Troponin C gene mutations on cardiac muscle cell and skeletal Regulation: A comprehensive review.

BACKGROUND: The troponin complex plays a crucial role in regulating skeletal and cardiac contraction. Congenital myopathies can occur due to several mutations in genes that encode skeletal troponin. Moreover, there is limited information regarding the composition of skeletal troponin. This review specifically examines a comprehensive review of the TNNC gene mutations on cardiac and skeletal regulations. MAIN BODY: Troponin C (TNNC) has been linked to a newly discovered inherited muscle disorder. Genetic variations in genes that encode skeletal troponin can impair the function of sarcomeres. Various treatment approaches have been employed to mitigate the impact of variations, including the use of troponin activators, the injection of wild-type protein via AAV gene therapy, and myosin modification to enhance muscle contraction. The processes responsible for the pathophysiological implications of the variations in genes that encode skeletal troponin are not fully understood. CONCLUSION: This comprehensive review will contribute to the understanding of the relationship between human cardiomyopathy and TNNC mutations and will guide the development of therapy approaches.

Increased Positive Selection in Highly Recombining Genes Does not Necessarily Reflect an Evolutionary Advantage of Recombination.

It is commonly thought that the long-term advantage of meiotic recombination is to dissipate genetic linkage, allowing natural selection to act independently on different loci. It is thus theoretically expected that genes with higher recombination rates evolve under more effective selection. On the other hand, recombination is often associated with GC-biased gene conversion (gBGC), which theoretically interferes with selection by promoting the fixation of deleterious GC alleles. To test these predictions, several studies assessed whether selection was more effective in highly recombining genes (due to dissipation of genetic linkage) or less effective (due to gBGC), assuming a fixed distribution of fitness effects (DFE) for all genes. In this study, I directly derive the DFE from a gene's evolutionary history (shaped by mutation, selection, drift, and gBGC) under empirical fitness landscapes. I show that genes that have experienced high levels of gBGC are less fit and thus have more opportunities for beneficial mutations. Only a small decrease in the genome-wide intensity of gBGC leads to the fixation of these beneficial mutations, particularly in highly recombining genes. This results in increased positive selection in highly recombining genes that is not caused by more effective selection. Additionally, I show that the death of a recombination hotspot can lead to a higher dN/dS than its birth, but with substitution patterns biased towards AT, and only at selected positions. This shows that controlling for a substitution bias towards GC is therefore not sufficient to rule out the contribution of gBGC to signatures of accelerated evolution. Finally, although gBGC does not affect the fixation probability of GC-conservative mutations, I show that by altering the DFE, gBGC can also significantly affect nonsynonymous GC-conservative substitution patterns.

The rate and nature of mitochondrial DNA mutations in human pedigrees.

We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.

A rare hemoglobinopathy duo: Hb Adana×Hb SEA in a 1-year-old patient - a case report and a brief literature review.

Introduction and importance: Alpha thalassemia, resulting from nondeletional mutations, typically presents a more severe clinical manifestation compared to deletional mutations. Severe outcomes, such as hydrops fetalis, are associated with two specific nondeletional mutations. Therefore, DNA-based investigation is crucial for suspected carriers exhibiting subtle hematological abnormalities to facilitate proper diagnosis and effective family counseling. Case presentation: In this report, the authors describe a phenotypically normal 1-year-old girl with a rare and unique alpha-thalassemia genotype due to the presence of Hb Adana, a nondeletional alpha-chain mutation compounded with Hb SEA, an alpha-globin gene deletion. Clinical discussion: Mutations determine the clinical manifestations of alpha-thalassemia. DNA testing is recommended for suspected carriers with relatively small hematological abnormalities, for precise diagnosis and family counseling. To provide clinicians with a reference for diagnostic assessment, the authors established a genotype-phenotype correlations based on reported cases of Hb Adana following an exhaustive literature review. Being interested in determining which ethnicities and genotypes are associated with a higher risk of complications, including hydrops fetalis and transfusion dependence, the authors formalized a diagnostic evaluation guide and a guide for early screening to improve outcomes. Conclusion: Precise genetic evaluation is important for the diagnosis of alpha thalassemia. Hematologists play a critical role in managing these disorders, understanding genotype-phenotype correlations, and highlighting the significance of genetic counseling for high-risk patients. Extensive studies on these various genophenotypes are required to improve the diagnosis and prognosis of such medical conditions and advocate preventative strategies.

