Assessment of KRASG12C inhibitors for colorectal cancer.

Colorectal cancer (CRC) is a highly prevalent and lethal cancer worldwide. Approximately 45% of CRC patients harbor a gain-in-function mutation in KRAS. KRAS is the most frequently mutated oncogene accounting for approximately 25% of all human cancers. Gene mutations in KRAS cause constitutive activation of the KRAS protein and MAPK/AKT signaling, resulting in unregulated proliferation and survival of cancer cells and other aspects of malignant transformation, progression, and metastasis. While KRAS has long been considered undruggable, the FDA recently approved two direct acting KRAS inhibitors, Sotorasib and Adagrasib, that covalently bind and inactivate KRASG12C. Both drugs showed efficacy for patients with non-small cell lung cancer (NSCLC) diagnosed with a KRASG12C mutation, but for reasons not well understood, were considerably less efficacious for CRC patients diagnosed with the same mutation. Thus, it is imperative to understand the basis for resistance to KRASG12C inhibitors, which will likely be the same limitations for other mutant specific KRAS inhibitors in development. This review provides an update on clinical trials involving CRC patients treated with KRASG12C inhibitors as a monotherapy or combined with other drugs. Mechanisms that contribute to resistance to KRASG12C inhibitors and the development of novel RAS inhibitors with potential to escape such mechanisms of resistance are also discussed.

A comprehensive preanalytical protocol for fresh solid tumor biospecimens.

Nearly seventy percent of diagnostic lab test errors occur due to variability in preanalytical factors. These are the parameters involved with all aspects of tissue processing, starting from the time tissue is collected from the patient in the operating room, until it is received and tested in the laboratory. While there are several protocols for transporting fixed tissue, organs, and liquid biopsies, such protocols are lacking for transport and handling of live solid tumor tissue specimens. There is a critical need to establish preanalytical protocols to reduce variability in biospecimen integrity and improve diagnostics for personalized medicine. Here, we provide a comprehensive protocol for the standard collection, handling, packaging, cold-chain logistics, and receipt of solid tumor tissue biospecimens to preserve tissue viability.

A Gold Standard-Derived Modular Barcoding Approach to Cancer Transcriptomics.

A challenge with studying cancer transcriptomes is in distilling the wealth of information down into manageable portions of information. In this resource, we develop an approach that creates and assembles cancer type-specific gene expression modules into flexible barcodes, allowing for adaptation to a wide variety of uses. Specifically, we propose that modules derived organically from high-quality gold standards such as The Cancer Genome Atlas (TCGA) can accurately capture and describe functionally related genes that are relevant to specific cancer types. We show that such modules can: (1) uncover novel gene relationships and nominate new functional memberships, (2) improve and speed up analysis of smaller or lower-resolution datasets, (3) re-create and expand known cancer subtyping schemes, (4) act as a "decoder" to bridge seemingly disparate established gene signatures, and (5) efficiently apply single-cell RNA sequencing information to other datasets. Moreover, such modules can be used in conjunction with native spreadsheet program commands to create a powerful and rapid approach to hypothesis generation and testing that is readily accessible to non-bioinformaticians. Finally, we provide tools for users to create and interpret their own modules. Overall, the flexible modular nature of the proposed barcoding provides a user-friendly approach to rapidly decoding transcriptome-wide data for research or, potentially, clinical uses.

Preanalytical protocol for fresh solid tumor biospecimens.

Nearly seventy percent of diagnostic lab test errors occur due to variability in preanalytical factors. 1-4 These are the parameters involved with all aspects of tissue processing, starting from the time tissue is collected from the patient in the operating room, until it is received and tested in the laboratory. While there are several protocols for transporting fixed tissue, organs, and liquid biopsies, such protocols are lacking for transport and handling of live solid tumor tissue specimens. There is a critical need to establish preanalytical protocols to reduce variability in biospecimen integrity and improve diagnostics for personalized medicine. 2,5 Here, we provide a comprehensive protocol for the standard collection, handling, packaging, cold-chain logistics, and receipt of solid tumor tissue biospecimens to preserve tissue viability.

