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Understanding the functional impact of genetic mutations on protein structures is essential for advancing cancer research and developing targeted therapies. The main challenge lies in accurately mapping these mutations to protein structures and analysing their effects on protein function. To address this, Mut-Map (https://genemutation.org/) is a comprehensive computational pipeline designed to integrate mutation data from the Catalogue Of Somatic Mutations In Cancer database with protein structural data from the Protein Data Bank and AlphaFold models. The pipeline begins by taking a UniProt ID and proceeds through mapping corresponding Protein Data Bank structures, renumbering residues, and assessing disorder percentages. It then overlays mutation data, categorizes mutations based on structural context, and visualizes them using advanced tools like MolStar. This approach allows for a detailed analysis of how mutations may disrupt protein function by affecting key regions such as DNA interfaces, ligand-binding sites, and dimer interactions. To validate the pipeline, a case study on the TP53 gene, a critical tumour suppressor often mutated in cancers, was conducted. The analysis highlighted the most frequent mutations occurring at the DNA-binding interface, providing insights into their potential role in cancer progression. Mut-Map offers a powerful resource for elucidating the structural implications of cancer-associated mutations, paving the way for more targeted therapeutic strategies and advancing our understanding of protein structure-function relationships., (© The Author(s) 2024. Published by Oxford University Press.)

Background The overuse of medical testing, be it ancillary testing or imaging, has been identified as a problem in all healthcare systems in the world. As the Kingdom of Saudi Arabia marches towards the 2030 vision of healthcare transformation, we have sought to get a perspective on medically unnecessary tests being conducted in Saudi Arabian emergency departments (EDs), the reasons behind this phenomenon, and possible solutions to it. Methods This is a cross-sectional survey among emergency medicine physicians (EMPs) working in Saudi Arabian EDs, taken through a self-filled online questionnaire, about their ordering habits, what they believe to be unnecessary testing in their practice, the practice of their colleagues, and other Saudi EMPs as a whole. Subjects have also been asked about the reasons why such practices are occurring and possible solutions to reduce such overuse of unnecessary tests in Saudi EDs. Results A total of 182 EMPs were surveyed from the different regions of the Kingdom, and CT head for patients presenting with asymptomatic stroke, and asymptomatic TBI were the most overused scans (both 44%). The most overused advanced body imaging was CT kidney-ureters-bladder (KUB) at 41.5%, while the most overused ancillary tests were complete blood count (CBC) and liver transaminases. The most common reason for the practice was found to be fear of medicolegal proceedings (70.9%). Continuous education of EMPs and increasing ED staffing were found to be the most helpful solutions to reduce unnecessary testing in the ED (70.9% and 67%, respectively). Conclusion It is clear from our data that overuse of medical tests and imaging is still a prominent practice. CT head in asymptomatic patients seems to be the most commonly overused imaging in Saudi EDs. Ancillary testing and unnecessary ordering of CBCs and transaminases seem to stem from fear of EMPs from legal consequences. More control over medical test ordering needs to be exercised to reduce these practices., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Research Ethics Committee of Armed Forces Hospitals issued approval REC 643. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, AlSulami et al.)

Objectives: Publication is one of the crucial parameters in research, and the inability to publish has been noted in many medical students' projects due to different reasons. This cross-sectional study aimed to determine the obstacles that prevented medical students in a health science university from publishing their research from 2018 to 2021. First, an online survey was distributed to assess the obstacles to publication perceived by the medical students. Second, a total of 81 research projects were evaluated by scientific reviewers and their final decision about the publication was recorded., Results: In total, 162 students filled out the survey. The barriers faced by the students were various. They included an unsupportive research supervisor, a lack of time, an insufficient sample size, and many others. In the reviewer's evaluation, out of 81 projects, 70 projects (86.4%) were recommended to be published after minor or major modifications, while 11 projects (13.6%) were rejected due to poor writing style, poor results interpretation, and incorrect methodology., Conclusion: Articulating the barriers to undergraduate medical research publication is important in boosting publication rates and research experience of graduating medical students. Medical research educators and research supervisors should strongly consider creating a framework that tackles existing obstacles and any future matters., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The presence of protein structures with atypical folds in the Protein Data Bank (PDB) is rare and may result from naturally occurring knots or crystallographic errors. Proper characterisation of such folds is imperative to understanding the basis of naturally existing knots and correcting crystallographic errors. If left uncorrected, such errors can frustrate downstream experiments that depend on the structures containing them. An atypical fold has been identified in P. falciparum dihydrofolate reductase ( Pf DHFR) between residues 20-51 (loop 1) and residues 191-205 (loop 2). This enzyme is key to drug discovery efforts in the parasite, necessitating a thorough characterisation of these folds. Using multiple sequence alignments (MSA), a unique insert was identified in loop 1 that exacerbates the appearance of the atypical fold-giving it a slipknot-like topology. However, Pf DHFR has not been deposited in the knotted proteins database, and processing its structure failed to identify any knots within its folds. The application of protein homology modelling and molecular dynamics simulations on the DHFR domain of P. falciparum and those of two other organisms ( E. coli and M. tuberculosis ) that were used as molecular replacement templates in solving the Pf DHFR structure revealed plausible unentangled or open conformations of these loops. These results will serve as guides for crystallographic experiments to provide further insights into the atypical folds identified.

