Clinical and Genomic Characterization of ERBB2-Altered Gallbladder Cancer: Exploring Differences Between an American and a Chilean Cohort.

PURPOSE: Gallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations. METHODS: Patients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: A total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024). CONCLUSION: The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

Homologous recombination deficiency gene panel analysis results in synchronous endometrial and ovarian cancers.

OBJECTIVE: The objective of this study was to analyze the genetic alterations of tumors within the scope of the homologous recombination deficiency gene panel in patients diagnosed with synchronous endometrial ovarian cancer who have been followed for over 5 years using next-generation sequencing. METHODS: DNA was isolated from the patient's formalin-fixed, paraffin-embedded tissue blocks. Next-generation sequencing was performed using the Illumina capture-based sequencing method. Samples were sequenced using the Sophia HR Solution DNA Kit. RESULTS: Seven patients were included in this study. The ratios of likely pathogenic (LP)/pathogenic (P) somatic mutations in ATM (serine/threonine kinase or Ataxia-telangiectasia mutated gene), BRCA2 (breast cancer type 2 susceptibility gene), BARD1 (BRCA1 associated RING domain 1), TP53 (tumor protein p53), BIRP1 (BRCA1-interacting helicase 1 gene), PALB2 (partner and localizer of BRCA2), and CHECK2 were 21 (48.8%), 8 (18.6%), 5 (11.6%), 3 (6.9%), 2 (4.6%), 2 (4.6%), and 2 (4.6%), respectively, in endometrium, and the ratios of somatic mutations in ATM, BRCA2, TP53, BARD1, RAD54L (DNA repair/recombination protein like), BIRP1, and RAD51D (RAD51 recombinase paralog D) were 24 (60%), 6 (15%), 5 (12.5%), 2 (5%), 2 (5%), 1 (2.5%), and 1 (2.5%), respectively, in ovary. In endometrioid-synchronous endometrial ovarian cancer cases, P/LP mutations were observed in ATM and CHECK2 genes in endometrium and ATM, BRCA2, and TP53 genes in ovary. In two non-endometrioid-synchronous endometrial ovarian cancer cases, CHEK2 (checkpoint kinase 2) mutations were observed in endometrium and ATM and TP53 mutations in ovary, whereas in one case, P/LP mutations in ATM and TP53 genes were common in both tissues. CONCLUSION: Pathogenic variations confirming the diagnosis of synchronous endometrial ovarian cancer with genetic alterations were identified in all but one case. ATM gene mutation emerged as the most common alteration and has a potential association with a favorable prognosis.

Nuclear compensatory evolution driven by mito-nuclear incompatibilities.

Mitochondrial function relies on the coordinated expression of mitochondrial and nuclear genes, exhibiting remarkable resilience despite high mitochondrial mutation rates. The nuclear compensation mechanism suggests deleterious mitochondrial alleles drive compensatory nuclear mutations to preserve mito-nuclear compatibility. However, prevalence and factors conditioning this phenomenon remain debated due to its conflicting evidence. Here, we investigate how mito-nuclear incompatibilities impact substitutions in a model for species radiation. Mating success depends on genetic compatibility (nuclear DNA) and spatial proximity. Populations evolve from partially compatible mito-nuclear states, simulating mitochondrial DNA (mtDNA) introgression. Mutations do not confer advantages nor disadvantages, but individual fecundity declines with increasing incompatibilities, selecting for mito-nuclear coordination. We find that selection for mito-nuclear compatibility affects each genome differently based on their initial state. In compatible gene pairs, selection reduces substitutions in both genomes, while in incompatible nuclear genes, it consistently promotes compensation, facilitated by more mismatches. Interestingly, high mitochondrial mutation rates can reduce nuclear compensation by increasing mtDNA rectification, while substitutions in initially compatible nuclear gene are boosted. Finally, the presence of incompatibilities accelerates species radiation, but equilibrium richness is not directly correlated to substitution rates, revealing the complex dynamics triggered by mitochondrial introgression and mito-nuclear coevolution. Our study provides a perspective on nuclear compensation and the role of mito-nuclear incompatibilities in speciation by exploring extreme scenarios and identifying trends that empirical data alone cannot reveal. We emphasize the challenges in detecting these dynamics and propose analyzing specific genomic signatures could shed light on this evolutionary process.

