During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and ...Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
Charge transfer mechanisms lay at the heart of chemistry and biochemistry. Proton coupled electron transfers (PCET) are central in biological processes such as photosynthesis and in the respiratory ...chain, where they mediate long-range charge transfers. These mechanisms are normally difficult to harness experimentally due to the intrinsic complexity of the associated biological systems. Metal-peptide cations experience both electron and proton transfers upon photoexcitation, proving an amenable model system to study PCET. We report on a time-resolved experiment designed to follow this dual charge transfer kinetics in HG3W+Ag+ (H = histidine, G = glycine, W = tryptophan) on time scales ranging from femtoseconds to milliseconds. While electron transfer completes in less than 4 ps, it triggers a proton transfer lasting over hundreds of microseconds. Molecular dynamics simulations show that conformational dynamic plays an important role in slowing down this reaction. This combined experimental and computational approach provides a view of PCET as a single phenomenon despite its very wide time-domain span.
OBJECTIVES:Few outcome data are available about convulsive status epilepticus managed in the intensive care unit. We studied 90-day functional outcomes and their determinants in patients with ...convulsive status epilepticus.
DESIGN:Two hundred forty-eight convulsive status epilepticus patients admitted to 18 intensive care units in 2005–2007 were included in a prospective observational cohort study. The main outcome measure was a Glasgow Outcome Scale score of 5 (good recovery) on day 90.
MAIN RESULTS:Convulsive status epilepticus occurred out of hospital in 177 (67%) patients, and all but 15 patients were still seizing at medical team arrival. The median time from convulsive status epilepticus onset to anticonvulsant drug initiation was 40 mins (interquartile range, 5–80). Total seizure duration was 85 mins (interquartile range, 46.5–180). Convulsive status epilepticus was refractory in 49 (20%) patients. The most common causes of convulsive status epilepticus were anticonvulsive agent withdrawal (36.4%) in patients with previous epilepsy and stroke (27.7%) in inaugural convulsive status epilepticus. Mechanical ventilation was needed in 210 (85%) patients. On day 90, 42 (18.8%) patients were dead, 87 (38.8%) had marked functional impairments (Glasgow Outcome Scale score, 2–4), and 95 (42.4%) had a good recovery (Glasgow Outcome Scale score, 5). Factors showing independent positive associations with poor outcome (Glasgow Outcome Scale score, <5) were older age (odds ratio, 1.04/year; 95% confidence interval, 1.02–1.05; p = .0005), cerebral insult (odds ratio, 2.70; 95% confidence interval, 1.37–5.26; p = .007), longer seizure duration (odds ratio, 1.72/120 min; 95% confidence interval, 1.05–2.86; p = .03), on-scene focal neurologic signs (odds ratio, 2.08; 95% confidence interval, 1.03–4.16; p = .04), and refractory convulsive status epilepticus (odds ratio, 2.70; 95% confidence interval, 1.02–7.14; p = .045).
CONCLUSIONS:Ninety days after intensive care unit admission for convulsive status epilepticus, half the survivors had severe functional impairments. Longer seizure duration, cerebral insult, and refractory convulsive status epilepticus were strongly associated with poor outcomes, suggesting a role for early neuroprotective strategies.
The laser lightning rod project Produit, Thomas; Walch, Pierre; Herkommer, Clemens ...
European physical journal. Applied physics,
02/2021, Letnik:
93, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Lightning is highly destructive due to its high power density and unpredictable character. Directing lightning away would allow to protect sensitive sites from its direct and indirect impacts ...(electromagnetic perturbations). Up to now, lasers have been unable to guide lightning efficiently since they were not offering simultaneously terawatt peak powers and kHz repetition rates. In the framework of the Laser Lightning Rod project, we develop a laser system for lightning control, with J-range pulses of 1 ps duration at 1 kHz. The project aims at investigating its propagation in the multiple filamentation regime and its ability to control high-voltage discharges. In particular, a field campaign at the Säntis mountain will assess the laser ability to trigger upward lightning.
Sub-μm thin samples are essential for spectroscopic purposes. The development of flat micro-jets enabled novel spectroscopic and scattering methods for investigating molecular systems in the liquid ...phase. However, the temperature of these ultra-thin liquid sheets in vacuum has not been systematically investigated. Here, we present a comprehensive temperature characterization using optical Raman spectroscopy of sub-micron flatjets produced by two different methods: colliding of two cylindrical jets and a cylindrical jet compressed by a high pressure gas. Our results reveal the dependence of the cooling rate on the material properties and the source characteristics, i.e., nozzle-orifice size, flow rate, and pressure. We show that materials with higher vapor pressures exhibit faster cooling rates, which is illustrated by comparing the temperature profiles of water and ethanol flatjets. In a sub-μm liquid sheet, the temperature of the water sample reaches around 268 K and the ethanol around 253 K close to the flatjet's terminus.
Laser-induced water condensation in air Kasparian, Jérôme; Rohwetter, Philipp; Stelmaszczyk, Kamil ...
Nature photonics,
07/2010, Letnik:
4, Številka:
7
Journal Article
Recenzirano
Triggering rain on demand is an old dream of mankind, with a huge potential socio-economical benefit. To date, efforts have mainly focused on cloud-seeding using silver salt particles. We demonstrate ...that self-guided ionized filaments generated by ultrashort laser pulses are also able to induce water-cloud condensation in the free, sub-saturated atmosphere. Potential contributing mechanisms include photo-oxidative chemistry and electrostatic effects. As well as revealing the potential for influencing or triggering water precipitation, laser-induced water condensation provides a new tool for the remote sensing of nucleation processes in clouds.
Potassium niobate nonlinear nanoparticles are used for the first time to monitor the evolution of embryonic stem cells (ESC) by second harmonic microscopy. These particles feature the complete ...absence of photo‐bleaching and unlimited excitation wavelength flexibility. The potential of this approach is made evident for tissue‐regeneration studies and applications, by capturing a high‐speed movie of ESC‐derived cardiomyocytes autonomously beating within a cluster. Time‐resolved data are analyzed to retrieve 3D information of the contraction pattern at the cellular level.
Harmonic nanoparticles, thanks to the absence of bleaching and blinking, together with the possibility to be excited at any wavelength, are perfectly suited for long‐term tracking and depth tissue imaging of differentiating stem cell structures with straightforward applications in regenerative medicine. Their potential is made evident by capturing and analyzing a high‐speed movie of embryonic‐stem‐cell‐derived cardiomyocytes autonomously beating.
Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the ...Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJC172A, acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1β. Finally, IL-1β within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.
► The Yersinia effector YopJ increases gut permeability and bacterial translocation ► YopJ acetylates RICK and TAK1 and reduces the affinity of RICK for NOD2 ► As a result, NOD2 is free to interact and activate caspase-1 ► Caspase-1 promotes IL-1β secretion, resulting in epithelial barrier dysfunction
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