Resistance to KRAS inhibition in advanced non-small cell lung cancer.

Lung cancer remains the leading cause of cancer death globally. More than 50% of new cases are diagnosed in an advanced or metastatic stage, thus contributing to the poor survival of such patients. Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in nearly a third of lung adenocarcinoma and have for decades been deemed an 'undruggable' target. Yet, in recent years, a growing number of small molecules, such as the GTPase inhibitors, has been investigated in clinical trials of lung cancer patients harboring KRAS mutations, yielding promising results with improved outcomes. Currently, there are only two approved targeted therapies (adagrasib and sotorasib) for advanced or metastatic KRAS-mutated NSCLC from the second-line setting onwards. In this narrative review, we will focus on KRAS, its molecular basis, the role of its co-mutations, clinical evidence for its inhibition, putative mutation to resistance, and future strategies to overcome resistance to KRAS inhibition.

Rational design of unrestricted pRN1 derivatives and their application in the construction of a dual plasmid vector system for Saccharolobus islandicus.

Saccharolobus islandicus REY15A represents one of the very few archaeal models with versatile genetic tools, which include efficient genome editing, gene silencing, and robust protein expression systems. However, plasmid vectors constructed for this crenarchaeon thus far are based solely on the pRN2 cryptic plasmid. Although this plasmid coexists with pRN1 in its original host, early attempts to test pRN1-based vectors consistently failed to yield any stable host-vector system for Sa. islandicus. We hypothesized that this failure could be due to the occurrence of CRISPR immunity against pRN1 in this archaeon. We identified a putative target sequence in orf904 encoding a putative replicase on pRN1 (target N1). Mutated targets (N1a, N1b, and N1c) were then designed and tested for their capability to escape the host CRISPR immunity by using a plasmid interference assay. The results revealed that the original target triggered CRISPR immunity in this archaeon, whereas all three mutated targets did not, indicating that all the designed target mutations evaded host immunity. These mutated targets were then incorporated into orf904 individually, yielding corresponding mutated pRN1 backbones with which shuttle plasmids were constructed (pN1aSD, pN1bSD, and pN1cSD). Sa. islandicus transformation revealed that pN1aSD and pN1bSD were functional shuttle vectors, but pN1cSD lost the capability for replication. These results indicate that the missense mutations in the conserved helicase domain in pN1c inactivated the replicase. We further showed that pRN1-based and pRN2-based vectors were stably maintained in the archaeal cells either alone or in combination, and this yielded a dual plasmid system for genetic study with this important archaeal model.

Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions.

The epidermis, the outermost layer of the skin, serves as a protective barrier against external factors. Epidermal differentiation, a tightly regulated process essential for epidermal homeostasis, epidermal barrier formation and skin integrity maintenance, is orchestrated by several players, including signaling molecules, calcium gradient and junctional complexes such as gap junctions (GJs). GJ proteins, known as connexins facilitate cell-to-cell communication between adjacent keratinocytes. Connexins can function as either hemichannels or GJs, depending on their interaction with other connexons from neighboring keratinocytes. These channels enable the transport of metabolites, cAMP, microRNAs, and ions, including Ca2+, across cell membranes. At least ten distinct connexins are expressed within the epidermis and mutations in at least five of them has been linked to various skin disorders. Connexin mutations may cause aberrant channel activity by altering their synthesis, their gating properties, their intracellular trafficking, and the assembly of hemichannels and GJ channels. In addition to mutations, connexin expression is dysregulated in other skin conditions including psoriasis, chronic wound and skin cancers, indicating the crucial role of connexins in skin homeostasis. Current treatment options for conditions with mutant or altered connexins are limited and primarily focus on symptom management. Several therapeutics, including non-peptide chemicals, antibodies, mimetic peptides and allele-specific small interfering RNAs are promising in treating connexin-related skin disorders. Since connexins play crucial roles in maintaining epidermal homeostasis as shown with linkage to a range of skin disorders and cancer, further investigations are warranted to decipher the molecular and cellular alterations within cells due to mutations or altered expression, leading to abnormal proliferation and differentiation. This would also help characterize the roles of each isoform in skin homeostasis, in addition to the development of innovative therapeutic interventions. This review highlights the critical functions of connexins in the epidermis and the association between connexins and skin disorders, and discusses potential therapeutic options.