Ursolic acid interaction with transcription factors BRAF, V600E, and V600K: a computational approach towards new potential melanoma treatments.

CONTEXT: Melanoma is one of the cancers with the highest mortality rate for its ability to metastasize. Several targets have undergone investigation for the development of drugs against this pathology. One of the main targets is the kinase BRAF (RAF, rapidly accelerated fibrosarcoma). The most common mutation in melanoma is BRAFV600E and has been reported in 50-90% of patients with melanoma. Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ursolic acid (UA) is a pentacyclic triterpene with a privileged structure, the pentacycle scaffold, which allows to have a broad variety of biological activity; the most studied is its anticancer capacity. In this work, we reported the interaction profile of vemurafenib-OMe, dabrafenib, and UA, to define whether UA has binding capacity to BRAFWT, BRAFV600E, and BRAFV600K. Homology modeling of BRAFWT, V600E, and V600K; molecular docking; and molecular dynamics simulations were carried out and interactions and residues relevant to the binding of the inhibitors were obtained. We found that UA, like the inhibitors, presents hydrogen bond interactions, and hydrophobic interactions of van der Waals, and π-stacking with I463, Q530, C532, and F583. The ΔG of ursolic acid in complex with BRAFV600K (- 63.31 kcal/mol) is comparable to the ΔG of the selective inhibitor dabrafenib (- 63.32 kcal/mol) in complex to BRAFV600K and presents a ΔG like vemurafenib-OMe with BRAFWT and V600E. With this information, ursolic acid could be considered as a lead compound for design cycles and to optimize the binding profile and the selectivity towards mutations for the development of new selective inhibitors for BRAFV600E and V600K to new potential melanoma treatments. METHODS: The homology modeling calculations were executed on the public servers I-TASSER and ROBETTA, followed by molecular docking calculations using AutoGrid 4.2.6, AutoDockGPU 1.5.3, and AutoDockTools 1.5.6. Molecular dynamics and metadynamics simulations were performed in the Desmond module of the academic version of the Schrödinger-Maestro 2020-4 program, utilizing the OPLS-2005 force field. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

First Brazilian Case Report of Unrelated Patients with Identical ISG15 Mutation.

BACKGROUND: ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy. OBJECTIVE: To characterize the laboratory and molecular features of two patients from different families affected by the same ISG15 variant. METHODS: We began with clinical characterization and investigation, assessed IL-12/IFN-γ production, performed genetic characterization through WES and Sanger sequencing, conducted an in silico molecular analysis of the genetic ISG15 variant's protein impact, and utilized RNAseq for transcriptome analysis to understand pathway impacts on ISG15-deficient subjects from unrelated families. RESULTS: A mutation in the ISG15 gene was identified, affecting two patients treated in different hospitals and cities in Brazil (Fortaleza and Sao Paulo), who are also members of unrelated families. Both patients showed low IFN-γ production when stimulated with BCG or BCG + IL-12. ISG15 deficiency presented with two distinct clinical phenotypes: infectious and neurological. It was identified that both patients are homozygous for the variant (c.83 T > A). Furthermore, it was observed that the mutant protein p.L28Q results in an unstable protein with increased flexibility (ΔΔG: -2.400 kcal/mol). Transcriptome analysis revealed 1321 differentially expressed genes, with significant upregulation in interferon pathways, showing higher expression in patients compared to controls. CONCLUSION: This study describes the first reported cases in Brazil of two unrelated patients with the same ISG15 mutation c.83 T > A, exhibiting infectious features such as mycobacterial infections and systemic candidiasis, neurological findings, and skin lesions, without adverse reactions to the BCG vaccine. CLINICAL IMPLICATIONS: Reporting ISG15 gene mutations in Brazilian patients enhances understanding of genetic susceptibilities, guiding effective diagnostics and treatment. Identifying high-risk individuals aids clinical practices, genetic counseling, and influences public health policies. We have identified the first case in Brazil of the same ISG15 variant c.83 T > A that was identified in two unrelated patients with distinct clinical phenotypes, infectious and neurological.

Identification of mutations in canine oral mucosal melanomas by exome sequencing and comparison with human melanomas.

