Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis

Activated in response to chemotherapy, senescence is a tumor suppressive mechanism that induces a permanent loss of proliferation. However, in response to treatment, it is not really known how cells can escape senescence and how irreversible or incomplete this pathway is. We have recently described that cells that escape senescence are more transformed than non-treated parental cells, they resist anoikis and rely on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that Akt was activated as a feedback pathway during the early step of senescence. The inhibition of the kinase prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 downregulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. The inactivation of Noxa prevented apoptosis and increased the number of emergent cells. Using either RNA interference or p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its downregulation improved treatment efficacy through apoptosis induction. Therefore, although senescence is an efficient suppressive mechanism, it also generates more aggressive cells as a consequence of apoptosis inhibition. We therefore propose that senescence-inducing therapies should be used sequentially with drugs favoring cell death such as Akt inhibitors. This should reduce cell emergence and tumor relapse through a combined induction of senescence and apoptosis.     

Evaluation of safety and efficacy as an adjuvant for the chitosan-based vaccine delivery vehicle ViscoGel in a single-blind randomised Phase I/IIa clinical trial

ViscoGel, a chitosan-based hydrogel, has earlier been shown to improve humoral and cell-mediated immune responses in mice. In this study, a Phase I/IIa clinical trial was conducted to primarily evaluate safety and secondarily to study the effects of ViscoGel in combination with a model vaccine, Act-HIB to Haemophilus influenzae type b, administered as a single intramuscular injection. Healthy volunteers of both sexes, ages 22–50 and not previously vaccinated to HIB, were recruited. The trial had two phases. In Phase A, three ascending dose levels of ViscoGel (25, 50 and 75 mg) were evaluated for safety in 3 × 10 subjects. Phase B had a single-blind, randomised, parallel-group design evaluating safety and efficacy in five groups, 20 subjects/group, comparing vaccination with 0.2 μg or 2 μg Act-HIB alone or combined with ViscoGel (50 mg) and one group receiving the standard Act-HIB dose (10 μg). No safety or tolerability concerns were identified. Local, transient reactions at the injection site were the most common adverse events. These were more frequent in groups receiving Act-HIB + ViscoGel, while other AEs were recorded at similar frequency in Act-HIB and Act-HIB + ViscoGel groups. Efficacy was evaluated by measuring serum anti-HIB antibodies and cellular responses in peripheral blood mononuclear cells (PBMC). There was a large variation in baseline anti-HIB antibody titres and no adjuvant effect was observed on the anti-HIB antibody production in groups vaccinated with Act-HIB + ViscoGel. ELISpot analyses revealed increased interferon-γ (IFN-γ) responses to Act-HIB in PBMCs from subjects vaccinated with Act-HIB in combination with ViscoGel, compared to groups receiving Act-HIB alone. Moreover, ViscoGel counteracted an inhibitory effect of Act-HIB vaccination on the IFN-γ response to both the vaccine itself and an irrelevant influenza antigen. In summary, ViscoGel was found to be safe and well-tolerated, supporting further examination of ViscoGel as a new innovative vehicle for vaccine development.     

The reporting of race and ethnicity information in the dental public health literature

Objectives: To document how race and ethnicity are identified, categorized, and utilized in contemporary dental public health literature. Methods: Two researchers independently performed a literature review of all articles in Community Dentistry and Oral Epidemiology and the Journal of Public Health Dentistry over a 5‐year period (2004‐2009). Articles pertaining to the study of US‐based populations with any mention of race or ethnicity were included. The following data were abstracted from each article: a) how each article broadly described race and/or ethnicity; b) the terms used to specifically define the races and/or ethnicities captured; c) the location of any mention of the concept of race and/or ethnicity; d) the stated purpose for including race and/or ethnicity concepts; e) the stated analytic use of race and/or ethnicity concepts; and f) the stated method used to assess race and/or ethnicity concepts. Results: Overall, race and/or ethnicity concepts were most commonly referred to within the text of the results section. Fifty percent of articles did not state their purpose for including race and/or ethnicity concepts within their studies, while 34.3 percent omitted stating their analytic use of these concepts. When assessing these concepts, 41.4 percent relied upon subject self‐report. Conclusion: These data showed that there was inconsistent documentation of how race and ethnicity was measured. While race and ethnicity are important measures for public health studies and are frequently reported in dental public health research, there is no clear system for classifying these measures.     

