Abstract: “Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus with a well-established causal role in several cancers. Recent studies have provided compelling epidemiological and mechanistic evidence for a causal role of EBV in multiple sclerosis (MS). MS is the most prevalent chronic inflammatory and neurodegenerative disease of the central nervous system and is thought to be triggered in genetically predisposed individuals by an infectious agent, with EBV as the lead candidate. How a ubiquitous virus that typically leads to benign latent infections can promote cancer and autoimmune disease in at-risk populations is not fully understood. Here we review the evidence that EBV is a causal agent for MS and how various risk factors may affect EBV infection and immune control. We focus on EBV contributing to MS through reprogramming of latently infected B lymphocytes and the chronic presentation of viral antigens as a potential source of autoreactivity through molecular mimicry. We consider how knowledge of EBV-associated cancers may be instructive for understanding the role of EBV in MS and discuss the potential for therapies that target EBV to treat MS.”

Soldan SS, Lieberman PM. Epstein-Barr virus and multiple sclerosis. Nat Rev Microbiol. 2022 Aug 5. doi: 10.1038/s41579-022-00770-5. Epub ahead of print. PMID: 35931816.

https://pubmed.ncbi.nlm.nih.gov/35931816/

 

 

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Background: Increasing evidence highlights that accumulating sitting time in prolonged bouts is detrimental to cardiometabolic health.   Objectives:  This systematic review aimed to compare the effects of fractionating prolonged sitting with frequent short bouts of standing and light-intensity walking on cardiometabolic health markers and conduct a meta-analysis for differences in systolic blood pressure (SBP), postprandial glucose and insulin.

Conclusions: Frequent short interruptions of standing significantly attenuated postprandial glucose compared to prolonged sitting; however, light-intensity walking was found to represent a superior physical activity break. The feasibility and longitudinal implications of breaking sedentary behaviour with light-intensity walking should be investigated in a free-living setting.

Buffey, A.J., Herring, M.P., Langley, C.K. et al. The Acute Effects of Interrupting Prolonged Sitting Time in Adults with Standing and Light-Intensity Walking on Biomarkers of Cardiometabolic Health in Adults: A Systematic Review and Meta-analysis. Sports Med 52, 1765–1787 (2022). https://doi.org/10.1007/s40279-022-01649-4

https://link.springer.com/article/10.1007/s40279-022-01649-4

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(1)
Abbreviated Excerpt:  ”Most breast cancer cases show low concentrations of the breast cancer type 1 susceptibility protein (BRCA1). Surprisingly, only a small number of these patients have a mutated BRCA1 gene. Studies estimated that BRCA1 and BRCA2 mutations account for less than 5% of all breast cancer cases and less than 25% of familial breast cancer patients. These low numbers are consistent across the globe. For instance, an American study showed that only 3.3% of the women diagnosed with breast cancer had a mutation in their BRCA1 gene. A British study showed that only 3% of the studied breast cancer patients had mutated BRCA1/2 genes. A genetic study, done on 204 North Indian breast cancer patients, showed that only 6 patients (2.9%) had a BRCA1/2 mutation. Similarly, low numbers have been shown in a Chinese study that identified a mutation in the BRCA1/2 genes in only 7 out of 645 (1.1%) of the women with breast cancer.

Although the observed decrease in BRCA1 gene expression in the majority of the non-heritable or sporadic breast cancer cases is of great interest to the scientific and medical community, the cause is still unknown. In this paper, we use the Microcompetition Model to show how certain latent viruses, which are frequently detected in breast cancer, can decrease the expression of the BRCA1 gene and cause the development of breast tumors……. Studies also found Epstein Barr Virus (EBV) in breast cancer patients. One European study, which included 196 breast cancer specimens, found EBV DNA in 33.2% of the cases using real-time quantitative PCR (real-time PCR). Interestingly, the EBV-positive breast cancers tended to be tumors with a more aggressive phenotype. These EBV-positive tumors were also more frequently estrogen receptor negative and had a higher histological grade. A large meta-analysis of 24 studies, which included 1535 cases from all over the world, found an EBV infection in 29.3% of the patients with breast cancer. Also, patients with a positive EBV status showed a significant increase in breast malignancy risk. These studies provide evidence that EBV is statistically associated with an increased risk of breast cancer, especially of some specific types of breast cancer, such as lobular breast carcinoma . …..”