Mapping COVID-19's potential infection risk based on land use characteristics: A case study of commercial activities in two Egyptian cities.

The contagious COVID-19 has recently emerged and evolved into a world-threatening pandemic outbreak. After pursuing rigorous prophylactic measures two years ago, most activities globally reopened despite the emergence of lethal genetic strains. In this context, assessing and mapping activity characteristics-based hot spot regions facilitating infectious transmission is essential. Hence, our research question is: How can the potential hotspots of COVID-19 risk be defined intra-cities based on the spatial planning of commercial activity in particular? In our research, Zayed and October cities, Egypt, characterized by various commercial activities, were selected as testbeds. First, we analyzed each activity's spatial and morphological characteristics and potential infection risk based on the Centre for Disease Control and Prevention (CDCP) criteria and the Kriging Interpolation method. Then, using Google Mobility, previous reports, and semi-structured interviews, points of interest and population flow were defined and combined with the last step as interrelated horizontal layers for determining hotspots. A validation study compared the generated activity risk map, spatial COVID-19 cases, and land use distribution using logistic regression (LR) and Pearson coefficients (rxy). Through visual analytics, our findings indicate the central areas of both cities, including incompatible and concentrated commercial activities, have high-risk peaks (LR = 0.903, rxy = 0.78) despite the medium urban density of districts, indicating that urban density alone is insufficient for public health risk reduction. Health perspective-based spatial configuration of activities is advised as a risk assessment tool along with urban density for appropriate decision-making in shaping pandemic-resilient cities.

Spatial congruency or discrepancy? Exploring the spatiotemporal dynamics of built-up expansion patterns and flood risk.

Most coastal cities have been experiencing unprecedented urbanization-induced flood risk, climatic events, and haphazard anthropogenic activities, jeopardizing residents' lives and building environments. Despite mounting flood-related studies, analyzing the correlation between the spatiotemporal dynamics of Built-up Expansion patterns (BE) and flood risk remains unknown and holds divergent perspectives. In this context, the coastal city of Alexandria, Egypt, characterized by multiple urban patterns and experiencing heavy rainfall annually, was selected as a testbed. Our method defined the spatiotemporal rates of BE from 1995 to 2023, quantified flood risk spatially, and finally investigated the correlation between BE and flood risk through spatial and statistical analysis. Our results show the built-up area occupied 30.32 % of the total city area till 2023, and the infilling pattern dominated the BE growth by 45.21 % of the total built-up area, followed by leapfrogging and edge expansion by 33.25 % and 21.55 %, respectively. The unplanned-infilling pattern is predominantly highly correlated with the flood-vulnerable peaks (correlation coefficient (rk) = 0.975, p-value < 0.05) and lowers dramatically towards planned-infilling regions with flood protections. Meanwhile, a spatial mismatch exists between high-risk peaks and leapfrogging and edge expansion (rk = 0.118 and 0.662, respectively, with a p-value < 0.01), indicating that controlling the built-up amount is inadequate for mitigating flood risk. Porosity-based urban configuration and spatial distribution of built-up patches in harmony with nature-based solutions are recommended for shaping flood-resilient and effective urban planning.

An inflammatory myofibroblastic tumor of the ampulla of Vater, an exceptional location: a case report.

Introduction and importance: Inflammatory myofibroblastic tumors constitute a group of mesenchymal tumors associated with inflammatory infiltration. They occur mainly in young patients. It is classified by the World Health Organization as a borderline neoplasm. They are observed in many organs, particularly the lungs. Digestive localization is rare, and localization into the ampulla of Vater has been reported once. Case presentation: We report the case of a 39-year-old patient who was admitted for cholestatic jaundice with right hypochondrium pain. Computed tomography and magnetic resonance imaging revealed a tumor at the biliopancreatic junction. A cephalic duodenopancreatectomy was performed, and a histological examination of the surgical specimen revealed an inflammatory myofibroblastic tumor of the ampulla of Vater. The postoperative evolution was without any complications. Clinical discussion: This is the second case of localization of an inflammatory myofibroblastic tumor in Vater's ampulla. The therapeutic approach is the complete excision of these inflammatory tumors, thus reducing the risk of local recurrence. In the literature, all cases of incomplete excision have resulted in recurrences. Conclusion: Inflammatory myofibroblastic tumors are rare. The diagnosis was based on histopathological findings and confirmed using immunohistochemical techniques.