Oral mucosal melanomas (OMMs) are aggressive neoplasms commonly found in dogs but rare in humans. Utilizing whole exome sequencing (WES), which focuses on protein-coding regions to reveal mutation profiles, we conducted a comparative analysis of canine OMM and human melanomas. This study involved DNA extraction, exome enrichment, and sequencing from three canine OMM cell lines (CMGD-2, CMGD-5, TLM-1), five canine OMM frozen samples, a human OMM cell line (MEMO), and a human commercial skin melanoma cell line (SK-MEL-28). The sequencing and subsequent analysis of FASTQ files yielded final variant files, leading to the identification of mutations. Our findings revealed a total of 500 mutated genes in canine OMM, including significant ones such as EP300, FAT4, JAK3, LRP1B, NCOR1, and NOTCH1. Notably, 82 shared mutations were identified between human melanomas and canine OMM genomes. These mutations were categorized based on the gene functions. The identification of these mutations provides critical insights that can pave the way for the development of novel therapeutic strategies for both canine and human OMM, offering hope for more effective treatments in the future.

Síndrome do QT longo em criança assintomática com mutação LMNA e TTN. Uma doença em constante evolução / Long QT syndrome in an asymptomatic child with LMNA e TTN mutation. A constantly evolving disease

INTRODUÇÃO: Quadros de síndrome de QT longo (SQTL) são responsáveis pela maioria dos casos de morte súbita (MS) em coração estruturalmente normal. Desde sua descrição inicial na forma autossômica dominante, o diagnóstico e novas variantes encontram-se em evolução. O avanço da medicina de precisão e o maior uso do Exoma, evidencia cada vez mais quadros de overlap entre doenças elétricas e miocárdicas genéticas. Mutações no LMNA associam-se à miocardiopatia dilatada, MS por arritmia ventricular, bradicardia e bloqueio atrioventricular avançado. Mutações no TTN também se associam à miocardiopatia dilatada. Até o momento, esses genes não estão associados à SQTL. OBJETIVO: Relatar caso em criança com fenótipo de SQTL, escore de Schwartz de alta probabilidade e mutações provavelmente patológicas nos genes LMNA e TTN na ausência de miocardiopatia dilatada. RELATO DO CASO: Masculino, 7 anos, sem história de MS familiar, com transtorno do espectro autista - TEA, sem queixas cardiológicas. Em avaliação pré-uso de medicação para TEA observou prolongamento do QTc e bradicardia (Tabela de Davignon). Apresentava QTc 563 ms e FC variável (70 a 100) em diversas avaliações eletrocardiográficas. O escore de Schwartz atribuído foi de 3,5. A avaliação ecocardiográfica e eletromiográfica não evidenciou doença cardíaca ou muscular. A avaliação genética por Exoma evidenciou variante provavelmente patogênica no LMNA(associada à miocardiopatia dilatada e distrofia muscular) e TTN (associada à cardiomiopatia hipertrófica e distrofia muscular). Receitado propranolol 3 mg kg dia, espironolactona 1 mg kg dia e reposição de magnésio 50 mg kg dia. Afamília foi orientada sobre sinais de alarme, medicações que prolongam o QTc e receberá treinamento de suporte básico de vida. Aavaliação genética familiar está em andamento. CONCLUSÃO: 1) ASQTL apresenta amplo espectro clínico e genético e seus estudos seguem em constante evolução 2) Novas variantes genéticas são possíveis e quadros de overlap se tornarão cada vez mais frequentes com a evolução e popularização da medicina de precisão 3) A abordagem do paciente deve ser multidisciplinar e incluir orientação genética, farmacológica, psicológica e treinamento em RCPpara adultos próximos à criança.

Cluster classification of a Brazilian gastric cancer cohort reveals remarkable populational differences in normal p53 rate.