Polansky H and Schwab H: How latent viruses cause breast cancer: An explanation based on the microcompetition model. Bosn. J. Basic Med. Sci. 19(3): 221-226 (2019).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716096/

(2)
Abstract:An association of Epstein-Barr virus (EBV) infection with breast carcinoma (BC) risk has so far been disputed in the literature. Therefore, we performed a meta-analysis to clarify this relationship. An electronic database search for eligible case-control studies was performed using PubMed, Embase, Web of Science, the Cochrane Library, CNKI, and Wanfang Data until May 17, 2018. The pooled OR and 95% CI were used to estimate the relationship between EBV infection and BC risk using a fixed or random-effects model depending on heterogeneity. Subgroup analysis and meta-regression were used to explore the heterogeneity. Publication bias was assessed using Egger’s and Harbord’s tests. A total of 16 studies with 1,279 patients and 814 controls were reviewed based on our inclusion and exclusion criteria. Compared with the control group, EBV infection had a significant association with BC risk (OR 4.75, 95% CI 2.53-8.92, p < 0.01) with significant heterogeneity observed (I2 = 65.3%). The subgroup analysis revealed that region and tissue type might explain potential sources of heterogeneity. The sensitivity analyses yielded stable results. No significant publication bias was observed. The current results suggest that EBV infection is significantly associated with increased risk of BC.”

Jin Q, Su J, Yan D, Wu S. Epstein-Barr Virus Infection and Increased Sporadic Breast Carcinoma Risk: A Meta-Analysis. Med Princ Pract. 2020;29(2):195-200. doi: 10.1159/000502131. Epub 2019 Jul 17. PMID: 31311020; PMCID: PMC7098296.

https://pubmed.ncbi.nlm.nih.gov/31311020/

 

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Bierhansl, L., Hartung, HP., Aktas, O. et al. Thinking outside the box: non-canonical targets in multiple sclerosis. Nat Rev Drug Discov 21, 578–600 (2022). https://doi.org/10.1038/s41573-022-00477-5

https://www.nature.com/articles/s41573-022-00477-5

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Abstract:
“Healthspan is the period of our life without major debilitating diseases. In the modern world where unhealthy lifestyle choices and chronic diseases taper the healthspan, which lead to an enormous economic burden, finding ways to promote healthspan becomes a pressing goal of the scientific community. Exercise, one of humanity’s most ancient and effective lifestyle interventions, appears to be at the center of the solution since it can both treat and prevent the occurrence of many chronic diseases. Here, we will review the current evidence and opinions about regular exercise promoting healthspan through enhancing the functionality of our organ systems and preventing diseases.”

Guan Y, Yan Z. Molecular Mechanisms of Exercise and Healthspan. Cells. 2022 Mar 3;11(5):872. doi: 10.3390/cells11050872. PMID: 35269492; PMCID: PMC8909156.

