bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–07–11
nineteen papers selected by
Ayesh Seneviratne, University of Toronto
  1. Sphingosine-1-Phosphate Receptor 3 Potentiates Inflammatory Programs in Normal and Leukemia Stem Cells to Promote Differentiation.
  2. Still a burning question: the interplay between inflammation and fibrosis in myeloproliferative neoplasms.
  3. The therapeutic promises of NAD+ boosters.
  4. TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response.
  5. Does immunosenescence drive organismal ageing via inflammageing?
  6. Toward More Complete Prognostication for Patients with Clonal Hematopoiesis.
  7. Senescent cells in cancer therapy: why and how to remove them.
  8. Strenuous Physical Training, Physical Fitness, Body Composition and Bacteroides to Prevotella Ratio in the Gut of Elderly Athletes.
  9. Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes.
  10. Active Aging In Long-Term Care Facilities In Korea : Beyond The Lexical Meaning.
  11. Myeloid-Derived Suppressor Cells as a Potential Biomarker and Therapeutic Target in COVID-19.
  12. Short-chain fatty acids in blood pressure, friend or foe.
  13. Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.
  14. Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia.
  15. Common features of aging fail to occur in Drosophila raised without a bacterial microbiome.
  16. Audio Interview: How Well Are Covid-19 Vaccines Working?
  17. Dissecting Clonal Hematopoiesis in Tissues of Patients with Classic Hodgkin Lymphoma.
  18. Ketogenic Diet Therapy for Epilepsy Associated With Aicardi Syndrome.
  19. Clinical Features and Outcome of COVID-19 positive children from a tertiary healthcare Hospital in Karachi.
  1. Cancer Discov. 2021 Jan;2(1): 32-53
    Sphingosine-1-Phosphate Receptor 3 Potentiates Inflammatory Programs in Normal and Leukemia Stem Cells to Promote Differentiation.
    Stephanie Z Xie, Kerstin B Kaufmann, Weijia Wang, Michelle Chan-Seng-Yue, Olga I Gan, Elisa Laurenti, Laura Garcia-Prat, Shin-Ichiro Takayanagi, Stanley W K Ng, ChangJiang Xu, Andy G X Zeng, Liqing Jin, Jessica McLeod, Elvin Wagenblast, Amanda Mitchell, James A Kennedy, Qiang Liu, Héléna Boutzen, Melissa Kleinau, Joseph Jargstorf, Gareth Holmes, Yang Zhang, Veronique Voisin, Gary D Bader, Jean C Y Wang, Yusuf A Hannun, Chiara Luberto, Timm Schroeder, Mark D Minden, John E Dick.
      Acute myeloid leukemia (AML) is a caricature of normal hematopoiesis driven from leukemia stem cells (LSC) that share some hematopoietic stem cell (HSC) programs including responsiveness to inflammatory signaling. Although inflammation dysregulates mature myeloid cells and influences stemness programs and lineage determination in HSCs by activating stress myelopoiesis, such roles in LSCs are poorly understood. Here, we show that S1PR3, a receptor for the bioactive lipid sphingosine-1-phosphate, is a central regulator that drives myeloid differentiation and activates inflammatory programs in both HSCs and LSCs. S1PR3-mediated inflammatory signatures varied in a continuum from primitive to mature myeloid states across cohorts of patients with AML, each with distinct phenotypic and clinical properties. S1PR3 was high in LSCs and blasts of mature myeloid samples with linkages to chemosensitivity, whereas S1PR3 activation in primitive samples promoted LSC differentiation leading to eradication. Our studies open new avenues for therapeutic target identification specific for each AML subset. SIGNIFICANCE: S1PR3 is a novel regulator of myeloid fate in normal hematopoiesis that is heterogeneously expressed in AML. S1PR3 marks a subset of less primitive AML cases with a distinct inflammatory signature and therefore has clinical implications as both a therapeutic target and a biomarker to distinguish primitive from mature AML.See related commentary by Yang et al., p. 3.This article is highlighted in the In This Issue feature, p. 1.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0155
  2. Curr Opin Hematol. 2021 Jul 06.
    Still a burning question: the interplay between inflammation and fibrosis in myeloproliferative neoplasms.