BACKGROUND: Queiroz et al. showed that the application of cluster methodology for classifying gastric cancer is suitable and efficient within a Brazilian cohort, which is known for its population heterogeneity. The study highlighted the potential utilization of this method within public health services due to its low-cost, presenting a viable means to improve the diagnosis and prognosis of gastric cancer. BACKGROUND: Our Brazilian cohort with gastric cancer has a distinct distribution between mutated and normal p53. BACKGROUND: New genetic marker-based classifications improve gastric cancer diagnosis accuracy. BACKGROUND: Machine learning integration enhances predictive value in gastric cancer diagnosis. BACKGROUND: Molecular biomarkers complement clinical decisions, advancing personalized medicine. OBJECTIVE: Gastric adenocarcinoma remains an aggressive disease with a poor prognosis, as evidenced by a 5-year survival rate of approximately 31%. The histological classifications already proposed do not accurately reflect the high biological heterogeneity of this neoplasm, particularly in diverse populations, and new classification systems using genetic markers have recently been proposed. Following these newly proposed models, we aimed to assess the cluster distribution in a Brazilian cohort. Furthermore, we evaluated whether the inclusion of other clinical and histological parameters could enhance the predictive value. METHODS: We used a previously described four-immunohistochemistry/EBER-ISH marker to classify a cohort of 30 Brazilian patients with gastric adenocarcinoma into five different clusters and compared the distribution with other genetically diverse populations. Furthermore, we used artificial intelligence methods to evaluate whether other clinical and pathological parameters could improve the results of the methodology. RESULTS: Disclosing the genetic variability between populations, we observed a more balanced distribution of the aberrant/normal p53 ratio (0.6) between patients negative for the other markers tested, unlike previous studies with Asian and North American populations. In addition, decision tree analysis reinforced the efficiency of these new classifications, as the stratification accuracy was not altered with or without additional data. CONCLUSION: Our study underscores the importance of local research in characterizing diverse populations and highlights the complementary role of molecular biomarkers in personalized medicine for gastric adenocarcinoma, enhancing diagnostic accuracy and potentially improving survival rates.

Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia.

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

Rare primary vasculitis: update on multiple complex diseases and the new kids on the block.

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

In silico and in vitro study of FLT3 inhibitors and their application in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common hematological cancer in the adult population worldwide. Approximately 35% of patients with AML present internal tandem duplication (ITD) mutations in the FMS­like tyrosine kinase 3 (FLT3) receptor associated with poor prognosis, and thus, this receptor is a relevant target for potential therapeutics. Tyrosine kinase inhibitors (TKIs) are used to treat AML; however, their molecular interactions and effects on leukemic cells are poorly understood. The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild­type (WT)­FLT3 and ITD­mutated (ITD­FLT3) structural models of FLT3, in its inactive aspartic acid­phenylalanine­glycine motif (DFG­out) and active aspartic acid­phenylalanine­glycine motif (DFG­in) conformations. Furthermore, the present study evaluated the effects of the second­generation TKIs gilteritinib and quizartinib on cancer cell viability, apoptosis and proliferation in the MV4­11 (ITD­FLT3) and HL60 (WT­FLT3) AML cell lines. Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were included as an FLT3­negative group. Molecular docking analysis indicated higher affinities of second­generation TKIs for WT­FLT3/DFG­out and WT­FLT3/DFG­in compared with those of the first­generation TKIs. However, the ITD mutation changed the affinity of all TKIs. The in vitro data supported the in silico predictions: MV4­11 cells presented high selective sensibility to gilteritinib and quizartinib compared with the HL60 cells, whereas the drugs had no effect on PBMCs. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD­mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.

Resistance and virulence genes characteristic of a South Asia Clade (I) Candida auris strain isolated from blood in Beijing.

INTRODUCTION: Candida auris is a globally disseminated invasive ascomycetous yeast, that imposes a substantial burden on healthcare systems. It has been documented to have spread to over 40 countries across six continents, necessitating in-depth comprehension through advanced techniques like Whole-Genome Sequencing. METHOD: This study entailed the isolation and Whole-Genome Sequencing of a fluconazole-resistant C. auris strain (CA01) obtained from a patient's blood in Beijing. Genome analysis was conducted to classify the strain, and molecular docking was performed to understand the impact of mutations on drug resistance. RESULTS: Genome analysis revealed that CA01 belongs to the South Asia Clade (I) and shares the closest genetic relationship with previously reported strains BJCA001 and BJCA002. Notably, unlike BJCA001, CA01 exhibits significant resistance to fluconazole primarily due to the A395T mutation in the ERG11 gene. Molecular docking studies demonstrated that this mutation leads to geometric changes in the active site where fluconazole binds, resulting in decreased binding affinity. Additionally, the present findings have identified several core virulence genes in C. auris, such as RBF1. DISCUSSION: The findings from this study expand the understanding of the genetic diversity and adaptive mechanisms of C. auris within the South Asia Clade (I). The observed fluconazole resistance driven by the ERG11 mutation A395T highlights the need for heightened awareness and adaptation in clinical treatment strategies in China. This study provides critical insights into drug resistance and virulence profiles at a genetic level, which could guide future therapeutic and management strategies for C. auris infections.

The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts.

Parkinson's disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD. We found that the GBA1 K198E fibroblasts but not WT fibroblasts showed reduced catalytic activity of heterozygous mutant GCase by -70% but its expression levels increased by 3.68-fold; increased the acidification of autophagy vacuoles (e.g., autophagosomes, lysosomes, and autolysosomes) by +1600%; augmented the expression of autophagosome protein Beclin-1 (+133%) and LC3-II (+750%), and lysosomal-autophagosome fusion protein LAMP-2 (+107%); increased the accumulation of lysosomes (+400%); decreased the mitochondrial membrane potential (∆Ψm) by -19% but the expression of Parkin protein remained unperturbed; increased the oxidized DJ-1Cys106-SOH by +900%, as evidence of oxidative stress; increased phosphorylated LRRK2 at Ser935 (+1050%) along with phosphorylated α-synuclein (α-Syn) at pathological residue Ser129 (+1200%); increased the executer apoptotic protein caspase 3 (cleaved caspase 3) by +733%. Although exposure of WT fibroblasts to environmental neutoxin rotenone (ROT, 1 µM) exacerbated the autophagy-lysosomal system, oxidative stress, and apoptosis markers, ROT moderately increased those markers in GBA1 K198E fibroblasts. We concluded that the K198E mutation endogenously primes skin fibroblasts toward autophagy dysfunction, OS, and apoptosis. Our findings suggest that the GBA1 K198E fibroblasts are biochemically and molecularly equivalent to the response of WT GBA1 fibroblasts exposed to ROT.

The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T>C ZRS Variant: A Case Report.

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from "uncertain significance" to "likely pathogenic" according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype-genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS.

Mapping variants in HTLV-1 genome to analyze their impacts on the HAM/TSP development: A systematic review.

The reasons that lead some individuals living with the Human T Lymphotropic Virus 1 (HTLV-1) to develop HAM/TSP are still unclear. To better understand the viral genetic factors that may be associated with the development of HAM/TSP, this study aims to evaluate the impact of HTLV-1 genome mutations on the development of this disease through a systematic review. This review followed the PRISMA guidelines and was registered in the PROSPERO database. The search for articles was performed in PMC, PubMed, Lilacs, SciELO, and Embase databases using the following search descriptors: HTLV-1, HAM/TSP, mutation, polymorphism, genetic variation, and sequenc*. From the 1,929 articles found in the search, 20 were selected according to the pre-defined inclusion and exclusion criteria. A total of 619 HAM/TSP cases were compared with 555 AC controls. The mutations possibly related to the disease progression were detected in hbz (R119Q), tax (A7959V), ORF-I (R88K, P86S, S69G, P45L, L40F, C39R, CR9Y), and gp46 (V247I, N93D, S72G) genetic regions. The data collected and analyzed here indicate that mutations in the HTLV-1 genome could play an important role in the chronic inflammatory state and may be related to the development of HAM/TSP.

A New Case Report of Traboulsi Syndrome: A Literature Review and Insights Into Genotype-Phenotype Correlations.

Traboulsi syndrome is a rare genetic disorder characterized by facial dysmorphism, lens subluxation, anterior segment anomalies, and spontaneous filtering blebs. The syndrome is due to mutations in the ASPH gene, which plays a crucial role in the development and maintenance of the lens. This case report describes the clinical and genetic findings in a Mexican male with Traboulsi syndrome, highlighting the identification of a novel ASPH variant. A 21-year-old male presented with trauma to the right eye while playing soccer. He had a history of lens subluxation and dysmorphic facial features. Ophthalmic examination revealed right eye lens subluxation into the anterior chamber (with signs of a previous episode of acute angle closure) and left eye posterior and inferior lens subluxation with sectorial iris atrophy. Genetic analysis identified a pathogenic ASPH variant (NM_004318.3:c.1892G>A, p.Trp631*) and a novel likely pathogenic variant (deletion of exons 20-21), confirming Traboulsi syndrome. This is the first instance of Traboulsi syndrome in the Mexican population. The absence of spontaneous filtering blebs in this patient supports previous reports of the wide phenotypic variability that could be related to the type of mutation. This novel ASPH variant expands the known genetic heterogeneity of Traboulsi syndrome.

Fibronectin and Hand2 influence tubulogenesis during pronephros development and mesonephros regeneration in zebrafish (Danio rerio).

