. Front Cell Dev Biol. 2023 ;11 1121231
    Epigenetic clocks and female fertility timeline: A new approach to an old issue?
    Letizia Li Piani, Paola Vigano', Edgardo Somigliana.
      Worldwide increase in life expectancy has boosted research on aging. Overcoming the concept of chronological age, higher attention has been addressed to biological age, which reflects a person's real health state, and which may be the resulting combination of both intrinsic and environmental factors. As epigenetics may exert a pivotal role in the biological aging, epigenetic clocks were developed. They are based on mathematical models aimed at identifying DNA methylation patterns that can define the biological age and that can be adopted for different clinical scopes (i.e., estimation of the risks of developing age-related disorders or predicting lifespan). Recently, epigenetic clocks have gained a peculiar attention in the fertility research field, in particular in the female counterpart. The insight into the possible relations between epigenetic aging and women's infertility might glean additional information about certain conditions that are still not completely understood. Moreover, they could disclose significant implications for health promotion programs in infertile women. Of relevance here is that the impact of biological age and epigenetics may not be limited to fertility status but could translate into pregnancy issues. Indeed, epigenetic alterations of the mother may transfer into the offspring, and pregnancy itself as well as related complications could contribute to epigenetic modifications in both the mother and newborn. However, even if the growing interest has culminated in the conspicuous production of studies on these topics, a global overview and the availability of validated instruments for diagnosis is still missing. The present narrative review aims to explore the possible bonds between epigenetic aging and fertility timeline. In the "infertility" section, we will discuss the advances on epigenetic clocks focusing on the different tissues examined (endometrium, peripheral blood, ovaries). In the "pregnancy" section, we will discuss the results obtained from placenta, umbilical cord and peripheral blood. The possible role of epigenetic aging on infertility mechanisms and pregnancy outcomes represents a question that may configure epigenetic clock as a bond between two apparently opposite worlds: infertility and pregnancy.
    Keywords:  aging; epigenetic; epigenetic clock; infertility; newborn; pregnancy
    DOI:  https://doi.org/10.3389/fcell.2023.1121231
  17. Blood. 2023 Apr 05. pii: blood.2022018071. [Epub ahead of print]
    Human CD34+ hematopoietic stem cell hierarchy: how far are we with its delineation at the most primitive level?
    Fernando Anjos-Afonso, Dominique Bonnet.
      The ability to isolate and characterize different HSPC (hematopoietic stem/progenitor cell) populations opens avenues to understand how hematopoiesis is regulated during development, homeostasis and regeneration, as well as in age-related conditions such as clonal hematopoiesis and leukemogenesis. Significant progress has been made in the past few decades in determining the composition of the cell types that exist in this system, but the most significant advances have come from mouse studies. However, recent breakthroughs have made significant strides that have enhanced the resolution of the human primitive hematopoietic compartment. Therefore, we aim to review this subject not only from a historical perspective but also to discuss the progress made in the characterization of the human post-natal CD34+ HSC-enriched populations. This approach will enable us to shed light on the potential future translational applicability of human HSCs.
    DOI:  https://doi.org/10.1182/blood.2022018071
  18. N Engl J Med. 2023 Apr 06. 388(14): 1252-1254
    Why Diverse Clinical Trial Participation Matters.
    Aaron L Schwartz, Marcella Alsan, Alanna A Morris, Scott D Halpern.
      
    DOI:  https://doi.org/10.1056/NEJMp2215609
This page is being maintained by Thomas Krichel. It was last updated on 2023‒04‒22 at 18:09:30.