bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–06–27
thirteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Murine models of clonal hematopoiesis to assess mechanisms of cardiovascular disease.
  2. TIM-3 in normal and malignant hematopoiesis: structure, function and signaling pathways.
  3. Dietary Bioactive Lipids: A Review on Absorption, Metabolism, and Health Properties.
  4. Screening for regenerative therapy responders in heart failure.
  5. Niches that regulate stem cells and hematopoiesis in adult bone marrow.
  6. Acute graft-versus-host disease after double lung transplantation.
  7. Blood clots, COVID-19 vaccines and the contraceptive pill: are we heading for a repeat of the 1995 pill scare?
  8. Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish.
  9. Dimethyl fumarate for COVID-19.
  10. Levothyroxine Use in the United States, 2008-2018.
  11. Dissecting Clonal Hematopoiesis in Tissues of Classical Hodgkin Lymphoma Patients.
  12. Lipid droplet screen in human hepatocytes identifies TRRAP as a regulator of cellular triglyceride metabolism.
  13. Statin associated lower cancer risk and related mortality in patients with heart failure.
  1. Cardiovasc Res. 2021 Jun 23. pii: cvab215. [Epub ahead of print]
    Murine models of clonal hematopoiesis to assess mechanisms of cardiovascular disease.
    Ying Wang, Soichi Sano, Hayato Ogawa, Keita Horitani, Megan A Evans, Yoshimitsu Yura, Emiri Miura-Yura, Heather Doviak, Kenneth Walsh.
      Clonal hematopoiesis (CH) is a phenomenon whereby somatic mutations confer a fitness advantage to hematopoietic stem and progenitor cells (HSPC) and thus facilitate their aberrant clonal expansion. These mutations are carried into progeny leukocytes leading to a situation whereby a substantial fraction of an individual's blood cells originate from the HSPC mutant clone. Although this condition rarely progresses to a hematological malignancy, circulating blood cells bearing the mutation have the potential to affect other organ systems as they infiltrate into tissues under both homeostatic and disease conditions. Epidemiological and clinical studies have revealed that CH is highly prevalent in the elderly and is associated with an increased risk of cardiovascular disease and mortality. Recent experimental studies in murine models have assessed the most commonly mutated "driver" genes associated with CH, and have provided evidence for mechanistic connections between CH and cardiovascular disease. A deeper understanding of the mechanisms by which specific CH mutations promote disease pathogenesis is of importance, as it could pave the way for individualized therapeutic strategies targeting the pathogenic CH gene mutations in the future. Here, we review the epidemiology of CH and the mechanistic work from studies using murine disease models, with a particular focus on the strengths and limitations of these experimental systems. We intend for this review to help investigators select the most appropriate models to study CH in the setting of cardiovascular disease.
    Keywords:  ARCH; CHIP; cardiovascular disease; insulin resistance; somatic mosaicism
    DOI:  https://doi.org/10.1093/cvr/cvab215
  2. Cancer Sci. 2021 Jun 22.
    TIM-3 in normal and malignant hematopoiesis: structure, function and signaling pathways.
    Yoshikane Kikushige.
      Acute myeloid leukemia (AML) is hierarchically organized by self-renewing leukemic stem cells (LSCs). LSCs originate from hematopoietic stem cells (HSCs) by acquiring multistep leukemogenic events. To specifically eradicate LSCs, while keeping normal HSCs intact, the discrimination of LSCs from HSCs is important. We have identified T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as an LSC-specific surface molecule in human myeloid malignancies, and demonstrated its essential function in maintaining the self-renewal ability of LSCs. TIM-3 has been intensively investigated as a "co-inhibitory" or "immune checkpoint" molecule of T cells. However, little is known about its distinct function in T cells and myeloid malignancies. In this review, we discuss the structure of TIM-3, its function in normal blood cells and LSCs, emphasizing the specific signaling pathways involved, as well as the therapeutic applications of TIM-3 molecules in human myeloid malignancies.
    Keywords:  T-cell immunity; TIM-3; acute myeloid leukemia; and immune checkpoint inhibitor; leukemic stem cells
    DOI:  https://doi.org/10.1111/cas.15042
  3. J Agric Food Chem. 2021 Jun 23.
    Dietary Bioactive Lipids: A Review on Absorption, Metabolism, and Health Properties.
    Yan Zhang, Tianyi Zhang, Yan Liang, Lianzhou Jiang, Xiaonan Sui.
      Dietary lipids are an indispensable source of energy and nutrition in human life. Numerous studies have shown that dietary bioactive lipids have many health benefits, including prevention or treatment of chronic diseases. The different chemical compositions and structural characteristics of bioactive lipids not only affect their digestion, absorption, and metabolism but also affect their health properties. In this review, the major dietary bioactive lipids (fatty acids, carotenoids, phytosterols, phenolic lipids, fat-soluble vitamins, and sphingomyelins) in foods are systematically summarized, from the aspects of composition, digestion, absorption, metabolism, source, structural characteristics, and their health properties. In particular, the relationship between the compositional and structural changes of bioactive lipids and their absorption and metabolism is discussed as well as their effect on health properties. This review provides a comprehensive summary toward health properties of dietary bioactive lipids.