Effectiveness of full Pulpotomy compared with Root canal treatment in managing teeth with signs and symptOms indicative of irreversible pulpitis: a protocol for prospectiVE meta-analysis of individual participant data of linked randomised clinical trials (PROVE).

BACKGROUND: Full pulpotomy has been proposed as an alternative to root canal treatment in teeth with signs and symptoms indicative of irreversible pulpitis (IRP), but the evidence is limited, relying on underpowered studies with a high risk of bias. The aim of this study is to conduct a prospective meta-analysis (PMA) of individual participant data of a series of individual randomised trials to provide robust evidence on the clinical and cost-effectiveness of pulpotomy compared with root canal treatment. METHODS: Individual participant data will be obtained from a series of randomised trials designed and conducted by a consortium of multi-national investigators with an interest in vital pulp treatment. These individualised trials will be conducted using a specified protocol, defined outcomes, and outcome measures. Ten parallel-group randomised trials currently being conducted in 10 countries will provide data from more than 500 participants. The primary outcome is a composite measure defined as (1) the absence of pain indicative of IRP, (2) the absence of signs and symptoms indicative of acute or chronic apical periodontitis, and (3) the absence of radiographic evidence of failure including radiolucency or resorption. Individual participant data will be obtained, assessed, and checked for quality by two independent reviewers prior to the PMA. Pooled estimates on treatment effects will be generated using a 2-stage meta-analysis approach. The first stage involves a standard regression analysis in each trial to produce aggregate data on treatment effect estimates followed by an inverse variance weighted meta-analysis to combine these aggregate data and produce summary statistics and forest plots. Cost-effectiveness analysis based on the composite outcome will be undertaken as a process evaluation to evaluate treatment fidelity and acceptability by patients and dentists. RESULTS: The research question and trial protocol were developed and approved by investigators in all 10 sites. All sites use shared resources including study protocols, data collection forms, participant information leaflets, and consent forms in order to improve flow, consistency, and reproducibility. Each site obtained its own Institutional Review Board approval, and trials were registered in appropriate open access platforms. Patient recruitment has started in most sites, as of July 2023. DISCUSSION: PMA offers a rigorous, flexible, and efficient methodology to answer this important research question and provide results with improved generalisability and external validity compared with traditional trials and retrospective meta-analyses. The results of this study will have implications for both the delivery of clinical practice and structured clinical guidelines' development. TRIAL REGISTRATION: PROSPERO CRD42023446809. Registered on 08 February 2023.

Urban flood numerical modeling and hydraulic performance of a drainage network: A case study in Algiers, Algeria.

Urban sewer system management is challenging due to its higher vulnerability to flooding caused by rapid urbanization and climate change. For local decision-makers, storm water management is essential for urban planning and development. Therefore, the main objective of this study is to develop a numerical model for the sewerage network of the central catchment area of Algiers since it has experienced frequent overflows during the winter season. For this purpose, to model the sewerage networks, the model was built by coupling ArcGIS with MIKE URBAN. Its calibration and validation were performed using real-time measurements with a time step of 15 min. The model was evaluated by several statistical indicators, such as the coefficient of determination (R2), Nash-Sutcliffe efficiency (NSE), root mean square error (RMSE), and percent bias (PBIAS). The model results showed acceptable model performance, with an NSE superior to 0.50, R2 of approximately 0.63, RMSE of 7%, and PBIAS of 10% during the validation of the model. The performance parameters prove the reliability of the developed model. The employed model can be applied in other regions and could be helpful for policymakers and managers to improve flood mitigation measures based on the model prediction of the sewerage network.

Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells.

A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI50 of 1.28 µM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC50 of 2.81 µM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC50 of 4.82 µM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.

Assessing the effectiveness of nature-based solutions-strengthened urban planning mechanisms in forming flood-resilient cities.