Stress as a trigger of attacks in Menière's disease. A case-crossover study

BACKGROUND: Menière's disease is defined as the presence of recurrent, spontaneous episodic vertigo, hearing loss (HL), aural fullness, and tinnitus. The occurrence of attacks is unpredictable. The etiology is still unknown, but the disease has a pathologic correlate in hydropic distension of the endolymphatic system. Earlier studies have shown increased incidence of stress on the same day as vertigo attacks, but it has not been determined whether stress occurring on the day of the vertiginous episode came before or after the onset of the vertigo. METHODS: A case-crossover study including 46 patients with active Menière's disease. MAIN OUTCOME MEASURE: Relative risks with 95% confidence intervals (CI). FINDINGS: During the study period, 153 Menière's attacks were reported. Twenty-four (52%) of the 46 patients reported attacks. Twelve of the 153 (8%) attacks occurred within 3 hours after exposure to emotional stress. The relative risk of having an attack was 5.10 (95% CI 2.37-10.98) during 3 hours after being exposed to emotional stress. Twenty-nine percent of the patients with attacks had at least one attack after exposure to emotional stress. For mental stress, the relative risk was 4.16 (95% CI 1.46-11.83) and the hazard period 1 hour, but only five attacks were exposed. No excess risk was found after physical stress. INTERPRETATION: Being exposed to emotional stress increases the risk of getting an attack of Menière's disease during the next hour, and the hazard period is possibly extended up to 3 hours.     

Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors

Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.     

Respiratory muscle metabolic activity on PET/CT correlates with obstructive ventilatory defect severity and prognosis in patients undergoing lung cancer surgery

Background and Objective

Respiratory muscle activity is increased in patients with chronic respiratory disease. ¹⁸F-FDG-PET/CT can assess respiratory muscle activity. We hypothesized that respiratory muscles metabolism was correlated to lung function impairment and was associated to prognosis in patients undergoing lung cancer surgery based on the research question whether respiratory muscle metabolism quantitatively correlates with the severity of lung function impairment in patients? Does respiratory muscle hypermetabolism have prognostic value?

Methods

Patients undergoing ¹⁸F-FDG-PET/CT and pulmonary function tests prior to lung cancer surgery were identified. Maximum Standardized Uptake Value (SUVm) were measured in each respiratory muscle group (sternocleidomastoid, scalene, intercostal, diaphragm), normalized against deltoid SUVm. Respiratory muscle hypermetabolism was defined as SUVm >90th centile in any respiratory muscle group. Clinical outcomes were collected from a prospective cohort.

Results

One hundred fifty-six patients were included, mostly male [110 (71%)], 53 (34%) with previous diagnosis of COPD. Respiratory muscle SUVm were: scalene: 1.84 [1.51–2.25], sternocleidomastoid 1.64 [1.34–1.95], intercostal 1.01 [0.84–1.16], diaphragm 1.79 [1.41–2.27]. Tracer uptake was inversely correlated to FEV1 for the scalene (r = −0.29, p < 0.001) and SCM (r = −0.17, p = 0.03) respiratory muscle groups and positively correlated to TLC for the scalene (r = 0.17, p = 0.04). Respiratory muscle hypermetabolism was found in 45 patients (28.8%), who had a lower VO₂ max (15.4 [14.2–17.5] vs. 17.2 mL/kg/min [15.2–21.1], p = 0.07) and poorer overall survival when adjusting to FEV1% (p < 0.01).

Conclusion

Our findings show respiratory muscle hypermetabolism is associated with lung function impairment and has prognostic significance. ¹⁸F-FDG/PET-CT should be considered as a tool for assessing respiratory muscle activity and to identify high-risk patients.