Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans ...and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the ...long-term benefits of such an aggressive approach.
In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival OS > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.
At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio HR = 0.58, 95% confidence interval CI = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.
This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.
We review the properties and applications of ultrashort laser pulses in the atmosphere, with a particular focus on filamentation. Filamentation is a non-linear propagation regime specific of ...ultrashort and ultraintense laser pulses in the atmosphere. Typical applications include remote sensing of atmospheric gases and aerosols, lightning control, laser-induced spectroscopy, coherent anti-stokes Raman scattering, and the generation of sub-THz radiation.
Organometal halide perovskite-based solar cells have recently been reported to be highly efficient, giving an overall power conversion efficiency of up to 15%. However, much of the fundamental ...photophysical properties underlying this performance has remained unknown. Here, we apply photoluminescence, transient absorption, time-resolved terahertz and microwave conductivity measurements to determine the time scales of generation and recombination of charge carriers as well as their transport properties in solution-processed CH3NH3PbI3 perovskite materials. We found that electron–hole pairs are generated almost instantaneously after photoexcitation and dissociate in 2 ps forming highly mobile charges (25 cm2 V–1 s–1) in the neat perovskite and in perovskite/alumina blends; almost balanced electron and hole mobilities remain very high up to the microsecond time scale. When the perovskite is introduced into a TiO2 mesoporous structure, electron injection from perovskite to the metal oxide is efficient in less than a picosecond, but the lower intrinsic electron mobility of TiO2 leads to unbalanced charge transport. Microwave conductivity measurements showed that the decay of mobile charges is very slow in CH3NH3PbI3, lasting up to tens of microseconds. These results unravel the remarkable intrinsic properties of CH3NH3PbI3 perovskite material if used as light absorber and charge transport layer. Moreover, finding a metal oxide with higher electron mobility may further increase the performance of this class of solar cells.
MET
is altered by skipping exon 14 or gene amplification in 1 to 2% of patients with non–small-cell lung cancer. Capmatinib, a
MET
-specific tyrosine kinase inhibitor, led to a response in 40% of ...previously treated patients and in 67% of previously untreated patients whose tumors had
MET
alterations, with a median response duration of 9 months and 12 months, respectively.
While chemotherapy is one of the most used treatments in oncology, the systemic administration of chemotherapeutics generally results in undesired damages to healthy tissues and cells, side effects ...such as severe nausea and leukopenia, and reduced efficacy due to multidrug resistance and poor target accessibility. The limitations of conventional chemotherapy formulation have prompted the development of alternative nanomaterials‐based strategies to achieve targeted and stimuli sensitive payload delivery to reach optimal local drug concentration at tumor sites. In this study, the anticancer drug chlorambucil (Clb) was conjugated to the surface of silica coated lithium niobate (LNO) harmonic nanoparticles (HNPs) using a photocaging tether based on coumarin‐4‐yl methyl derivative. Upon laser pulsed femtosecond irradiation at 790 nm, the second harmonic emission from the metal oxide core induced the efficient release of Clb, with concomitant contribution from the nonlinear absorption of the coumarin (CM)‐based moiety.
We present a 0.2 TW sub-two-cycle 1.8 µm carrier-envelope-phase stable source based on two-stage pulse compression by filamentation for driving high-order harmonic generation extending beyond the ...oxygen K absorption edge. The 1 kHz repetition rate, high temporal resolution enabled by the short 11.8 fs driving pulse duration, and bright high-order harmonics generated in helium make this an attractive source for solid-state and molecular-dynamics studies.
Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 ...immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov , number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five 4% of 117 patients), pneumonitis (four 3%), and diarrhoea (three 3%). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.
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