Cities have experienced rapid urbanization-induced harsh climatic events, especially flooding, inevitably resulting in negative and irreversible consequences for urban resilience and endangering residents' lives. Numerous studies have analyzed the effects of anthropogenic practices (land use changes and urbanization) on flood forecasting. However, non-structural mitigation's effectiveness, like Nature-Based Solutions (NBS), has yet to receive adequate attention, particularly in the Middle East and North Africa (MENA) region, which have become increasingly significant and indispensable for operationalizing cities efficiently. Therefore, our study investigated the predictive influence of incorporating one of the most common NBS strategies called low-impact development tools (LID) (such as rain gardens, bio-retention cells, green roofs, infiltration trenches, permeable pavement, and vegetative swale) during the urban planning of Alexandria, Egypt, which experiences the harshest rainfall annually and includes various urban patterns. City characteristics-dependent 14 LID scenarios were simulated with recurrence intervals ranging from 2 to 100 years using the LID Treatment Train Tool (LID TTT), depending on calibrated data from 2015 to 2020, by the Nash-Sutcliffe efficiency index and deterministic coefficient, and root-mean-square error with values of 0.97, 0.91, and 0.31, respectively. Our findings confirmed the significant effectiveness of combined LID tools on total flood runoff volume reduction by 73.7%, revealing that different urban patterns can be used in flood-prone cities, provided LID tools are considered in city planning besides grey infrastructure to achieve optimal mitigation. These results, which combined multiple disciplines and were not explicitly mentioned in similar studies in developing countries, may assist municipalities' policymakers in planning flood-resistant, sustainable cities.

Impact of Covid-19 lockdown regulations on PM2.5 and trace gases (NO2, SO2, CH4, HCHO, C2H2O2 and O3) over Lahore, Pakistan.

The COVID-19 pandemic altered the human mobility and economic activities immensely, as authorities enforced unprecedented lock down regulations. In order to reduce the spread of COVID-19, a complete lockdown was observed between 24 March - 31 May 2020 in Pakistan. This paper aims at investigating the PM2.5, AOD and column amounts of six trace gases (NO2, SO2, CH4, HCHO, C2H2O2, and O3) by comparing periods of reduced emissions during lockdown periods with reference periods without emission reductions over Lahore, Pakistan. HYSPLIT cluster trajectory analyses were performed, which confirmed similar meteorological flow conditions during lockdown and reference periods. This provides confidence that any change in air quality conditions would be due to changes in human activities and associated emissions. The results show about 38% reduction in ambient surface PM2.5 levels during the lockdown period. This change also positively correlated with MODISDB and AERONETAOD data with a decrease of AOD by 42% and 35%, respectively. Reductions for tropospheric columns of NO2 and SO2 were about 20% and 50%, respectively during a semi lockdown period, while no reduction in the CH4, C2H2O2, HCHO and O3 levels occurred. During the lockdown period NO2, O3 and CH4 were about 50%, 45% and 25% lower, respectively, but no reduction in SO2, C2H2O2 and HCHO levels were noticed compared to the reference lockdown period for Lahore. HYSPLIT cluster trajectory analysis revealed the greatest impact on Lahore air quality through local emissions and regional transport from the east (agricultural burning and industry).

A hitchhiker's guide to cancer models.

Cancer is a complex and uniquely personal disease. More than 1.7 million people in the United States are diagnosed with cancer every year. As the burden of cancer grows, so does the need for new, more effective therapeutics and for predictive tools to identify optimal, personalized treatment options for every patient. Cancer models that recapitulate various aspects of the disease are fundamental to making advances along the continuum of cancer treatment from benchside discoveries to bedside delivery. In this review, we use a thought experiment as a vehicle to arrive at four broad categories of cancer models and explore the strengths, weaknesses, opportunities, and threats for each category in advancing our understanding of the disease and improving treatment strategies.

Structural optimization of 4-(imidazol-5-yl)pyridine derivatives affords broad-spectrum anticancer agents with selective B-RAFV600E/p38α kinase inhibitory activity: Synthesis, in vitro assays and in silico study.