https://pubmed.ncbi.nlm.nih.gov/35269492/

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1.
Long-term changes in time spent walking and subsequent cognitive and structural brain changes in older adults.
Best JR, Rosano C, Aizenstein HJ, Tian Q, Boudreau RM, Ayonayon HN, Satterfield S, Simonsick EM, Studenski S, Yaffe K, Liu-Ambrose T; Health, Aging and Body Composition Study.
Neurobiol Aging. 2017 Jun 6;57:153-161. doi: 10.1016/j.neurobiolaging.2017.05.023. [Epub ahead of print]
PMID: 28648916
2.
Physical Exercise with Music Reduces Gray and White Matter Loss in the Frontal Cortex of Elderly People: The Mihama-Kiho Scan Project.
Tabei KI, Satoh M, Ogawa JI, Tokita T, Nakaguchi N, Nakao K, Kida H, Tomimoto H.
Front Aging Neurosci. 2017 Jun 7;9:174. doi: 10.3389/fnagi.2017.00174. eCollection 2017.
PMID: 28638338
3.
At least eighty percent of brain grey matter is modifiable by physical activity: A review study.
Batouli SAH, Saba V.
Behav Brain Res. 2017 Aug 14;332:204-217. doi: 10.1016/j.bbr.2017.06.002. Epub 2017 Jun 7. Review.
PMID: 28600001
4.
Neuroprotective Effects of Physical Activity: Evidence from Human and Animal Studies.
Chieffi S, Messina G, Villano I, Messina A, Valenzano A, Moscatelli F, Salerno M, Sullo A, Avola R, Monda V, Cibelli G, Monda M.
Front Neurol. 2017 May 22;8:188. doi: 10.3389/fneur.2017.00188. eCollection 2017. Review.
PMID: 28588546
.
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Abstract: “Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19), with effective versus dysregulated responses influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the diverse genetic backgrounds of the Collaborative Cross founder strains crossed to K18-hACE2 transgenic mice that confers high susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, survival was associated with early type I interferon (IFN) expression and a phased proinflammatory response distinct from mice with severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding antiviral immunity and evaluating countermeasures.“

Robertson SJ, Bedard O, McNally KL, Lewis M, Clancy C, Shaia C, Broeckel RM, Chiramel AI, Sturdevant GL, Forte E, Preuss C, Baker CN, Harder J, Brunton C, Munger S, Sturdevant DE, Martens C, Holland SM, Rosenthal NA, Best SM. Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation and cytokine responses in COVID-19. bioRxiv [Preprint]. 2022 Feb 24:2021.09.17.460664. doi: 10.1101/2021.09.17.460664. PMID: 35233576; PMCID: PMC8887079.

https://pubmed.ncbi.nlm.nih.gov/35233576/

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Abbreviated Abstract:

People who have COVID-19 can experience symptoms for months. Studies on long COVID in the population lack representative samples and longitudinal data focusing on new-onset symptoms occurring with COVID while accounting for pre-infection symptoms. We use a sample representing the U.S. community population from the Understanding America Study COVID-19 Survey, which surveyed around 8000 respondents bi-weekly from March 2020 to March 2021. Our final sample includes 308 infected individuals who were interviewed one month before, around the time of, and 12 weeks after infection. About 23% of the sample experienced new-onset symptoms during infection which lasted for more than 12 weeks, and thus can be considered as having long COVID. The most common new-onset persistent symptoms among those included in the study were headache (22%), runny or stuffy nose (19%), abdominal discomfort (18%), fatigue (17%), and diarrhea (13%). Long COVID was more likely among obese individuals  and those who experienced hair loss, headache, and sore throat during infection. There was a lack of evidence relating risk to age, gender, race/ethnicity, education, current smoking status, or comorbid chronic conditions. This work provides national estimates of long COVID in a representative sample after accounting for pre-infection symptoms.

Wu, Q., Ailshire, J.A. & Crimmins, E.M. Long COVID and symptom trajectory in a representative sample of Americans in the first year of the pandemic. Sci Rep 12, 11647 (2022). https://doi.org/10.1038/s41598-022-15727-0

https://www.nature.com/articles/s41598-022-15727-0

 

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Abstract

Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C.

Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants.

Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C.

Interpretation: We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.

Davalos V, García-Prieto CA, Ferrer G, Aguilera-Albesa S, Valencia-Ramos J, Rodríguez-Palmero A, Ruiz M, Planas-Serra L, Jordan I, Alegría I, Flores-Pérez P, Cantarín V, Fumadó V, Viadero MT, Rodrigo C, Méndez-Hernández M, López-Granados E, Colobran R, Rivière JG, Soler-Palacín P, Pujol A, Esteller M. Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study. EClinicalMedicine. 2022 Jun 25;50:101515. doi: 10.1016/j.eclinm.2022.101515. PMID: 35770252; PMCID: PMC9233426.

https://pubmed.ncbi.nlm.nih.gov/35770252/

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340733/

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