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Background: This study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD. Methods: A retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children's Hospital of Fujian Province in China. Results: Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation. Conclusions: The clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients. [ABSTRACT FROM AUTHOR]

Background: Temporal lobe epilepsy is the most common type of focal epilepsy, but hereditary factors are usually overlooked. Reelin (RELN) is considered to be the second most common pathogenic gene implicated in autosomal dominant lateral temporal epilepsy (ADLTE). However, this mutation is not frequently discovered in the Chinese population. Additionally, there are few clinical studies regarding the connection between RELN and glioma. Case presentation: The healthcare records of an 8-year-old child who experienced generalized tonic-clonic seizures (GTCS) during sleep for 7 years were retrospectively analyzed. In addition to experiencing his first seizure at the age of one, his mother also suffered from GTCS during her pregnancy, and a glioma was discovered. An investigation involving gene sequencing was conducted on the proband and his parents. He was diagnosed with ADLTE once a missense mutation in RELN (c.1799 C > T) was identified as the causal factor. The mutation was inherited from his mother. He was taking levetiracetam (500 mg twice a day) to avoid seizures, but his mother died of status epilepticus caused by glioma recurrence two years earlier. Conclusions: Genetic issues should be given more consideration in cases of temporal lobe epilepsy. If the source of the seizures is determined to be inherited, anti-seizure medications should be used for prolonged periods. Furthermore, more research is required to determine whether mutations in RELN are related to the occurrence and progression of gliomas. [ABSTRACT FROM AUTHOR]

Background: Presence of Germline mutations in the BRCA1 and BRCA2 genes is the most significant epidemiological factor for breast cancer (BC), where germline BRCA1 (gBRCA 1) mutation increases the risk for BC by 59–87% and gBRCA 2 mutation increases the risk by 38–80%. In this retrospective study, we have analyzed NGS-based genetic data for samples received at our laboratory for genetic testing over a three-year period to understand the prevalence and pattern if any of BRCA1 and BRCA2 mutations in Indian breast cancer patients. Results: BRCA gene sequencing using NGS was performed in 395 consecutive cases of BC referred for testing to our lab between 2021 and 2023. Genetic analysis of mutations BRCA 1 and BRCA 2 genes resulted in 115 (29%) positive patients. Out of 115 patients, 79 reported BRCA1 mutations, whereas 36 had BRCA2 mutations. Exon 10 (57.3%) of BRCA1 and exon 11 (52%) of BRCA2 were the most mutated exons observed in this study. The c.1961delA (26.4%) variant, followed by the c.68_69delAG (22.7%) variant in BRCA1, and the c.6373delA (20.5%) variant in BRCA2, were the most common mutations found in our study. Our data shows positive correlation of younger age group (20–45 years) with BRCA positive status (Chi-square p value = 0.001). Conclusion: BRCA mutation prevalence was 29.1% in our data which is higher than Western countries. Based on our findings BRCA screening looks imperative for women with BC especially younger women (< 50 years), as family history based BRCA testing would miss out many BRCA positive candidates which could benefit from PARP therapy options. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors. The analysis further identified C21ORF2 as a strongly connected protein. The role of C21ORF2 in neurons and in the nervous system, and of ALS-associated C21ORF2 variants is largely unknown. Therefore, we combined human iPSC-derived motor neurons with other models and different molecular cell biological approaches to characterize the potential pathogenic effects of C21ORF2 mutations in ALS. First, our data show C21ORF2 expression in ALS-relevant mouse and human neurons, such as spinal and cortical motor neurons. Further, the prominent ALS-associated variant C21ORF2-V58L caused increased apoptosis in mouse neurons and movement defects in zebrafish embryos. iPSC-derived motor neurons from C21ORF2-V58L-ALS patients, but not isogenic controls, show increased apoptosis, and changes in DNA damage response, mitochondria and neuronal excitability. In addition, C21ORF2-V58L induced post-transcriptional downregulation of NEK1, an ALS-associated protein implicated in apoptosis and DDR. In all, our study defines the pathogenic molecular and cellular effects of ALS-associated C21ORF2 mutations and implicates impaired post-transcriptional regulation of NEK1 downstream of mutant C21ORF72 in ALS. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a clonal disorder arising from the differentiation arrest of myeloid precursor and malignant proliferation of a bone marrow derived, self-renewing stem or progenitor cells inside the bone marrow (BM) and blood due to numerous genetic mutations. Some mutations can also adjust DNA methylation and may play a critical function in pathogenesis in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML). Somatic mutations in DNMT3a were pronounced in approximately 20% and ∼30–35% of overall AML and CN-AML, respectively. Most DNMT3a mutations in AML have been observed to be heterozygous, A missense mutation, R882, located inside Hot spot exon 23, has been found to be the maximum common mutation. This is a preliminary study conducted on 20 adult Egyptian patients newly diagnosed as AML where Sanger sequencing of Hotspot Exon 23 of DNMT3a gene was performed on their initial bone marrow samples and were followed up to 3 months post-induction therapy. Only De Novo AML patients were included in our study. Results: Our results revealed that overall DNMT3a mutations were present in 25% of our patients, 10% having the R882 (rs147001633) mutation being 5% R882C and 5% R882H. Immunophenotyping analysis among Mutated DNMT3a (R882 and Non R882) and Wild DNMT3a revealed that AML markers exhibited no significant differences except for myeloperoxidase positivity which was significant among the groups (0.050). Regarding cytogenetics, only one case of the mutated DNMT3a had positive FISH inv (16), where the rest were FISH negative. After 28 days of induction, 75% of all our patients achieved complete response (CR), 20% achieve partial response (PR) out of which 75% are DNMT3a mutated. After 3 months follow-up, 10% of all patients faced mortality where 5% was DNMT3a wild type (died due to treatment-related mortality) and 5% was R882 mutated DNMT3a. Conclusion: DNMT3a mutations are present in 25% (5/20) of our AML patients, with 10% (2/20) having the R882 mutation being 5% (1/20) R882C and 5% (1/20) R882H. R882 mutation is associated with resistance to chemotherapy, and poorer outcomes, highlighting its poorer prognostic significance in AML. [ABSTRACT FROM AUTHOR]

Congenital myopathies (CMs) are a kind of non-progressive or slow-progressive muscle diseases caused by genetic mutations, which are currently defined and categorized mainly according to their clinicopathological features. CMs exhibit pleiotropy and genetic heterogeneity. Currently, supportive treatment and pharmacological remission are the mainstay of treatment, with no cure available. Some adeno-associated viruses show promising prospects in the treatment of MTM1 and BIN1-associated myopathies; however, such gene-level therapeutic interventions target only specific mutation types and are not generalizable. Thus, it is particularly crucial to identify the specific causative genes. Here, we outline the pathogenic mechanisms based on the classification of causative genes: excitation-contraction coupling and triadic assembly (RYR1, MTM1, DNM2, BIN1), actin-myosin interaction and production of myofibril forces (NEB, ACTA1, TNNT1, TPM2, TPM3), as well as other biological processes. Furthermore, we provide a comprehensive overview of recent therapeutic advancements and potential treatment modalities of CMs. Despite ongoing research endeavors, targeted strategies and collaboration are imperative to address diagnostic uncertainties and explore potential treatments. [ABSTRACT FROM AUTHOR]

