Selected cutaneous adverse events in patients treated with ICI monotherapy and combination therapy: a retrospective pharmacovigilance study and meta-analysis

Introduction: Cutaneous adverse events are commonly reported immune-related adverse events (irAEs), some of which are serious or even life-threatening, and it is essential to study these specific cutaneous AEs to understand their characteristics and risk.Methods: We performed a meta-analysis of published clinical trials for immune checkpoint inhibitors (ICIs) to evaluate the incidence of cutaneous adverse events, using data from PubMed, Embase, and the Cochrane Library databases.Results: A total of 232 trials with 45,472 patients were involved. Results showed that anti-PD-1 and targeted therapy combinations were associated with higher risk for most of the selected cutaneous adverse events. In addition, a retrospective pharmacovigilance study was conducted using the Food and Drug Administration (FDA) Adverse Events System database. Reporting odds ratio (ROR) and Bayesian information components (IC) were used to perform the disproportionality analysis. Cases were extracted from January 2011 to September 2020. We identified 381 (20.24%) maculopapular rash, 213 (11.32%) vitiligo, 215 (11.42%) Stevens‐Johnson syndrome (SJS), and 165 (8.77%) toxic epidermal necrolysis (TEN) cases. For vitiligo, anti-PD-1/L1 combined with anti-CTLA-4 therapy showed the strongest signal (ROR: 55.89; 95% CI: 42.34–73.78; IC025: 4.73). Palmar-plantar erythrodysesthesia (PPE) was reported with the most significant association with combined anti-PD-1/L1 and VEGF (R)-TKIs (ROR: 18.67; 95% CI: 14.77–23.60; IC025: 3.67). For SJS/TEN, antiPD-1 inhibitors showed the strongest signal (ROR: 3.07; 95% CI: 2.68–3.52; IC025: 1.39). The median onset time of vitiligo and SJS/TEN was 83 and 24 days, respectively.Conclusion: Overall, in selected cutaneous AEs, each of them showed specific characteristics. It is necessary to realize their differences and take appropriate interventions in patients with different regimens

Sequence specificity incompletely defines the genome-wide occupancy of Myc

BACKGROUND: The Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes. Genome occupancy of Myc-Max is thought to be driven by Enhancer box (E-box) DNA elements, CACGTG or variants, to which the heterodimer binds in vitro. RESULTS: By analyzing ChIP-Seq datasets, we demonstrate that the positions occupied by Myc-Max across the human genome correlate with the RNA polymerase II, Pol II, transcription machinery significantly better than with E-boxes. Metagene analyses show that in promoter regions, Myc is uniformly positioned about 100 bp upstream of essentially all promoter proximal paused polymerases with Max about 15 bp upstream of Myc. We re-evaluate the DNA binding properties of full length Myc-Max proteins. Electrophoretic mobility shift assay results demonstrate Myc-Max heterodimers display significant sequence preference, but have high affinity for any DNA. Quantification of the relative affinities of Myc-Max for all possible 8-mers using universal protein-binding microarray assays shows that sequences surrounding core 6-mers significantly affect binding. Compared to the in vitro sequence preferences, Myc-Max genomic occupancy measured by ChIP-Seq is largely, although not completely, independent of sequence specificity. CONCLUSIONS: We quantified the affinity of Myc-Max to all possible 8-mers and compared this with the sites of Myc binding across the human genome. Our results indicate that the genomic occupancy of Myc cannot be explained by its intrinsic DNA specificity and suggest that the transcription machinery and associated promoter accessibility play a predominant role in Myc recruitment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-014-0482-3) contains supplementary material, which is available to authorized users

