Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.     

Adhesion molecules in inflammatory bowel disease.

The ability of leucocytes to adhere to endothelium is essential for leucocyte migration into inflammatory sites. Some of these adhesion molecules are released from the cell surface and can be detected in serum. The soluble adhesion molecules intercellular adhesion molecule 1 (ICAM-1), E selectin, and vascular cell adhesion molecule 1 (VCAM-1) were studied in the serum of patients with Crohn's disease, ulcerative colitis, and healthy controls. A second blood sample was taken from patients with active disease after one month of treatment and a third two months after remission was achieved. Tissue expression of the same adhesion molecules was studied by immunohistology. Circulating VCAM-1 concentrations were significantly higher in patients with active ulcerative colitis (n = 11, median = 165 U/ml) compared with patients with inactive ulcerative colitis (n = 10, median = 117 U/ml, p < 0.005), active Crohn's disease (n = 12, median = 124 U/ml, p < 0.02), and controls (n = 90, median = 50 U/ml, p < 0.0001). Within each disease group there were no significant differences in E selectin or ICAM-1 concentrations between the active and inactive states, however, patients with active Crohn's disease had significantly higher ICAM-1 concentrations (n = 12, median = 273 ng/ml) than controls (n = 28, median = 168, p < 0.003). VCAM-1 concentrations fell significantly from pretreatment values to remission in active ulcerative colitis (p < 0.01). In Crohn's disease there was a significant fall in ICAM-1 both during treatment (p < 0.01) and two months after remission (p < 0.02). Vascular expression of ICAM-1 occurred more often and was more intense in inflamed tissue sections from patients with ulcerative colitis and Crohn's disease than from controls. Vascular labelling with antibody to E selectin also occurred more often in patients with active inflammatory bowel disease. In conclusion, increased circulating concentrations of selected adhesion molecules are associated with inflammatory bowel disease. There is also evidence of local upregulation, particularly of ICAM-1. Differential expression of adhesion molecules in tissue may play a part in the initiation of leucocyte migration and local inflammation; the function of circulating adhesion molecules is unknown, but may play a physiological part in blocking adhesion.     

Detection of low bone mineral density by dual energy x ray absorptiometry in unsuspected suboptimally treated coeliac disease.

Patients with coeliac disease may present with calcium malabsorption but it is unclear whether this results in longterm impairment of bone mineralisation. Dual energy x ray absorptiometry (DXA) was used to study bone mineral density in 34 asymptomatic coeliac disease patients, treated with a gluten free diet for at least two years, and also in 10 newly diagnosed or untreated patients. As expected, untreated patients had low bone mineral density in all regions. In the 29 treated female coeliac disease patients, overall mean values for age adjusted bone mineral density expressed as Z scores were normal although there were many patients with low values, particularly of the lumbar spine and total body. Scores in the postmenopausal patients were significantly worse than in the premenopausal patients and low mean Z scores were found in the five treated male patients. The subjects who had reduced bone mineral density could not be predicted clinically but, despite being asymptomatic, were more likely to have subtotal or partial villous atrophy on small intestinal biopsy (p < 0.0275). In conclusion, although many treated coeliac disease patients have normal bone mineral density, suboptimally treated and newly diagnosed or untreated patients have osteopenia. To reduce the risk of osteoporotic fractures, it is recommended that bone mineral density be measured in all treated coeliac disease patients and those with osteopenia have a repeat intestinal biopsy to assess disease activity.     

Pilot study investigating the effect of enteral and parenteral nutrition on the gastrointestinal microbiome post-allogeneic transplantation

Nutrition support is frequently required post-allogeneic haematopoietic progenitor cell transplantation (HPCT); however, the impact of mode of feeding on the gastrointestinal microbiome has not been explored. This study aimed to determine if there is a difference in the microbiome between patients receiving enteral nutrition (EN) and parenteral nutrition (PN) post-allogeneic HPCT. Twenty-three patients received either early EN or PN when required. Stool samples were collected at 30 days post-transplant and analysed with shotgun metagenomic sequencing. There was no difference in microbial diversity between patients who received predominantly EN (n = 13) vs. PN (n = 10) however patients who received predominantly EN had greater abundance of Faecalibacterium (P < 0·001) and ruminococcus E bromii (P = 0·026). Patients who had minimal oral intake for a longer duration during provision of nutrition support had a different overall microbial profile (P = 0·044), lower microbial diversity (P = 0·004) and lower abundance of faecalibacterium prausnitzii_C (P = 0·030) and Blautia (P = 0·007) compared to patients with greater oral intake. Lower microbial diversity was found in patients who received additional beta lactam antibiotics (P = 0·042) or had a longer length of hospital stay (P = 0·019). Post-HPCT oral intake should be encouraged to maintain microbiota diversity and, if nutrition support is required, EN may promote a more optimal microbiota profile.     

Mass-producible 2D-WS2 bulk modified screen printed electrodes towards the hydrogen evolution reaction

A screen-printable ink that contained varying percentage mass incorporations of two dimensional tungsten disulphide (2D-WS₂) was produced and utilized to fabricate bespoke printed electrodes (2D-WS₂-SPEs). These WS₂-SPEs were then rigorously tested towards the Hydrogen Evolution Reaction (HER) within an acidic media. The mass incorporation of 2D-WS₂ into the 2D-WS₂-SPEs was found to critically affect the observed HER catalysis with the larger mass incorporations resulting in more beneficial catalysis. The optimal (largest possible mass of 2D-WS₂ incorporation) was the 2D-WS₂-SPE_40%, which displayed a HER onset potential, Tafel slope value and Turn over Frequency (ToF) of −214 mV (vs. RHE), 51.1 mV dec⁻¹ and 2.20 , respectively. These values significantly exceeded the HER catalysis of a bare/unmodified SPE, which had a HER onset and Tafel slope value of −459 mV (vs. RHE) and 118 mV dec⁻¹, respectively. Clearly, indicating a strong electrocatalytic response from the 2D-WS₂-SPEs. An investigation of the signal stability of the 2D-WS₂-SPEs was conducted by performing 1000 repeat cyclic voltammograms (CVs) using a 2D-WS₂-SPE_10% as a representative example. The 2D-WS₂-SPE_10% displayed remarkable stability with no variance in the HER onset potential of ca. −268 mV (vs. RHE) and a 44.4% increase in the achievable current over the duration of the 1000 CVs. The technique utilized to fabricate these 2D-WS₂-SPEs can be implemented for a plethora of different materials in order to produce large numbers of uniform and highly reproducible electrodes with bespoke electrochemical signal outputs.

Two dimensional tungsten disulphide screen-printed electrodes display efficient electrocatalysis towards the hydrogen evolution reaction.     

SAMP8 mice have altered hippocampal gene expression in long term potentiation,phosphatidylinositol signaling,and endocytosis pathways

The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta (Aβ) peptide accumulation at 12 months. To detect differences in gene expression in SAMP8 mice, we used a control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMs). We then compared gene expression in the hippocampus of 4- and 12-month-old SAMP8 and control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the long term potentiation (6 genes), phosphatidylinositol signaling (6 genes), and endocytosis (10 genes) pathways. The changes in long term potentiation included mitogen-activated protein kinase (MAPK) signaling (N-ras, cAMP responsive element binding protein [CREB], protein phosphatase inhibitor 1) and Ca-dependent signaling (inositol triphosphate [ITP] receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through phosphatidylinositol-3-kinase, and Western blotting revealed phosphorylation changes in serine/threonine protein kinase AKT and 70S6K. Changes in the endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered gene expression in 3 SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways might provide new therapeutic targets in addition to targeting Aβ metabolism itself.     

Affective School Engagement and Self-Concept: How are Irish Boys and Girls Faring?

Internationally and in Ireland, much of the research around gender and educational engagement has centred on the academic differences between boys and girls (Warrington and Younger 2000; Francis 2009; O’Connor 2007). Less is known however about the factors shaping affective school engagement and student self-concept and how this can affect participation in learning. Children and young people emphasise the affective or emotional as much as the learning aspects of school life (Alexander 2008). Drawing on data from the 9-year cohort of the Growing Up in Ireland study, this paper examines self-concept among boys and girls in Irish primary schools. The findings show important differences in terms of the affective elements of school engagement, with boys more likely than girls to score significantly lower levels on measures of ‘good’ behaviour and intellectual school status, while girls score significantly lower on freedom from anxiety than boys. The findings also illustrate that predictors of disengagement are about more than the child’s gender – in that working class children and students with special educational needs are faring less well in terms of affective engagement in school.     