Background: Motor difficulties are common in many, but not all, autistic individuals. These difficulties can co-occur with other problems, such as delays in language, intellectual, and adaptive functioning. Biological mechanisms underpinning such difficulties are less well understood. Poor motor skills tend to be more common in individuals carrying highly penetrant rare genetic mutations. Such mechanisms may have downstream consequences of altering neurophysiological excitation-inhibition balance and lead to enhanced behavioral motor noise. Methods: This study combined publicly available and in-house datasets of autistic (n = 156), typically-developing (TD, n = 149), and developmental coordination disorder (DCD, n = 23) children (age 3–16 years). Autism motor subtypes were identified based on patterns of motor abilities measured from the Movement Assessment Battery for Children 2nd edition. Stability-based relative clustering validation was used to identify autism motor subtypes and evaluate generalization accuracy in held-out data. Autism motor subtypes were tested for differences in motor noise, operationalized as the degree of dissimilarity between repeated motor kinematic trajectories recorded during a simple reach-to-drop task. Results: Relatively 'high' (n = 87) versus 'low' (n = 69) autism motor subtypes could be detected and which generalize with 89% accuracy in held-out data. The relatively 'low' subtype was lower in general intellectual ability and older at age of independent walking, but did not differ in age at first words or autistic traits or symptomatology. Motor noise was considerably higher in the 'low' subtype compared to 'high' (Cohen's d = 0.77) or TD children (Cohen's d = 0.85), but similar between autism 'high' and TD children (Cohen's d = 0.08). Enhanced motor noise in the 'low' subtype was also most pronounced during the feedforward phase of reaching actions. Limitations: The sample size of this work is limited. Future work in larger samples along with independent replication is important. Motor noise was measured only on one specific motor task. Thus, a more comprehensive assessment of motor noise on many other motor tasks is needed. Conclusions: Autism can be split into at least two discrete motor subtypes that are characterized by differing levels of motor noise. This suggests that autism motor subtypes may be underpinned by different biological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Mitochondria adjust their shape in response to the different energetic and metabolic requirements of the cell, through extremely dynamic fusion and fission events. Several highly conserved dynamin-like GTPases are involved in these processes and, among those, the OPA1 protein is a key player in the fusion of inner mitochondrial membranes. Hundreds of monoallelic or biallelic pathogenic gene variants have been described in OPA1, all associated with a plethora of clinical phenotypes without a straightforward genotypephenotype correlation. Methods: Here we report two patients harboring novel de novo variants in OPA1. DNA of two patients was analyzed using NGS technology and the pathogenicity has been evaluated through biochemical and morphological studies in patient's derived fibroblasts and in yeast model. Results: The two patients here reported manifest with neurological signs resembling Leigh syndrome, thus further expanding the clinical spectrum associated with variants in OPA1. In cultured skin fibroblasts we observed a reduced amount of mitochondrial DNA (mtDNA) and altered mitochondrial network characterized by more fragmented mitochondria. Modeling in yeast allowed to define the deleterious mechanism and the pathogenicity of the identified gene mutations. Conclusion: We have described two novel-single OPA1 mutations in two patients characterized by early-onset neurological signs, never documented, thus expanding the clinical spectrum of this complex syndrome. Moreover, both yeast model and patients derived fibroblasts showed mitochondrial defects, including decreased mtDNA maintenance, correlating with patients' clinical phenotypes. [ABSTRACT FROM AUTHOR]

Background: Minichromosome maintenance complex component 3 associated protein (MCM3AP) is a gene in which mutations can result in autosomal recessive peripheral neuropathy with or without impaired intellectual development. The MCM3AP genotype-phenotype correlation and prognosis remain unclear. The aim of this study was to explore the genotype-phenotype correlations pertaining to MCM3AP. Methods: Whole-exome sequencing (WES) combined with copy number variation sequencing (CNV-seq) were performed on the genomic DNA isolated from a Chinese family, and Sanger sequencing, quantitative PCR and cDNA analyses were performed to examine the mutations. The retrospective study was conducted on 28 individuals with biallelic MCM3AP mutation-related diseases, including features such as mutations, motor development impairment, intellectual disability, weakness/atrophy, and cerebral magnetic resonance imaging abnormalities. Results: Sequencing identified novel compound heterozygous mutations in MCM3AP, namely, a paternal variant c.1_5426del (loss of exons 1-25) and a maternal splicing variant c.1858 + 3A>G. Functional studies revealed that the variant c.1858 + 3A>G resulted in the heterozygous deletion of exon 5, thereby affecting splicing functionality. Furthermore, the compound heterozygous mutation may affect the functionality of the protein domain. Retrospective analysis revealed different genotype-phenotype correlations for the pathogenic variants in biallelic MCM3AP: all individuals (100%) with mutations outside the Sac3 domain exhibited early-onset symptoms, motor developmental delays, and cognitive abnormalities, conversely, the proportions of individuals carrying mutations within the domain were 26.7% (motor delays) and 46.7% (cognitive abnormalities). Conclusion: Our findings further expand the genetic mutation spectrum of biallelic MCM3AP and highlight the genotype-phenotype associations. Additionally, we elaborate on the importance of rehabilitation intervention. [ABSTRACT FROM AUTHOR]

Mutating replication-dependent (RD) histone genes is an important tool for understanding chromatin-based epigenetic regulation. Deploying this tool in metazoans is particularly challenging because RD histones in these organisms are typically encoded by many genes, often located at multiple loci. Such gene arrangements make the ability to generate homogenous histone mutant genotypes by site-specific gene editing quite difficult. Drosophila melanogaster provides a solution to this problem because the RD histone genes are organized into a single large tandem array that can be deleted and replaced with transgenes containing mutant histone genes. In the last ∼15 years several different RD histone gene replacement platforms were developed using this simple strategy. However, each platform contains weaknesses that preclude full use of the powerful developmental genetic capabilities available to Drosophila researchers. Here we describe the development of a newly engineered platform that rectifies many of these weaknesses. We used CRISPR to precisely delete the RD histone gene array (HisC), replacing it with a multifunctional cassette that permits site-specific insertion of either one or two synthetic gene arrays using selectable markers. We designed this cassette with the ability to selectively delete each of the integrated gene arrays in specific tissues using site-specific recombinases. We also present a method for rapidly synthesizing histone gene arrays of any genotype using Golden Gate cloning technologies. These improvements facilitate the generation of histone mutant cells in various tissues at different stages of Drosophila development and provide an opportunity to apply forward genetic strategies to interrogate chromatin structure and gene regulation. [ABSTRACT FROM AUTHOR]

Observations of genetically repeated evolution (repeatability) in complex organisms are incongruent with the Fisher–Orr model, which implies that repeated use of the same gene should be rare when mutations are pleiotropic (i.e. affect multiple traits). When spatially divergent selection occurs in the presence of migration, mutations of large effect are more strongly favored, and hence, repeatability is more likely, but it is unclear whether this observation is limited by pleiotropy. Here, we explore this question using individual-based simulations of a two-patch model incorporating multiple quantitative traits governed by mutations with pleiotropic effects. We explore the relationship between fitness trade-offs and repeatability by varying the alignment between mutation effect and spatial variation in trait optima. While repeatability decreases with increasing trait dimensionality, trade-offs in mutation effects on traits do not strongly limit the contribution of a locus of large effect to repeated adaptation, particularly under increased migration. These results suggest that repeatability will be more pronounced for local rather than global adaptation. Whereas pleiotropy limits repeatability in a single-population model, when there is local adaptation with gene flow, repeatability can occur if some loci are able to produce alleles of large effect, even when there are pleiotropic trade-offs. [ABSTRACT FROM AUTHOR]

