An Expert Delphi Consensus on Risk Factors for Adverse Events After Endovascular Aortic Aneurysm Repair: Tier 1 Study From the International RIsk Stratification in EVAR (IRIS-EVAR) Working Group.

PURPOSE: Tier 1 of the International RIsk Stratification in EndoVascular Aneurysm Repair (IRIS-EVAR) project aimed to identify important risk factors for adverse events following endovascular aneurysm repair (EVAR). MATERIALS AND METHODS: Initially, the steering committee proposed a number of risk factors for adverse events following EVAR. A Delphi consensus was performed as expert panelists were presented with risk factors and provided the opportunity to propose additional risk factors during the process. Experts in EVAR completed an online survey via 3 structured rounds. The first round opened in July 2022, and the third round closed in December 2022. Panelists rated risk factors using a 4-point Likert scale. Consensus was defined as >70% of participants agreeing/strongly agreeing or disagreeing/strongly disagreeing with a statement in each round. RESULTS: Thirty-five panelists from 12 countries completed the 3 rounds of surveys. Of a total of 64 individual risk factors assessed by the panelists, 37 (58%) had consensus that they were important for adverse events following EVAR. Risk factors were stratified in 4 domains: 14 (38%) were related to preoperative anatomy, 3 (8%) related to the aortic device selection, 8 (22%) related to the procedure performance, and 12 (32%) related to postoperative surveillance. Factors with the highest consensus in each domain were as follows: proximal aortic neck length <15 mm (98% consensus), anatomy non-compliant with instructions for use (94% consensus), length of achieved proximal aortic neck post implantation <10 mm (98% consensus), and non-satisfactory seal at landing or overlapping zones/sac expansion/kink or stenosis (100% consensus each), respectively. CONCLUSIONS: Clinically important risk factors for adverse events after EVAR were identified via expert consensus. These factors will be used to develop an expert consensus-informed risk stratification and surveillance strategies. CLINICAL IMPACT: This is the first study to apply an in-depth Delphi methodology to achieve an expert consensus on risk factors for adverse events after endovascular aneurysm repair (EVAR). Important risk factors were stratified in 4 domains: preoperative anatomy (14 factors), aortic device (3 factors), EVAR procedure (8 factors), and postoperative surveillance (12 factors). This study will potentially influence future clinical practice by providing evidence informed by experts regarding predictors of adverse events following EVAR that can be taken into account during decision making and developing post-EVAR surveillance strategies. These findings will inform a risk stratification tool for everyday use by vascular surgeons.

Identification of genetic loci in lettuce mediating quantitative resistance to fungal pathogens.

KEY MESSAGE: We demonstrate genetic variation for quantitative resistance against important fungal pathogens in lettuce and its wild relatives, map loci conferring resistance and predict key molecular mechanisms using transcriptome profiling. Lactuca sativa L. (lettuce) is an important leafy vegetable crop grown and consumed globally. Chemicals are routinely used to control major pathogens, including the causal agents of grey mould (Botrytis cinerea) and lettuce drop (Sclerotinia sclerotiorum). With increasing prevalence of pathogen resistance to fungicides and environmental concerns, there is an urgent need to identify sources of genetic resistance to B. cinerea and S. sclerotiorum in lettuce. We demonstrated genetic variation for quantitative resistance to B. cinerea and S. sclerotiorum in a set of 97 diverse lettuce and wild relative accessions, and between the parents of lettuce mapping populations. Transcriptome profiling across multiple lettuce accessions enabled us to identify genes with expression correlated with resistance, predicting the importance of post-transcriptional gene regulation in the lettuce defence response. We identified five genetic loci influencing quantitative resistance in a F6 mapping population derived from a Lactuca serriola (wild relative) × lettuce cross, which each explained 5-10% of the variation. Differential gene expression analysis between the parent lines, and integration of data on correlation of gene expression and resistance in the diversity set, highlighted potential causal genes underlying the quantitative trait loci.

Molecular basis of USP7 inhibition by selective small-molecule inhibitors.

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

Architecture and Dynamics of the Jasmonic Acid Gene Regulatory Network.

Jasmonic acid (JA) is a critical hormonal regulator of plant growth and defense. To advance our understanding of the architecture and dynamic regulation of the JA gene regulatory network, we performed a high-resolution RNA-seq time series of methyl JA-treated Arabidopsis thaliana at 15 time points over a 16-h period. Computational analysis showed that methyl JA (MeJA) induces a burst of transcriptional activity, generating diverse expression patterns over time that partition into distinct sectors of the JA response targeting specific biological processes. The presence of transcription factor (TF) DNA binding motifs correlated with specific TF activity during temporal MeJA-induced transcriptional reprogramming. Insight into the underlying dynamic transcriptional regulation mechanisms was captured in a chronological model of the JA gene regulatory network. Several TFs, including MYB59 and bHLH27, were uncovered as early network components with a role in pathogen and insect resistance. Analysis of subnetworks surrounding the TFs ORA47, RAP2.6L, MYB59, and ANAC055, using transcriptome profiling of overexpressors and mutants, provided insights into their regulatory role in defined modules of the JA network. Collectively, our work illuminates the complexity of the JA gene regulatory network, pinpoints and validates previously unknown regulators, and provides a valuable resource for functional studies on JA signaling components in plant defense and development.

Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains.

A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).

Synthesis of functionalized maoecrystal V core structures.

Two strategies toward the total synthesis of maoecrystal V (1) culminating in the construction of core structures 2 and 3 are described.

Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets.

This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.

High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors.

In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.

New synthesis of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones and 3-amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones: Pd-catalyzed cross-coupling of imidoyl chlorides with organoboronic acids.

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.