    Keywords:  absorption; bioactive lipids; health properties; metabolism
    DOI:  https://doi.org/10.1021/acs.jafc.1c01369
  4. Biomark Med. 2021 Jun 25.
    Screening for regenerative therapy responders in heart failure.
    Satsuki Yamada, Ryounghoon Jeon, Armin Garmany, Atta Behfar, Andre Terzic.
      Risk of outcome variability challenges therapeutic innovation. Selection of the most suitable candidates is predicated on reliable response indicators. Especially for emergent regenerative biotherapies, determinants separating success from failure in achieving disease rescue remain largely unknown. Accordingly, (pre)clinical development programs have placed increased emphasis on the multi-dimensional decoding of repair capacity and disease resolution, attributes defining responsiveness. To attain regenerative goals for each individual, phenotype-based patient selection is poised for an upgrade guided by new insights into disease biology, translated into refined surveillance of response regulators and deep learning-amplified clinical decision support.
    Keywords:  biomarkers; deep learning; heart failure; heterogeneity; imaging; prediction; regenerative medicine; stem cells; stratification
    DOI:  https://doi.org/10.2217/bmm-2020-0683
  5. Dev Cell. 2021 Jun 12. pii: S1534-5807(21)00478-0. [Epub ahead of print]
    Niches that regulate stem cells and hematopoiesis in adult bone marrow.
    Stefano Comazzetto, Bo Shen, Sean J Morrison.
      In mammals, hematopoietic stem cells (HSCs) engage in hematopoiesis throughout adult life within the bone marrow, where they produce the mature cells necessary to maintain blood cell counts and immune function. In the bone marrow and spleen, HSCs are sustained in perivascular niches (microenvironments) associated with sinusoidal blood vessels-specialized veins found only in hematopoietic tissues. Endothelial cells and perivascular leptin receptor+ stromal cells produce the known factors required to maintain HSCs and many restricted progenitors in the bone marrow. Various other cells synthesize factors that maintain other restricted progenitors or modulate HSC or niche function. Recent studies identified new markers that resolve some of the heterogeneity among stromal cells and refine the localization of restricted progenitor niches. Other recent studies identified ways in which niches regulate HSC function and hematopoiesis beyond growth factors. We summarize the current understanding of hematopoietic niches, review recent progress, and identify important unresolved questions.
    Keywords:  bone marrow; endothelial cell; hematopoietic stem cell; niche; restricted hematopoietic progenitor
    DOI:  https://doi.org/10.1016/j.devcel.2021.05.018
  6. JAAD Case Rep. 2021 Jul;13 62-64
    Acute graft-versus-host disease after double lung transplantation.
    Nicole Kim, Nadia Kashetsky, Yuliya Velykoredko, Michelle Murray, Lianne Singer, Zaid Saeed Kamil, Danny Ghazarian, An-Wen Chan.
      
    Keywords:  GVHD, graft-versus-host disease; POD, postoperative day; graft-versus-host disease; lung transplantation; organ transplantation; solid organ transplantation
    DOI:  https://doi.org/10.1016/j.jdcr.2021.05.009
  7. BMJ Sex Reprod Health. 2021 Jun 22. pii: bmjsrh-2021-201219. [Epub ahead of print]
    Blood clots, COVID-19 vaccines and the contraceptive pill: are we heading for a repeat of the 1995 pill scare?
    Anita Mitra.
      
    Keywords:  COVID-19; contraception behavior; hormonal contraception
    DOI:  https://doi.org/10.1136/bmjsrh-2021-201219
  8. Blood Adv. 2021 Jul 13. 5(13): 2687-2700
    Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish.
    Emanuele Gioacchino, Cansu Koyunlar, Joke Zink, Hans de Looper, Madelon de Jong, Tomasz Dobrzycki, Christopher B Mahony, Remco Hoogenboezem, Dennis Bosch, Paulina M H van Strien, Martin E van Royen, Pim J French, Eric Bindels, Kirsten J Gussinklo, Rui Monteiro, Ivo P Touw, Emma de Pater.
      The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2b-deficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b.
    DOI:  https://doi.org/10.1182/bloodadvances.2020002993
  9. BMJ Support Palliat Care. 2021 Jun 25. pii: bmjspcare-2021-003250. [Epub ahead of print]
    Dimethyl fumarate for COVID-19.
    Yashdeep Singh Pathania.
      
    Keywords:  COVID-19; hospital care; neurological conditions; pharmacology; respiratory conditions
    DOI:  https://doi.org/10.1136/bmjspcare-2021-003250
  10. JAMA Intern Med. 2021 Jun 21.
    Levothyroxine Use in the United States, 2008-2018.
    Juan P Brito, Joseph S Ross, Omar M El Kawkgi, Spyridoula Maraka, Yihong Deng, Nilay D Shah, Kasia J Lipska.
      
    DOI:  https://doi.org/10.1001/jamainternmed.2021.2686
  11. Blood Cancer Discov. 2021 May;2(3): 216-225
    Dissecting Clonal Hematopoiesis in Tissues of Classical Hodgkin Lymphoma Patients.
    Alessandra Venanzi, Andrea Marra, Gianluca Schiavoni, Sara G Milner, Roberto Limongello, Alessia Santi, Valentina Pettirossi, Simona Ultimo, Luisa Tasselli, Alessandra Pucciarini, Lorenza Falini, Sofia Sciabolacci, Maria Paola Martelli, Paolo Sportoletti, Stefano Ascani, Brunangelo Falini, Enrico Tiacci.
      Clonal hematopoiesis predisposes to hematological malignancies. However, clonal hematopoiesis is understudied in classical Hodgkin lymphoma (cHL), a mature B-cell neoplasm exhibiting the most abundant microenvironment. We analyzed clonal hematopoiesis in 40 cHL cases by sequencing microdissected tumor cells and matched normal cells from blood and/or lymph nodes. Five patients had blood and/or tissue clonal hematopoiesis. In three of five patients (all failing first-line therapy), clonal hematopoiesis spread through the tissue microenvironment extensively, and featured mutant DNMT3AR882H , KRASG60D and DNMT3AR882H +TET2Q1274 * in 33%, 92% and 60% of non-neoplastic cells, respectively. In the latter case, DNMT3A/TET2-mutant clonal hematopoiesis seeded the neoplastic clone, which was infected by the Epstein-Barr virus and showed almost no other somatic mutations exome-wide. In the former case, DNMT3A-mutant clonal hematopoiesis did not originate the neoplastic clone despite dominating the blood and B-cell lineage (~94% leukocytes; ~96% mature blood B cells), yet led to NPM1-mutated acute myeloid leukemia 6 years after therapy for cHL. Our results expand to cHL the spectrum of hematologic malignancies associated with clonal hematopoiesis.
    Keywords:  Acute myeloid leukemia; Clonal hematopoiesis; DNMT3A; Hodgkin lymphoma; Microenvironment; NPM1
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0203
  12. Clin Transl Sci. 2021 Jun 22.
    Lipid droplet screen in human hepatocytes identifies TRRAP as a regulator of cellular triglyceride metabolism.
    Deepti Abbey, Donna Conlon, Christopher Rainville, Susannah Elwyn, Katherine Quiroz-Figueroa, Jeffrey Billheimer, David C Schultz, Nicholas J Hand, Sara Cherry, Daniel J Rader.
      Hepatocytes store triglycerides (TGs) in the form of lipid droplets (LDs), which are increased in hepatosteatosis. The regulation of hepatic LDs is poorly understood and new therapies to reduce hepatosteatosis are needed. We performed a siRNA kinase and phosphatase screen in HuH-7 cells using high-content automated imaging of LDs. Changes in accumulated lipids were quantified with developed pipeline that measures intensity, area, and number of LDs. Selected "hits," which reduced lipid accumulation, were further validated with other lipid and expression assays. Among several siRNAs that resulted in significantly reduced LDs, one was targeted to the nuclear adapter protein, transformation/transcription domain-associated protein (TRRAP). Knockdown of TRRAP reduced triglyceride accumulation in HuH-7 hepatocytes, in part by reducing C/EBPα-mediated de novo synthesis of TGs. These findings implicate TRRAP as a novel regulator of hepatic TG metabolism and nominate it as a potential drug target for hepatosteatosis.
    DOI:  https://doi.org/10.1111/cts.12988
  13. Eur Heart J. 2021 Jun 22. pii: ehab325. [Epub ahead of print]
    Statin associated lower cancer risk and related mortality in patients with heart failure.
    Qing-Wen Ren, Si-Yeung Yu, Tiew-Hwa Katherine Teng, Xue Li, Ka-Shing Cheung, Mei-Zhen Wu, Hang-Long Li, Pui-Fai Wong, Hung-Fat Tse, Carolyn S P Lam, Kai-Hang Yiu.
       AIMS: Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse.
    METHODS AND RESULTS: Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to <2 years), the adjusted SHR was 0.99 (95% CI, 0.87-1.13) for 2 to <4 years of use, 0.82 (95% CI, 0.70-0.97) for 4 to <6 years of use, and 0.78 (95% CI, 0.65-0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR = 0.74; 95% CI, 0.67-0.81).
    CONCLUSION: Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.
    Keywords:  Cancer; Cardio-oncology; Heart failure; Prevention; Statin
    DOI:  https://doi.org/10.1093/eurheartj/ehab325
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