Molecular analysis of genetic mutations in non-small cell lung cancer in Morocco.

Non-small cell lung cancer (NSCLC) is a significant global health issue with diverse molecular profiles affecting treatment responses. Yet, NSCLC's molecular epidemiology in Morocco is largely unexplored. This study focuses on NSCLC genetic mutations, specifically in adenocarcinoma, among Moroccan patients to contribute to understanding NSCLC in this population. Ninety-four patients diagnosed with lung adenocarcinoma were analyzed. Formalin-fixed paraffin-embedded tissue samples were processed, and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) was extracted using standardized protocols. Mutations were detected using the AmoyDx Pan Lung Cancer Polymerase Chain Reaction (PCR) Panel kit, and their frequencies were assessed through statistical analysis. Epidermal Growth Factor Receptor (EGFR) mutations were detected in 22.34% of patients, predominantly exon 19 deletions (66.66%) and exon 21 L858R mutations (23.80%). Anaplastic lymphoma kinase (ALK) gene fusion was observed in 3.19% of patients, and KRAS mutations in 1.06%. No mutations were found in other tested genes. A slightly higher mutation rate was noted in females (54.16%) compared to males (45.84%). The study reveals a distinct mutation profile in Moroccan NSCLC patients, with a notable prevalence of EGFR mutations, albeit lower than in some Asian populations. The significance of EGFR mutations in treatment response aligns with global findings, highlighting the importance of understanding regional molecular variations for personalized therapy. Despite limitations in sample size and clinical data, this study sheds light on the genetic landscape of NSCLC in Morocco. The observed mutation rates, particularly in EGFR, underscore the potential for targeted therapies in Moroccan NSCLC patients, emphasizing the need for further research to refine treatment strategies tailored to this population.

Small cell neuroendocrine carcinoma and poorly differentiated rhabdomyosarcomas of the urinary bladder in adults-A comparative analysis in favor of a common histogenesis.

Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related other genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.

Understanding iron homeostasis in MDS: the role of erythroferrone.

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal stem cell disorders characterized by dysplasia and cytopenia in one or more cell lineages. Anemia is a very common symptom that is often treated with blood transfusions and/or erythropoiesis stimulating factors. Iron overload results from a combination of these factors together with the disease-associated ineffective erythropoiesis, that is seen especially in MDS cases with SF3B1 mutations. A growing body of research has shown that erythroferrone is an important regulator of hepcidin, the master regulator of systemic iron homeostasis. Consequently, it is of interest to understand how this molecule contributes to regulating the iron balance in MDS patients. This short review evaluates our current understanding of erythroferrone in general, but more specifically in MDS and seeks to place in context how the current knowledge could be utilized for prognostication and therapy.

Molecular and Epidemiological Investigation of Fluconazole-resistant Candida parapsilosis-Georgia, United States, 2021.

Background: Reports of fluconazole-resistant Candida parapsilosis bloodstream infections are increasing. We describe a cluster of fluconazole-resistant C parapsilosis bloodstream infections identified in 2021 on routine surveillance by the Georgia Emerging Infections Program in conjunction with the Centers for Disease Control and Prevention. Methods: Whole-genome sequencing was used to analyze C parapsilosis bloodstream infections isolates. Epidemiological data were obtained from medical records. A social network analysis was conducted using Georgia Hospital Discharge Data. Results: Twenty fluconazole-resistant isolates were identified in 2021, representing the largest proportion (34%) of fluconazole-resistant C parapsilosis bloodstream infections identified in Georgia since surveillance began in 2008. All resistant isolates were closely genetically related and contained the Y132F mutation in the ERG11 gene. Patients with fluconazole-resistant isolates were more likely to have resided at long-term acute care hospitals compared with patients with susceptible isolates (P = .01). There was a trend toward increased mechanical ventilation and prior azole use in patients with fluconazole-resistant isolates. Social network analysis revealed that patients with fluconazole-resistant isolates interfaced with a distinct set of healthcare facilities centered around 2 long-term acute care hospitals compared with patients with susceptible isolates. Conclusions: Whole-genome sequencing results showing that fluconazole-resistant C parapsilosis isolates from Georgia surveillance demonstrated low genetic diversity compared with susceptible isolates and their association with a facility network centered around 2 long-term acute care hospitals suggests clonal spread of fluconazole-resistant C parapsilosis. Further studies are needed to better understand the sudden emergence and transmission of fluconazole-resistant C parapsilosis.

Characterization of Patients with EGFR Mutation-Positive NSCLC Following Emergence of the Osimertinib Resistance Mutations, L718Q or G724S: A Multicenter Retrospective Observational Study in France.

Purpose: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is an effective first-line therapy for patients with common EGFR mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients become resistant to treatment. In some patients, emergence of tertiary EGFR mutations is implicated as a resistance mechanism. This study describes patients with NSCLC who acquired the rare EGFR mutations, L718Q or G724S, following EGFR TKI treatment. Patients and Methods: This was a retrospective, observational study undertaken in France from Feb-Nov 2021, in patients with EGFR mutation-positive NSCLC with an acquired L718Q or G724S mutation. Primary objectives were description of tumor characteristics, progression, and progression under treatment. Results: Nine eligible patients were identified. Acquired resistance to initial EGFR TKI treatment was associated with T790M emergence in six patients, who then received osimertinib monotherapy. Overall, eight patients received osimertinib monotherapy treatment at some point (average treatment duration: 18.3 months). Following the emergence of L718Q or G724S, patients received chemotherapy (n = 4; two of whom subsequently received afatinib), nivolumab (n = 2), afatinib (n = 2), or immunochemotherapy (n = 1). In the four patients who received afatinib after identification of L718Q or G724S, 2 achieved a partial response, one had stable disease and one had progressive disease. Treatment duration was 1.6-31.7 months. In patients with controlled disease (n = 3), progression-free survival was 6.1-31.7 months. Two of these patients had previously received osimertinib. Conclusion: Currently, there is no consensus regarding the treatment of EGFR mutation-positive NSCLC following emergence of the osimertinib resistance mutations, L718Q or G724S. Afatinib appears to be a promising treatment option in this setting.

Zoonotic spillover and viral mutations from low and middle-income countries: improving prevention strategies and bridging policy gaps.

The increasing frequency of zoonotic spillover events and viral mutations in low and middle-income countries presents a critical global health challenge. Contributing factors encompass cultural practices like bushmeat consumption, wildlife trade for traditional medicine, habitat disruption, and the encroachment of impoverished settlements onto natural habitats. The existing "vaccine gap" in many developing countries exacerbates the situation by allowing unchecked viral replication and the emergence of novel mutant viruses. Despite global health policies addressing the root causes of zoonotic disease emergence, there is a significant absence of concrete prevention-oriented initiatives, posing a potential risk to vulnerable populations. This article is targeted at policymakers, public health professionals, researchers, and global health stakeholders, particularly those engaged in zoonotic disease prevention and control in low and middle-income countries. The article underscores the importance of assessing potential zoonotic diseases at the animal-human interface and comprehending historical factors contributing to spillover events. To bridge policy gaps, comprehensive strategies are proposed that include education, collaborations, specialized task forces, environmental sampling, and the establishment of integrated diagnostic laboratories. These strategies advocate simplicity and unity, breaking down barriers, and placing humanity at the forefront of addressing global health challenges. Such a strategic and mental shift is crucial for constructing a more resilient and equitable world in the face of emerging zoonotic threats.

Total Pancreatectomy with Islet Auto Transplantation Outcomes in Pancreatitis Patients of Genetic Etiology: A Single Center Experience with a Large Cohort of Patients.

PURPOSE: Total pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment for patients with chronic pancreatitis (CP) when other interventions are unsuccessful. CP has many etiologies including heredity. Metabolic and pain relief outcomes following TPIAT are presented among patients with a genetic CP etiology when compared to those with a nongenetic etiology in a large cohort of patients who underwent this procedure at our center. METHODS: A retrospective analysis was performed of 237 TPIAT patients from 2006 to 2023. We analyzed the differences in patients with genetic (n = 56) versus nongenetic (n = 181) CP etiologies in terms of pre-TPIAT factors including patient characteristics and disease state, results from the isolation process, and outcomes such as long-term glycemic and pain control. RESULTS: Patients with genetic CP underwent TPIAT at a significantly younger age (32.3 years vs 41.3 years nongenetic, p < 0.0001) and endured symptoms for a significantly longer period (10 vs 6 years, p < 0.01). A significantly lower mass of islets was isolated from patients with genetic CP (p < 0.01), which increased with body mass index in both groups. Despite lower yields, genetic CP patients maintained metabolic function like nongenetic CP patients, as indicated by insulin independence and C-peptide, blood glucose, and hemoglobin A1c levels after TPIAT. Posttransplant narcotic usage and pain scores significantly decreased compared to pre-TPIAT, and more genetic CP patients were pain free and narcotic free post-TPIAT. CONCLUSIONS: Our data validate TPIAT as a beneficial procedure for patients enduring CP of genetic etiology. Pain that is inevitably recurrent after minor interventions due to the nature of the disease and favorable TPIAT outcomes should be considered in the decision to perform early TPIAT in cases of genetic CP.

Optical coherence tomography biomarkers in MYO7A-inherited retinal dystrophy: longitudinal study in pediatric patients.

PURPOSE: This study aims to answer a key question: is MYO7A-inherited retinal dystrophy (MYO7A-IRD) a photoreceptor-first or retinal pigment epithelium-first disease? A second aim was to determine the most useful biomarkers to monitor disease progression in pediatric patients with Usher syndrome type 1B (USH1) secondary to MYO7A mutation. METHODS: Fifty-two eyes from 26 patients with genetically-confirmed MYO7A-IRD underwent swept-source optical coherence tomography (SS-OCT). Structural abnormalities were evaluated and correlated with follow-up time and best corrected visual acuity (BCVA). All patients were evaluated at baseline and after ≥ 40 months of follow-up. RESULTS: The mean (SD) patient age was 9.92 (± 4.1) years. Mean follow-up time was 43 (± 3.2) months. At the final evaluation, the most common qualitative abnormalities in the subfoveal area were alterations in the photoreceptor outer segments (76.9% of eyes) and in the interdigitation zone (IZ) (80.8%). The presence of cystoid macular edema at baseline was independently associated with worse BCVA at the final assessment (increase in LogMAR estimate = 0.142; t(45.00) = 2.78, p = 0.009). The mean width of the ellipsoid and interdigitation zones decreased significantly (by 668 µm and 278 µm, respectively; both p < 0.001). CONCLUSION: This study shows that disruption of the photoreceptor outer segments and the IZ are the first alterations detected by SS-OCT in the early phases of MYO7A-IRD. These data highlight the potential value of measuring the width of the ellipsoid and IZ to evaluate disease progression. These findings also demonstrate the utility of monitoring for the emergence of cystic lesions as biomarkers of worse visual prognosis in patients with MYO7A-IRD.

The clinical features and prognostic implications of the co-mutated TP53 gene in advanced non-small cell lung cancer.

BACKGROUND: TP53 is a frequently mutated oncogene within non-small cell lung cancer (NSCLC). However, the clinical and prognostic significance of co-mutations in TP53 in patients with advanced NSCLC has not been fully elucidated. METHODS: A total of 174 patients with advanced NSCLC were enrolled in this study. All patients were subjected to sequencing analysis of tumor-related genes and information such as PD-L1 expression, TMB, and co-mutation changes were collected. Patients were categorized into TP53 mutant and TP53 wild-type groups according to their TP53 mutation status and then statistically analyzed. RESULTS: TP53 mutations were the most common among all patients, accounting for 56.32%, followed by epidermal growth factor receptor mutations at 48.27%. The most common mutation sites in the TP53 mutation group were exons 5-8.TP53 mutations were significantly associated with PD-L1 and TMB levels. Univariate Cox analysis showed that gender and EGFR mutation affected the prognosis of TP53-mutated NSCLC patients, and multivariate Cox regression analysis identified EGFR mutation as an independent risk factor. The OS of NSCLC patients in the TP53 mutation group was significantly shorter than that of the TP53wt group. Survival curves in the TP53/EGFR combined mutation group showed that patients with combined EGFR mutation had a lower survival rate. DISCUSSION: TP53 mutations are associated with different clinical indicators and have important implications in clinical treatment. TP53 is a poor prognostic factor for NSCLC patients, and TP53/EGFR co-mutation will affect the survival time of patients. TP53/EGFR co-mutation may be a new prognostic marker for NSCLC.

