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Cureus Nov 2023Durvalumab is an immune checkpoint inhibitor (ICI) belonging to the anti-programmed death-ligand 1 (PD-L1) class, and it is used in the treatment of various end-stage...
Durvalumab is an immune checkpoint inhibitor (ICI) belonging to the anti-programmed death-ligand 1 (PD-L1) class, and it is used in the treatment of various end-stage malignancies. Immune checkpoint inhibitors are associated with various systemic and cutaneous adverse events. Psoriasiform drug eruptions have been clinically observed in patients who have a personal history of psoriasis being treated with ICIs. We present a unique case of de novo psoriasis in a patient being treated for poorly differentiated adenocarcinoma of the lung. The patient responded well to topical treatment and did not require discontinuation of durvalumab. Our case highlights the importance of clinician familiarity with psoriasis presentation, its association with durvalumab therapy, and treatment options for durvalumab-induced psoriasis.
PubMed: 38074037
DOI: 10.7759/cureus.48453 -
BMC Bioinformatics Sep 2023The study of de novo variation is important for assessing biological characteristics of new variation and for studies related to human phenotypes. Software programs...
BACKGROUND
The study of de novo variation is important for assessing biological characteristics of new variation and for studies related to human phenotypes. Software programs exist to call de novo variants and programs also exist to test the burden of these variants in genomic regions; however, I am unaware of a program that fits in between these two aspects of de novo variant assessment. This intermediate space is important for assessing the quality of de novo variants and to understand the characteristics of the callsets. For this reason, I developed an R package called acorn.
RESULTS
Acorn is an R package that examines various features of de novo variants including subsetting the data by individual(s), variant type, or genomic region; calculating features including variant change counts, variant lengths, and presence/absence at CpG sites; and characteristics of parental age in relation to de novo variant counts.
CONCLUSIONS
Acorn is an R package that fills a critical gap in assessing de novo variants and will be of benefit to many investigators studying de novo variation.
Topics: Humans; Genomics; Phenotype; Software
PubMed: 37660114
DOI: 10.1186/s12859-023-05457-z -
Cells Sep 2023Purines are required for fundamental biological processes and alterations in their metabolism lead to severe genetic diseases associated with developmental defects whose...
Purines are required for fundamental biological processes and alterations in their metabolism lead to severe genetic diseases associated with developmental defects whose etiology remains unclear. Here, we studied the developmental requirements for purine metabolism using the amphibian as a vertebrate model. We provide the first functional characterization of purine pathway genes and show that these genes are mainly expressed in nervous and muscular embryonic tissues. Morphants were generated to decipher the functions of these genes, with a focus on the adenylosuccinate lyase (), which is an enzyme required for both salvage and de novo purine pathways. knockdown led to a severe reduction in the expression of the myogenic regulatory factors (MRFs: Myod1, Myf5 and Myogenin), thus resulting in defects in somite formation and, at later stages, the development and/or migration of both craniofacial and hypaxial muscle progenitors. The reduced expressions of and , which are two genes specific to the salvage and de novo pathways, respectively, resulted in similar alterations. In conclusion, our data show for the first time that de novo and recycling purine pathways are essential for myogenesis and highlight new mechanisms in the regulation of MRF gene expression.
Topics: Animals; Xenopus laevis; Muscle, Skeletal; Purines; Muscle Development
PubMed: 37830593
DOI: 10.3390/cells12192379 -
Intractable & Rare Diseases Research Nov 2023Developmental and epileptic encephalopathy 45 (DEE45) is an autosomal dominant disease caused by variation in the gamma-aminobutyric acid type A receptor subunit beta 1...
Developmental and epileptic encephalopathy 45 (DEE45) is an autosomal dominant disease caused by variation in the gamma-aminobutyric acid type A receptor subunit beta 1 () gene. Affected individuals have severely impaired intellectual development, hypotonia, and other persistent neurological deficits. However, DEE45 is rare; only four infants with DEE45 have been reported worldwide and no case has been reported in China. Confirming a diagnosis of DEE45 is of great significance for guiding further treatment, assessing patient prognosis, and genetic counseling. The clinical characteristics of DEE45 and the medical history of DEE45 patients requires supplementation and clarification. Here, we present the clinical and genetic findings of a 7-year-old girl with DEE45 carrying a novel mutation (c.858_859delinsTT, p.286_287delinsIleSer) identified by whole exome sequencing (WES). The mutation is phylogenetic conserved in the second helix of the β1-subunit's transmembrane region. Western blot and RT-qPCR both indicated significant increase in the expression levels of GABRB1 mutant when compared with wild. The proband has epileptic encephalopathy and experienced refractory epilepsy onset at age 2 months and showed developmental delay at age 8 months. Electroencephalography (EEG) displayed hypsarrhythmia. Magnetic resonance imaging (MRI) showed no significant abnormalities in the internal structure of the patient's brain, which is displayed in two previously reported cases. The patient's symptoms of hypotonia, ataxia, profound mental retardation, and dysmetria became evident with development. In summary, we report the genetic and clinical characteristics of the first Chinese patient with DEE45 and explores the relationship between mutation and clinical symptoms.
PubMed: 38024579
DOI: 10.5582/irdr.2023.01092 -
MedRxiv : the Preprint Server For... Apr 2024Insertion of active retroelements-L1s, s, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of retroelements...
