Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.
Nitrate supplementation improves endothelial function, blood pressure, ejection fraction and overall weight. It also may attenuate the hypoxic ventilatory response (HVR) in healthy individuals. Hypoxic ventilatory response is increased in obese humans when compared to healthy individuals. Therefore, we hypothesize that HVR increases in a rat model of obesity and this increase is mitigated by nitrite supplementation. Two experiments were conducted. In the first, 12 Fischer 344 rats were broken into two groups: Rats fed a standard diet with additional nitrite supplementation (Nitrite) and rats fed a standard diet with no additional supplementation. After 2 months of nitrite supplementation, plethysmography was used to measure ventilation at oxygen levels of 21%, 15%, 12%, and 9%. In the second experiment, 21 Fischer 344 rats were divided into 3 groups: rats fed a high fat diet (HFD), rats fed a high fat diet with nitrite supplementation in their drinking water (HFD‐N), and rats fed a standard diet (Control). After 14 months of diet and nitrite supplementation, all three groups underwent identical plethysmographic measurements to the first cohort. In the first group, as expected, nitrite supplementation significantly reduced HVR. In the second group, contrary to data in humans, the obesity rat model presented a decreased HVR when compared to controls. Nitrite did not alter this obesity induced decrease in ventilation. Nitrite did cause a significant increase in VO2 when compared to both groups. Future studies are needed to determine the mechanisms behind the impact of these interventions on HVR. Support or Funding Information This project was funded by the College of Liberal Arts and Sciences and the Health and Human Physiology department at the university of Iowa This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Sleep apnea is highly prevalent in patients with multiple myeloma, a rare and incurable cancer of malignant plasma cells, and is associated with poor outcomes. Chronic intermittent hypoxia (CIH), a feature of sleep apnea, facilitates myeloma development in mice. However, the mechanism by which CIH contributes to myeloma progression remains unknown. Our objective was to test the hypothesis that CIH provides a fertile environment for malignant cell engraftment via polarization of bone marrow macrophages. We exposed mice to chronic intermittent hypoxia (12 cycles/hr,10 hr/day) or 21% oxygen (control), harvested bone marrow, and assessed the impact of CIH on the percentage of bone marrow macrophages, B cells, plasma cells, T cells flow cytometry. Expression of Arg1, Mrc1, and Chi3l3 in bone marrow macrophages (CD11b+ F4/80+ ) of CIH-exposed mice was quantified by qPCR. We evaluated the transcriptome alteration in bone marrow cells of mice exposed to CIH and normoxia by conducting bulk RNA sequencing and single-cell RNA sequencing. Overall, CIH did not impact the number of macrophages in the bone marrow microenvironment but increased transcription of Arg1, Mrc1, and Chi3l3, transcripts associated with tumor associated-macrophages, relative to the transcription of IL-1β, TNF-α, and iNOS, transcripts associated with anti-tumorigenic macrophages. RNA sequencing of whole bone marrow supports the increased expression of macrophage markers consistent with tumor-associated macrophages, and pathway analysis further highlights the role of macrophages. Single-cell sequencing demonstrated that CIH-induced genes co-localize to a single cell population. In conclusion, we found that CIH exposure causes changes to myeloid cell populations in the bone marrow of mice and increases the transcription of genes relevant to myeloma tumor development in macrophages.
Autism Spectrum Disorder (ASD) is a neurobiological developmental condition that can impact communication, sensory processing, and social interaction. ASD) is a developmental disability that can cause significant social, communication and behavioral challenges. For a long time now, the scientific community has been grappling with the enigma of what causes the developmental deficits in people on the autism spectrum, the causes of the ASD symptoms, and the timing of the manifestation of ASD in infants that occurs on or after 6 months. Several research studies show that the main cause of autism appears on account of the enlargement of the brain, specifically the amygdala, which could lead to communication and physical deficits, as well as sensory and light sensitivity. The research on the causes for ASD is still at the nascent stage as there are still many unanswered questions including about the causes of ASD. It appears that few if any ASD Research studies have a representative sampling for gender and the majority of research focuses on male individuals with ASD. This literature review reveals that more research is required to bridge the gaps in our understanding of ASD . The enigma of the developmental causes in individuals with Autism Spectrum Disorder continues to be of interest to the scientific community and there is potential for further research regarding factors for pre-onset of ASD.
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