Cancer-causing genome instability is a major concern during space travel due to exposure of astronauts to potent sources of high-linear energy transfer (LET) ionizing radiation. Hematopoietic stem cells (HSCs) are particularly susceptible to genotoxic stress, and accumulation of damage can lead to HSC dysfunction and oncogenesis. Our group recently demonstrated that aging human HSCs accumulate microsatellite instability coincident with loss of MLH1 , a DNA Mismatch Repair (MMR) protein, which could reasonably predispose to radiation-induced HSC malignancies. Therefore, in an effort to reduce risk uncertainty for cancer development during deep space travel, we employed an Mlh1 +/− mouse model to study the effects high-LET 56 Fe ion space-like radiation. Irradiated Mlh1 +/− mice showed a significantly higher incidence of lymphomagenesis with 56 Fe ions compared to γ-rays and unirradiated mice, and malignancy correlated with increased MSI in the tumors. In addition, whole exome sequencing analysis revealed high SNVs and INDELs in lymphomas being driven by loss of Mlh1 and frequently mutated genes had a strong correlation with human leukemias. Therefore, the data suggest that age-related MMR deficiencies could lead to HSC malignancies after space radiation, and that countermeasure strategies will be required to adequately protect the astronaut population on the journey to Mars.
Inflammatory bowel disease (IBD) is a chronic condition characterized by periods of spontaneous intestinal inflammation and is increasing in industrialized populations. Combined with host genetic predisposition, both diet and gut bacteria are thought to be prominent environmental features contributing to IBD, but little is known about the precise mechanisms. We show that low dietary fiber promotes bacterial erosion of the protective colonic mucus layer, leading to lethal colitis in interleukin-10-deficient mice. This diet-induced inflammation is specifically driven by mucin-degrading bacteria-mediated Th1 immune responses and is preceded by expansion of natural killer T cells and reduced immunoglobulin A coating of specific bacterial species. Low fiber, exclusive enteral nutrition reduced disease in part by increasing bacterial production of the metabolite isobutyrate, which was dependent on the presence of soy protein in the diet. Our results highlight a mechanistic framework to unravel the complex web of potentially opposing diet, host and microbial factors that combine to influence IBD development.
OBJECTIVE To determine long-term outcome for rhesus macaques (Macaca mulatta) with endometriosis that underwent surgical treatment and identify factors potentially associated with long-term outcome. DESIGN Retrospective case series. ANIMALS 11 female rhesus macaques. PROCEDURES Medical records of female rhesus macaques in which endometriosis was diagnosed between 2007 and 2011 and that underwent abdominal exploratory surgery were reviewed. RESULTS In 5 macaques, the only clinical abnormality was a caudal abdominal mass identified during a routine physical examination, and in 6 macaques, overt clinical signs of endometriosis, including anorexia, dysmenorrhea, and lethargy during menses, were reported. Five macaques had histologically confirmed complete ovarian removal, and another 5 had incomplete ovarian removal (ovarian tissue was not examined histologically in 1 macaque). Nine animals survived at least 12 months after surgery, and 6 survived at least 60 months after surgery. Macaques that did not have overt clinical signs were significantly more likely to survive at least 60 months after surgery. However, extent of ovarian removal was not significantly associated with survival 12 or 60 months after surgery. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, in select situations, surgery (ovariectomy or ovariohysterectomy) may be curative in macaques with endometriosis and may result in long-term survival. Further, findings suggested that monitoring until clinical signs appear before performing surgery is not warranted in adult female macaques suspected to have endometriosis that only have a caudal abdominal mass and no other overt clinical signs.
Buprenorphine is commonly used to control postoperative pain in rodents. Short-acting formulations of buprenorphine (bup-HCl) require frequent handling and restraint of animals for appropriate dosing, which can be stressful and confound research outcomes. Ethiqa XR (bup-ER) is an FDA-indexed extended-release buprenorphine formulation that is an alternative to bup-HCl in mice and rats. In the current study, we first evaluated the pharmacokinetics of bup-ER in male C57BL/6J mice by sampling blood at 10 time points, ranging from 30 min to 72 h after administration (n = 3 mice per time point). Average plasma concentrations fell below therapeutic levels at 48 h after administration. We also evaluated the safety of bup-ER when administered prior to surgery in combination with common anesthetics and the efficacy of bup-ER in mouse laparotomy. Anesthetic safety was studied by measuring respiratory rate, rectal temperature, and recovery time in groups of mice (n = 8) given bup-HCl, bup-ER, or saline in combination with isoflurane or ketamine-xylazine anesthesia. No differences were seen between analgesic treatment groups with either of the general anesthetics. To evaluate efficacy, mice (n = 10) were randomly allocated to receive either bup-ER (3.25 mg/kg) once presurgically, bup-HCl (0.1 mg/kg) presurgically and then every 8 h, or saline once before surgery. Mice underwent a sham laparotomy and were assessed for pain based on changes in weight, cageside ethogram, nesting consolidation test, rearing frequency, and nociception to von Frey testing at 6, 12, 24, 48, and 72 h after surgery. Cageside ethogram, rearing frequency, and von Frey testing showed significant differences between bup-ER-treated mice and saline controls in the early postoperative period. No significant effects between treatment groups were seen in daily weights or nesting consolidation scores. This study demonstrates that bup-ER can be safely administered before surgery and provides analgesia for up to 48 h after administration based on pharmacokinetic and behavioral data.
One of the major health concerns on long‐duration space missions will be radiation exposure to the astronauts. Outside the earth's magnetosphere, astronauts will be exposed to galactic cosmic rays (GCR) and solar particle events that are principally composed of protons and He, Ca, O, Ne, Si, Ca, and Fe nuclei. Protons are by far the most common species, but the higher atomic number particles are thought to be more damaging to biological systems. Evaluation and amelioration of risks from GCR exposure will be important for deep space travel. The hematopoietic system is one of the most radiation‐sensitive organ systems, and is highly dependent on functional DNA repair pathways for survival. Recent results from our group have demonstrated an acquired deficiency in mismatch repair (MMR) in human hematopoietic stem cells (HSCs) with age due to functional loss of the MLH1 protein, suggesting an additional risk to astronauts who may have significant numbers of MMR deficient HSCs at the time of space travel. In the present study, we investigated the effects gamma radiation, proton radiation, and 56Fe radiation on HSC function in Mlh1+/+ and Mlh1‐/‐ marrow from mice in a variety of assays and have determined that while cosmic radiation is a major risk to the hematopoietic system, there is no dependence on MMR capacity. stem cells translational medicine 2018;7:513–520
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