Worldwide incidence of kidney diseases has been rising. Thus, recent research has focused on zebrafish, whose fast development and innate regeneration capacity allow identifying factors influencing renal processes. Among these poorly studied factors are extracellular matrix (ECM) proteins like Fibronectin (Fn) essential in various tissues but not yet evaluated in a renal context. We utilized early nat and han zebrafish mutant embryos and carrier adults to investigate Fn's role during kidney development and regeneration. The locus natter (nat) encodes Fn and the locus han encodes Hand2, which results in increased Fn deposition. Our results show that Fn impacts identity maintenance and morphogenesis during development and influences conditions for neonephrogenic cluster formation during regeneration. Histological analysis revealed disrupted pronephric structures and increased blood cell accumulation in Fn mutants. Despite normal expression of specification markers (pax2, ATPα1a.1), structural abnormalities were evident. Differences between wild-type and mutation-carriers suggest a haploinsufficiency scenario. These findings reveal a novel function for ECM in renal development and regeneration, with potential implications for understanding and treating kidney diseases.

Mutagenicity of the agriculture pesticide chlorothalonil assessed by somatic mutation and recombination test in Drosophila melanogaster.

Chlorothalonil (CTL) is a pesticide widely used in Brazil, yet its mutagenic potential is not fully determined. Thus, we assessed the mutagenicity of CTL and its bioactivation metabolites using the somatic mutation and recombination test (SMART) in Drosophila melanogaster, by exposing individuals, with basal and high bioactivation capacities (standard and high bioactivation cross offspring, respectively), from third instar larval to early adult fly stages, to CTL-contaminated substrate (0.25, 1, 10 or 20 µM). This substrate served as food and as physical medium. Increased frequency of large single spots in standard cross flies' wings exposed to 0.25 µM indicates that, if CTL is genotoxic, it may affect Drosophila at early life stages. Since the total spot frequency did not change, CTL cannot be considered mutagenic in SMART. The same long-term exposure design was performed to test whether CTL induces oxidative imbalance in flies with basal (wild-type, WT) or high bioactivation (ORR strain) levels. CTL did not alter reactive oxygen species and antioxidant capacity against peroxyl radicals levels in adult flies. However, lipid peroxidation (LPO) levels were increased in WT male flies exposed to 1 µM CTL. SMART and LPO alterations were observed only in flies with basal bioactivation levels, pointing to direct CTL toxicity to DNA and lipids. Survival, emergence and locomotor behavior were not affected, indicating no bias due to lethality, developmental and behavioral impairment. We suggest that, if related to CTL exposure, DNA and lipid damages may be residual damage of earlier life stages of D. melanogaster.

Alzheimer's Disease Immunotherapy and Mimetic Peptide Design for Drug Development: Mutation Screening, Molecular Dynamics, and a Quantum Biochemistry Approach Focusing on Aducanumab::Aß2-7 Binding Affinity.

Seven treatments are approved for Alzheimer's disease, but five of them only relieve symptoms and do not alter the course of the disease. Aducanumab (Adu) and lecanemab are novel disease-modifying antiamyloid-ß (Aß) human monoclonal antibodies that specifically target the pathophysiology of Alzheimer's disease (AD) and were recently approved for its treatment. However, their administration is associated with serious side effects, and their use is limited to early stages of the disease. Therefore, drug discovery remains of great importance in AD research. To gain new insights into the development of novel drugs for Alzheimer's disease, a combination of techniques was employed, including mutation screening, molecular dynamics, and quantum biochemistry. These were used to outline the interfacial interactions of the Aducanumab::Aß2-7 complex. Our analysis identified critical stabilizing contacts, revealing up to 40% variation in the affinity of the Adu chains for Aß2-7 depending on the conformation outlined. Remarkably, two complementarity determining regions (CDRs) of the Adu heavy chain (HCDR3 and HCDR2) and one CDR of the Adu light chain (LCDR3) accounted for approximately 77% of the affinity of Adu for Aß2-7, confirming their critical role in epitope recognition. A single mutation, originally reported to have the potential to increase the affinity of Adu for Aß2-7, was shown to decrease its structural stability without increasing the overall binding affinity. Mimetic peptides that have the potential to inhibit Aß aggregation were designed by using computational outcomes. Our results support the use of these peptides as promising drugs with great potential as inhibitors of Aß aggregation.