Since COVID‐19 took a strong hold around the globe causing considerable morbidity and mortality, a lot of effort was dedicated to manufacturing effective vaccines against SARS‐CoV‐2. Many questions have since been raised surrounding the safety of the vaccines, and a lot of media attention to certain side effects. This caused a state of vaccine hesitancy that may prove problematic in the global effort to control the virus. This review was undertaken with the aim of putting together all the reported cardiovascular and haematological events post COVID‐19 vaccination in published literature and to suggest possible mechanisms to explain these rare phenomena.
The coronavirus disease 2019 (COVID-19) pandemic has affected millions of individuals worldwide. The global scientific effort to design an effective vaccine against this virus has led to the development of several vaccine candidates. The expedited rollout of these vaccines has created some public distrust regarding the safety of these new vaccines. This review compiles clinical data from reports of diagnosed immune-related neurological events that have occurred after COVID-19 vaccine administration with the exception of those secondary to hematological abnormalities. A systematic literature search was performed, using several databases, to identify reports of postvaccination adverse neurological events. The search resulted in 18 studies that met our criteria. These studies included 61 patients who had received COVID-19 vaccines and experienced at least 1 neurological adverse effect. The most common neurological event was facial nerve palsy (50% of all events). Other less frequently reported events included the reactivation of herpes zoster, Guillain-Barre syndrome, other demyelinating diseases, and neuropathy. The underlying mechanism was hypothesized to be related to vaccine-induced type 1 interferon production leading to decreased tolerance of the myelin sheath antigens. Other hypotheses include vaccine-induced transient lymphopenia and immune dysregulation. Most of the reported events were time limited and resolved spontaneously. Given the rarity of reported neurological events compared to the total number of vaccines administered, and the similarity in the incidence of events between COVID-19 vaccines and other more common vaccines, there is little evidence to support a causal relationship between COVID-19 vaccines and adverse neurological events.
Background and Objectives: Breast cancer is among the most common cancer in women with 2.1 million new cases detected each year. Numerous studies have demonstrated a connection between body mass index (BMI) and cancer incidence, with obesity (BMI ≥ 30) being responsible for the development of at least 13 types of cancer, and 15% to 20% of total cancer-related mortality. The effects of extracellular vesicles (EVs) derived from the obese adipose tissue microenvironment on breast cancer have not yet been clearly elucidated. Methods: EVs were obtained from media conditioned with human breast adipose tissue from reduction mammoplasty (n=31). Women were healthy at the time of surgery and had no history of breast cancer. Patient samples were stratified based on their body mass index (BMI), with a BMI < 25 considered healthy and a BMI ≥ 25 considered overweight/obese. Breast adipose tissue-derived EVs (AT-EVs) were characterized (Quantitative Mass Spectrometry) and used to treat human breast cancer cell lines, including the ER+ MCF7 and triple negative breast cancer (TNBC) MDA-MB-231. Effects on cell proliferation and migration in vitro, and on tumor growth in a mouse xenograft model, were examined after long-term education with EVs. RNA sequencing was performed to investigate potential reprogramming induced by AT-EVs. Results: We found a positive correlation between protein amount per AT-EV and BMI. Quantitative proteomics of AT-EVs revealed 46 proteins that were significantly higher and 54 proteins that were significantly lower in specimens from women with a BMI ≥ 25 compared to women with a BMI < 25. AT-EVs from patients with a BMI ≥ 25 induced proliferation of MCF7 cells compared to AT-EVs from patients with a BMI < 25. Obese EVs induced a more aggressive phenotype in MDA-MB-231 cells, increasing their invasiveness in vitro. Obese EVs also increased the growth of MCF7 and MDA-MB-231 cells in vivo. Ingenuity pathway analysis of RNA-Seq data identified significant differences in mTOR signaling and canonical pathways associated with altered mitochondrial function. Conclusion: Our studies identify a novel mechanism to explain the obesity-breast cancer link in older women. Namely, that in obesity, the breast microenvironment produces EVs capable of reprogramming breast cancer cells to grow faster and be more aggressive. Identifying which cargo in breast AT-EV mediates these effects may provide new targets for intervention.
Breast adipose tissue is an important contributor to the obesity-breast cancer link. Dysregulated cell metabolism is now an accepted hallmark of cancer. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we found that long-term education of breast cancer cells (MCF7, T47D) with EVs from breast adipose tissue of women who are overweight or obese (O-EVs) leads to sustained increased proliferative potential. RNA-Seq of O-EV-educated cells demonstrates increased expression of genes, such as ATP synthase and NADH: ubiquinone oxidoreductase, involved in oxidative phosphorylation. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. Mitochondrial complex I inhibitor, metformin, reverses O-EV-induced cell proliferation. Several miRNAs, miR-155-5p, miR-10a-3p, and miR-30a-3p, which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing the metabolic reprogramming of ER+ breast cancer cells.
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