Ataxia-telangiectasia and Rad3-related (ATR) is an essential DNA damage response kinase that protects genome integrity by controlling cell cycle checkpoints, regulating origin firing, stabilizing replication forks, and signaling DNA repair. Due to hyper-proliferation, cancer cells depend on ATR for survival, implicating ATR inhibitors as promising therapeutics. However, variable tumor responses to ATR inhibitors highlights the need to uncover the determinants of cell fate. Here, we show breast cancer sensitivity to ATR inhibition correlates with the appearance of pan-nuclear DNA damage. The fate of these cells is driven by a p53-p21-RB1 axis that triggers a G2-to-G0-like cell cycle exit and is buffered by the p53 inhibitor MDM2. MDM2 inhibition lowers the DNA damage threshold for cell cycle exit and robustly targets ATR inhibitor-resistant cells. Our work reveals cell cycle plasticity as a mechanism determining cell fate during ATR inhibition and identifies MDM2 as a target for increasing ATR inhibitor efficacy.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of the vasculature associated with mucocutaneous telangiectasia and visceral arteriovenous malformations (AVMs). These manifestations can frequently lead to chronic blood loss and iron deficiency anemia. In some cases, anemia can be severe and transfusion-dependent, reflecting an advanced disease phenotype with persistent vascular involvement and cumulative blood loss. This report presents a case of a 58-year-old female with a known diagnosis of HHT who presented with fatigue, dizziness, and chronic melena, and was found to have a hemoglobin level of 4.7 g/dL. Imaging revealed persistent pulmonary AVM disease, which may increase cardiopulmonary demand, particularly in the setting of severe anemia, and may contribute to complications if left untreated. The patient required transfusion of five units of packed red blood cells and underwent endoscopic ablation of multiple telangiectasias in the stomach and duodenum. This case underscores the persistent nature of HHT-related gastrointestinal bleeding and the cardiopulmonary consequences of multi-system AVM burden. It emphasizes the necessity for multidisciplinary care and ongoing surveillance in patients with HHT to prevent symptom progression.

Here we describe the different TOP1 poisons used a "payload" for tumor-targeted anticancer therapies in comparison with the widely used first generation TOP1 poisons: Topotecan, Irinotecan and Belotecan. We review the determinants of response to tumor-targeted TOP1 poison inhibitors (TTTis) as candidate companion diagnostic (Dx) biomarkers for precision medicine and patient selection, such as high expression of surface epitopes for ADCs (Antibody Drug Conjugates), high tumor proliferation (Ki67), Schlafen 11 (SLFN11) expression, homologous recombination deficiencies (HRD/BRCAness) and expression of drug efflux transporters such as (BCRP (MXR) encoded by ABCG2. We also summarize the mechanistic rationale for combining TTTis with small molecule inhibitors of poly(ADPribose) polymerase (PARP), ATR (Ataxia Telangiectasia and Rad3-related), CHK1 (Checkpoint Kinase 1) and ATM (Ataxia Telangiectasia Mutated).

Postoperative radiotherapy is effective for reducing recurrence of auricular keloids, yet the optimal dose fractionation remains debated. This retrospective cohort study compared single-fraction 10 Gy versus fractionated 10 Gy (2×5 Gy) electron beam radiotherapy following keloid excision. Seventy-seven patients were enrolled, with 37 receiving a single 10 Gy fraction (group A) and 40 receiving 5 Gy×2 fractions (group B). All patients underwent complete surgical excision and initiated radiotherapy within 24 hours postoperatively. The primary endpoint was local recurrence; secondary endpoints included scar aesthetic quality assessed using the Patient and Observer Scar Assessment Scale (POSAS 2.0) and radiotherapy-related complications. With a median follow-up of 19.0 months in both groups, the recurrence rate was 2.7% in group A and 7.5% in group B (P=0.616). The total observer POSAS score was significantly lower in group A (14.3±3.7 versus 16.5±4.3, P=0.019), indicating superior objective scar quality, while patient-reported scores showed no significant difference. Both regimens were well-tolerated, with no severe adverse events and comparable rates of acute dermatitis, pigmentary changes, and telangiectasia. In conclusion, single-fraction 10 Gy electron beam radiotherapy achieves comparable local control to fractionated 10 Gy and yields superior objective aesthetic outcomes. Combined with its convenience and health economic advantages, single-fraction 10 Gy represents a safe and preferred clinical option for auricular keloids.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by abnormal blood vessel formation, frequently involving the gastrointestinal (GI) tract. GI involvement can result in diffuse mucosal telangiectasis, chronic bleeding, iron-deficiency anemia, and transfusion dependence. Conventional treatments often provide limited benefit in patients with widespread disease. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has emerged as a potential disease-modifying agent through its anti-angiogenic properties. We report a case of a male patient with genetically confirmed HHT and comorbid pulmonary arterial hypertension who presented with recurrent GI bleeding. The patient had a long-standing history of GI bleeding requiring multiple endoscopic interventions, with findings of arteriovenous malformations throughout the GI tract. Prior management with conventional therapies provided only a transient benefit. The patient subsequently received intravenous bevacizumab induction therapy. Bevacizumab therapy resulted in marked clinical improvement, including hemoglobin stabilization, reduction in overt bleeding, and decreased transfusion requirements. Recurrence of bleeding following therapy discontinuation further supports a direct therapeutic effect. This case contributes to the growing body of evidence that VEGF inhibition is a biologically rational and clinically effective salvage strategy for refractory GI bleeding in HHT. Prospective studies are needed to define optimal dosing, maintenance strategies, and long-term outcomes.