Insertion of active retroelements-L1s, s, and SVAs-can disrupt proper genome function and lead to various disorders including cancer. However, the role of retroelements (DNRTs) in birth defects and childhood cancers has not been well characterized due to the lack of adequate data and efficient computational tools. Here, we examine whole-genome sequencing data of 3,244 trios from 12 birth defect and childhood cancer cohorts in the Gabriella Miller Kids First Pediatric Research Program. Using an improved version of our tool xTea (x-Transposable element analyzer) that incorporates a deep-learning module, we identified 162 DNRTs, as well as 2 pseudogene insertions. Several variants are likely to be causal, such as a insertion that led to the ablation of a whole exon in the gene in a proband with brain tumor. We observe a high SVA insertion burden in both high-intolerance loss-of-function genes and exons as well as more frequent insertions of paternal origin. We also identify potential mosaic DNRTs from embryonic stages. Our study reveals the important roles of DNRTs in causing birth defects and predisposition to childhood cancers.
PubMed: 38699361
DOI: 10.1101/2024.04.15.24305733 -
Annals of Medicine and Surgery (2012) Nov 2023A subgaleal abscess is a collection of pus in a potential space between the galea aponeurotica and pericranium. De novo subgaleal abscesses are a subset of subgaleal...
INTRODUCTION AND IMPORTANCE
A subgaleal abscess is a collection of pus in a potential space between the galea aponeurotica and pericranium. De novo subgaleal abscesses are a subset of subgaleal abscesses that develop in the absence of identifiable risk factors such as head trauma or procedures. However, these have rarely been reported in the literature.
CASE PRESENTATION
We present the case of a 65-year-old woman who presented with a headache for two and a half months, followed by swelling of the right parieto-occipital scalp. She denied any history of trauma, procedures, or anticoagulant use. A diagnosis of subgaleal abscess complicated by osteomyelitis and epidural abscess was made after obtaining a computed tomography of the head. Surgical treatment consisting of drainage, debridement, and craniectomy was performed, and the disease was successfully treated with a 6-week course of antibiotics.
CLINICAL DISCUSSION
It is uncommon to have a de novo subgaleal abscess with spontaneous osteomyelitis and an epidural abscess as concurrent complications. The symptoms can be subtle, such as chronic headaches which can lead to delayed hospital visits. Computed tomography of the head is sufficient to make a definitive diagnosis. Appropriate antibiotic therapy and surgical intervention are necessary, which may encompass incision, drainage, debridement, and occasionally a craniectomy in order to achieve full resolution.
CONCLUSIONS
One should be vigilant when evaluating scalp swelling for possible underlying abscesses. Prompt diagnosis and appropriate surgical treatment with adequate antibiotics are preferred treatment options for de novo subgaleal abscesses.
PubMed: 37915632
DOI: 10.1097/MS9.0000000000001285 -
Frontiers in Cell and Developmental... 2023
PubMed: 37645249
DOI: 10.3389/fcell.2023.1241606 -
Nature Communications Dec 2023De novo peptide sequencing, which does not rely on a comprehensive target sequence database, provides us with a way to identify novel peptides from tandem mass spectra....
De novo peptide sequencing, which does not rely on a comprehensive target sequence database, provides us with a way to identify novel peptides from tandem mass spectra. However, current de novo sequencing algorithms suffer from low accuracy and coverage, which hinders their application in proteomics. In this paper, we present PepNet, a fully convolutional neural network for high accuracy de novo peptide sequencing. PepNet takes an MS/MS spectrum (represented as a high-dimensional vector) as input, and outputs the optimal peptide sequence along with its confidence score. The PepNet model is trained using a total of 3 million high-energy collisional dissociation MS/MS spectra from multiple human peptide spectral libraries. Evaluation results show that PepNet significantly outperforms current best-performing de novo sequencing algorithms (e.g. PointNovo and DeepNovo) in both peptide-level accuracy and positional-level accuracy. PepNet can sequence a large fraction of spectra that were not identified by database search engines, and thus could be used as a complementary tool to database search engines for peptide identification in proteomics. In addition, PepNet runs around 3x and 7x faster than PointNovo and DeepNovo on GPUs, respectively, thus being more suitable for the analysis of large-scale proteomics data.
Topics: Humans; Tandem Mass Spectrometry; Sequence Analysis, Protein; Peptides; Amino Acid Sequence; Neural Networks, Computer; Algorithms; Peptide Library
PubMed: 38042873
DOI: 10.1038/s41467-023-43010-x -
Current Opinion in Structural Biology Jun 2024Engineering new molecules with desirable functions and properties has the potential to extend our ability to engineer proteins beyond what nature has so far evolved.... (Review)
Review
Engineering new molecules with desirable functions and properties has the potential to extend our ability to engineer proteins beyond what nature has so far evolved. Advances in the so-called 'de novo' design problem have recently been brought forward by developments in artificial intelligence. Generative architectures, such as language models and diffusion processes, seem adept at generating novel, yet realistic proteins that display desirable properties and perform specified functions. State-of-the-art design protocols now achieve experimental success rates nearing 20%, thus widening the access to de novo designed proteins. Despite extensive progress, there are clear field-wide challenges, for example, in determining the best in silico metrics to prioritise designs for experimental testing, and in designing proteins that can undergo large conformational changes or be regulated by post-translational modifications. With an increase in the number of models being developed, this review provides a framework to understand how these tools fit into the overall process of de novo protein design. Throughout, we highlight the power of incorporating biochemical knowledge to improve performance and interpretability.
Topics: Artificial Intelligence; Proteins; Protein Engineering; Models, Molecular; Protein Conformation
PubMed: 38663170
DOI: 10.1016/j.sbi.2024.102794 -
Molecular Cancer Research : MCR Jan 2024Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is...
UNLABELLED
Small cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis.
IMPLICATIONS
SCLC tumors preferentially utilize either the de novo or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Purines; Purine Nucleotides; Hypoxanthine Phosphoribosyltransferase; Lung Neoplasms
PubMed: 37773022
DOI: 10.1158/1541-7786.MCR-23-0386