Association of matrix metalloproteinase 2 plasma level with response and survival in patients treated with bevacizumab for recurrent high-grade glioma

Background

A predictive marker of bevacizumab activity is an unmet medical need. We evaluated the predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent high-grade glioma treated with bevacizumab.

Methods

Analyzed in plasma were a set of 11 prebiomakers of interest (vascular endothelial growth factor receptor [VEGF]; VEGF receptor 2; basic fibroblast growth factor; stromal cell derived factor 1; placenta growth factor; urokinase-type plasminogen activator; plasminogen activator inhibitor 1; matrix metalloproteinases 2, 7, and 9; and adrenomedulline), using ELISA, at baseline and 2 weeks after bevacizumab initiation in a prospective cohort of 26 patients (Cohort 1). Correlations were validated in a separate retrospective cohort (Cohort 2; n = 50) and tested in cohort patients treated with cytotoxic agents without bevacizumab (Cohort 3; n = 34). Dosages were correlated to objective response, progression-free survival (PFS), and overall survival (OS).

Results

In Cohort 1, high MMP2 baseline level was associated with a probability of objective response of 83.3% versus 15.4% for low MMP2 level (P = .001). In multivariate analysis, baseline level of MMP2 correlated with PFS (hazard ratio, 3.92; 95% confidence interval [CI]:1.46–10.52; P = .007) and OS (hazard ratio, 4.62; 95% CI: 1.58–13.53; P = .005), as decrease of VEGF (P = .038 for PFS and P = .013 for OS) and MMP9 (P = .016 for PFS and P = .025 for OS). In Cohort 2, MMP2, but not MMP9, confirmed its predictive significance. In Cohort 3, no association was found between MMP2, MMP9, and outcome.

Conclusion

In patients with recurrent high-grade glioma treated with bevacizumab, but not with cytotoxic agent, high MMP2 plasma levels are associated with prolonged tumor control and survival. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role reassessed.     

Spatial Distribution and Burden of Emerging Arboviruses in French Guiana

Despite the health, social and economic impact of arboviruses in French Guiana, very little is known about the extent to which infection burden is shared between individuals. We conducted a large multiplexed serological survey among 2697 individuals from June to October 2017. All serum samples were tested for IgG antibodies against DENV, CHIKV, ZIKV and MAYV using a recombinant antigen-based microsphere immunoassay with a subset further evaluated through anti-ZIKV microneutralization tests. The overall DENV seroprevalence was estimated at 73.1% (70.6–75.4) in the whole territory with estimations by serotype at 68.9% for DENV-1, 38.8% for DENV-2, 42.3% for DENV-3, and 56.1% for DENV-4. The overall seroprevalence of CHIKV, ZIKV and MAYV antibodies was 20.3% (17.7–23.1), 23.3% (20.9–25.9) and 3.3% (2.7–4.1), respectively. We provide a consistent overview of the burden of emerging arboviruses in French Guiana, with useful findings for risk mapping, future prevention and control programs. The majority of the population remains susceptible to CHIKV and ZIKV, which could potentially facilitate the risk of further re-emergences. Our results underscore the need to strengthen MAYV surveillance in order to rapidly detect any substantial changes in MAYV circulation patterns.     

Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest

Background

Arterial carbon dioxide tension (PaCO₂) affects neuronal function and cerebral blood flow. However, its association with outcome in patients admitted to intensive care unit (ICU) after cardiac arrest (CA) has not been evaluated.

Methods and results

Observational cohort study using data from the Australian New Zealand (ANZ) Intensive Care Society Adult-Patient-Database (ANZICS-APD). Outcomes analyses were adjusted for illness severity, co-morbidities, hypothermia, treatment limitations, age, year of admission, glucose, source of admission, PaO₂ and propensity score.We studied 16,542 consecutive patients admitted to 125 ANZ ICUs after CA between 2000 and 2011. Using the APD-PaCO₂ (obtained within 24 h of ICU admission), 3010 (18.2%) were classified into the hypo- (PaCO₂ < 35 mmHg), 6705 (40.5%) into the normo- (35–45 mmHg) and 6827 (41.3%) into the hypercapnia (>45 mmHg) group. The hypocapnia group, compared with the normocapnia group, had a trend toward higher in-hospital mortality (OR 1.12 [95% CI 1.00–1.24, p = 0.04]), lower rate of discharge home (OR 0.81 [0.70–0.94, p < 0.01]) and higher likelihood of fulfilling composite adverse outcome of death and no discharge home (OR 1.23 [1.10–1.37, p < 0.001]). In contrast, the hypercapnia group had similar in-hospital mortality (OR 1.06 [0.97–1.15, p = 0.19]) but higher rate of discharge home among survivors (OR 1.16 [1.03–1.32, p = 0.01]) and similar likelihood of fulfilling the composite outcome (OR 0.97 [0.89–1.06, p = 0.52]). Cox-proportional hazards modelling supported these findings.

Conclusions

Hypo- and hypercapnia are common after ICU admission post-CA. Compared with normocapnia, hypocapnia was independently associated with worse clinical outcomes and hypercapnia a greater likelihood of discharge home among survivors.     

The Generation,Detection, and Effects of Reactive Drug Metabolites

The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein‐reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug–drug interactions that may ensue. One important class of protein‐reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.     