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors-including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin-have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable.

The Ataxia Telangiectasia Mutated (ATM) protein kinase is a well recognized master regulator of the DNA damage response (DDR) and cell cycle control whose dysfunction leads to the rare neurological disorder Ataxia Telangiectasia (AT). A mounting body of evidence has revealed unequivocally that ATM relevance extends far beyond its DDR role and includes critical non-canonical functions. This minireview summarizes the current knowledge on ATM role in neural stem progenitor cell (NSPC) biology and in neurogenesis. In particular, herein we highlight how ATM is crucial for NSPC proliferation, differentiation, and survival, acting not only as a guardian of genomic integrity but also as a key orchestrator of developmental timing. Furthermore, we discuss how ATM deficiency in AT leads to dysregulated NSPC proliferation, premature neuronal maturation, and impaired quality control during neurogenesis, potentially contributing to progressive neurodegeneration and complex neurological symptoms associated with this pediatric disorder. By integrating canonical and non-canonical mechanisms, this review may offer a more comprehensive understanding of ATM key role in maintaining brain homeostasis integrity from the stem cell level. Moreover, it adds a more complex perspective on AT pathogenesis and opens novel avenues for future therapeutic interventions.

Vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of retinal and choroidal neovascularization, as well as macular edema (ME), in retinal disorders such as diabetic retinopathy, retinal vein occlusion (RVO), and age-related macular degeneration (ARMD). The advent of intravitreal anti-VEGF therapy has revolutionized their management. More recently, these agents have been explored in several other retinal pathologies characterized by secondary neovascularization, either in vascular or non-vascular disorders. This review summarizes current evidence on the role of anti-VEGF agents in retinal disorders other than ARMD, including central serous chorioretinopathy (CSCR), macular telangiectasia type 2 (MacTel), choroidal osteoma, retinopathy of prematurity (ROP), tubercular granuloma, inherited retinal dystrophies, Coats' disease, angioid streaks, and retinal vasoproliferative tumors (RVPTs).

Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between an artery and a vein without an intervening capillary component. Most PAVMs are congenital, caused by hereditary hemorrhagic telangiectasia, but around 20% are acquired. The most common presenting symptom is dyspnoea on exertion, but patients can be completely asymptomatic. Furthermore, Gestational trophoblastic neoplasia (GTN) is a group of rare tumors that arise from abnormal growth of trophoblastic tissue which includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor can progress, invade, metastasize, and lead to death if left untreated. In the majority of GTNs, the disease is limited to the uterus where the abnormal trophoblast proliferation and localized hCG production may lead to focal vascular changes, including the formation of AVMs. Most patients with GTN present with abnormal vaginal bleeding but they can also present with bleeding from metastatic sites. Symptoms of pulmonary metastasis from GTN often include cough, hemoptysis, and chest pain. However, PAVMs are not typically listed as a direct consequence of this metastatic spread. Here, we report a rare case of metastatic GTN initially presented with pulmonary vascular malformation.

[This retracts the article DOI: 10.3892/ol.2014.2444.].

Adenosine diphosphate (ADP) ribosylation (ADPr) regulates multiple stress responses, yet substrates in the apoptotic machinery remain elusive. We show that a single, DNA damage-induced ADPr event controls proapoptotic PIDDosome (PIDD1/RAIDD/caspase-2) formation in response to unresolved interstrand DNA cross-links (ICL). ADPr targets conserved E783 in the PIDD1 death domain (DD); is catalyzed by poly(ADP-ribose) polymerase 4 (PARP4), a phylogenetically orphan PARP of previously unknown function; is reversed by the ribosylhydrolase activity of PARP14; and is triggered by Ataxia Telangiectasia and RAD3-related (ATR) phosphorylation-induced, PIAS1-mediated SUMOylation of the PIDD1 DD, which enables PARP4 docking. PIDD1 ADPr is dispensable for the recruitments of RAIDD and caspase-2 but essential for the dimerization of the caspase. Hence, denying E783 ADPr spares the onset of PIDDosome assembly but blocks its completion, thus eliminating caspase-2 activation and ensuing apoptosis. Conversely, removal of PARP14 forces apoptosis, even in cells with tolerable damage. The data identify PARP4 as an ICL response effector and illuminate a three-step modification sequence of the PIDD1 DD that conducts PIDDosome assembly from initiation to completion.