MiR126-targeted-nanoparticles combined with PI3K/AKT inhibitor as a new strategy to overcome melanoma resistance.

Metastatic melanoma poses significant challenges as a highly lethal disease. Despite the success of molecular targeting using BRAFV600E inhibitors (BRAFis) and immunotherapy, the emergence of early recurrence remains an issue and there is the need for novel therapeutic approaches. This study aimed at creating a targeted delivery system for the oncosuppressor microRNA 126 (miR126) and testing its effectiveness in combination with a phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor for treating metastatic melanoma resistant to BRAFis. To achieve this, we synthesized chitosan nanoparticles containing a chemically modified miR126 sequence. These nanoparticles were further functionalized with an antibody specific to the chondroitin sulfate proteoglycan 4 (CSPG4) melanoma marker. After evaluation in vitro, the efficacy of this treatment was evaluated through an in vivo experiment using mice bearing resistant human melanoma. The co-administration of miR126 and the PI3K/AKT inhibitor in these experiments significantly reduced tumor growth and inhibited the formation of liver and lung metastases. These results provide evidence for a strategy to target an oncosuppressive nucleic acid sequence to tumor cells while simultaneously protecting it from plasma degradation. The system described in this study exhibits encouraging potential for the effective treatment of therapy-resistant metastatic melanoma while also presenting a prospective approach for other forms of cancer.

Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase 3 trial in mantle cell lymphoma.

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood [PB] and bone marrow [BM]), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression [TTP] hazard ratio [HR], 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/).

Ablation of Paroxysmal Atrial Fibrillation: between Present and Future.

Pulmonary vein isolation (PVI) is the established cornerstone for atrial fibrillation (AF) ablation, indeed current guidelines recognize PVI as the gold standard for first-time AF ablation, regardless of if it is paroxysmal or persistent. Since 1998 when Haïssaguerre pioneered AF ablation demonstrating a burden reduction after segmental pulmonary vein (PV) ablation, our approach to PVI was superior in terms of methodology and technology. This review aims to describe how paroxysmal atrial fibrillation ablation has evolved over the last twenty years. We will focus on available techniques, a mechanistic understanding of paroxysmal AF genesis and the possibility of a tailored approach for the treatment of AF, before concluding with a future perspective.

Grey Matter Volume Reductions of the Left Hippocampus and Amygdala in PTSD: A Coordinate-Based Meta-Analysis of Magnetic Resonance Imaging Studies.

INTRODUCTION: In recent years, research on posttraumatic stress disorder (PTSD) focused on the description of different biological correlates of illness. Morphological changes of different brain regions were involved in PTSD neurophysiopathology, being related to trauma or considered a resilience biomarker. In this meta-analysis, we aimed to investigate the grey matter changes reported in magnetic resonance imaging (MRI) studies on patients who have developed PTSD compared to exposed subjects who did not show a clinical PTSD onset. METHODS: We meta-analysed eight peer-reviewed MRI studies conducted on trauma-exposed patients and reported results corrected for false positives. We then conducted global and intergroup comparisons from neuroimaging data of two cohorts of included subjects. The included studies were conducted on 250 subjects, including 122 patients with PTSD and 128 non-PTSD subjects exposed to trauma. RESULTS: Applying a family-wise error correction, PTSD subjects compared to trauma-exposed non-PTSD individuals showed a significant volume reduction of a large left-sided grey matter cluster extended from the parahippocampal gyrus to the uncus, including the amygdala. CONCLUSIONS: These volumetric reductions are a major structural correlate of PTSD and can be related to the expression of symptoms. Future studies might consider these and other neural PTSD correlates, which may lead to the development of clinical applications for affected patients.

The COVID-19 Outbreak and Subjects With Mental Disorders Who Presented to an Italian Psychiatric Emergency Department.

ABSTRACT: We performed a retrospective study from January to May 2020 to establish the sociodemographic and clinical characteristics of patients with mental health problems who arrived at an Italian emergency department during the COVID-19 outbreak. We divided the sample into two groups taking as a watershed March 11, when the World Health Organization announced COVID-19 outbreak as a pandemic. Chi-square/t-tests, adjusted p values (Bonferroni method), and regression analysis were performed. Patients who arrived at the emergency department during the lockdown decreased by 56%; showed greater active suicidal ideation, more tension, and more severe psychopathological state; were living alone more frequently; and were taking home treatment mainly based on second-generation antipsychotics. According to our study, it seems that patients with mental disorders have consulted psychiatric services less frequently during the pandemic, but the economic, health, and social distress may be linked with an increase in suicidal risk and the severity of the psychopathological state.