In the current article, we introduce design of a new series of 4-(imidazol-5-yl)pyridines with improved anticancer activity and selective B-RAFV600E/p38α kinase inhibitory activity. Based on a previous work, a group of structural modifications were applied affording the new potential antiproliferative agents. Towards extensive biological assessment of the target compounds, an in vitro anticancer assay was conducted over NCI 60-cancer cell lines panel representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. Compounds 7c, 7d, 8b, 9b, 9c, 10c, 10d, and 11b exhibited the highest potency among the tested compounds and demonstrated sub-micromolar or one-digit micromolar GI50 values against the majority of the employed cell lines. Compound 10c emerged as the most potent agent with nano-molar activity over most of the cells and incredible activity against melanoma (MDA-MB-435) cell line (GI50 70 nM). It is much more potent than sorafenib, the clinically used anticancer drug, against almost all the NCI-60 cell lines. Further cell-based mechanistic assays showed that compound 10c induced cell cycle arrest and promoted apoptosis in K562, MCF-7 and HT29 cancer cell lines. In addition, compound 10c induced autophagy in the three cancer cell lines. Kinase profiling of 10c showed its inhibitory effects and selectivity towards B-RAFV600E and p38α kinases with IC50 values of 1.84 and 0.726 µM, respectively. Docking of compound 10c disclosed its high affinity in the kinases pockets. Compound 10c represent a promising anticancer agent, that could be optimized in order to improve its kinase activity aiming at developing potential anticancer agents. The conformational stability of compound 10c in the active site of B-RAFV600E and p38α kinases was studied by applying molecular dynamic simulation of the compound in the two kinases for 600 ns in comparison to the native ligands.

A protocol for the Development of Core Outcome Sets for Endodontic Treatment modalities (COSET): an international consensus process.

BACKGROUND: The outcome of endodontic treatment is generally assessed using a range of patient and clinician-centred, non-standardised clinical and radiographic outcome measures. This makes it difficult to synthesise evidence for systematic analysis of the literature and the development of clinical guidelines. Core outcome sets (COS) represent a standardised list of outcomes that should be measured and reported in all clinical studies in a particular field. Recently, clinical researchers and guideline developers have focussed on the need for the integration of a patient-reported COS with clinician-centred measures. This study aims to develop a COS that includes both patient-reported outcomes and clinician-centred measures for various endodontic treatment modalities to be used in clinical research and practice. METHODS: To identify reported outcomes (including when and how they are measured), systematic reviews and their included clinical studies, which focus on the outcome of endodontic treatment and were published between 1990 and 2020 will be screened. The COSs will be defined by a consensus process involving key stakeholders using semi-structured interviews and an online Delphi methodology followed by an interactive virtual consensus meeting. A heterogeneous group of key 'stakeholders' including patients, general dental practitioners, endodontists, endodontic teachers, clinical researchers, students and policy-makers will be invited to participate. Patients will establish, via interactive interviews, which outcomes they value and feel should be included in a COS. In the Delphi process, other stakeholders will be asked to prioritise outcomes identified from the literature and patient interviews and will have the opportunity at the end of the first round to add outcomes that are not included, but which they consider relevant. Feedback will be provided in the second round, when participants will be asked to prioritise the list again. If consensus is reached, the remaining outcomes will be discussed at an online meeting and agreement established via defined consensus rules of outcome inclusion. If consensus is not reached after the second round, a third round will be conducted with feedback, followed by the online meeting. Following the identification of a COS, we will proceed to identify how and when these outcomes are measured. DISCUSSION: Using a rigorous methodology, the proposed consensus process aims to develop a COS for endodontic treatment that will be relevant to stakeholders. The results of the study will be shared with participants and COS users. To increase COS uptake, it will also be actively shared with clinical guideline developers, research funders and the editors of general dental and endodontology journals. TRIAL REGISTRATION: COMET 1879. 21 May 2021.

Discovery of New Imidazo[2,1-b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising In Vitro and In Vivo Anti-melanoma Activity.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.

Evaluating Population Density as a Parameter for Optimizing COVID-19 Testing: Statistical Analysis.

BACKGROUND: SARS-CoV-2 transmission risk generally increases with the proximity of those shedding the virus to those susceptible to infection. Thus, this risk is a function of both the number of people and the area they occupy. However, the latter continues to evade the COVID-19 testing policy. OBJECTIVE: The aim of this study is to analyze per capita COVID-19 testing data reported for Alabama to evaluate whether testing realignment along population density, rather than density agnostic per capita, would be more effective. METHODS: Descriptive statistical analyses were performed for population, density, COVID-19 tests administered, and positive cases for all 67 Alabama counties. RESULTS: Tests reported per capita appeared to suggest widespread statewide testing. However, there was little correlation (r=0.28, P=.02) between tests per capita and the number of cases. In terms of population density, new cases were higher in areas with a higher population density, despite relatively lower test rates as a function of density. CONCLUSIONS: Increased testing in areas with lower population density has the potential to induce a false sense of security even as cases continue to rise sharply overall.

Outcome measures to assess the effectiveness of endodontic treatment for pulpitis and apical periodontitis for use in the development of European Society of Endodontology (ESE) S3 level clinical practice guidelines: a protocol.

The European Society of Endodontology (ESE) is in the process of developing S3Level Clinical Practice Guidelines for the treatment of pulpal and apical disease for the benefit of clinicians and patients. In order to ensure a homogenous review process in the development of the clinical practice guidelines, it is essential that the core outcomes for all endodontic treatments are standardized and recommendations are made regarding minimum follow-up time specific to each outcome measure. In the absence of a recognized core outcome set in Endodontics, the current project aimed to follow an established consensus process to define the most appropriate clinician and patient-reported outcomes. As part of the project, recommendations will also be agreed regarding an acceptable minimum follow-up period for studies by literature review and group discussion. The selected outcome measures and follow-up periods will be used in subsequent systematic analyses of the literature to investigate the effectiveness of endodontic treatment to alleviate pulpitis and apical periodontitis. In this paper, previous reviews, ESE Guidelines and Position Statements were searched in order to compile a list of potentially important outcome measures for the treatment of pulpitis (working group 1), the nonsurgical treatment of apical periodontitis (working group 2), the surgical treatment of apical periodontitis (working group 3) and the regenerative treatment of apical periodontitis (working group 4). Initially, the two S3 guideline leads selected two independent senior clinical academics with experience of evidence-based dentistry to lead each of the four working groups forming a 10-member steering group. The working group leads in turn selected 32 academics with experience of evidence-based dentistry to lead the individual systematic reviews contained within the respective working groups. These 42 individuals make up the Guideline Development Group (GDG). Prior to the selected systematic reviewers commencing writing and submitting the review protocol, the complete list of outcome variables identified in this document will be ranked by the 42 members of the GDG in their importance to the individual patient using a 9-point Likert scale. A summary of the survey scores will thereafter be shared with the members of the group and the final list of clinician and patient-reported outcome measures rated as critical for decision making (7-9 on Likert scale by majority of survey participants) to guide systematic reviews will be consented and confirmed during an online meeting of the steering group. In this online meeting, another aspect with regard to meaningfulness of clinical trial results to be addressed in systematic reviews will be consented: length of follow-up. In order to develop high quality guidelines, it is suggested that the follow-up period after treatment should be related to the specific outcome measure being addressed; however, a minimum of one year for assessing the effectiveness of treatments for pulpitis and apical periodontitis should be considered. It is accepted, that selected research questions that focus on pain, swelling, medication taken or investigating diagnostic accuracy are likely to have shorter follow-up periods. As a result of the GDG consensus process, the outcome measures and length of follow-up will, alongside the use of standard instruments to assess the methodological quality of clinical trials and other comparative studies, be applied to all the commissioned systematic reviews that will inform the subsequent process when developing the ESE S3 Level Clinical Practice Guidelines.

Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors.

The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAFV600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC50 values against BRAFV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRAFV600E/p38α inhibitor with IC50 values of 2.49 and 85 nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 value of 96.3 nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC50 value of 13 µM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9 µM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRAFV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma.