Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M ...HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK).
We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2.
From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR < 2: 37%, P=0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77).
Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.
Objective
We examined the relationship between biological rhythms and severity of depressive symptoms in subjects with bipolar disorder and the effects of biological rhythms alterations on functional ...impairment.
Method
Bipolar patients (n = 260) and healthy controls (n = 191) were recruited from mood disorders programs in three sites (Spain, Brazil, and Canada). Parameters of biological rhythms were measured using the Biological Rhythms Assessment in Neuropsychiatry (BRIAN), an interviewer administered questionnaire that assesses disruptions in sleep, eating patterns, social rhythms, and general activity.
Results
Multivariate analyses of covariance showed significant intergroup differences after controlling for potential confounders (Pillai's F = 49.367; df = 2, P < 0.001). Depressed patients had the greatest biological rhythms disturbance, followed by patients with subsyndromal symptoms, euthymic patients, and healthy controls. Biological rhythms and HAMD scores were independent predictors of poor functioning (F = 12.841, df = 6, P < 0.001, R2 = 0.443).
Conclusion
Our study shows a dose‐dependent association between the severity of depressive symptoms and degree of biological rhythms disturbance. Biological rhythms disturbance was also an independent predictor of functional impairment. Although the directionality of this relationship remains unknown, our results suggest that stability of biological rhythms should be an important target of acute and long‐term management of bipolar disorder and may aid in the improvement of functioning.
Effects of 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SkQ1) and 10-(6′-plastoquinonyl) decylrhod-amine 19 (SkQR1) on rat models of H
2
O
2
- and ischemia-induced heart arrhythmia, heart ...infarction, kidney ischemia, and stroke have been studied
ex vivo
and
in vivo
. In all the models listed, SkQ1 and/or SkQR1 showed pronounced protective effect. Supplementation of food with extremely low SkQ1 amount (down to 0.02 nmol SkQ1/kg per day for 3 weeks) was found to abolish the steady heart arrhythmia caused by perfusion of isolated rat heart with H
2
O
2
or by ischemia/reperfusion. Higher SkQ1 (125–250 nmol/kg per day for 2–3 weeks) was found to decrease the heart infarction region induced by an
in vivo
ischemia/reperfusion and lowered the blood levels of lactate dehydrogenase and creatine kinase increasing as a result of ischemia/reperfusion. In single-kidney rats, ischemia/reperfusion of the kidney was shown to kill the majority of the animals in 2–4 days, whereas one injection of SkQ1 or SkQR1 (1 μmol/kg a day before ischemia) saved lives of almost all treated rats. Effect of SkQR1 was accompanied by decrease in ROS (reactive oxygen species) level in kidney cells as well as by partial or complete normalization of blood creatinine and of some other kidney-controlled parameters. On the other hand, this amount of SkQ1 (a SkQ derivative of lower membrane-penetrating ability than SkQR1) saved the life but failed to normalize ROS and creatinine levels. Such an effect indicates that death under conditions of partial kidney dysfunction is mediated by an organ of vital importance other than kidney, the organ in question being an SkQ1 target. In a model of compression brain ischemia/reperfusion, a single intraperitoneal injection of SkQR1 to a rat (1 μmol/kg a day before operation) effectively decreased the damaged brain area. SkQ1 was ineffective, most probably due to lower permeability of the blood-brain barrier to this compound.
Mitochondria-targeted cationic plastoquinone derivative SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) has been investigated as a potential tool for treating a number of ROS-related ocular ...diseases. In OXYS rats suffering from a ROS-induced progeria, very small amounts of SkQ1 (50 nmol/kg per day) added to food were found to prevent development of age_induced cataract and retinopathies of the eye, lipid peroxidation and protein carbonylation in skeletal muscles, as well as a decrease in bone mineralization. Instillation of drops of 250 nM SkQ1 reversed cataract and retinopathies in 3-12-month-old (but not in 24-month-old) OXYS rats. In rabbits, experimental uveitis and glaucoma were induced by immunization with arrestin and injections of hydroxypropyl methyl cellulose to the eye anterior sector, respectively. Uveitis was found to be prevented or reversed by instillation of 250 nM SkQ1 drops (four drops per day). Development of glaucoma was retarded by drops of 5 μM SkQ1 (one drop daily). SkQ1 was tested in veterinarian practice. A totally of 271 animals (dogs, cats, and horses) suffering from retinopathies, uveitis, conjunctivitis, and cornea diseases were treated with drops of 250 nM SkQ1. In 242 cases, positive therapeutic effect was obvious. Among animals suffering from retinopathies, 89 were blind. In 67 cases, vision returned after SkQ1 treatment. In ex vivo studies of cultivated posterior retina sector, it was found that 20 nM SkQ1 strongly decreased macrophagal transformation of the retinal pigmented epithelial cells, an effect which might explain some of the above SkQ1 activities. It is concluded that low concentrations of SkQ1 are promising in treating retinopathies, cataract, uveitis, glaucoma, and some other ocular diseases.
Calcium silicate cements (CSCs) are the choice materials for vital pulp therapy because of their bioactive properties, promotion of pulp repair, and dentin bridge formation. Despite the significant ...progress made in understanding CSCs’ mechanisms of action, the key events that characterize the early interplay between CSC-dentin-pulp are still poorly understood. To address this gap, a microfluidic device, the “tooth-on-a-chip,” which was developed to emulate the biomaterial-dentin-pulp interface, was used to test 1) the effect of CSCs (ProRoot, Biodentine, and TheraCal) on the viability and proliferation of human dental pulp stem cells, 2) variations of pH, and 3) release within the pulp chamber of transforming growth factor–β (TGFβ) as a surrogate of the bioactive dentin matrix molecules. ProRoot significantly increased the extraction of TGFβ (P < 0.05) within 24 to 72 h and, along with Biodentine, induced higher cell proliferation (P > 0.05), while TheraCal decreased cell viability and provoked atypical changes in cell morphology. No correlation between TGFβ levels and pH was observed. Further, we established a biofilm of Streptococcus mutans on-chip to model the biomaterial-biofilm-dentin interface and conducted a live and dead assay to test the antimicrobial capability of ProRoot in real time. In conclusion, the device allows for direct characterization of the interaction of bioactive dental materials with the dentin-pulp complex on a model of restored tooth while enabling assessment of antibiofilm properties at the interface in real time that was previously unattainable.
Polymer of intrinsic microporosity (PIM-1) was prepared according to a new procedure – precipitation polycondensation in DMSO solution. The permeability coefficients were determined in the “as cast” ...and ethanol treated samples of this material. It was shown that permeability of the novel polymer is higher than that of PIM-1 samples prepared according to the traditional methods, while selectivity was lower. Free volume in the novel PIM-1 was studied using the PALS technique. Positron life time parameters and the radii of free volume elements were virtually the same as in PIM-1 samples investigated earlier. The samples of novel PIM-1 were subjected to treatment by supercritical CO2 and annealing of free films and films in strained state. The treatment with scCO2 leads qualitatively to the same results as insertion of the films into EtOH (increase in gas permeability) although the observed Pi values are somewhat lower. Annealing of the films in strained and free state causes significant decrease in gas permeability with respect to all the gases but increase in selectivity. This effect is rather strong, so some the data points are even located above the Upper Bound 2008 in Robeson diagrams. Aging of PIM-1 samples for 30–60 days was also studied, and its mechanism is considered.
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•Polymer of intrinsic microporosity (PIM-1) was investigated in various states.•The films tested were as cast, ethanol treated, aged, supercritical CO2 treated and annealed in free and in strained state.•Gas permeability and positron life time parameters were used for characterization of these states of the films.•It was shown how different treatments can be used to control the location of data points above the Upper Bound 2008.
Quantitative MRI (qMRI) of cartilage morphology is a promising tool for disease-modifying osteoarthritis drug (DMOAD) development. Recent studies at single sites have indicated that measurements at ...3.0 Tesla (T) are more reproducible (precise) than those at 1.5 T. Precision errors and stability in multicentre studies with imaging equipment from various vendors have, however, not yet been evaluated.
A total of 158 female participants (97 Kellgren and Lawrence grade (KLG) 0, 31 KLG 2 and 30 KLG 3) were imaged at 7 clinical centres using Siemens Magnetom Trio and GE Signa Excite magnets. Double oblique coronal acquisitions were obtained at baseline and at 3 months, using water excitation spoiled gradient echo sequences (1.0x0.31x0.31 mm3 resolution). Segmentation of femorotibial cartilage morphology was performed using proprietary software (Chondrometrics GmbH, Ainring, Germany).
The precision error (root mean square coefficient of variation (RMS CV)%) for cartilage thickness/volume measurements ranged from 2.1%/2.4% (medial tibia) to 2.9%/3.3% (lateral weight-bearing femoral condyle) across all participants. No significant differences in precision errors were observed between KLGs, imaging sites, or scanner manufacturers/types. Mean differences between baseline and 3 months ranged from <0.1% (non-significant) in the medial to 0.94% (p<0.01) in the lateral femorotibial compartment, and were 0.33% (p<0.02) for the total femorotibial subchondral bone area.
qMRI performed at 3.0 T provides highly reproducible measurements of cartilage morphology in multicentre clinical trials with equipment from different vendors. The technology thus appears sufficiently robust to be recommended for large-scale multicentre trials.
This study determined whether in vivo positron emission tomography (PET) of arterial inflammation (
F-fluorodeoxyglucose
F-FDG) or microcalcification (
F-sodium fluoride
F-NaF) could predict ...restenosis following PTA.
Restenosis following lower limb percutaneous transluminal angioplasty (PTA) is common, unpredictable, and challenging to treat. Currently, it is impossible to predict which patient will suffer from restenosis following angioplasty.
In this prospective observational cohort study, 50 patients with symptomatic peripheral arterial disease underwent
F-FDG and
F-NaF PET/computed tomography (CT) imaging of the superficial femoral artery before and 6 weeks after angioplasty. The primary outcome was arterial restenosis at 12 months.
Forty subjects completed the study protocol with 14 patients (35%) reaching the primary outcome of restenosis. The baseline activities of femoral arterial inflammation (
F-FDG tissue-to-background ratio TBR 2.43 interquartile range (IQR): 2.29 to 2.61 vs. 1.63 IQR: 1.52 to 1.78; p < 0.001) and microcalcification (
F-NaF TBR 2.61 IQR: 2.50 to 2.77 vs. 1.69 IQR: 1.54 to 1.77; p < 0.001) were higher in patients who developed restenosis. The predictive value of both
F-FDG (cut-off TBR
value of 1.98) and
F-NaF (cut-off TBR
value of 2.11) uptake demonstrated excellent discrimination in predicting 1-year restenosis (Kaplan Meier estimator, log-rank p < 0.001).
Baseline and persistent femoral arterial inflammation and micro-calcification are associated with restenosis following lower limb PTA. For the first time, we describe a method of identifying complex metabolically active plaques and patients at risk of restenosis that has the potential to select patients for intervention and to serve as a biomarker to test novel interventions to prevent restenosis.
The hippocampal formation, to which new neurons are added on a daily basis throughout life, is important in spatial learning. Surviving de novo produced cells integrate into the functional circuitry, ...where they can influence both normal and pathological behaviors. In this study, we examined the effect of the water-maze (a hippocampal-dependent spatial task) on neurogenesis. Learning in this task can be divided into two phases, an early phase during which performance improves rapidly, and a late phase during which asymptotic levels of performance are reached. Here we demonstrate that the late phase of learning has a multifaceted effect on neurogenesis depending on the birth date of new neurons. The number of newly born cells increased contingently with the late phase and a large proportion of these cells survived for at least 4 weeks and differentiated into neurons. In contrast, late-phase learning decreased the number of newly born cells produced during the early phase. This decline in neurogenesis was positively correlated with performance in the water-maze. Thus, rats with the highest de novo cell number were less able to acquire and use spatial information than those with low numbers of new cells. These results show that learning has a complex effect on hippocampal neurogenesis, and reveals a novel mechanism through which neurogenesis may influence normal and pathological behaviors.
► Effect of electrolyte additive on performances of silicon electrode for Li-ion batteries. ► Vinylene carbonate (VC) does not prevent cracks formation. ► VC creates a SEI which limits contacts ...between the electrode and the electrolyte. ► Silicon remains rather dense with VC whereas it becomes highly porous without VC. ► Electrochemical analysis coupled with SEM and AFM characterization.
Silicon which has a theoretical capacity around 3500mAhg−1 and low insertion/deinsertion potentials is one of the most promising candidates to replace graphite as a negative electrode in lithium-ion batteries. Electrochemical performances of Si electrodes are highly dependent on the quality of the SEI. Therefore, the effect of an electrolyte additive, the vinylene carbonate (VC) on electrochemical performances was investigated on sputtered silicon thin films which constitute a simple system (avoiding the use of binders or any conducting additive material). The addition of only 2% of VC significantly improves the capacity retention as well as the coulombic efficiency leading to a capacity retention of 84% after 500 cycles and a coulombic efficiency around 99.5%. To explain the behaviour differences, thorough electrochemical analyses (capacity, coulombic efficiency, polarization at half charge…) combined with scanning electron and atomic force microscopies were carried out. Some correlations have been established between the electrochemical performances and the morphology evolution of the electrode. Thus, VC limits the formation of cracks induced by repeated expansion/contraction cycles and the liquid electrolyte/electrode interactions. In addition, the mechanical pressure locally applied to the thin film allows to maintain a dense morphology and hence has a beneficial effect, too. These two key parameters limit the deterioration of the electrode over cycles.
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