Mutations in hallmark genes are believed to be the main drivers of cancer progression. These mutations are reported in the Catalogue of Somatic Mutations in Cancer (COSMIC). Structural appreciation of where these mutations appear, in protein-protein interfaces, active sites or deoxyribonucleic acid (DNA) interfaces, and predicting the impacts of these mutations using a variety of computational tools are crucial for successful drug discovery and development. Currently, there are 723 genes presented in the COSMIC Cancer Gene Census. Due to the complexity of the gene products, structures of only 87 genes have been solved experimentally with structural coverage between 90% and 100%. Here, we present a comprehensive, user-friendly, web interface (https://cancer-3d.com/) of 714 modelled cancer-related genes, including homo-oligomers, hetero-oligomers, transmembrane proteins and complexes with DNA, ribonucleic acid, ligands and co-factors. Using SDM and mCSM software, we have predicted the impacts of reported mutations on protein stability, protein-protein interfaces affinity and protein-nucleic acid complexes affinity. Furthermore, we also predicted intrinsically disordered regions using DISOPRED3., (© The Author(s) 2021. Published by Oxford University Press.)

Viruses often encode proteins that mimic host proteins in order to facilitate infection. Little work has been done to understand the potential mimicry of the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, particularly the receptor-binding motifs, which could be important in determining tropism and druggability of the virus. Peptide and epitope motifs have been detected on coronavirus spike proteins using sequence homology approaches; however, comparing the three-dimensional shape of the protein has been shown as more informative in predicting mimicry than sequence-based comparisons. Here, we use structural bioinformatics software to characterize potential mimicry of the three coronavirus spike protein receptor-binding motifs. We utilize sequence-independent alignment tools to compare structurally known protein models with the receptor-binding motifs and verify potential mimicked interactions with protein docking simulations. Both human and non-human proteins were returned for all three receptor-binding motifs. For example, all three were similar to several proteins containing EGF-like domains: some of which are endogenous to humans, such as thrombomodulin, and others exogenous, such as Plasmodium falciparum MSP-1. Similarity to human proteins may reveal which pathways the spike protein is co-opting, while analogous non-human proteins may indicate shared host interaction partners and overlapping antibody cross-reactivity. These findings can help guide experimental efforts to further understand potential interactions between human and coronavirus proteins., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly growing infectious disease, widely spread with high mortality rates. Since the release of the SARS-CoV-2 genome sequence in March 2020, there has been an international focus on developing target-based drug discovery, which also requires knowledge of the 3D structure of the proteome. Where there are no experimentally solved structures, our group has created 3D models with coverage of 97.5% and characterized them using state-of-the-art computational approaches. Models of protomers and oligomers, together with predictions of substrate and allosteric binding sites, protein-ligand docking, SARS-CoV-2 protein interactions with human proteins, impacts of mutations, and mapped solved experimental structures are freely available for download. These are implemented in SARS CoV-2 3D, a comprehensive and user-friendly database, available at https://sars3d.com/. This provides essential information for drug discovery, both to evaluate targets and design new potential therapeutics., (© The Author(s) 2021. Published by Oxford University Press.)