The elongation of Caenorhabditis elegans embryos allows examination of mechanical interactions between adjacent tissues. Muscle contractions during late elongation induce the remodeling of epidermal circumferential actin filaments through mechanotransduction. Force inputs from the muscles deform circumferential epidermal actin filament, which causes them to be severed, eventually reformed, and shortened. This squeezing force drives embryonic elongation. We investigated the possible role of the nonmuscle myosins NMY-1 and NMY-2 in this process using nmy-1 and nmy-2 thermosensitive alleles. Our findings show these myosins act redundantly in late elongation, since double nmy-2(ts); nmy-1(ts) mutants immediately stop elongation when raised to 25°C. Their inactivation does not reduce muscle activity, as measured from epidermis deformation, suggesting that they are directly involved in the multistep process of epidermal remodeling. Furthermore, NMY-1 and NMY-2 inactivation is reversible when embryos are kept at the nonpermissive temperature for a few hours. However, after longer exposure to 25°C double mutant embryos fail to resume elongation, presumably because NMY-1 was seen to form protein aggregates. We propose that the two C. elegans nonmuscle myosin II act during actin remodeling either to bring severed ends or hold them. [ABSTRACT FROM AUTHOR]

Microcephaly, epilepsy and diabetes syndrome 1 (MEDS1) is a rare autosomal recessive disorder caused by defects in the immediate early response 3 interacting protein 1 (IER3IP1) gene. Only nine cases have been described in the literature. MEDS1 manifests as microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes. A simplified gyral pattern has been described in all cases reported to date. Diagnosis is made by demonstration of specific mutations in the IER3IP1 gene. In this study, we present an additional case of a patient with MEDS1 who was homozygous for the c.53C>T p.(Ala18Val) variant. This case, the first to be reported from Turkey, differs from other cases due to the absence of a typical simplified gyral pattern on early brain magnetic resonance imaging, the late onset of diabetes, and the presence of a new genetic variant. The triad of microcephaly, generalized seizures and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. [ABSTRACT FROM AUTHOR]

Dyshormonogenesis (DG) is the failure of thyroid hormone production due to a defect in thyroid hormonogenesis. Loss-of-function mutations in the thyroglobulin (TG) gene are a cause of DG, leading to gland stimulation by thyroid-stimulating hormone (TSH), resulting in goiter. We report a mitotically active follicular nodule in an 11-year-old female with a novel mutation in the TG gene. The patient had been under follow-up for congenital hypothyroidism (CH) since the neonatal period, and she had normal TSH levels on replacement therapy. Genetic test revealed a novel compound heterogeneous mutation [c.2149C>T (p.R717*) (P.Arg717Ter) / c.5361_5362delCCinsG (p.H1787Qfs*3) (p.His1787GlnfsTer3)] in the TG gene. She underwent total thyroidectomy for a thyroid nodule that was reported as Bethesda IV on fine needle aspiration biopsy (FNAB) and noted as suspicious for noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Pathological examination revealed a 16 mm, well-demarcated follicular nodule with a solid/insular pattern. Mitotic activity and Ki67 proliferation index were unusually high (10 mitoses/mm2 and 10%, respectively). Marked cellular pleomorphism and nuclear atypia are well-known diagnostic pitfalls in patients with dyshormonogenetic goiter. However, high mitotic activity is a feature that is less commonly reported in dyshormonogenetic goiter and may raise suspicion of poorly differentiated carcinoma when observed together with a solid pattern. The absence of signs of invasion, history of CH, and awareness of the presence of mutations compatible with dyshormonogenetic goiter can prevent the overinterpretation of such lesions. The risk of cancer development in the dyshormonogenetic thyroid gland is possible in childhood. The close follow-up is life-saving and prevents morbidities and possible mortality. [ABSTRACT FROM AUTHOR]

Objective: Maturity onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. Methods: MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. Results: A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n= 3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral anti-diabetic treatment. Conclusion: This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only. [ABSTRACT FROM AUTHOR]

Mendelian forms of renin–angiotensin–aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant subset of hypertensive disorders characterized by genetic mutations that disrupt the normal physiological mechanisms of blood pressure regulation. This review focuses on elucidating the germline mutations affecting RAAS pathways that lead to distinct forms of heritable hypertension. By understanding the pathophysiological basis of conditions such as Gordon’s syndrome, Liddle syndrome, congenital adrenal hyperplasia, and familial hyperaldosteronism types, this review aims to highlight the unique clinical features, diagnostic challenges, and therapeutic implications associated with these disorders. Recognizing specific clinical presentations and family histories indicative of monogenic hypertension is crucial for diagnosis, particularly as it often manifests as early-onset hypertension, abnormalities in potassium and blood pH, and occasionally, abnormal sexual development or related syndromes. Therefore, employing a targeted diagnostic approach through next-generation sequencing is essential to pinpoint the responsible genetic mutations, enabling accurate and individualized treatment plans. The critical importance of certain readily available specific channel blockers, such as thiazides or low-dose corticosteroids, in managing these disorders must be emphasized, as they play a key role in preventing serious complications, including cerebrovascular events. As advancements in genetic and molecular sciences continue to evolve, a deeper comprehension of the mechanisms underlying RAAS-related monogenic hypertension promises to revolutionize the management of this complex disorder, offering hope for more effective and individualized treatment options. [ABSTRACT FROM AUTHOR]

Imagawa-Matsumoto syndrome (IMMAS; MIM #618786) is an autosomal dominant syndrome characterized by overgrowth, dysmorphic features, musculoskeletal abnormalities, developmental delay, and intellectual disability. The first case was reported in 2017 and has subsequently been diagnosed in only another 12 patients. We also present the first IMMAS patient from Turkey. A 19-year-old female was admitted to the neurology outpatient clinic due to a behavioral disorder and intellectual disability. Her physical examination revealed macrocephaly and dysmorphic features like a round face, broad forehead, hypertelorism, and variable skeletal anomalies such as flat feet, clinodactyly, and macrocephaly. Cranial magnetic resonance imaging (MRI) showed agenesis of the corpus callosum and polymicrogyria. Chromosomal analysis results were consistent with a normal constitutional female karyotype and microarray analysis showed a de novo 1.5-MB size deletion on the long arm of chromosome 17; band q11.2 encompassing the Polycomb Repressive Complex 2 Subunit (SUZ12 gene, MIM *606245). This report will contribute to the limited information in the literature. [ABSTRACT FROM AUTHOR]