Global and local genomic features together modulate the spontaneous single nucleotide mutation rate.

Spontaneous mutations are evolutionary engines as they generate variants for the evolutionary downstream processes that give rise to speciation and adaptation. Single nucleotide mutations (SNM) are the most abundant type of mutations among them. Here, we perform a meta-analysis to quantify the influence of selected global genomic parameters (genome size, genomic GC content, genomic repeat fraction, number of coding genes, gene count, and strand bias in prokaryotes) and local genomic features (local GC content, repeat content, CpG content and the number of SNM at CpG islands) on spontaneous SNM rates across the tree of life (prokaryotes, unicellular eukaryotes, multicellular eukaryotes) using wild-type sequence data in two different taxon classification systems. We find that the spontaneous SNM rates in our data are correlated with many genomic features in prokaryotes and unicellular eukaryotes irrespective of their sample sizes. On the other hand, only the number of coding genes was correlated with the spontaneous SNM rates in multicellular eukaryotes primarily contributed by vertebrates data. Considering local features, we notice that local GC content and CpG content significantly were correlated with the spontaneous SNM rates in the unicellular eukaryotes, while local repeat fraction is an important feature in prokaryotes and certain specific uni- and multi-cellular eukaryotes. Such predictive features of the spontaneous SNM rates often support non-linear models as the best fit compared to the linear model. We also observe that the strand asymmetry in prokaryotes plays an important role in determining the spontaneous SNM rates but the SNM spectrum does not.

SpliceAPP: an interactive web server to predict splicing errors arising from human mutations.

BACKGROUND: Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequence variations within introns, particularly at branch sites. We have established a massively parallel splicing assay to assess the impact on splicing of 11,191 disease-relevant variants. Based on the experimental results, we then applied regression-based methods to identify factors determining splicing decisions and their respective weights. RESULTS: Our statistical modeling is highly sensitive, accurately annotating the splicing defects of near-exon intronic variants, outperforming state-of-the-art predictive tools. We have incorporated the algorithm and branchpoint information into a web-based tool, SpliceAPP, to provide an interactive application. This user-friendly website allows users to upload any genetic variants with genome coordinates (e.g., chr15 74,687,208 A G), and the tool will output predictions for splicing error scores and evaluate the impact on nearby splice sites. Additionally, users can query branch site information within the region of interest. CONCLUSIONS: In summary, SpliceAPP represents a pioneering approach to screening pathogenic intronic variants, contributing to the development of precision medicine. It also facilitates the annotation of splicing motifs. SpliceAPP is freely accessible using the link https://bc.imb.sinica.edu.tw/SpliceAPP . Source code can be downloaded at https://github.com/hsinnan75/SpliceAPP .

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Assessment of genome mutation analysis for tumor-informed detection of circulating tumor DNA in patients with breast cancer.

INTRODUCTION: Breast cancer, one of the most aggressive types of cancer, poses significant challenges for diagnosis and treatment. Emerging as a promising biomarker, circulating tumor DNA (ctDNA) can be used to identify and monitor disease risk. This study sought to examine the impact of mutations in various genes on the progression of breast cancer. Genetic variants associated with breast cancer have been examined in individuals diagnosed with the disease worldwide. METHODS: Fifty female participants underwent breast cancer testing. Sanger sequencing was used to analyze peripheral blood DNA from these individuals to detect disease-causing mutations in the BRCA1, BRCA2, PTEN, TP53, and ATM genes. Genetic alterations linked to breast cancer were screened and the findings were compared with those of tumor genes. RESULTS: The development of hereditary/early onset breast cancer in this study was significantly associated with mutations in ATM, PTEN, TP53, and BRCA1/BRCA2, according to the analysis of sequencing data. CONCLUSION: This study demonstrates the feasibility of analyzing ctDNA in patients with breast cancer (BC) undergoing palliative treatment using an SS-based technique.