Oxidative Stress, Mutations and Chromosomal Aberrations Induced by In Vitro and In Vivo Exposure to Furan.

Furan is a volatile compound that is formed in foods during thermal processing. It is classified as a possible human carcinogen by international authorities based on sufficient evidence of carcinogenicity from studies in experimental animals. Although a vast number of studies both in vitro and in vivo have been performed to investigate furan genotoxicity, the results are inconsistent, and its carcinogenic mode of action remains to be clarified. Here, we address the mutagenic and clastogenic activity of furan and its prime reactive metabolite cis-2 butene-1,4-dial (BDA) in mammalian cells in culture and in mouse animal models in a search for DNA lesions responsible of these effects. To this aim, Fanconi anemia-derived human cell lines defective in the repair of DNA inter-strand crosslinks (ICLs) and Ogg1-/- mice defective in the removal of 8-hydroxyguanine from DNA, were used. We show that both furan and BDA present a weak (if any) mutagenic activity but are clear inducers of clastogenic damage. ICLs are strongly indicated as key lesions for chromosomal damage whereas oxidized base lesions are unlikely to play a critical role.

Mir-370-3p Impairs Glioblastoma Stem-Like Cell Malignancy Regulating a Complex Interplay between HMGA2/HIF1A and the Oncogenic Long Non-Coding RNA (lncRNA) NEAT1.

Glioblastoma (GBM) is the most aggressive and prevalent form of a human brain tumor in adults. Several data have demonstrated the implication of microRNAs (miRNAs) in tumorigenicity of GBM stem-like cells (GSCs). The regulatory functions of miRNAs in GSCs have emerged as potential therapeutic candidates for glioma treatment. The current study aimed at investigating the function of miR-370-3p in glioma progression, as aberrant expression of miR-370-3p, is involved in various human cancers, including glioma. Analyzing our collection of GBM samples and patient-derived GSC lines, we found the expression of miR-370-3p significantly downregulated compared to normal brain tissues and normal neural stem cells. Restoration of miR-370-3p expression in GSCs significantly decreased proliferation, migration, and clonogenic abilities of GSCs, in vitro, and tumor growth in vivo. Gene expression analysis performed on miR-370-3p transduced GSCs, identified several transcripts involved in Epithelial to Mesenchymal Transition (EMT), and Hypoxia signaling pathways. Among the genes downregulated by the restored expression of miR-370-3p, we found the EMT-inducer high-mobility group AT-hook 2 (HMGA2), the master transcriptional regulator of the adaptive response to hypoxia, Hypoxia-inducible factor (HIF)1A, and the long non-coding RNAs (lncRNAs) Nuclear Enriched Abundant Transcript (NEAT)1. NEAT1 acts as an oncogene in a series of human cancers including gliomas, where it is regulated by the Epidermal Growth Factor Receptor (EGFR) pathways, and contributes to tumor growth and invasion. Noteworthy, the expression levels of miR-370-3p and NEAT1 were inversely related in both GBM tumor specimens and GSCs, and a dual-luciferase reporter assay proved the direct binding between miR-370-3p and the lncRNAs NEAT1. Our results identify a critical role of miR-370-3p in the regulation of GBM development, indicating that miR-370-3p acts as a tumor-suppressor factor inhibiting glioma cell growth, migration and invasion by targeting the lncRNAs NEAT1, HMGA2, and HIF1A, thus, providing a potential candidate for GBM patient treatment.

Can sustained exposure to PFAS trigger a genotoxic response? A comprehensive genotoxicity assessment in mice after subacute oral administration of PFOA and PFBA.