    Hélène F E Gleitz, Adam Benabid, Rebekka K Schneider.
       PURPOSE OF REVIEW: Bone marrow fibrosis is the progressive replacement of blood-forming cells by reticulin fibres, caused by the acquisition of somatic mutations in hematopoietic stem cells. The molecular and cellular mechanisms that drive the progression of bone marrow fibrosis remain unknown, yet chronic inflammation appears to be a conserved feature in most patients suffering from myeloproliferative neoplasms.
    RECENT FINDINGS: Here, we review recent literature pertaining to the role of inflammation in driving bone marrow fibrosis, and its effect on the various hematopoietic and nonhematopoietic cell populations.
    SUMMARY: Recent evidence suggests that the pathogenesis of MPN is primarily driven by the hematopoietic stem and progenitor cells, together with their mutated progeny, which in turn results in chronic inflammation that disrupts the bone marrow niche and perpetuates a disease-permissive environment. Emerging data suggests that specifically targeting stromal inflammation in combination with JAK inhibition may be the way forward to better treat MPNs, and bone marrow fibrosis specifically.
    DOI:  https://doi.org/10.1097/MOH.0000000000000669
  3. Cell Metab. 2021 Jul 06. pii: S1550-4131(21)00278-3. [Epub ahead of print]33(7): 1274-1275
    The therapeutic promises of NAD+ boosters.
    Claudia Montllor-Albalate, Zehan Song, Danica Chen.
      Numerous preclinical studies implicate the decline in NAD+ signaling in developing aging- and obesity-associated metabolic disorders. Yoshino et al. (2021) now provide the clinical evidence that an NAD+ booster increases muscle insulin sensitivity in postmenopausal prediabetic women, validating the therapeutic promises of NAD+ boosters in humans.
    DOI:  https://doi.org/10.1016/j.cmet.2021.06.008
  4. JCI Insight. 2021 Jul 08. pii: 146076. [Epub ahead of print]6(13):
    TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response.
    Soichi Sano, Ying Wang, Hayato Ogawa, Keita Horitani, Miho Sano, Ariel H Polizio, Anupreet Kour, Yoshimitsu Yura, Heather Doviak, Kenneth Walsh.
      Therapy-related clonal hematopoiesis (t-CH) is often observed in cancer survivors. This form of clonal hematopoiesis typically involves somatic mutations in driver genes that encode components of the DNA damage response and confer hematopoietic stem and progenitor cells (HSPCs) with resistance to the genotoxic stress of the cancer therapy. Here, we established a model of TP53-mediated t-CH through the transfer of Trp53 mutant HSPCs to mice, followed by treatment with a course of the chemotherapeutic agent doxorubicin. These studies revealed that neutrophil infiltration in the heart significantly contributes to doxorubicin-induced cardiac toxicity and that this condition is amplified in the model of Trp53-mediated t-CH. These data suggest that t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors who have been treated with genotoxic agents.
    Keywords:  Cardiology; Cardiovascular disease
    DOI:  https://doi.org/10.1172/jci.insight.146076
  5. Immun Ageing. 2021 Jul 06. 18(1): 31
    Does immunosenescence drive organismal ageing via inflammageing?
    Graham Pawelec.
      
    DOI:  https://doi.org/10.1186/s12979-021-00242-z
  6. Cancer Discov. 2021 May;2(3): 192-194
    Toward More Complete Prognostication for Patients with Clonal Hematopoiesis.
    Barbara Spitzer, Ross L Levine.
      The study of clonal hematopoiesis is rapidly evolving, with the highest prevalence in aging populations and wide-ranging implications for health and disease, including an increased risk of subsequent myeloid malignancies and cardiovascular disease. In their article, Feusier and colleagues report on an expanded driver mutation list for capture of higher-risk clonal hematopoiesis mutations implicated in leukemia transformation. They also describe the prevalence of clonal hematopoiesis in several additional large studies, including, most importantly, in the pediatric context, which has not yet been extensively studied with respect to clonal hematopoiesis and clonal hematopoiesis-related sequelae.See related article by Feusier et al., p. 226.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0025
  7. Cancer Lett. 2021 Jul 05. pii: S0304-3835(21)00327-X. [Epub ahead of print]
    Senescent cells in cancer therapy: why and how to remove them.
    Jian-Wei Zhang, Dan Zhang, Bao-Ping Yu.
      Cellular senescence is a stress response that imposes a growth arrest on cancer and nonmalignant cells during cancer therapy. By secreting a plethora of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP), therapy-induced senescent cells can promote tumorigenesis. Moreover, the SASP from senescent cells is also able to drive therapy resistance and mediate many adverse effects of cancer therapy. Because senescent cell production often occurs during cancer therapy, it is important to carefully consider these potential detrimental effects. Senotherapy, which refers to selective removal of senescent cells, has been proposed as a promising adjuvant approach to eliminate the adverse effects of senescent cells. Thus, in this review we summarize in detail the mechanisms by which senescent cells contribute to tumorigenesis and therapeutic resistance. Also, we thoroughly discuss the potential strategies regarding how to effectively circumvent the undesirable effects of therapy-induced senescent cells.
    Keywords:  Cancer therapy; Cellular senescence; SASP; Senolysis; Senotherapy
    DOI:  https://doi.org/10.1016/j.canlet.2021.07.002
  8. Front Physiol. 2021 ;12 670989
    Strenuous Physical Training, Physical Fitness, Body Composition and Bacteroides to Prevotella Ratio in the Gut of Elderly Athletes.
    Katarína Šoltys, Leonard Lendvorský, Ivan Hric, Eva Baranovičová, Adela Penesová, Ivan Mikula, Miroslav Bohmer, Jaroslav Budiš, Silvia Vávrová, Jozef Grones, Marian Grendar, Martin Kolísek, Viktor Bielik.
      Regular physical activity seems to have a positive effect on the microbiota composition of the elderly, but little is known about the added possible benefits of strenuous endurance training. To gain insight into the physiology of the elderly and to identify biomarkers associated with endurance training, we combined different omics approaches. We aimed to investigate the gut microbiome, plasma composition, body composition, cardiorespiratory fitness, and muscle strength of lifetime elderly endurance athletes (LA) age 63.5 (95% CI 61.4, 65.7), height 177.2 (95% CI 174.4, 180.1) cm, weight 77.8 (95% CI 75.1, 80.5) kg, VO2max 42.4 (95% CI 39.8, 45.0) ml.kg-1.min-1 (n = 13) and healthy controls age 64.9 (95% CI 62.1, 67.7), height 174.9 (95% CI 171.2, 178.6) cm, weight 83.4 (95% CI 77.1, 89.7) kg, VO2max 28.9 (95% CI 23.9, 33.9), ml.kg-1.min-1 (n = 9). Microbiome analysis was performed on collected stool samples further subjected to 16S rRNA gene analysis. NMR-spectroscopic analysis was applied to determine and compare selected blood plasma metabolites mostly linked to energy metabolism. The machine learning (ML) analysis discriminated subjects from the LA and CTRL groups using the joint predictors Bacteroides 1.8E + 00 (95% CI 1.1, 2.5)%, 3.8E + 00 (95% CI 2.7, 4.8)% (p = 0.002); Prevotella 1.3 (95% CI 0.28, 2.4)%, 0.1 (95% CI 0.07, 0.3)% (p = 0.02); Intestinimonas 1.3E-02 (95% CI 9.3E-03, 1.7E-02)%, 5.9E-03 (95% CI 3.9E-03, 7.9E-03)% (p = 0.002), Subdoligranulum 7.9E-02 (95% CI 2.5E-02, 1.3E-02)%, 3.2E-02 (95% CI 1.8E-02, 4.6E-02)% (p = 0.02); and the ratio of Bacteroides to Prevotella 133 (95% CI -86.2, 352), 732 (95% CI 385, 1079.3) (p = 0.03), leading to an ROC curve with AUC of 0.94. Further, random forest ML analysis identified VO2max, BMI, and the Bacteroides to Prevotella ratio as appropriate, joint predictors for discriminating between subjects from the LA and CTRL groups. Although lifelong endurance training does not bring any significant benefit regarding overall gut microbiota diversity, strenuous athletic training is associated with higher cardiorespiratory fitness, lower body fat, and some favorable gut microbiota composition, all factors associated with slowing the rate of biological aging.
    Keywords:  VO2max; aging; body fat; exercise; microbiome
    DOI:  https://doi.org/10.3389/fphys.2021.670989
  9. Front Pharmacol. 2021 ;12 662020
    Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes.
    Laura Marquez-Exposito, Lucia Tejedor-Santamaria, Laura Santos-Sanchez, Floris A Valentijn, Elena Cantero-Navarro, Sandra Rayego-Mateos, Raul R Rodrigues-Diez, Antonio Tejera-Muñoz, Vanessa Marchant, Ana B Sanz, Alberto Ortiz, Roel Goldschmeding, Marta Ruiz-Ortega.
      Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells ("immunosenescence") are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.
    Keywords:  acute kidney injury; aging; apoptosis; cellular senescence; immunosenescence; inflammation; klotho; necroptosis
    DOI:  https://doi.org/10.3389/fphar.2021.662020
  10. J Gerontol Soc Work. 2021 Jul 07. 1-16
    Active Aging In Long-Term Care Facilities In Korea : Beyond The Lexical Meaning.
    Hyun-Jeong Kim, Yumi Shin, Jung-Hwa Ha, Yaeji Kim-Knauss.
      The discourse of active aging, as introduced by the WHO, aims at optimizing older adults' opportunities for health, participation, and security that could eventually enhance their social integration and quality of life. Considering that even those with frailty could strive for active aging in the given circumstances, we examined the meaning of active aging in long-term care settings and care strategies to promote it based on the WHO's framework. We conducted interviews with a total of 35 participants. The interpretative analyses revealed that the activities taken place in LTCFs have various scopes depending on older adults' physical and cognitive functional ability, and it captures the forms of activities that go beyond its lexical meaning. By defining being "active," the present findings could contribute to an understanding of how the three elements of active aging can be carried out in LTCFs.
    Keywords:  Institutional care/residential care; framework analysis; quality of life
    DOI:  https://doi.org/10.1080/01634372.2021.1948940
  11. Front Immunol. 2021;12:12 697405
    Myeloid-Derived Suppressor Cells as a Potential Biomarker and Therapeutic Target in COVID-19.
    Marianna Rowlands, Florencia Segal, Dominik Hartl.
      Clinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease.
    Keywords:  COVID-19; MDSC; biomarkers; immunity; immunology
    DOI:  https://doi.org/10.3389/fimmu.2021.697405
  12. Chin Med J (Engl). 2021 Jun 30.
    Short-chain fatty acids in blood pressure, friend or foe.
    Xiao-Feng Chen, Si-Chong Ren, Guo Tang, Chuan Wu, Xiangqi Chen, Xiao-Qiang Tang.
      
    DOI:  https://doi.org/10.1097/CM9.0000000000001578
  13. Nat Metab. 2021 Jul 05.
    Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.
    Elizabeth K Wiese, Sadae Hitosugi, Sharon T Loa, Annapoorna Sreedhar, Lindsey G Andres-Beck, Kiran Kurmi, Yuan-Ping Pang, Larry M Karnitz, Wilson I Gonsalves, Taro Hitosugi.
      Pharmacological activation of the glycolytic enzyme PKM2 or expression of the constitutively active PKM1 isoform in cancer cells results in decreased lactate production, a phenomenon known as the PKM2 paradox in the Warburg effect. Here we show that oxaloacetate (OAA) is a competitive inhibitor of human lactate dehydrogenase A (LDHA) and that elevated PKM2 activity increases de novo synthesis of OAA through glutaminolysis, thereby inhibiting LDHA in cancer cells. We also show that replacement of human LDHA with rabbit LDHA, which is relatively resistant to OAA inhibition, eliminated the paradoxical correlation between the elevated PKM2 activity and the decreased lactate concentration in cancer cells treated with a PKM2 activator. Furthermore, rabbit LDHA-expressing tumours, compared to human LDHA-expressing tumours in mice, displayed resistance to the PKM2 activator. These findings describe a mechanistic explanation for the PKM2 paradox by showing that OAA accumulates and inhibits LDHA following PKM2 activation.
    DOI:  https://doi.org/10.1038/s42255-021-00424-5
  14. Cancer Discov. 2021 Jul 01. pii: bloodcandisc.0012.2021. [Epub ahead of print]
    Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia.
    Kyle A Romine, Tamilla Nechiporuk, Daniel Bottomly, Sophia Jeng, Shannon K McWeeney, Andy Kaempf, M Ryan Corces, Ravindra Majeti, Jeffrey W Tyner.
      To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic dataset and performed genome-wide CRISPR screens on BETi- sensitive and BETi- resistant AML cells. Both strategies revealed regulators of monocytic differentiation, SPI1, JUNB, FOS, and aryl-hydrocarbon receptor signaling (AHR/ARNT), as determinants of BETi response. AHR activation synergized with BETi while inhibition antagonized BETi-mediated cytotoxicity. Consistent with BETi sensitivity dependence on monocytic differentiation, ex vivo sensitivity to BETi in primary AML patient samples correlated with higher expression of monocytic markers CSF1R, LILRs, and VCAN. In addition, HL-60 cell line differentiation enhanced its sensitivity to BETi. Further, screens to rescue BETi sensitivity identified BCL2 and CDK6 as druggable vulnerabilities.¬¬ Finally, monocytic AML patient samples refractory to venetoclax ex vivo were significantly more sensitive to combined BETi + venetoclax. Together, our work highlights mechanisms that could predict BETi response and identifies combination strategies to overcome resistance.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-21-0012
  15. iScience. 2021 Jul 23. 24(7): 102703
    Common features of aging fail to occur in Drosophila raised without a bacterial microbiome.
    Arvind Kumar Shukla, Kory Johnson, Edward Giniger.
      Lifespan is limited both by intrinsic decline in vigor with age and by accumulation of external insults. There exists a general picture of the deficits of aging, one that is reflected in a pattern of age-correlated changes in gene expression conserved across species. Here, however, by comparing gene expression profiling of Drosophila raised either conventionally, or free of bacteria, we show that ∼70% of these conserved, age-associated changes in gene expression fail to occur in germ-free flies. Among the processes that fail to show time-dependent change under germ-free conditions are two aging features that are observed across phylogeny, declining expression of stress response genes and increasing expression of innate immune genes. These comprise adaptive strategies the organism uses to respond to bacteria, rather than being inevitable components of age-dependent decline. Changes in other processes are independent of the microbiome and can serve as autonomous markers of aging of the individual.
    Keywords:  Biological sciences; microbiology; microbiome; physiology
    DOI:  https://doi.org/10.1016/j.isci.2021.102703
  16. N Engl J Med. 2021 07 08. 385(2): e15
    Audio Interview: How Well Are Covid-19 Vaccines Working?
    Eric J Rubin, Lindsey R Baden, Stephen Morrissey.
      
    DOI:  https://doi.org/10.1056/NEJMe2111369
  17. Cancer Discov. 2021 May;2(3): 216-225
    Dissecting Clonal Hematopoiesis in Tissues of Patients with Classic Hodgkin Lymphoma.
