Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort.

Purpose Treatment with pembrolizumab, an anti-programmed death-1 antibody, at 10 mg/kg administered once every 2 weeks, displayed durable antitumor activity in programmed death-ligand 1 (PD-L1) -positive recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 trial. Results from the expansion cohort, in which patients with HNSCC, irrespective of biomarker status, received a fixed dose of pembrolizumab at a less frequent dosing schedule, are reported. Patients and Methods Patients with R/M HNSCC, irrespective of PD-L1 or human papillomavirus status, received pembrolizumab 200 mg intravenously once every 3 weeks. Imaging was performed every 8 weeks. Primary end points were overall response rate (ORR) per central imaging vendor (Response Evaluation Criteria in Solid Tumors v1.1) and safety. Secondary end points included progression-free survival, overall survival, and association of response and PD-L1 expression. Patients who received one or more doses of pembrolizumab were included in analyses. Results Of 132 patients enrolled, median age was 60 years (range, 25 to 84 years), 83% were male, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, ≥ 2 to ≥ 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1-positive versus -negative patients (22% v 4%; P = .021). Treatment-related adverse events of any grade and grade ≥ 3 events occurred in 62% and 9% of patients, respectively. Conclusion Fixed-dose pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful ORR with evidence of durable responses, which supports further development of this regimen in patients with advanced HNSCC

Self-rated health in middle-aged and elderly Chinese : distribution, determinants and associations with cardio-metabolic risk factors

Background: Self-rated health (SRH) has been demonstrated to be an accurate reflection of a person's health and a valid predictor of incident mortality and chronic morbidity. We aimed to evaluate the distribution and factors associated with SRH and its association with biomarkers of cardio-metabolic diseases among middle-aged and elderly Chinese. Methods: Survey of 1,458 men and 1,831 women aged 50 to 70 years, conducted in one urban and two rural areas of Beijing and Shanghai in 2005. SRH status was measured and categorized as good (very good and good) vs. not good (fair, poor and very poor). Determinants of SRH and associations with biomarkers of cardio-metabolic diseases were evaluated using logistic regression. Results: Thirty two percent of participants reported good SRH. Males and rural residents tended to report good SRH. After adjusting for potential confounders, residence, physical activity, employment status, sleep quality and presence of diabetes, cardiovascular disease, and depression were the main determinants of SRH. Those free from cardiovascular disease (OR 3.68; 95%CI 2.39; 5.66), rural residents (OR 1.89; 95% CI 1.47; 2.43), non-depressed participants (OR 2.50; 95% CI 1.67; 3.73) and those with good sleep quality (OR 2.95; 95% CI 2.22; 3.91) had almost twice or over the chance of reporting good SRH compared to their counterparts. There were significant associations -and trend- between SRH and levels of inflammatory markers, insulin levels and insulin resistance. Conclusion: Only one third of middle-aged and elderly Chinese assessed their health status as good or very good. Although further longitudinal studies are required to confirm our findings, interventions targeting social inequalities, lifestyle patterns might not only contribute to prevent chronic morbidity but as well to improve populations' perceived health

Observation of An Evolving Magnetic Flux Rope Prior To and During A Solar Eruption

Explosive energy release is a common phenomenon occurring in magnetized plasma systems ranging from laboratories, Earth's magnetosphere, the solar corona and astrophysical environments. Its physical explanation is usually attributed to magnetic reconnection in a thin current sheet. Here we report the important role of magnetic flux rope structure, a volumetric current channel, in producing explosive events. The flux rope is observed as a hot channel prior to and during a solar eruption from the Atmospheric Imaging Assembly (AIA) telescope on board the Solar Dynamic Observatory (SDO). It initially appears as a twisted and writhed sigmoidal structure with a temperature as high as 10 MK and then transforms toward a semi-circular shape during a slow rise phase, which is followed by fast acceleration and onset of a flare. The observations suggest that the instability of the magnetic flux rope trigger the eruption, thus making a major addition to the traditional magnetic-reconnection paradigm.Comment: 13 pages, 3 figure

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

Stress across the life course and depression in a rapidly developing population: The Guangzhou Biobank Cohort Study

postprin

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis

Role of dimensional crossover on spin-orbit torque efficiency in magnetic insulator thin films