Objective: The phosphoinositide 3-kinase (PI3K) pathway is an important signaling mechanism for cell proliferation and metabolism. Mutations that activate PIK3CA may make cells p110α dependent, but when phosphatase tensin homolog (PTEN) is lost, the p110β isoform of PI3Ks becomes more important. However, the exact mechanism underlying the prevalence of p110s remains unclear. In this study, our aim was to elucidate the processes behind PI3K isoform dependency in a cellular model of embryonic development. Material and Methods: In order to understand PI3K isoform prevalence, mouse embryonic fibroblasts (MEFs) were used and p110β, PTEN and Rac1 activity was modulated using retroviral plasmids. Expression levels and cellular growth were assessed by performing immunoblots and crystal violet assays. Results: The levels of PTEN had only a partial effect on the prevalence of PI3K isoforms in MEFs. The dependency on p110α diminished when PTEN was depleted. Of note, when PTEN expression was repressed, there was no full transition in dependency from one PI3K isoform to the other. Interestingly, the viability of PTEN-depleted MEFs became less dependent on p110α and more dependent on p110β when p110β was overexpressed. Nevertheless, the overexpression of p110β in conjunction with PTEN knock-downs did not result in a complete shift of isoforms in PI3Ks. Finally, we investigated Rac1 activation with a mutant allele and determined a more potent increase in p110β prominence in MEFs. Conclusion: These findings suggest that multiple cellular parameters, including PTEN status, PI3K isoform levels, and Rac1 activity, combine to influence PI3K isoform prevalence, rather than a single determinant. [ABSTRACT FROM AUTHOR]

Background: Recent advancements in advanced non‐small‐cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first‐line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first‐line treatment for KRAS‐mutant NSCLC. Methods: We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression‐free survival (PFS) and overall survival (OS). A random‐effects network meta‐analysis was conducted to perform direct and indirect comparisons among treatment groups. Results: Six RCTs were eligible for inclusion. In the network meta‐analysis for KRAS‐mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22–0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47–0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49–0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34–0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48–0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56–0.92). Regarding OS in wild‐type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50–1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63–0.99). Conclusion: The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS‐mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first‐line treatment. [ABSTRACT FROM AUTHOR]

Objective: It has been shown that clonal mutations occur in hematopoietic stem cells with advancing age and increase the risk of death due to atherosclerotic vascular diseases, similarly to myeloproliferative neoplasms. Endothelial cells (ECs) and hematopoietic stem cells develop from common stem cells called hemangioblasts in the early embryonic period. However, the presence of hemangioblasts in the postnatal period is controversial. In this study, JAK2 gene variants were examined in patients with atherosclerotic carotid disease and without any hematological malignancies. Materials and Methods: Ten consecutive patients (8 men and 2 women) with symptomatic atherosclerotic carotid stenosis were included in this study. ECs (CD31+CD45-) were separated from tissue samples taken by carotid endarterectomy. JAK2 variants were examined in ECs, peripheral blood mononuclear cells, and oral epithelial cells of the patients with next-generation sequencing. Results: The median age of the patients was 74 (range: 58-80) years and the median body mass index value was 24.44 (range: 18.42- 30.85) kg/m2. Smoking history was present in 50%, hypertension in 80%, diabetes in 70%, and ischemic heart disease in 70% of the cases. The JAK2V617F mutation was detected in the peripheral blood mononuclear cells of 3 of the 10 patients, and 2 patients also had the JAK2V617F mutation in their ECs. The JAK2V617F mutation was not found in the oral epithelial cells of any of the patients. Conclusion: In this study, for the first time in the literature, we showed that the JAK2V617F mutation was found somatically in both peripheral blood cells and ECs in patients with atherosclerosis. This finding may support that ECs and hematopoietic cells originate from a common clone or that somatic mutations can be transmitted to ECs by other mechanisms. Examining the molecular and functional changes caused by the JAK2V617F mutation in ECs may help open a new avenue for treating atherosclerosis. [ABSTRACT FROM AUTHOR]

Adenosine deaminase 2 (ADA2) deficiency is an autosomal recessively inherited autoinflammatory disorder caused by loss-of-function mutations in the ADA2 gene. Although the pathogenesis involves the triggering of a proinflammatory cascade due to increased production of inflammatory cytokines such as tumor necrosis factor (TNF)-α and dysregulation of neutrophil extracellular trap formation resulting from an excess accumulation of extracellular adenosine, the pathogenetic mechanism still needs further clarification due to the broad clinical spectrum. In addition to the initially described vasculitis-related symptoms, hematological, immunological, and autoinflammatory symptoms are now well recognized. The diagnosis is made by demonstration of pathogenic variants of ADA2 with biallelic loss of function and identification of low plasma ADA2 catalytic activity. Currently, TNF-α inhibitors are the treatment of choice for controlling vasculitis manifestations and preventing strokes. However, in patients presenting with severe hematologic findings, TNF-α inhibitors are not the treatment of choice and hematopoietic stem cell transplantation has been shown to be successful in selected cases. Recombinant ADA2 protein and gene therapy are promising treatment modalities for the future. In conclusion, ADA2 deficiency has a broad phenotype and should be considered in the differential diagnosis of different clinical situations. In this review, we summarize the disease manifestations of ADA2 deficiency and available treatment options. [ABSTRACT FROM AUTHOR]

Type IV collagen is an integral component of basement membranes. Mutations in COL4A1, one of the key genes encoding Type IV collagen, can result in a variety of diseases. It is clear that a significant proportion of mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. Here, we analyzed exonic mutations and intronic mutations described in the COL4A1 gene using bioinformatics programs and identified candidate mutations that may alter the normal splicing pattern through a minigene system. We identified seven variants that induce splicing alterations by disrupting normal splice sites, creating new ones, or altering splice regulatory elements. These mutations are predicted to impact protein function. Our results help in the correct molecular characterization of variants in COL4A1 and may help develop more personalized treatment options. [ABSTRACT FROM AUTHOR]

Glycogen storage diseases (GSDs) are abnormally inherited glycogen metabolism mainly affecting the liver, muscles, and heart. Deficiency of proteins involved in glycogen metabolism caused by genetic mutations are responsible for different subtype of GSDs. However, there are still some challenges in diagnosing GSD. This study includes 39 suspected GSDs patients from unrelated families in China. Next‐generation sequencing (NGS) was used to investigate the reason for their diseases at the genetic level. Finally, all 39 patients were diagnosed with GSDs, including 20 GSD‐Ia, 4 GSD‐VI, and 15 GSD IX (12 GSD‐IXa patients and 3 GSD‐IXb patients). Thirty‐two mutations in G6PC1, PYGL, PHKA2, and PHKB genes were identified, with 14 of them being novel variants. The pathogenicity of novel variants was classified according to ACMG guildlines and predicted by in slico algorithms. Mutations p.L216L and p.R83H in G6PC1 gene may be the hot spot mutation in Chinese. Hearing impairment is a rare clinical feature of GSD Ia, which has also been observed in our cohort. The severity of GSD VI and IX was indicated by our patients. Close follow‐up should be applied to GSD VI and IX patients. Our findings provided evidence for building the phenotype–genotype of GSDs and expanded the mutation spectrum of related genes. [ABSTRACT FROM AUTHOR]

Undifferentiated gastric carcinoma, characterized by anaplastic cells lacking distinct features of cytological or architectural differentiation, poses diagnostic and therapeutic challenges. Recent studies have suggested an association between this carcinoma and deficiencies in the SWI/SNF complex, particularly mutations in subunits such as SMARCA4. We herein report six cases of SMARCA4-deficient undifferentiated gastric carcinoma with molecular findings, highlighting the rarity and diagnostic pitfalls of this malignancy. Predominantly occurring in males over 50 years, these cases presented with nonspecific symptoms and were often diagnosed at an advanced stage. Histologically, the tumors exhibited a sheet-like growth pattern, reduced or absent epithelial markers, and loss of BRG-1 expression, with molecular analysis confirming SMARCA4 gene mutations. The response to conventional chemotherapy was poor, underscoring the importance of complete surgical resection and the development of alternative treatment modalities. [ABSTRACT FROM AUTHOR]

Leaders' use of directive leadership has been found to increase when they face an unprecedented crisis. However, extant literature has failed to answer how directive leadership functions in this specific situation. Using the return‐to‐work after COVID‐19 lockdown as an example, we drew upon regulatory focus theory and conducted three studies to investigate the temporal effects of directive leadership on followers' regulatory foci and work role performance. In Study 1, we conducted an experience sampling method (ESM) study tracking a sample of 250 employees over 1 week when the COVID‐19 was originally reported in China. In Study 2, we conducted another ESM study on 125 employees over 2 weeks when the Omicron variant was surging in China. Both studies showed that the positive effect of daily directive leadership on followers' work promotion focus was strongest on the first day upon returning to work after lockdowns but decreased over time. In contrast, the positive effect of daily directive leadership on followers' work prevention focus increased throughout our sampling periods and became strongest on the last day. Moreover, our results indicate that daily directive leadership interacts with the elapsed time to influence two forms of work role performance – task proactivity and task proficiency – through the mediating roles of promotion focus and prevention focus, respectively. In Study 3, we conducted a vignette experiment employing a within‐ and between‐subject design on a sample of 171 U.S. participants. The results further supported the moderating role of elapsed time after returning to work in the differential effects of directive leadership on followers' two regulatory foci. [ABSTRACT FROM AUTHOR]

Reproductive biotechnologies can separate concepts of parenthood into genetic, gestational and social dimensions, often leading to a fragmentation of heteronormative kinship models and posing a challenge to historical methods of establishing legal and/or moral parenthood. Using fictional cases, this article will demonstrate that the issues surrounding the intersection of current and emerging reproductive biotechnologies with definitions of parenthood are already leading to confusion regarding social and legal family ties for offspring, which is only expected to increase as new technologies develop. Rather than opposing these new technologies to reassert traditional concepts of the family, however, this article will explore the opportunities that these technologies represent for re‐imagining various culturally cherished values of family‐making in a way that is inclusive of diverse genders, sexualities and cultures. It will consider IVF, gametogenesis, mitochondrial donation, surrogacy, artificial gestation, CRISPR‐Cas9 gene editing, foster care and adoption as some of many possible pathways to parenthood, including for members of the LGBTIAUQ+ community. [ABSTRACT FROM AUTHOR]

Context.--Posttransplant lymphoproliferative disorder (PTLD) remains a significant complication in pediatric patients undergoing solid organ transplant (SOT). The majority involve Epstein-Barr virus (EBV)-driven CD20+ B-cell proliferations, which respond to reduction of immuno-suppression and anti-CD20-directed immunotherapy. Owing to the low overall incidence, prospective studies of pediatric PTLD are scarce, leading to a lack of comprehensive under-standing of this disorder in pediatric populations. This review aims to bridge this knowledge gap by providing a comprehensive analysis of the clinical, morphologic, and molecular genetic features of PTLD in children, adolescents, and young adults after SOT. Objective.--To examine the clinical features, pathogenesis, and classification of pediatric PTLDs after SOT. Data Sources.--Personal experiences and published works in PubMed. Conclusions.--PTLD includes a broad and heterogeneous spectrum of disorders, ranging from nonmalignant lympho- proliferations to lymphomas. While most pediatric PTLDs are EBV+, an increasing number of EBV- PTLDs have been recognized. The pathologic classification of PTLDs has evolved in recent decades, reflecting advancements in understanding the underlying pathobiology. Nevertheless, there remains a great need for further research to elucidate the biology, identify patients at higher risk for aggressive dis-ease, and establish optimal treatment strategies for relapsed/ refractory disease. [ABSTRACT FROM AUTHOR]

Context.--Intraductal papillary neoplasm of the bile duct (IPNB) is classified into types 1 and 2 based on criteria proposed in 2019. Recent studies investigated the clinico-pathologic and molecular features of IPNB, which contributed to a more detailed understanding of this undercharacterized neoplasm. Objective.--To summarize driver gene mutations, radiologic tumor evolution, and a potentially unique pattern of tumor progression in IPNB. Data Sources.--Data were derived from a literature review and personal clinical and research experiences. Conclusions.--In contrast to de novo cholangiocarcinoma, type 1 IPNB often has mutations in APC, CTNNB1, STK11, and GNAS. These molecular features are shared with intraductal papillary mucinous neoplasm of the pancreas; however, the frequencies of individual gene abnormalities differ between these 2 neoplasms. A radiologic review of sequential images suggested that type 1 IPNB is a slow-growing neoplasm, with an ~1-cm increase in size every 2 to 3 years, and remains in a noninvasive state for many years. A similar papillary neoplasm may develop in the biliary tree years after the complete surgical resection of IPNB. The second neoplasm has the same genetic abnormalities as the first neoplasm, indicating intrabiliary implantation rather than multifocal lesions. In contrast to type 1 IPNB, most cases of type 2 IPNB have invasive malignancy at the initial presentation. Type 2 IPNB shares many clinicopathologic and molecular features with de novo cholangiocarcinoma, questioning the distinctness of this tumor entity. The molecular mechanisms underlying malignant transformation in IPNB warrant further study. [ABSTRACT FROM AUTHOR]

Context.--Pancreatic neuroendocrine neoplasms (Pan- NENs) represent a heterogeneous group of epithelial tumors of the pancreas showing neuroendocrine differentiation. These neoplasms are classified into well-differentiated pancreatic neuroendocrine tumors (PanNETs), which include G1, G2, and G3 tumors, and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs), which are G3 by definition. This classification mirrors clinical, histologic, and behavioral differences and is also supported by robust molecular evidence. Objective.--To summarize and discuss the state of the art regarding neoplastic progression of PanNENs. A better comprehension of the mechanisms underpinning neoplas- tic evolution and progression of these neoplasms may open new horizons for expanding biologic knowledge and ultimately for addressing new therapeutic strategies for patients with PanNENs. Data Sources.--Literature review of published studies and the authors' own work. Conclusions.--PanNETs can be seen as a unique category, where G1-G2 tumors may progress to G3 tumors mainly driven by DAXX/ATRX mutations and alternative lengthening of telomeres. Conversely, PanNECs display totally different histomolecular features more closely related to pancreatic ductal adenocarcinoma, including TP53 and Rb alterations. They seem to derive from a nonneuroendocrine cell of origin. Even the study of PanNEN precursor lesions corroborates the rationale of considering PanNETs and PanNECs as separate and distinct entities. Improving the knowledge regarding this dichotomous distinction, which guides tumor evolution and progression, will represent a critical basis for PanNEN precision oncology. [ABSTRACT FROM AUTHOR]

Context.--There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature. Objectives.--To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with a and b human papillomavirus (a-HPV and b-HPV) genotypes, and describe relevant underlying genetic mutations. Design.--Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed. Results.--Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both a-HPVs and b-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found. Conclusions.--We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with a-HPV and b-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status. [ABSTRACT FROM AUTHOR]