    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 hematologic malignancies. However, clonal hematopoiesis is understudied in classic 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 DNMT3A R882H, KRAS G60D, and DNMT3A R882H+TET2 Q1274* in 33%, 92%, and 60% of nonneoplastic 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. SIGNIFICANCE: Clonal hematopoiesis can be present in the cHL tissue, can give rise to the tumor clone, and can spread to large parts of its microenvironment. Even when massive, clonal hematopoiesis does not always give rise to the neoplastic clone of multiple myeloid and lymphoid neoplasms occurring in the same patient.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-20-0203
  18. J Child Neurol. 2021 Jul 09. 8830738211023335
    Ketogenic Diet Therapy for Epilepsy Associated With Aicardi Syndrome.
    Miguel A Ramirez Sanchez, Mackenzie C Cervenka, Stacey K Bessone, Eric H Kossoff.
       INTRODUCTION: Aicardi syndrome is a rare neurodevelopmental disorder associated with epilepsy in females. Ketogenic diet therapy represents a possible nonpharmacologic treatment in Aicardi syndrome patients.
    METHODS: All patients with Aicardi syndrome seen at Johns Hopkins Hospital (Baltimore, MD) and Johns Hopkins All Children's Hospital (St Petersburg, FL) treated with ketogenic diet therapy since 1994 were evaluated retrospectively.
    RESULTS: Fifteen patients, ages 4 months to 34 years, were identified. Ten (67%) patients experienced a ≥50% seizure reduction after 3 months, with 3 (20%) having a ≥90% reduction. Only 1 patient was seizure-free for a short period of time. The number of drugs tried prior to ketogenic diet therapy initiation was correlated with ≥50% seizure reduction at 3 months, 5.8 vs 2.6 in responders versus nonresponders (P = .01). In addition, the mean number of drugs actively received also correlated, 3.0 vs 1.2, P = .005. Ketogenic diet therapy was slightly more successful in those without infantile spasms, 78% vs 50%, P = .33.
    CONCLUSION: Ketogenic diet therapy was helpful in Aicardi syndrome, although seizure freedom was rare. It was especially helpful for those who were more drug-resistant and did not have infantile spasms at ketogenic diet therapy onset.
    Keywords:  Aicardi; diet; ketogenic; ketosis; seizures
    DOI:  https://doi.org/10.1177/08830738211023335
  19. J Med Virol. 2021 Jul 06.
    Clinical Features and Outcome of COVID-19 positive children from a tertiary healthcare Hospital in Karachi.
    Saba Shahid, Mohammad Raza, Samina Junejo, Sidra Maqsood.
       BACKGROUND AND OBJECTIVES: As COVID-19 pandemic continues to evolve; differences in epidemiological and clinical features among pediatrics have been noticed across different countries. We describe spectrum of COVID-19 in pediatric patients treated in tertiary health care.
    METHODS: We conducted a retrospective chart review of pediatric patients admitted to, Indus Hospital & Health care network, Korangi campus, Karachi; from 1st April 2020 to 31st July 2020.
    RESULTS: Total 141 COVID-19 cases were reported, males were 81(57%) and median age was 8 (0.3-17) years. Eighty-eight (62%), 36(26%) and 17(12%) children had a-symptomatic, moderate and severe disease. Fever (50%) was the most common clinical feature. The SF ratio<264 was significantly associated with severe disease (p<0.05). Lab investigations which differed significantly across disease severity groups included, IL-6 levels (p<0.01) and Prothrombin time (p<0.05).Majority children were advised home isolation 89(63%), 29(20.5 %) were admitted while mortality was observed in 10(7%) children. No significant difference was observed between children with and without malignancy.
    CONCLUSION: Pre-existing comorbidities are significantly associated with COVID-19 infections among children. Reduced SF ratio, elevated Prothrombin time and IL-6 levels are associated with greater disease severity. This article is protected by copyright. All rights reserved.
    Keywords:  COVID-19; Multisystem inflammatory syndrome (MIS-C); infections; interleukin-6; pandemics; pediatrics; tertiary healthcare
    DOI:  https://doi.org/10.1002/jmv.27178
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