The role of the slope of oxygen consumption and EMG activity on freely chosen pedal rate selection

The objective of this study was to verify the following hypothesis: the pedal rate that minimizes root mean square (RMS) slope and the slow component amplitude of oxygen consumption could be close to the freely chosen pedal rate (FCPR) used by well-trained cyclists. Nine male competitive cyclists performed a 21 min submaximal exercise on a cycle ergometer at a workload of 65% of their respective peak aerobic power. For each session, the subject's pedal rate was freely chosen or assigned to 60, 75, 90 or 105 rev min(-1). When pedal rates were imposed, the electromyographic root mean square slope, the oxygen uptake during the third minute and the 20th min, and the slow component amplitude of oxygen consumption were used in the analysis. In order to determine the optimal pedal rate (OPR), a quadratic function was fitted to the data by regression, for each variable measured. The mean values of OPR relative to oxygen uptake during the third min (71+/-9 rev min(-1)) were lower than the mean values of the OPR relative to the slow component amplitude of oxygen consumption (82+/-8 rev min(-1)), the electromyographic root mean square slope (80+/-7 rev min(-1)) and freely chosen pedal rate (86+/-13 rev min(-1)). Freely chosen pedal rate was not significantly different from the OPR in reference to the amplitude of the slow component of oxygen consumption, electromyographic root mean square slope, and oxygen uptake during the 20th min. OPR for RMS slope was correlated (R=0.72) to FCPR. Expert cyclists were likely to use a spontaneous pedal rate that minimizes neuromuscular fatigue.     

Vestibulo-ocular reflex and motion sickness in figure skaters

In order to determine the effect of figure skating on the functional plasticity of the vestibular system, we quantified vestibulo-ocular reflex (VOR) and motion sickness (MS) intensity in 11 female figure skaters and 11 matched control subjects. Vestibular stimulation consisted of three cycles of sinusoidal rotation (0.025 Hz, ±60°/s) and two velocity steps of 60°/s (acceleration 60°/s²). Nauseogenic stimulation consisted of a constant velocity (60°/s) off vertical axis rotation (OVAR) using a 15° tilt angle. Subjective sickness symptoms were rated immediately after OVAR with the Pensacola diagnostic index. During sinusoidal stimulations, the skaters’ VOR, as compared with that of the controls, demonstrates a gain that is 27% lower (0.44 ± 0.12 vs. 0.58 ± 0.10; P < 0.01) and a phase advance (10 ± 12° vs. −0.3 ± 6.4°; P < 0.05). During velocity steps, the VOR gain is 32% lower among the skaters (0.52 ± 0.14 vs. 0.71 ± 0.12; P < 0.01), but there is no difference in time constant (10.8 ± 1.8 s vs. 10.5 ± 2.7 s; P = 0.78). Nauseogenic stimulation evokes significantly less MS in figure skaters than in control subjects (2.8 ± 2.8 vs. 16.2 ± 13.7; P < 0.01). Quantitative alterations in VOR parameters observed in figure skaters probably result from vestibular habituation induced by repeated unusual stimulations when practicing figure skating.     

Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes

STUDY OBJECTIVES: Individual sleep timing differs and is governed partly by circadian oscillators, which may be assessed by hormonal markers, or by clock gene expression. Clock gene expression oscillates in peripheral tissues, including leukocytes. The study objective was to determine whether the endogenous phase of these rhythms, assessed in the absence of the sleep-wake and light-dark cycle, correlates with habitual sleep-wake timing. DESIGN: Observational, cross-sectional. SETTING: Home environment and Clinical Research Center. PARTICIPANTS: 24 healthy subjects aged 25.0 +/- 3.5 (SD) years. MEASUREMENTS: Actigraphy and sleep diaries were used to characterize sleep timing. Circadian rhythm phase and amplitude of plasma melatonin, cortisol, and BMAL1, PER2, and PER3 expression were assessed during a constant routine. RESULTS: Circadian oscillations were more robust for PER3 than for BMAL1 or PER2. Average peak timings were 6:05 for PER3, 8:06 for PER2, 15:06 for BMAL1, 4:20 for melatonin, and 10:49 for cortisol. Individual sleep-wake timing correlated with the phases of melatonin and cortisol. Individual PER3 rhythms correlated significantly with sleep-wake timing and the timing of melatonin and cortisol, but those of PER2 and BMAL1 did not reach significance. The correlation between sleep timing and PER3 expression was stronger in individuals homozygous for the variant of the PER3 polymorphism that is associated with morningness. CONCLUSIONS: Individual phase differences in PER3 expression during a constant routine correlate with sleep timing during entrainment. PER3 expression in leukocytes represents a useful molecular marker of the circadian processes governing sleep-wake timing.     

Gene deletion and allelic replacement in the filamentous fungus <Emphasis Type="Italic">Podospora anserina</Emphasis>

Gene replacement via homologous recombination is a fundamental tool for the analysis of gene function. However, this event is rare in organisms like the filamentous fungus Podospora anserina. We show here that deletion of the PaKu70 gene is an efficient strategy for improving gene manipulation in this organism. By using the ΔPaKu70 strain, it is now possible (1) to produce deletion mutants with an efficiency of 100%, (2) to achieve allelic exchange by introducing a mutated allele associated with a selection cassette at the locus, (3) to introduce a mutation in a gene without co-insertion of a selectable marker and without any modification of the target locus.