Context.--Macroscopic precursor lesions of the pancreas represent a complex clinical management problem. Molecular characterization of pancreatic cysts has helped to confirm and refine clinical and pathologic classifications of these lesions, inform our understanding of tumorigenesis in the pancreas, and provide opportunities for preoperative diagnosis. Objective.--To review the pathologic classification of macroscopic cystic lesions of the pancreas: intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), intraductal oncocytic papillary neoplasms (IOPNs), and intraductal tubulopapillary neoplasms (ITPNs), and to describe our current state of understanding of their molecular underpinnings, relationship to invasive carcinomas, and implications for diagnosis and prognostication. Data Sources.--We assessed the current primary literature and current World Health Organization Classification of Digestive System Tumours. Conclusions.--Macroscopic cystic lesions of the pancreas are morphologically and molecularly diverse. IPMNs and MCNs share mucinous cytoplasm with papillae. MCNs are defined by ovarian-type stroma. IOPNs have granular eosinophilic cytoplasm, prominent nucleoli, and complex, arborizing papillae. ITPNs demonstrate complex, back-to-back tubules and anastomosing papillae and lack prominent intracellular mucin. IPMNs and MCNs are characterized by driver mutations in KRAS/GNAS (IPMNs) and KRAS (MCNs), with later driver events in RNF43, CDKN2A, SMAD4, and TP53. In contrast, IOPNs and ITPNs have recurrent rearrangements in PRKACA/PRKACB and MAPK-associated genes, respectively. The recurrent alterations described in cysts provide an opportunity for diagnosis using aspirated cyst fluid. Molecular characterization of IPMNs shows a striking spatial and mutational heterogeneity, challenging traditional models of neoplastic development and creating challenges to interpretation of cyst fluid sequencing results. [ABSTRACT FROM AUTHOR]

Background The activity of PARP inhibitors (PARPi) in patients with homologous recombination repair (HRR) mutations and metastatic castration-resistant prostate cancer has been established. We hypothesized that the benefit of PARPi can be maintained in the absence of androgen deprivation therapy (ADT) in an HRR-mutated population. We report the results of a phase II clinical trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Methods This was a multi-center, single-arm phase II trial (NCT03413995) for patients with asymptomatic, mHSPC. Patients were required to have a pathogenic germline mutation in an HRR gene for eligibility. All patients received rucaparib 600 mg by mouth twice daily, without androgen deprivation. The primary endpoint was a confirmed PSA50 response rate. Results Twelve patients were enrolled, 7 with a BRCA1/2 mutation and 5 with a CHEK2 mutation. The confirmed PSA50 response rate to rucaparib was 41.7% (N = 5/12, 95% CI: 15.2-72.3%, one-sided P  = .81 against the 50% null), which did not meet the pre-specified efficacy boundary to enroll additional patients. In patients with measurable disease, the objective response rate was 60% (N = 3/5), all with a BRCA2 mutation. The median radiographic progression-free survival on rucaparib was estimated at 12.0 months (95% CI: 8.0-NR months). The majority of adverse events were grade ≤2, and expected. Conclusion Rucaparib can induce clinical responses in a biomarker-selected metastatic prostate cancer population without concurrent ADT. However, the pre-specified efficacy threshold was not met, and enrolment was truncated. Although durable responses were observed in a subset of patients, further study of PARPi treatment without ADT in mHSPC is unlikely to change clinical practice. [ABSTRACT FROM AUTHOR]

Glioblastoma, the most common malignant brain tumor in adults, is associated with a median overall survival duration of less than 2 years. Extraneural metastases occur in less than 1% of all patients with glioblastoma. The mechanism of extraneural metastasis is unclear. We present a case of extensive extraneural, extraosseous, epidural, and soft-tissue metastasis of glioblastoma. The diagnosis of metastatic glioblastoma was made only after next-generation sequencing (NGS) of the metastatic paraspinal lesions was completed. The CDK4, pTERT, PTEN, and TP53 molecular alterations seen in the initial intracranial glioblastoma were found in the paraspinal tumor, along with the addition of MYC, which is implicated in angiogenesis and epidermal-to-mesenchymal transition. Immunohistochemical stains showed that neoplastic cells were negative for GFAP. In conclusion, this case raises awareness about the role of NGS in the diagnosis of extraneural glioblastoma. This diagnosis was not possible with histology alone and only became evident after molecular profiling of the metastatic lesions and its comparison to the original tumor. [ABSTRACT FROM AUTHOR]

Background The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. Materials and Methods This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. Results Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. Conclusion Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care. [ABSTRACT FROM AUTHOR]

Background Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF , NRAS , or CKIT targeting, has rarely been reported. Materials and Methods By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF , NRAS , or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Results We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11 , MAP2K1 , FYCO1-RAF1 , HRAS , ATM , CCND1 , MDM2/CDK4 , and CDKN2A/NRAS alterations. Conclusions High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments. [ABSTRACT FROM AUTHOR]

Introduction Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. Methods De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. Results Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n  = 217). Copy number loss was the most common genomic alteration (64%, n  = 138) of POLE/POLD1, followed by copy number amplifications (18%, n  = 40) and short variant mutations (18%, n  = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2 , and RET mutations. Conclusion Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Current treatment guidelines for patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (mNSCLC) recommend EGFR tyrosine kinase inhibitors (TKIs) as the standard of care for first-line treatment, with third-generation osimertinib the preferred choice. However, most patients develop resistance to targeted therapy, and subsequent systemic chemotherapy is recommended. The aim of this study was to characterize the subsequent line of therapy (LOT) following osimertinib in patients with EGFR-mNSCLC. Methods: Medical and pharmacy claims of adults who initiated a subsequent LOT (index) after initial osimertinib discontinuation between November 2015 and September 2019 were analyzed retrospectively. Results: A total of 135 patients met the inclusion criteria. After metastatic diagnosis, 22.2% and 49.6% of patients were treated with osimertinib in the first and second line, respectively. After osimertinib discontinuation, most patients were treated with a platinum-based chemotherapy regimen (57%), of which 40.3% included immuno-oncology therapy. Reuse or continuation of EGFR TKIs was also common (24%). Overall, the median time to treatment discontinuation for the index LOT was 2.4 months. Proportions of patients with ≥ 1 inpatient or emergency department visit were 31.9% and 35.6%, respectively. Conclusions: The duration of the LOT following osimertinib was short and associated with tolerability issues underscoring a high unmet need for new therapies to address EGFR TKI resistance. [ABSTRACT FROM AUTHOR]

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Tumor‐agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor‐agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability‐high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor‐agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody‐drug conjugate (Her2‐positive–immunohistochemistry 3+ expression) with pan‐cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue‐agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide and is a known etiological agent of hepatocellular carcinoma (HCC). The molecular mechanisms of HCV-mediated carcinogenesis are not fully understood. This review article focuses on the oncogenic potential of NS3, a viral protein with transformative effects on cells, although the precise mechanisms remain elusive. Unlike the more extensively studied Core and NS5A proteins, NS3's roles in cancer development are less defined but critical. Research indicates that NS3 is implicated in several carcinogenic processes such as proliferative signaling, cell death resistance, genomic instability and mutations, invasion and metastasis, tumor-related inflammation, immune evasion, and replicative immortality. Understanding the direct impact of viral proteins such as NS3 on cellular transformation is crucial for elucidating HCV's role in HCC development. Overall, this review sheds light on the molecular mechanisms used by NS3 to contribute to hepatocarcinogenesis, and highlights its significance in the context of HCV-associated HCC, underscoring the need for further investigation into its specific molecular and cellular actions. [ABSTRACT FROM AUTHOR]

WhatIs Known and Objective. Anti‐EGFR (epidermal growth factor receptor) drugs are indicated for non‐small‐cell lung cancer (NSCLC). This review summarises the information available to date on the first anti‐EGFRs granted market authorisation: erlotinib TARCEVA®, gefitinib IRESSA®, afatinib GIOTRIF®, dacomitinib VIZIMPRO®, and osimertinib TAGRISSO®. Methods. A literature search was conducted in the PubMed database including studies published in English using the terms gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. Furthermore, bibliographies of selected references were also studied for relevant articles. Clinical trial (CT) data were extracted from clinicaltrials.gov (ongoing trials and adverse events (AEs)). Assessment of AEs for these drugs was conducted using global pharmacovigilance data from VigiBase®. Results and Discussion. Erlotinib and gefitinib are first‐generation anti‐EGFR drugs, able to bind competitively and reversibly to the ATP‐ (adenosine triphosphate‐) binding site of the EGFR exon 19 and exon 21 mutations. Afatinib and dacomitinib are second‐generation anti‐EGFRs able to bind covalently and irreversibly to the ATP site and inhibit EGFR and HER (human epidermal growth factor receptor) such as HER2 and HER4 enzyme activity. Osimertinib is a third‐generation PKI and overcomes the EGFR T790M gatekeeper mutation through covalent binding at the ATP site. Medical interactions with these drugs are reported, notably with cytochrome P450 inducers or inhibitors. The most reported AEs in CTs are cutaneous reactions and gastrointestinal disorders. The occurrence of cutaneous reactions is less reported with third generation than with first‐ and second‐generation anti‐EGFR drugs. These results are consistent with the results from the VigiBase® global pharmacovigilance database. What Is New and Conclusion. This review summarises current knowledge regarding five anti‐EGFRs in the literature. The third‐generation anti‐EGFR appears to be more effective than the first and second generations and is indicated as first‐line therapy. This trial is registered with NCT01523587, NCT01466660, NCT01774721, NCT01360554, and NCT02296125. [ABSTRACT FROM AUTHOR]

Background: The respiratory chain plays a key role in the growth of Mycobacterium tuberculosis complex (MTBC). However, the exact regulatory mechanisms of this system still need to be elucidated, and only a few studies have investigated the impact of genetic mutations within the respiratory chain on MTBC transmission. This study aims to explore the impact of respiratory chain gene mutations on the global spread of MTBC. Results: A total of 13,402 isolates of MTBC were included in this study. The majority of the isolates (n = 6,382, 47.62%) belonged to lineage 4, followed by lineage 2 (n = 5,123, 38.23%). Our findings revealed significant associations between Single Nucleotide Polymorphisms (SNPs) of specific genes and transmission clusters. These SNPs include Rv0087 (hycE, G178T), Rv1307 (atpH, C650T), Rv2195 (qcrA, G181C), Rv2196 (qcrB, G1250T), Rv3145 (nuoA, C35T), Rv3149 (nuoE, G121C), Rv3150 (nuoF, G700A), Rv3151 (nuoG, A1810G), Rv3152 (nuoH, G493A), and Rv3157 (nuoM, A1243G). Furthermore, our results showed that the SNPs of atpH C73G, atpA G271C, qcrA G181C, nuoJ G115A, nuoM G772A, and nuoN G1084T were positively correlated with cross-country transmission clades and cross-regional transmission clades. Conclusions: Our study uncovered an association between mutations in respiratory chain genes and the transmission of MTBC. This important finding provides new insights for future research and will help to further explore new mechanisms of MTBC pathogenicity. By uncovering this association, we gain a more complete understanding of the processes by which MTBC increases virulence and spread, providing potential targets and strategies for preventing and treating tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Fear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population. Objectives: This cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options. Method: Participants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables. Results: A total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery. Conclusion: These data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR. [ABSTRACT FROM AUTHOR]

Preimplantation genetic testing (PGT) can minimize the risk of birth defects. However, the accuracy and applicability of routine PGT is confounded by uneven genome coverage and high allele drop‐out rate from existing single‐cell whole genome amplification methods. Here, a method to diagnose genetic mutations and concurrently evaluate embryo competence by leveraging the abundant mRNA transcript copies present in trophectoderm cells is developed. The feasibility of the method is confirmed with 19 donated blastocysts. Next, the method is applied to 82 embryos from 26 families with monogenic defects for simultaneous mutation detection and competence assessment. The accuracy rate of direct mutation detection is up to 95%, which is significantly higher than DNA‐based method. Meanwhile, this approach correctly predicted seven out of eight (87.5%) embryos that failed to implant. Of six embryos that are predicted to implant successfully, four met such expectations (66.7%). Notably, this method is superior at conditions for mutation detection that are challenging when using DNA‐based PGT, such as when detecting pathogenic genes with a high de novo rate, multiple pseudogenes, or an abnormal expansion of CAG trinucleotide repeats. Taken together, this study establishes the feasibility of an RNA‐based PGT that is also informative for assessing implantation competence. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of thyroid nodules and malignancies in the elderly is a growing concern. Thyroid nodules in this population have unique characteristics, requiring careful treatment strategies that balance risks and benefits. Oncocytic carcinoma of the thyroid (OCA) is a rare, aggressive subtype with diagnostic challenges. Methods: This case features an 84-year-old patient who presented with a neck mass and symptoms of asphyxia. Clinical evaluation, imaging studies, and biopsy were conducted to assess the nature of the thyroid lesion. Molecular testing, including genetic analysis, was performed to identify specific mutations associated with OCA and guide treatment decisions. Results: The patient was diagnosed with oncocytic carcinoma of the thyroid. The molecular testing revealed specific genetic mutations indicative of OCA, confirming the diagnosis. The presence of these mutations guided the treatment plan, emphasizing the importance of molecular diagnostics in managing thyroid malignancies, especially in the elderly. Discussion: This case illustrates the complexities of diagnosing and treating thyroid malignancies in the elderly. Biopsy and molecular testing provided diagnostic accuracy and informed treatment. Individualized approaches are essential for better outcomes, especially in aggressive subtypes, balancing the risks and benefits of intervention. [ABSTRACT FROM AUTHOR]

Previous studies have modified rice's resistant starch (RS) content by mutating single and double genes. These mutations include knocking out or reducing the expression of sbe1 or sbe2b genes, as well as overexpressing Wxa. However, the impact of triple mutant sbe2b/sbe1/OE-Wxa on RS contents remained unknown. Here, we constructed a double mutant with sbe2b/RNAi-sbe1, based on IR36ae with sbe2b, and a triple mutant with sbe2b/RNAi-sbe1/OE-Wxa, based on the double mutant. The results showed that the amylose and RS contents gradually increased with an increase in the number of mutated genes. The triple mutant exhibited the highest amylose and RS contents, with 41.92% and 4.63%, respectively, which were 2- and 5-fold higher than those of the wild type, which had 22.19% and 0.86%, respectively. All three mutants altered chain length and starch composition compared to the wild type. However, there was minimal difference observed among the mutants. The Wxa gene contributed to the improvement of 1000-grain weight and seed-setting rate, in addition to the highest amylose and RS contents. Thus, our study offers valuable insight for breeding rice cultivars with a higher RS content and yields. [ABSTRACT FROM AUTHOR]