Magnetic insulators (MIs) attract tremendous interest for spintronic applications due to low Gilbert damping and absence of Ohmic loss. Magnetic order of MIs can be manipulated and even switched by spin-orbit torques (SOTs) generated through spin Hall effect and Rashba-Edelstein effect in heavy metal/MI bilayers. SOTs on MIs are more intriguing than magnetic metals since SOTs cannot be transferred to MIs through direct injection of electron spins. Understanding of SOTs on MIs remains elusive, especially how SOTs scale with the film thickness. Here, we observe the critical role of dimensionality on the SOT efficiency by systematically studying the MI layer thickness dependent SOT efficiency in tungsten/thulium iron garnet (W/TmIG) bilayers. We first show that the TmIG thin film evolves from two-dimensional to three-dimensional magnetic phase transitions as the thickness increases, due to the suppression of long-wavelength thermal fluctuation. Then, we report the significant enhancement of the measured SOT efficiency as the thickness increases. We attribute this effect to the increase of the magnetic moment density in concert with the suppression of thermal fluctuations. At last, we demonstrate the current-induced SOT switching in the W/TmIG bilayers with a TmIG thickness up to 15 nm. The switching current density is comparable with those of heavy metal/ferromagnetic metal cases. Our findings shed light on the understanding of SOTs in MIs, which is important for the future development of ultrathin MI-based low-power spintronics

Cytosine-to-Uracil Deamination by SssI DNA Methyltransferase

The prokaryotic DNA(cytosine-5)methyltransferase M.SssI shares the specificity of eukaryotic DNA methyltransferases (CG) and is an important model and experimental tool in the study of eukaryotic DNA methylation. Previously, M.SssI was shown to be able to catalyze deamination of the target cytosine to uracil if the methyl donor S-adenosyl-methionine (SAM) was missing from the reaction. To test whether this side-activity of the enzyme can be used to distinguish between unmethylated and C5-methylated cytosines in CG dinucleotides, we re-investigated, using a sensitive genetic reversion assay, the cytosine deaminase activity of M.SssI. Confirming previous results we showed that M.SssI can deaminate cytosine to uracil in a slow reaction in the absence of SAM and that the rate of this reaction can be increased by the SAM analogue 5’-amino-5’-deoxyadenosine. We could not detect M.SssI-catalyzed deamination of C5-methylcytosine (m5C). We found conditions where the rate of M.SssI mediated C-to-U deamination was at least 100-fold higher than the rate of m5C-to-T conversion. Although this difference in reactivities suggests that the enzyme could be used to identify C5-methylated cytosines in the epigenetically important CG dinucleotides, the rate of M.SssI mediated cytosine deamination is too low to become an enzymatic alternative to the bisulfite reaction. Amino acid replacements in the presumed SAM binding pocket of M.SssI (F17S and G19D) resulted in greatly reduced methyltransferase activity. The G19D variant showed cytosine deaminase activity in E. coli, at physiological SAM concentrations. Interestingly, the C-to-U deaminase activity was also detectable in an E. coli ung+ host proficient in uracil excision repair

Individual rules for trail pattern formation in Argentine ants (Linepithema humile)

We studied the formation of trail patterns by Argentine ants exploring an empty arena. Using a novel imaging and analysis technique we estimated pheromone concentrations at all spatial positions in the experimental arena and at different times. Then we derived the response function of individual ants to pheromone concentrations by looking at correlations between concentrations and changes in speed or direction of the ants. Ants were found to turn in response to local pheromone concentrations, while their speed was largely unaffected by these concentrations. Ants did not integrate pheromone concentrations over time, with the concentration of pheromone in a 1 cm radius in front of the ant determining the turning angle. The response to pheromone was found to follow a Weber's Law, such that the difference between quantities of pheromone on the two sides of the ant divided by their sum determines the magnitude of the turning angle. This proportional response is in apparent contradiction with the well-established non-linear choice function used in the literature to model the results of binary bridge experiments in ant colonies (Deneubourg et al. 1990). However, agent based simulations implementing the Weber's Law response function led to the formation of trails and reproduced results reported in the literature. We show analytically that a sigmoidal response, analogous to that in the classical Deneubourg model for collective decision making, can be derived from the individual Weber-type response to pheromone concentrations that we have established in our experiments when directional noise around the preferred direction of movement of the ants is assumed.Comment: final version, 9 figures, submitted to Plos Computational Biology (accepted

Cover to Volume 3

The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth