Bone Marrow Osteoblast Damage by Chemotherapeutic Agents

Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche

Low potency toxins reveal dense interaction networks in metabolism

Background The chemicals of metabolism are constructed of a small set of atoms and bonds. This may be because chemical structures outside the chemical space in which life operates are incompatible with biochemistry, or because mechanisms to make or utilize such excluded structures has not evolved. In this paper I address the extent to which biochemistry is restricted to a small fraction of the chemical space of possible chemicals, a restricted subset that I call Biochemical Space. I explore evidence that this restriction is at least in part due to selection again specific structures, and suggest a mechanism by which this occurs. Results Chemicals that contain structures that our outside Biochemical Space (UnBiological groups) are more likely to be toxic to a wide range of organisms, even though they have no specifically toxic groups and no obvious mechanism of toxicity. This correlation of UnBiological with toxicity is stronger for low potency (millimolar) toxins. I relate this to the observation that most chemicals interact with many biological structures at low millimolar toxicity. I hypothesise that life has to select its components not only to have a specific set of functions but also to avoid interactions with all the other components of life that might degrade their function. Conclusions The chemistry of life has to form a dense, self-consistent network of chemical structures, and cannot easily be arbitrarily extended. The toxicity of arbitrary chemicals is a reflection of the disruption to that network occasioned by trying to insert a chemical into it without also selecting all the other components to tolerate that chemical. This suggests new ways to test for the toxicity of chemicals, and that engineering organisms to make high concentrations of materials such as chemical precursors or fuels may require more substantial engineering than just of the synthetic pathways involved

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Mineral Type and Solution Chemistry Affect the Structure and Composition of Actively Growing Bacterial Communities as Revealed by Bromodeoxyuridine Immunocapture and 16S rRNA Pyrosequencing

© 2016, Springer Science+Business Media New York. Understanding how minerals affect bacterial communities and their in situ activities in relation to environmental conditions are central issues in soil microbial ecology, as minerals represent essential reservoirs of inorganic nutrients for the biosphere. To determine the impact of mineral type and solution chemistry on soil bacterial communities, we compared the diversity, composition, and functional abilities of a soil bacterial community incubated in presence/absence of different mineral types (apatite, biotite, obsidian). Microcosms were prepared containing different liquid culture media devoid of particular essential nutrients, the nutrients provided only in the introduced minerals and therefore only available to the microbial community through mineral dissolution by biotic and/or abiotic processes. By combining functional screening of bacterial isolates and community analysis by bromodeoxyuridine DNA immunocapture and 16S rRNA gene pyrosequencing, we demonstrated that bacterial communities were mainly impacted by the solution chemistry at the taxonomic level and by the mineral type at the functional level. Metabolically active bacterial communities varied with solution chemistry and mineral type. Burkholderia were significantly enriched in the obsidian treatment compared to the biotite treatment and were the most effective isolates at solubilizing phosphorous or mobilizing iron, in all the treatments. A detailed analysis revealed that the 16S rRNA gene sequences of the OTUs or isolated strains assigned as Burkholderia in our study showed high homology with effective mineral-weathering bacteria previously recovered from the same experimental site

Prolactin regulation of cytological differentiation of mammary epithelial-cells in periparturient cows

The influence of periparturient secretion of PRL on cytological differentiation of mammary epithelial cells was studied in 17 multiparous, monotocous Holstein cows. Mammary tissue was obtained 10 days prepartum and 10 days postpartum from untreated cows and from cows treated with CB154 (2-Br-{alpha}-ergokryptin) or CB154 plus PRL. CB154 was administered from 12 days before expected parturition through 10 days postpartum to reduce serum PRL concentrations, whereas exogenous PRL was administered for 6 days during the periparturient period to mimic the normal periparturient surge of the hormone. On day 10 postpartum, mammary epithelial cells of cows given CB154 alone were classified 18% undifferentiated, 65% intermediately differentiated, and 18% fully differentiated. In contrast, there were no undifferentiated epithelial cells in either postpartum controls or cows treated with CB154 plus PRL, and 73% and 79% of epithelial cells, respectively, were fully differentiated. Ultrastructural analysis demonstrated a relative lack of cellular differentiation in cows given CB154 alone. Specifically, the rough endoplasmic reticulum occupied 24% and 27% of the epithelial cell area in postpartum controls and cows treated with CB154 plus PRL, respectively; but the rough endoplasmic reticulum occupied only 16% of the cellular area in cows treated with CB154 alone (P < 0.01). The relative area occupied by Golgi membranes and vacuoles was approximately 11% lower (P <0.01) in cows treated with CB154 than in lactating controls or cows that received PRL replacement therapy. The data demonstrate that periparturient secretion of PRL is necessary for complete structural differentiation of bovine mammary alveolar epithelium

Prolactin regulation of milk secretion and biochemical differentiation of mammary epithelial-cells in periparturient cows

PRL involvement in periparturient mammary development and onset of milk secretion was studied in 17 multiparous, monotocous Holstein cows. Mammary glands were obtained 10 days prepartum from untreated cows and 10 days postpartum from untreated cows and cows treated with CB154 (2-Br-{alpha}-ergokryptin) or CB154 plus PRL. CB154 was administered for 12 days before expected parturition through 10 days postpartum. PRL was infused continuously for 6 days immediately before parturition in cows receiving CB154 plus PRL. Treatment with CB154 reduced basal serum PRL concentrations approximately 80% and blocked the normal surges in serum PRL concentrations at parturition and during milking. Average milk production in cows given CB154 alone was 11.4 kg/day lower than in controls. Periparturient infusion of PRL in cows treated with CB154 (CB154 plus PRL) prevented reductions in milk production. Treatment with CB154 had no effect on feed intake or periparturient serum concentrations of GH, progesterone, and glucocorticoids. Mammary glands from postpartum controls or cows treated with either CB154 or CB154 plus PRL contained equivalent total amounts of DNA. Inhibition of PRL secretion reduced total mammary RNA content 36% and decreased the RNA/DNA ratio (1.38) relative to ratios in cows that received PRL replacement therapy (2.17) or untreated lactating controls (1.86). Thus, reduced milk yields among cows treated with CB154 were associated with reduced mammary secretory cell activity rather than reduced cell numbers. Biosynthetic rates of fatty acid and lactose synthesis were lower in mammary tissue from cows given CB154. These rates were related to decreased activities of acetyl coenzyme A carboxylase, fatty acid synthetase, and a-lactalbumin. For all mammary biochemical parameters, cows given CB154 plus PRL had values equal to those of controls. We conclude that periparturient secretion of PRL is essential for maximal synthesis of milk in the postpartum period and that PRL plays a critical role in mammary differentiation of key biochemical steps involved in synthesis of milk