Burnout of the US midwifery workforce and the role of practice environment

ObjectivesTo determine the prevalence of burnout among the midwifery workforce and the association between fixed personal and practice characteristics and modifiable organizational factors, specifically practice environment, to burnout among midwives in the United States.Data SourcePrimary data collection was conducted via an online survey of the complete national roster of certified nurse‐midwives and certified midwives over 3 weeks in April 2017.Study DesignThe study was a cross‐sectional observational survey consisting of 95 items about personal and practice characteristics, respondents'' practice environments, and professional burnout.Data Collection MethodsThe inclusion criterion was actively practicing midwifery in the United States. Data were analyzed with bivariate analyses to determine the association between personal and practice characteristics and burnout. A hierarchal multilinear regression evaluated the interrelationship between personal and practice characteristics, practice environment, and burnout.Principal FindingsOf the almost one third (30.9%) of certified nurse‐midwives and certified midwives who responded to the survey, 40.6% met criteria for burnout. Weak negative correlations existed between burnout and indicators of career longevity: age (r(2256) = −0.09, p < 0.01), years as a midwife (r(2267) = −0.07, p = 0.01), and years with employer (r(2271) = −0.05, p = 0.02). There were significant relationships between burnout score and patient workload indicators: patients per day in outpatient setting (F(5,2292) = 13.995, p < 0.01), birth volume (F(3,1864) = 8.35, p < 0.01), and patient acuity (F(2,2295) = 20.21, p < 0.01). When the practice environment was entered into the model with personal and practice characteristics, the explained variance increased from 6.4% to 26.5% (F(20,1478) = 27.98, p < 0.01).ConclusionsOur findings suggested that a key driver of burnout among US midwives was the practice environment, specifically practice leadership and participation and support for the midwifery model of care. Structural and personal characteristics contributed less to burnout score than the practice environment, implying that prevention of burnout may be achieved through organizational support and does not require structural changes to the provision of perinatal health.     

Intercostal nerve blockade with liposomal bupivacaine reduces length of stay after video assisted thoracic surgery (VATS) lobectomy

BackgroundIntercostal nerve blockade (INB) for thoracic surgery analgesia has gained popularity in practice, but evidence demonstrating its efficacy remains sparse and inconsistent. We investigated the effect of INB with standard bupivacaine (SB) with epinephrine versus liposomal bupivacaine (LB) versus a mixed solution of the two on postoperative pain control and outcomes in video assisted thoracoscopic lobectomy patients.MethodsSince 2014, our practice has shifted from using INBs with SB with epinephrine, to LB, to a mix of the two as the central component of multimodal analgesia after video assisted thoracoscopic surgery. The blocks are performed in a standardized fashion under thoracoscopic visualization consecutively from two rib spaces above to two below the outermost incisions. We retrospectively compared all minimally invasive lobectomies performed at our institution between January 2014 and July 2018 by type of local anesthetic used for INB. We examined median length of stay (LOS), opioid utilization, and subjective pain scores [0–10].ResultsOut of 302 minimally invasive lobectomy patients, 34 received SB with epinephrine, 222 received LB alone, and 46 received the mixed solution. LOS was almost a full day shorter in the LB group than in the SB group (34.8 vs. 56.5 hours, P=0.01). There was nearly 25% lower median total morphine equivalent utilization in the mixed solution cohort compared to the LB cohort (−7.1 mg, P=0.02). Additionally, IV morphine equivalent utilization was over 50% lower in the mixed solution group than in the SB with epinephrine group (−10.0 mg, P=0.03).ConclusionsOur study is by far the largest (N=302) to compare types of local anesthetic used for INB within a uniform case population. The reductions in LOS and opiate utilization observed in our study among patients receiving LB-based formulations were both statistically and clinically significant.