Sprint interval training in the postpartum period maintains the enhanced cardiac output of pregnancy: A case study.

During pregnancy an increased cardiac output ( Q ̇ $\dot{Q}$ ) and blood volume (BV) occur to support fetal growth. Increased Q ̇ $\dot{Q}$ and BV also occur during chronic endurance exercise training and benefit performance. We investigated if sprint interval training (SIT) undertaken early postpartum maintains the elevated Q ̇ $\dot{Q}$ and BV of pregnancy and benefits performance. The participant, a competitive field hockey player and former cyclist, visited our laboratory at 2 weeks of gestation (baseline) and postpartum pre-, mid- and post-intervention (PPpre, PPmid and PPpost). Delivery was uncomplicated and she felt ready to start the SIT programme 5 weeks postpartum. Inert gas rebreathing was used to measure peak exercise Q ̇ $\dot{Q}$ ( Q ̇ $\dot{Q}$ peak); V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ was measured with a metabolic cart; and postpartum haematological values were measured with carbon monoxide rebreathing. The 18 SIT sessions progressed from four to eight sprints at 130% of V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ peak power output. Q ̇ $\dot{Q}$ peak increased from baseline at all postpartum time points (baseline 16.2 vs. 17.5, 16.8 and 17.2 L/min at PPpre, PPmid and PPpost, respectively). Relative V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ remained below baseline values at all postpartum measurements (baseline 44.9 vs. 41.0, 42.3 and 42.5 mL/kg/min at PPpre, PPmid and PPpost, respectively) whereas absolute V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ rapidly reached baseline values postpartum (baseline 3.19 vs. 3.12, 3.23 and 3.18 L/min at PPpre, PPmid and PPpost, respectively). Postpartum BV (5257, 4271 and 5214 mL at PPpre, PPmid and PPpost, respectively) and Hbmass (654, 525 and 641 g at PPpre, PPmid and PPpost, respectively) were similar between PPpre and PPpost but decreased alongside Q ̇ $\dot{Q}$ peak at PPmid. Peak power was returned to pre-pregnancy values by intervention end (302 vs. 303 W, baseline vs. PPpost). These findings show that SIT undertaken early postpartum defends the elevated Q ̇ $\dot{Q}$ peak of pregnancy and rapidly returns absolute V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ and peak power to baseline levels. HIGHLIGHTS: What is the central question of this study? Can the enhanced cardiac output of pregnancy be maintained with strenous exercise training undertaken early postpartum. What is the main finding and its importance? Baseline values of absolute oxygen consumption, peak power output and peak exercise cardiac output can be regained rapidly or surpassed following 6 weeks of sprint interval training postpartum. Sprint interval training can be used by endurance trained females to safely resume training early postpartum, allowing a rapid and efficient return to baseline fitness levels.

The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance.

Small molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs that engage with cereblon hold the potential of unique phenotypic effects, and we therefore studied the novel protein homeostatic modulator (PHM™) BTX306 with a unique thiophene-fused scaffold bearing a substituted phenylurea and glutarimide. This agent much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations in the single nanomolar range versus micromolar values for lenalidomide or pomalidomide, and more potently activated caspases 3/8/9. While lenalidomide and pomalidomide induced greater degradation of Ikaros and Aiolos in myeloma cells, BTX306 more potently reduced levels of GSPT1, eRF1, CK1α, MCL-1, and c-MYC. Suppression of cereblon or overexpression of Aiolos or Ikaros induced relative resistance to BTX306, and this agent did not impact viability of murine hematopoietic cells in an in vivo model, demonstrating its specificity for human cereblon. Interestingly, BTX306 did show some reduced activity in lenalidomide-resistant cell line models but nonetheless retained its nanomolar potency in vitro, overcame bortezomib resistance, and was equipotent against otherwise isogenic cell line models with either wild-type or knockout TP53. Finally, BTX306 demonstrated strong activity against primary CD138-positive plasma cells, showed enhanced anti-proliferative activity in combination with bortezomib and dexamethasone, and was effective in an in vivo systemic model of multiple myeloma. Taken together, the data support further translational studies of BTX306 and its derivatives to the clinic for patients with relapsed and/or refractory myeloma. KEY MESSAGES: BTX306 has a unique thiophene-fused scaffold bearing phenylurea and glutarimide. BTX306 is more potent against myeloma cells than lenalidomide or pomalidomide. BTX306 overcomes myeloma cell resistance to lenalidomide or bortezomib in vitro. BTX306 is active against primary myeloma cells, and shows efficacy in vivo.

Histone deacetylase inhibitor MGCD0103 synergizes with gemcitabine in human pancreatic cells.

Histone deacetylase inhibitors are a group of recently developed compounds that modulate cell growth and survival. We evaluated the effects of the histone deacetylase inhibitor MGCD0103 on growth of pancreatic carcinoma models following single agent treatment and in combination with gemcitabine. MGCD0103 inhibited tumor cell growth and acted synergistically with gemcitabine to enhance its cytotoxic effects. Gene expression analysis identified the cell cycle pathway as one of the most highly modulated gene groups. Our data suggest that MGCD0103 + gemcitabine might be an effective treatment for gemcitabine-refractory pancreatic cancer.

A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.

BACKGROUND: The cytidine nucleoside analogs azacitidine (AZA) and decitabine (DAC) are used for the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Few non-clinical studies have directly compared the mechanisms of action of these agents in a head-to-head fashion, and the agents are often viewed as mechanistically similar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we compared their in vitro effects on several end points in human AML cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Both drugs effected DNA methyltransferase 1 depletion, DNA hypomethylation, and DNA damage induction, with DAC showing equivalent activity at concentrations 2- to 10-fold lower than AZA. At concentrations above 1 microM, AZA had a greater effect than DAC on reducing cell viability. Both drugs increased the sub-G1 fraction and apoptosis markers, with AZA decreasing all cell cycle phases and DAC causing an increase in G2-M. Total protein synthesis was reduced only by AZA, and drug-modulated gene expression profiles were largely non-overlapping. CONCLUSIONS/SIGNIFICANCE: These data demonstrate shared mechanisms of action of AZA and DAC on DNA-mediated markers of activity, but distinctly different effects in their actions on cell viability, protein synthesis, cell cycle, and gene expression. The differential effects of AZA may be mediated by RNA incorporation, as the distribution of AZA in nucleic acid of KG-1a cells was 65:35, RNA:DNA.

Azacitidine and decitabine have different mechanisms of action in non-small cell lung cancer cell lines.

Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8-10.5 µM), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 µM). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis.

Immunomodulatory drug CC-4047 is a cell-type and stimulus-selective transcriptional inhibitor of cyclooxygenase 2.

COX2 (prostaglandin G/H synthase, PTGS2) is a well-validated target in the fields of both oncology and inflammation. Despite their significant toxicity profile, non-steroidal anti-inflammatory drugs (NSAIDs) have become standard of care in the treatment of many COX2-mediated inflammatory conditions. In this report, we show that one IMiDs((R)) immunomodulatory drug, CC-4047, can reduce the levels of COX2 and the production of prostaglandins (PG) in human LPS-stimulated monocytes. The inhibition of COX2 by CC-4047 occurs at the level of gene transcription, by reducing the LPS-stimulated transcriptional activity at the COX2 gene. Because it is a transcriptional rather than an enzymatic inhibitor of COX2, CC-4047 inhibition of PG production is not susceptible to competition by exogenous arachadonic acid (AA). The distinct mechanisms of action allow CC-4047 and a COX2-selective NSAID to work additively to block PG secretion from monocytes. CC-4047 does not, however, block COX2 induction in or prostacyclin secretion from IL-1beta stimulated human umbilical vein endothelial cells (HUVEC) cells, nor does it inhibit COX1 in either monocytes or HUVEC cells. CC-4047 also inhibits COX2 and PG production in monocytes derived from patients with sickle cell disease (SCD). Taken together, the data in this manuscript suggest CC-4047 will provide important anti-inflammatory benefit to patients and will improve the safety of NSAIDs in the treatment of SCD or other inflammatory conditions.

Lead identification of a potent benzopyranone selective estrogen receptor modulator.

Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.

Differential response of estrogen receptors alpha and beta to SP500263, a novel potent selective estrogen receptor modulator.

We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-alpha and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.