Highly efficient blue OLED

Based on our work on deep blue OLED, very recently, we have synthesized a deep blue emitter TPEA. The anthracene groups are twisted from the central TPE moiety, which effectively prevents bathochromic shift of emission as shown in its crystallographic structure. In addition, a D-A structure was built by using methoxy and cyano to improve the charge balance in the devices. In addition, the material possesses high thermal stability with a Tg of 155 °C. The non-doped device achieved the high performance with a Von of 2.6 V at a luminance of 1 cd rrr2, a 77PE, max Of 11.1 lm W~1, a TJCE, max of 9.9 cd A '1, and a low 77ce roll-off. The doped device based on TPEA was fabricated to acquire deep blue emission with CIE coordinates of (0.15, 0.09), showing a tje x t, max up to 8.0% and the highest t j p e, max of 7.3 lm W"1 among all the TTF and HLCT deep-blue emitters. Inspired by these preliminary results, we believe that the combination of the merits of TTF-HLCT and AIE would be a promising molecular design principle for exploring highly efficient deep blue emitters

Experimental demonstration of cognitive provisioning and alien wavelength monitoring in multi-domain EON

This paper proposes a cognitive multi-domain EON architecture with machine-learning aided RMSA and alien wavelength monitoring. Testbed experiments show modulation format recognition, QoT monitoring and cognitive routing for a 160 GBd alien multi-wavelength lightpath.Peer ReviewedPostprint (published version

Functional Association of Gdown1 with RNA Polymerase II Poised on Human Genes

Most human genes are loaded with promoter-proximally paused RNA polymerase II (Pol II) molecules that are poised for release into productive elongation by P-TEFb. We present evidence that Gdown1, the product of the POLR2M gene that renders Pol II responsive to Mediator, is involved in Pol II elongation control. During in vitro transcription, Gdown1 specifically blocked elongation stimulation by TFIIF, inhibited the termination activity of TTF2, and influenced pausing factors NELF and DSIF, but did not affect the function of TFIIS or the mRNA capping enzyme. Without P-TEFb, Gdown1 led to the production of stably paused polymerases in the presence of nuclear extract. Supporting these mechanistic insights, ChIP-Seq demonstrated that Gdown1 mapped over essentially all poised polymerases across the human genome. Our results establish that Gdown1 stabilizes poised polymerases while maintaining their responsiveness to P-TEFb and suggest that Mediator overcomes a Gdown1-mediated block of initiation by allowing TFIIF function.National Human Genome Research Institute (U.S.) (Grant HG002668-05

Loop Interactions during Catalysis by Dihydrofolate Reductase fromMoritella profunda

Dihydrofolate reductase (DHFR) is often used as a model system to study the relation between protein dynamics and catalysis. We have studied a number of variants of the cold-adapted DHFR from Moritella profunda (MpDHFR), in which the catalytically important M20 and FG loops have been altered, and present a comparison with the corresponding variants of the wellstudied DHFR from Escherichia coli (EcDHFR). Mutations in the M20 loop do not affect the actual chemical step of transfer of hydride from reduced nicotinamide adenine dinucleotide phosphate to the substrate 7,8-dihydrofolate in the catalytic cycle in either enzyme; they affect the steady state turnover rate in EcDHFR but not in MpDHFR. Mutations in the FG loop also have different effects on catalysis by the two DHFRs. Despite the two enzymes most likely sharing a common catalytic cycle at pH 7, motions of these loops, known to be important for progression through the catalytic cycle in EcDHFR, appear not to play a significant role in MpDHFR

Thermal Adaptation of Dihydrofolate Reductase from the Moderate ThermophileGeobacillus stearothermophilus

The thermal melting temperature of dihydrofolate reductase from Geobacillus stearothermophilus (BsDHFR) is 30 °C higher than that of its homologue from the psychrophile Moritella profunda. Additional proline residues in the loop regions of BsDHFR have been proposed to enhance the thermostability of BsDHFR, but site-directed mutagenesis studies reveal that these proline residues contribute only minimally. Instead, the high thermal stability of BsDHFR is partly due to removal of water-accessible thermolabile residues such as glutamine and methionine, which are prone to hydrolysis or oxidation at high temperatures. The extra thermostability of BsDHFR can be obtained by ligand binding, or in the presence of salts or cosolvents such as glycerol and sucrose. The sum of all these incremental factors allows BsDHFR to function efficiently in the natural habitat of G. stearothermophilus, which is characterized by temperatures that can reach 75 °C