Background Lung cancer is estimated to be 12% of all new cases of cancer. It is one of the most common cancers in men and women, and it is the main cause of cancer-related death in the United States of America. More than 90% of small cell lung cancer (SCLC) patients are elderly, with a current or past history of smoking. In Saudi Arabia, lung cancer incidence is low as compared to the global incidence. In 2013, the age-standardized ratio (ASR) was 1.8 per 100,000 for females and 5.5 per 100,000 for males. In our study, we aimed to assess the outcomes of SCLC at King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. Methods This retrospective cohort study included all patients aged 14 years and older with a diagnosis of SCLC from 2007 to 2017 using electronic medical records at KAUH. Data analysis was performed using Stata SE, version 15.0 (StataCorp LLC, TX). The primary outcome of this study was the survival of patients diagnosed with SCLC. Survival was defined as the time the patient lived in months from the date of pathological diagnosis to the date of the last follow-up or death. We included all variables in a univariate and multivariate analysis to determine the hazard ratio for each variable. Results In our study, we initially collected 193 lung cancer cases diagnosed during the period of 2007 to 2017 at KAUH, which was then narrowed to 22 after the selection of only SCLC cases. Data obtained showed 20 males (90.91%) and two females (9.09%), the median age of diagnosis was 64 years, and 45% of patients are active smokers, 9% are ex-smokers, and the smoking status of 41% of patients is unknown. Our data showed an overall median survival of 6.4 months (interval=11). Conclusion We observed that more than half of our patients who received chemotherapy showed improvement and a higher survival rate than those who didn't. In addition, 19% who received radiation therapy showed improvement and a higher survival rate than those who didn't. Future efforts to address the major issues that surround SCLC survivors, and to formulate a comprehensive survivorship care plan are required to develop better outcomes in survival and to improve the overall quality of life to pretreatment levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Alhejaili et al.)

Genomics and genome screening are proving central to the study of cancer. However, a good appreciation of the protein structures coded by cancer genes is also invaluable, especially for the understanding of functions, for assessing ligandability of potential targets, and for designing new drugs. To complement the wealth of information on the genetics of cancer in COSMIC, the most comprehensive database for cancer somatic mutations available, structural information obtained experimentally has been brought together recently in COSMIC-3D. Even where structural information is available for a gene in the Cancer Gene Census, a list of genes in COSMIC with substantial evidence supporting their impacts in cancer, this information is quite often for a single domain in a larger protein or for a single protomer in a multiprotein assembly. Here, we show that over 60% of the genes included in the Cancer Gene Census are predicted to possess multiple domains. Many are also multicomponent and membrane-associated molecular assemblies, with mutations recorded in COSMIC affecting such assemblies. However, only 469 of the gene products have a structure represented in the PDB, and of these only 87 structures have 90-100% coverage over the sequence and 69 have less than 10% coverage. As a first step to bridging gaps in our knowledge in the many cases where individual protein structures and domains are lacking, we discuss our attempts of protein structure modelling using our pipeline and investigating the effects of mutations using two of our in-house methods (SDM2 and mCSM) and identifying potential driver mutations. This allows us to begin to understand the effects of mutations not only on protein stability but also on protein-protein, protein-ligand and protein-nucleic acid interactions. In addition, we consider ways to combine the structural information with the wealth of mutation data available in COSMIC. We discuss the impacts of COSMIC missense mutations on protein structure in order to identify and assess the molecular consequences of cancer-driving mutations., Competing Interests: The authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Astex Pharmaceuticals has no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

In the cyclic guanosine monophosphate (cGMP) signaling pathway, phosphodiesterase 6 (PDE6) maintains a critical balance of the intracellular concentration of cGMP by catalyzing it to 5' guanosine monophosphate (5'-GMP). To gain insight into the mechanistic impacts of the PDE6 somatic mutations that are implicated in cancer and retinitis pigmentosa, we first defined the structure and organization of the human PDE6 heterodimer using computational comparative modelling. Each subunit of PDE6αβ possesses three domains connected through long α-helices. The heterodimer model indicates that the two chains are likely related by a pseudo two-fold axis. The N-terminal region of each subunit is comprised of two allosteric cGMP-binding domains (Gaf-A & Gaf-B), oriented in the same way and interacting with the catalytic domain present at the C-terminal in a way that would allow the allosteric cGMP-binding domains to influence catalytic activity. Subsequently, we applied an integrated knowledge-driven in silico mutation analysis approach to understand the structural and functional implications of experimentally identified mutations that cause various cancers and retinitis pigmentosa, as well as computational saturation mutagenesis of the dimer interface and cGMP-binding residues of both Gaf-A, and the catalytic domains. We studied the impact of mutations on the stability of PDE6αβ structure, subunit-interfaces and Gaf-cGMP interactions. Further, we discussed the changes in interatomic interactions of mutations that are destabilizing in Gaf-A (R93L, V141 M, F162 L), catalytic domain (D600N, F742 L, F776 L) and at the dimer interface (F426A, F248G, F424 N). This study establishes a possible link of change in PDE6αβ structural stability to the experimentally observed disease phenotypes.