Background: Fosphenytoin (FOS) is a prodrug of phenytoin (PHT) with a metabolism that exhibits Michaelis–Menten-type kinetics. Genetic polymorphisms of the metabolic enzymes of PHT make it challenging to predict its plasma concentrations. High plasma PHT concentrations are typically problematic, and several causes have been elucidated. In contrast, cases of patients with low PHT plasma concentrations that did not increase despite the administration of appropriate PHT doses have been reported, and the causes may include changes in plasma protein-binding rates, genetic mutations, and concomitant use of drugs that induce liver enzymes; however, even these factors do not explain the low PHT plasma concentrations in some cases. Case presentation: We encountered the case of a patient with plasma PHT concentrations that were continuously < 0.7 µg/mL after daily use of FOS for seizures that occurred after cardiopulmonary arrest. We analyzed the protein-unbound fraction, urinary metabolites, and related genes to investigate the cause. False negatives due to the measurement method, errors in dosage and administration method, and increased excretion of PHT were excluded. Hepatic metabolic activity of PHT increased to 4.6–6.1 times the normal level. The S/R ratio of 5-(p-hydroxyphenyl)-5-phenylhydantoin-glucuronide, a major PHT metabolite, was normal at 15.2, suggesting increased activities of CYP2C9 and CYP2C19. Furthermore, the protein-unbound fraction of PHT was 5.2–6.9%, CYP2C19*17 was wild type, and there was no concomitant drug use to induce both enzymes. Conclusions: The low PHT plasma concentration in this patient was found to be caused by increased hepatic metabolic activity that could not be explained by known factors. Careful monitoring is necessary to consider the possibility of increased hepatic metabolic activity in similar cases. [ABSTRACT FROM AUTHOR]

The speciation of Salmonella occurred by acquisition of genomic islands from other bacterial species and continued to diverge into subspecies and serovars with diferent range of host. S. enterica serovar Typhimurium (STM) is a generalist pathogen infecting hosts that include birds, mice, and humans, whilst S. enterica serovar Typhi (STY) is a restricted-host pathogen, infecting only humans. Despite their ranges of hosts, STM and STY possess 97-98% identity. Gain of genes by horizontal transference and loss of genes by mutations, are believed essential for differentiation of Salmonella. Salmonella pathogenicity island 3 (SPI-3) is an example combining these two processes. SPI-3 encodes misL and marT, among other genes. In STM, misL is required for gut colonization. Furthermore, protein MarT, positively regulates expression of misL by binding to misL-promoter. On the other hand, in SPI-3 of STY, marT and misL are pseudogenes. Interestingly, the gene t3766 (gene involved in resistance to H2O2) is present only in STY and is negatively regulated when marTSTM is heterologously expressed in STY. Based on the view that MarT might regulate genes implicated in virulence, this work searched for new genes regulated by MarT. In silico searches for possible MarT target genes were performed, and 4 genes were selected for further analysis as they contained at least 2 copies of the consensus MarT-binding sequence in their promoters. Mutating marT in STM or heterologously expressing marTSTM in STY confirmed that MarT negatively regulates ORF STY1408 or STM14_2003, its homologue in STM. STY1408 encodes for a putative protein with homology to methyl accepting chemotaxis proteins, which participate in chemotaxis and motility. Therefore, STY1408 was named mrmI (MarT-regulated motility gene I). Motility assays confirmed that the product of mrmI modulates motility. In addition, in vitro infection of cells with STM and STY mutants in mrmI reduces association with cells at 1, 3 and 24 h post-infection. Oral infection of mice showed that a mrmI null mutant was defective in producing systemic disease. Therefore, we conclude that MarT regulated mrmI, is involved in virulence of Salmonella. While pseudogenization of marT might modulate the fitness of narrow host range STY. [ABSTRACT FROM AUTHOR]

Introduction: VEXAS syndrome, characterized by a UBA1 gene mutation, is a rare and severe systemic inflammatory disease predominantly affecting men. Since its initial description in 2020, it has been noted for its broad clinical phenotype and frequent misdiagnosis. Case Presentation: A 76-year-old Caucasian male patient diagnosed with VEXAS syndrome is presented in this case report. He presented with typical symptoms including pulmonary manifestations (infiltrates and effusions), systemic inflammation, and haematological abnormalities. The diagnosis was challenging due to the disease's heterogeneous presentation, often resembling autoimmune or haematological diseases. This patient's case featured ground-glass opacities and pleural effusions, underlining the significant pulmonary involvement seen in 50–67% of VEXAS patients. His condition was further complicated by recurrent fever and systemic inflammation affecting multiple organs. Conclusion: VEXAS syndrome demands an aggressive treatment approach due to its high mortality rate and refractory nature. This case underscores the importance of including VEXAS syndrome in differential diagnoses, particularly for patients with systemic inflammation and pulmonary symptoms, and calls for multidisciplinary management and extensive research to understand its full range of clinical phenotypes. Established facts and novel insights: VEXAS syndrome is a rare systemic inflammatory disease with UBA1 gene mutation. VEXAS syndrome involves various UBA 1 gene mutations, including the p.splice c.118-1G > C. It mainly affects men, often misdiagnosed due to its broad clinical phenotype. Novel insights: Significant pulmonary involvement in VEXAS, including ground-glass opacities and pleural effusions. Patients with the same mutation exhibit a broad range of disease phenotypes A specific UBA1 mutation as the p.splice c.118-1G > C cannot be directly linked to a distinct disease phenotype Need for aggressive treatment strategies targeting the mutated clone and cytokine storms [ABSTRACT FROM AUTHOR]

Introduction: Antimicrobial resistance in Mycobacterium tuberculosis (MTB) poses a significant challenge to tuberculosis (TB) management worldwide. Rifampicin resistance (RR) has been associated with the rpoB gene mutation. No study was conducted in Tanzania to determine the commonest mutation. The inconsistent findings from various studies support the need to determine whether reported mutation patterns are applicable in our setting. We determined the frequency of rpoB gene mutation and factors associated with RR, which were detected using GeneXpert MTB/RIF assay. Methods: We conducted a retrospective cross-sectional study involving data from the National Tuberculosis and Leprosy Program database from 2020 to 2022 for cases investigated using GeneXpert MTB/RIF assay. Descriptive analysis was performed to determine the frequency of categorical variables. The chi-square test and logistic regression analysis assessed the relationship between the independent variables and outcome. The 95% confidence interval and a significance level of p<0.05 were used to assess the strength of association. Results: A total of 56,004 participants had a status of MTB and RR, where 38,705/56,004 (69.11%) were males. Probe E mutation (codon 529–533), 89/219 (40.64%) was predominant. Human immunodeficiency virus (HIV)-positive patients had a higher gene mutation, 134/10601 (1.26%) than HIV-negative, 306/45016 (0.68%) (p<0.001). Patients with both pulmonary and extra-pulmonary TB had about four times greater odds of developing rifampicin resistance (AOR 3.88, 95%CI: 1.80–8.32). RR was nearly nine times higher in previously treated patients than new patients (AOR 8.66, 95% CI: 6.97–10.76). HIV-positive individuals had nearly twice the odds of developing RR than HIV-negative individuals (AOR 1.91, 95%CI: 1.51–2.42). Conclusion: The rate of RR was lower compared to other studies in Tanzania, with probe E mutations the most prevalent. Patients with disseminated TB, HIV co-infection and those with prior exposure to anti-TB had more risk of RR. The findings highlight the need to strengthen surveillance of multidrug-resistant TB among high risk patients. [ABSTRACT FROM AUTHOR]