PFAS (perfluoroalkyl substances) are considered non-genotoxic. However, PFAS exposure has been associated with the induction of oxidative stress in vitro and in vivo, and the possible induction of indirect genotoxic effects under sustained PFAS exposure has not been investigated. In order to shed light on this aspect, in this study a comprehensive assessment of genotoxicity was carried out in mice administered with perfluorooctanoic acid (PFOA, 0.1, 1 and 5 mg/kg body weight) and its C4 analogue perfluorobutyric acid (PFBA, 5 mg/kg body weight) for five weeks through drinking water. Markers of cell toxicity, oxidative stress and DNA strand breaks were measured in liver, the main target of toxicity of PFOA in rodents; systemic genotoxicity was also assessed by the analysis of micronuclei in reticulocytes and spleen lymphocytes, and germ cell effects by the Comet assay on testis cells. PFOA administration at the highest dose (5 mg/kg body weight) induced marked liver hypertrophy with signs of cell injury (elevated ALT and AST), with no concurrent evidence of lipid peroxidation and oxidative stress (decreased antioxidant capacity). Only mild liver hypertrophy, with no other signs of toxicity, was determined by PFBA administration. No evidence of treatment related genotoxicity was observed in any experimental group. Overall, data indicate that under the experimental conditions of this study, severe liver toxicity induced by PFOA administration is not associated with oxidative stress. Accordingly, no genotoxic effect is observed in liver and in the other tissues examined. Milder evidence of liver toxicity, with no genotoxicity, and a lower tendency to bioaccumulation were observed in PFBA treated mice.

Sir Hugh Cairns: a pioneering collaborator.

In April 1988, Peter Schurr delivered the twelfth Sir Hugh Cairns Memorial Lecture to the Society of British Neurological Surgeons. In his lecture, The Cairns Tradition, Schurr extolled the personal virtues of Cairns. He encouraged his colleagues to draw inspiration from Cairns' renowned determination, organisation, drive for perfection, compassion, and commitment to the training of those around him. Indeed, Cairns' own personality has come to define the specialty which he established in Britain. Today's neurosurgeons are, whether knowingly or not, formed in his image. But there is a side to Hugh Cairns that has been lost in the telling of his remarkable story, and yet it played a central role in his greatest achievements. This is the side of himself which he turned towards others. Throughout his career, Cairns received an inordinate number of personal accolades. His tutelage under Cushing during a formative trip to America and the impact of his role in caring for T. E. Lawrence are well known to many. But, more than thirty years after Peter Schurr's memorial lecture, and following the eightieth anniversary of the department of neurosurgery founded by Cairns in Oxford, it is his work as a pioneering collaborator which defines his legacy today, and which calls us to learn yet another lesson from his remarkable life. In this legacy article, we review the origins of Cairns' collaborative spirit and uncover the achievements he shared with Charles Hallpike, Howard Florey, Derek Denny-Brown, William Ritchie Russell, Ludwig Guttman, and Peter Medawar, among many others.

CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells.

OBJECTIVE: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. DESIGN: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents. RESULTS: The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368. CONCLUSIONS: LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.

Proliferation of Multiple Cell Types in the Skeletal Muscle Tissue Elicited by Acute p21 Suppression.

Although in the last decades the molecular underpinnings of the cell cycle have been unraveled, the acquired knowledge has been rarely translated into practical applications. Here, we investigate the feasibility and safety of triggering proliferation in vivo by temporary suppression of the cyclin-dependent kinase inhibitor, p21. Adeno-associated virus (AAV)-mediated, acute knockdown of p21 in intact skeletal muscles elicited proliferation of multiple, otherwise quiescent cell types, notably including satellite cells. Compared with controls, p21-suppressed muscles exhibited a striking two- to threefold expansion in cellularity and increased fiber numbers by 10 days post-transduction, with no detectable inflammation. These changes partially persisted for at least 60 days, indicating that the muscles had undergone lasting modifications. Furthermore, morphological hyperplasia was accompanied by 20% increases in maximum strength and resistance to fatigue. To assess the safety of transiently suppressing p21, cells subjected to p21 knockdown in vitro were analyzed for γ-H2AX accumulation, DNA fragmentation, cytogenetic abnormalities, ploidy, and mutations. Moreover, the differentiation competence of p21-suppressed myoblasts was investigated. These assays confirmed that transient suppression of p21 causes no genetic damage and does not impair differentiation. Our results establish the basis for further exploring the manipulation of the cell cycle as a strategy in regenerative medicine.

Paucisymptomatic post COVID-19 myocarditis in a young athlete during return to play workflow: possible usefulness of global longitudinal strain analysis.

A young competitive athlete undergoes the diagnostic investigations protocol before returning to competitive practice (return to play protocol) after COVID-19 infection. Despite the paucisymptomatic presentation of COVID-19 infection and the absence of relevant anomalies in standard first-level diagnostic investigations, echocardiographic examination findings especially speckle tracking analysis (global longitudinal strain) along with some clinical aspects suggested further second-level investigations eventually allowing the identification of inflammatory myocardial damage.

Sutureless and Rapid Deployment Prosthesis in Redo-Bentall Endocarditis.

Aortic valve replacement (AVR) in a patient with a bio-Bentall conduit can be very challenging, especially if there was a previous endocarditis process for significant morbidity and mortality. We report a case of sutureless AVR in an old patient with a bio-Bentall conduit (Carpentier-Edwards Perimount Magna Ease 25 aortic valve and Hemashield 30 aortic conduit), who developed an endocarditis on aortic prosthesis valve. We believe that sutureless AVR is the best option for redo-operation in older patients with a high surgical risk because it allows for easy rapid deployment implantation, avoids anchoring sutures on a fragile aortic anulus, and reduces cardiopulmonary and aortic cross-clamp times. In this setting, it should be considered as a safe and valid alternative not only to traditional prosthesis but also in selected cases to transcatheter valve-in-valve solutions.

Unfolding the Challenges To Prepare Single Crystalline Complex Oxide Membranes by Solution Processing.

The ability to prepare single crystalline complex oxide freestanding membranes has opened a new playground to access new phases and functionalities not available when they are epitaxially bound to the substrates. The water-soluble Sr3Al2O6 (SAO) sacrificial layer approach has proven to be one of the most promising pathways to prepare a wide variety of single crystalline complex oxide membranes, typically by high vacuum deposition techniques. Here, we present solution processing, also named chemical solution deposition (CSD), as a cost-effective alternative deposition technique to prepare freestanding membranes identifying the main processing challenges and how to overcome them. In particular, we compare three different strategies based on interface and cation engineering to prepare CSD (00l)-oriented BiFeO3 (BFO) membranes. First, BFO is deposited directly on SAO but forms a nanocomposite of Sr-Al-O rich nanoparticles embedded in an epitaxial BFO matrix because the Sr-O bonds react with the solvents of the BFO precursor solution. Second, the incorporation of a pulsed laser deposited La0.7Sr0.3MnO3 (LSMO) buffer layer on SAO prior to the BFO deposition prevents the massive interface reaction and subsequent formation of a nanocomposite but migration of cations from the upper layers to SAO occurs, making the sacrificial layer insoluble in water and withholding the membrane release. Finally, in the third scenario, a combination of LSMO with a more robust sacrificial layer composition, SrCa2Al2O6 (SC2AO), offers an ideal building block to obtain (001)-oriented BFO/LSMO bilayer membranes with a high-quality interface that can be successfully transferred to both flexible and rigid host substrates. Ferroelectric fingerprints are identified in the BFO film prior and after membrane release. These results show the feasibility to use CSD as alternative deposition technique to prepare single crystalline complex oxide membranes widening the range of available phases and functionalities for next-generation electronic devices.

Management of cerebral amyloid angiopathy and atrial fibrillation: We are still far from precision medicine.

The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy (CAA) and atrial fibrillation (AF). In fact, CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage. Nevertheless, many AF patients require oral systemic dose-adjusted warfarin, direct oral anticoagulants (such as factor Xa inhibitors) or direct thrombin inhibitors to control often associated with cardioembolic stroke risk. The prevalence of both CAA and AF is expected to rise, due to the aging of the population. This clinical dilemma is becoming increasingly common. In patients with coexisting AF and CAA, the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature. This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.

Machine learning approach for the development of a crucial tool in suicide prevention: The Suicide Crisis Inventory-2 (SCI-2) Short Form.

The Suicide Crisis Syndrome (SCS) describes a suicidal mental state marked by entrapment, affective disturbance, loss of cognitive control, hyperarousal, and social withdrawal that has predictive capacity for near-term suicidal behavior. The Suicide Crisis Inventory-2 (SCI-2), a reliable clinical tool that assesses SCS, lacks a short form for use in clinical settings which we sought to address with statistical analysis. To address this need, a community sample of 10,357 participants responded to an anonymous survey after which predictive performance for suicidal ideation (SI) and SI with preparatory behavior (SI-P) was measured using logistic regression, random forest, and gradient boosting algorithms. Four-fold cross-validation was used to split the dataset in 1,000 iterations. We compared rankings to the SCI-Short Form to inform the short form of the SCI-2. Logistic regression performed best in every analysis. The SI results were used to build the SCI-2-Short Form (SCI-2-SF) utilizing the two top ranking items from each SCS criterion. SHAP analysis of the SCI-2 resulted in meaningful rankings of its items. The SCI-2-SF, derived from these rankings, will be tested for predictive validity and utility in future studies.

Thromboembolic prevention in athletes: management of anticoagulation in sports players affected by atrial fibrillation.

Atrial fibrillation (AF) is a common cardiac arrhythmia that poses a significant risk of stroke and thromboembolic events. Anticoagulation therapy is essential for preventing stroke in patients with AF. An increasing number of people of all ages, including cardiac patients, approach physical activity as both a leisure-time exercise and a competitive sport. Therefore, patients at risk of AF are increasingly allowed to practice sports activities. Management of oral anticoagulant therapy (OAT) in these patients is extremely challenging because of the need to balance the risks and benefits of medications, considering both hemorrhagic (in case of trauma) and ischemic complications when the drugs are avoided. Official recommendations are limited for these patients and forbid sports that increase the risk of trauma and consequent bleeding in most cases. These recommendations are strongly influenced by the "traditional" management of OAT, which mainly involves coumarin derivatives. Non-vitamin K antagonist direct oral anticoagulants (DOACs), with their more favorable pharmacokinetic-pharmacodynamic profile than that of coumarin derivatives, may represent an opportunity to modify the approach to sports activity in patients with AF and indications for OAT. This study aimed to review the use of anticoagulants in athletes with AF, highlight their efficacy and safety, and provide practical considerations regarding their management.

Photon upconversion crystals doped bacterial cellulose composite films as recyclable photonic bioplastics.

Biopolymers currently utilized as substitutes for synthetic polymers in photonics applications are predominantly confined to linear optical color responses. Herein we expand their applications in non-linear optics by integrating with triplet-triplet annihilation photon upconversion crystals. A photon upconverting biomaterial is prepared by cultivating Pd(II) meso-tetraphenyl tetrabenzoporphine: 9,10-diphenyl anthracene (sensitizer: annihilator) crystals on bacterial cellulose hydrogel that serves both as host and template for the crystallization of photon upconversion chromophores. Coating with gelatin improves the material's optical transparency by adjusting the refractive indices. The prepared material shows an upconversion of 633 nm red light to 443 nm blue light, indicated by quadratic to linear dependence on excitation power density (non-linearly). Notably, components of this material are physically dis-assembled to retrieve 66 ± 1% of annihilator, at the end of life. Whereas, the residual clean biomass is subjected to biodegradation, showcasing the sustainability of the developed photonics material.

hMTH1 expression protects mitochondria from Huntington's disease-like impairment.

Huntington disease (HD) is a neurodegenerative disease caused by expansion of CAG repeats in the huntingtin (Htt) gene. The expression of hMTH1, the human hydrolase that degrades oxidized purine nucleoside triphosphates, grants protection in a chemical HD mouse model in which HD-like features are induced by the mitochondrial toxin 3-nitropropionic acid (3-NP). To further examine the relationship between oxidized dNTPs and HD-like neurodegeneration, we studied the effects of hMTH1 expression in a genetic cellular model for HD, such as striatal cells expressing mutant htt (Hdh(Q111)). hMTH1 expression protected these cells from 3-NP and H2O2-induced killing, by counteracting the mutant htt-dependent increased vulnerability and accumulation of nuclear and mitochondrial DNA 8-hydroxyguanine levels. hMTH1 expression reverted the decreased mitochondrial membrane potential characteristic of Hdh(Q111) cells and delayed the increase in mitochondrial reactive oxygen species associated with 3-NP treatment. Further indications of hMTH1-mediated mitochondrial protection are the partial reversion of 3-NP-induced alterations in mitochondrial morphology and the modulation of DRP1 and MFN1 proteins, which control fusion/fission rates of mitochondria. Finally, in line with the in vitro findings, upon 3-NP in vivo treatment, 8-hydroxyguanine levels in mitochondrial DNA from heart, muscle and brain are significantly lower in transgenic hMTH1-expressing mice than in wild-type animals.

MutT homolog-1 attenuates oxidative DNA damage and delays photoreceptor cell death in inherited retinal degeneration.

Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death-signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP.