Pulmonary vascular malformations (PVMs) are vascular complications that universally develop in patients with single ventricle congenital heart disease after Glenn surgery, yet the pathogenesis of single ventricle PVMs remains unknown. Using a surgical rat model of Glenn circulation, single-cell RNA sequencing (scRNAseq) on whole lung samples identified dramatic endothelial cell (EC) gene expression changes post-surgery, including decreased all-trans retinoic acid (ATRA) signaling. Many gene expression differences (∼17% of all EC differentially expressed genes), including decreased ATRA signaling, were shared with 2 independent models of hereditary hemorrhagic telangiectasia arteriovenous malformations (AVMs). Subsequent dietary modification of vitamin A (Vit A) intake in rats, identified that dietary deficiency of Vit A increased PVM shunting severity, which was mitigated with excess dietary Vit A intake. Collectively, our study of post-Glenn PVMs identified shared patho-mechanisms with hereditary hemorrhagic telangiectasia AVMs, including decreased EC ATRA signaling, which is a novel potential target for treating AVMs.

Intracellular microorganisms are widespread and housed within specialized host cells called bacteriocytes in many invertebrates. Although increasing attention has been devoted to understanding bacteriocyte development, differentiation, and proliferation, the molecular mechanisms that maintain these cells remain poorly understood. We previously showed that the transcription factor Adf-1 suppresses bacteriocyte cell death in whiteflies. Here, DNA affinity purification sequencing identified Adf-1 target genes involved in diverse cellular processes and revealed the DNA damage response kinase ataxia telangiectasia and Rad3-related (ATR) as a direct transcriptional target. Dual-luciferase reporter assays and RNA interference confirmed that Adf-1 binds the ATR promoter and positively regulates its expression in bacteriocytes, where ATR is highly expressed. Consistent with this regulatory relationship, silencing either Adf-1 or ATR increased DNA damage in bacteriocytes. ATR knockdown further promoted apoptosis and autophagy, reduced the proportion of dividing bacteriocytes, decreased bacteriocyte abundance, and lowered symbiont titers in whiteflies. In addition, yeast two-hybrid assays identified an interaction between Adf-1 and the ATP-dependent DNA helicase RecQ1, although RecQ1 silencing had no detectable effect on bacteriocyte abundance. Together, our findings demonstrate that Adf-1 preserves bacteriocyte homeostasis by promoting DNA damage repair through transcriptional activation of ATR. Given that bacteriocytes are exposed to persistent genotoxic stress associated with polyploidy and high metabolic activity, this work identifies DNA damage control as a key mechanism underlying bacteriocyte maintenance and symbiosis stability, and suggests that this pathway may represent a conserved feature of bacteriocyte biology.

Ataxia-telangiectasia (ATX-ATM) is a rare multisystem disorder caused by pathogenic variants in the ataxia-telangiectasia mutated (ATM) gene. The classic phenotype is characterized by childhood-onset progressive cerebellar ataxia and movement disorders, accompanied by telangiectasias, primary immunodeficiency, chronic pulmonary disease, endocrine abnormalities, and increased sensitivity to ionizing radiation, as well as a markedly elevated risk of malignancy. In contrast, variant ATX-ATM is associated with a milder and more heterogeneous phenotype, in which cerebellar ataxia may be absent, while dystonia and axonal sensorimotor neuropathy are common; immune and respiratory function are typically preserved, although the risk of malignancy remains increased. We report a 39-year-old man presenting with progressive ataxia, chorea, and telangiectasias, with two siblings exhibiting a similar phenotype. Notably, one sibling developed diffuse gastric adenocarcinoma and cutaneous melanoma, whereas his sister died from ovarian and colon cancer. Whole-exome sequencing identified compound heterozygous variants in the ATM gene in the two affected siblings: a pathogenic splice-site variant, c.2921 + 1G > A, and a heterozygous missense variant of uncertain significance, c.8083G > A; p.(Gly2695Ser). Segregation analysis confirmed that these variants were in trans, supporting the identification of a rare ATM variant associated with ATX-ATM in this family. The diagnosis of variant ATX-ATM remains challenging because of its marked phenotypic heterogeneity. Nevertheless, early recognition is essential given the substantially increased risk of malignancy and the need for appropriate oncologic surveillance and genetic counseling. The identification and reporting of ATM variants contribute to improved genotype-phenotype correlations and broaden the current understanding of disease variability.

The dual role of base excision repair (BER) in resolving DNA base lesions and enabling active DNA demethylation positions BER proteins as central regulators of both genetic and epigenetic integrity. While BER and active demethylation converge at the generation of AP sites, catalyzed by DNA glycosylases such as thymine DNA glycosylase (TDG), the relative contribution of each pathway to AP site formation and the cellular fate of these lesions remain unresolved. Using APE1-deficient mouse embryonic stem cells (mESCs), with inducible TDG depletion, we reveal that TDG activity accounts for a substantial fraction of AP sites in mESCs, establishing a direct link between active DNA demethylation and APE1-mediated BER. We demonstrate that APE1 is essential for mESC differentiation, underscoring its role in processing AP sites generated during epigenetic reprogramming. Through a genome-wide CRISPR/Cas9 screen designed to map the broader functional interactome of APE1, we identified unexpected genetic dependencies that extend beyond DNA repair. We also found that DNA double-strand break repair factors act outside their canonical pathways, cooperating with nucleotide excision repair and translesion synthesis to compensate for the loss of APE1. These findings highlight novel compensatory DNA end-processing mechanisms that safeguard genomic integrity in the absence of APE1, revealing a high level of plasticity of DNA repair in mESCs.

Macular telangiectasia type 2 (MacTel), a bilateral, neurodegenerative disease associated with photoreceptor loss, often leads to progressive scotomas, metamorphopsia, and impaired reading function. Revakinagene taroretcel-lwey, a Food and Drug Administration (FDA)-approved encapsulated cell-based therapy for adults with MacTel, is surgically inserted into the vitreous cavity and provides sustained intraocular delivery of recombinant human ciliary neurotrophic factor (CNTF). Results from two phase 3 randomized clinical trials support the efficacy and safety of revakinagene taroretcel-lwey; explant analyses have demonstrated bioactive CNTF release up to 14.5 years. This report summarizes the surgical procedure and techniques for revakinagene taroretcel-lwey implantation, including implant preparation, insertion, wound closure, and postoperative procedures, and highlights scenarios where expert guidance may help to prevent intraoperative errors and minimize the potential for postsurgical adverse events. Standardizing surgical steps and incorporating expert guidance into surgical technique may reduce adverse events, including migration and extrusion, wound leaks, and infections, supporting safe long-term CNTF delivery for treatment of MacTel.

Background Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, multisystem vascular disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). Pathogenic variants in ENG (endoglin), ACVRL1 (activin receptor-like kinase 1, ALK1), and SMAD4 (SMAD family member 4) disrupt signaling in the bone morphogenetic protein (BMP) 9/10 and transforming growth factor-beta (TGF-β) pathways, resulting in dysregulated angiogenesis and excess vascular endothelial growth factor (VEGF) activity. Clinically, HHT most commonly presents with recurrent epistaxis and chronic gastrointestinal (GI) bleeding, frequently leading to iron deficiency anemia and reduced quality of life (QoL). Complications from visceral AVMs involving the lungs, brain, and liver may also occur. Early diagnosis and systematic screening are essential to reduce preventable morbidity. Methods This narrative review synthesizes current primary literature on the diagnosis, screening, and treatment of HHT, with particular emphasis on evolving systemic therapies, supportive care strategies, and procedural interventions. Evidence from international guidelines, randomized trials, observational cohort studies, and narrowly focused systematic reviews was evaluated to summarize contemporary management approaches. Results HHT diagnosis is made with the Curaçao clinical criteria, genetic testing, and targeted imaging to identify visceral vascular malformations. Screening recommendations emphasize early detection of pulmonary and cerebral AVMs and ongoing surveillance for anemia and other complications. Therapeutic strategies increasingly prioritize systemic therapy over repeated local procedures. Antiangiogenic agents including intravenous bevacizumab, pomalidomide, thalidomide, and oral pazopanib have demonstrated efficacy in reducing bleeding severity, improving hemoglobin levels, and decreasing transfusion requirements in moderate-to-severe disease. Supportive care remains foundational and includes iron replacement, selective blood transfusion, routine monitoring, and assessment of patient-reported QoL. In patients with refractory epistaxis, surgical interventions such as septodermoplasty or nasal closure may provide durable bleeding control. Endovascular and neurosurgical management may also be required for selected vascular complications. Conclusions Management of HHT is undergoing a paradigm shift toward mechanism-based systemic therapy integrated with multidisciplinary care. Advances in antiangiogenic and precision-medicine approaches are improving bleeding control and long-term outcomes. Early recognition, comprehensive screening, individualized therapy, and coordinated management across specialties are critical for optimizing care in this complex multisystem disease.

Replication stress, defined as impaired DNA replication leading to genomic instability, is a central feature of tumour development and progression. In cancer cells, it arises from oncogene activation, transcription-replication conflicts, altered nucleotide metabolism and DNA secondary structures that hinder DNA synthesis. These pressures compromise accurate genome duplication and promote chromosomal instability and mutagenesis. Recent advances have clarified the molecular mechanisms that stabilize, remodel and restart stressed replication forks, and highlighted the essential role of the ataxia telangiectasia and Rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway in preventing excessive single-stranded DNA accumulation and catastrophic genome fragmentation. Although replication stress fuels tumour evolution and heterogeneity, it also creates dependencies on replication stress response pathways that can be therapeutically exploited. Inhibitors targeting ATR, CHK1 and WEE1 kinases, which override the G2 checkpoint, are in clinical development, whereas synthetic lethal strategies, including poly(ADP-ribose) polymerase (PARP) inhibition in BRCA1-deficient or BRCA2-deficient tumours and inhibition of the DNA helicase WRN in microsatellite-unstable cancers, illustrate how replication stress-associated vulnerabilities can be targeted. In this Review, we position replication stress as both a driver of cancer genome evolution and a tractable framework for precision oncology. We emphasize that replication stress in tumours is often chronic and sublethal, shaping genome evolution. We further highlight its integration with oncogenic and metabolic alterations and broader impact on tumour-microenvironment interactions, which create dynamic and context-dependent therapeutic vulnerabilities.

Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.

Rosacea is a chronic central face dermatosis caused by a combination of dysregulated innate and adaptive immunity and hyperreactive cutaneous neurovasculature. Although classically associated with lighter skin phototypes, rosacea may affect up to 2-4% of Black, Asian, Pacific Islander, and Hispanic/Latino American populations and its prevalence is likely underestimated given our current diagnostic reliance on phenotypic expression (e.g., fixed erythema with or without intermittent exacerbations, flushing, and/or telangiectasias) that may be difficult to appreciate in more heavily pigmented skin. In patients with richly pigmented skin, a careful history of symptoms to assess the minor/secondary criteria (i.e., burning or stinging, edema, dryness, flushing, low tolerance for over-the-counter products, symptoms with classic 'triggers', family history and/or ocular symptoms), along with patient participation during the physical exam to establish their baseline skin tone, may facilitate diagnosis. Rosacea treatment regimens are centered around presentation and can include over-the-counter agents, lifestyle modifications, prescription topical, systemic, and procedural therapies. Optimal regimens may be tailored to best address patient-perceived disease severity and concerns and to minimize any further irritation/inflammation which may drive pigmentary alteration.

Juvenile polyposis syndrome (JPS) is a rare autosomal-dominant disorder characterized by the presence of multiple hamartomatous polyps in the gastrointestinal tract. JPS has been established to be attributable to SMAD4 mutations, which are frequently associated with severe gastric phenotypes and hereditary hemorrhagic telangiectasia. We report the case of a 39-year-old woman with a history of immature teratoma, who presented with persistent anemia and upper gastrointestinal bleeding. Endoscopy revealed multiple gastric polyps, including a 5-cm polyp at the cardia. She underwent repeated endoscopic mucosal resections, with the initial histopathologic findings being consistent with hyperplastic polyps. Next-generation sequencing identified a pathogenic SMAD4 mutation, confirming the diagnosis of gastric juvenile-type polyposis. This case highlights the importance of considering hereditary polyposis syndromes in patients with multiple gastric polyps and anemia, even in the absence of a family history. Early genetic testing facilitates accurate diagnosis and enables appropriate endoscopic surveillance and management, as well as screening for extra-gastrointestinal manifestations.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder associated with immunodeficiency and an increased risk of malignancy. We report a young child with AT and severe combined immunodeficiency who initially presented with left periorbital swelling and was treated for a presumed periorbital infection. She later presented with fever and was diagnosed with pneumonia, requiring admission. Despite antimicrobial therapy and surgical drainage, the swelling persisted and progressed rapidly.MRI of the brain and orbits demonstrated complicated sinusitis with a medial extraconal lesion, suggesting an infectious process. However, there was no sustained clinical response, and microbiological studies remained negative. Repeat MRI showed a persistent lesion with extension into adjacent structures. Histopathological examination confirmed non-Hodgkin B-cell lymphoma with a high proliferative index (Ki-67~80%).This case highlights the importance of early reassessment in immunocompromised patients with an atypical clinical course.