Effectiveness of non-immersive virtual reality in the management of procedure-related pain in preschool children: a randomized clinical trial.

The objective of this study is to assess the effectiveness of non-immersive virtual reality as a pain-distraction measure in children between the ages of 3 and 5 years undergoing painful injection procedures in an outpatient setting. We carried out a randomized, unmasked clinical trial in children undergoing venipuncture or intramuscular injection procedures. Patients were randomized to a distraction virtual reality video or standard care. After the procedure, three independent observers (parents, researchers, nursing staff) rated pain on the LLANTO pain scale. We recruited 122 subjects, half of which were randomized to virtual reality. The median age was of approximately 60 months (IQR: 15 months), and the sample was balanced with regard to sex. There were significant differences in LLANTO scales scores between the VR subjects and controls of - 3.34 (95% CI - 4.15; - 2.54), - 3.02 (95% CI - 3.90; - 2.14), and - 2.98 (95% CI - 3.87; - 2.09), as rated by parents, researchers, and nursing staff, respectively. Agreement between raters was high for all three types of observers, with Cohen Kappas over 0.79 in all cases. Bivariate analysis showed reductions in the risk of obtaining higher scores in the LLANTO scale. Linear regression models showed a reduction of approximately 3 points in the scale, regardless of the type of observer. These models were adjusted for sex, age, kind of procedure, use of prior analgesia, and recruitment center. CONCLUSIONS: Non-immersive virtual reality is an effective adjunctive therapy for the reduction of pain in children undergoing painful injection procedures in an outpatient setting. This strategy may be used to improve the quality of care in pediatric outpatient services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03985930 (Registered June 14, 2019). WHAT IS KNOWN: •The use of immersive virtual reality (VR) has been described as an effective adjunctive distraction method during painful procedures in children over 5 years. WHAT IS NEW: •The utility of non-immersive VR in children below that age is not yet clear. This randomized clinical trial comparing non-immersive VR vs. standard care showed an average reduction of three points in the LLANTO pain scale favoring non-immersive VR. Non-immersive VR is an effective and inexpensive non-pharmacological technique that reduces fear and pain in pediatric patients.

Surgical management of spontaneous middle cranial fossa defects: a systematic review and meta-analysis of available reconstructive techniques and materials.

Different materials and techniques have been proposed for surgical repair of spontaneous middle cranial fossa (MCF) defects. However, conclusive evidence supporting their selection and impact on clinical outcomes is lacking. The study aims to conduct a systematic review and meta-analysis on materials and techniques employed to repair MCF defects and evaluate complications and rates of recurrent cerebrospinal fluid (CSF) leaks. A PRISMA-guided systematic review and meta-analysis were performed using MESH terms and specific keywords including studies published before May 2022. Primary outcomes included recurrence of CSF leak and complication rates by type of reconstructive material and technique utilized. Meta-analyses of proportions were performed using random effects and confidence intervals for individual proportions were calculated using the Clopper-Pearson method. Twenty-nine studies were included (n = 471 cases). Materials employed for repair were categorized according to defect size: 65% of defects were of unknown size, 24% were small (< 1 cm), and 11% were large (≥ 1 cm). Rigid reconstruction (RR) was significantly favored over soft reconstruction (SR) for larger defects (94% of cases, p < 0.05). Complications and recurrent CSF leak rates of SR and RR techniques were comparable for defects of all sizes (p > 0.05). Complication rates reported for these procedures are low regardless of technique and material. RR was universally preferred for larger defects and analysis of complication and recurrence rates did not reveal differences regardless of defect size. While RR was more frequently reported in smaller defects, SR was used by several centers, particularly for smaller MCF floor defects.

Peripheral neuropathy in leprosy: Clinical manifestations and disability in a Colombian national referral center.

To aim of the paper was to describe the neurological features of the physical examination in patients with Hansen's disease who were treated in Bogotá, Colombia. We carried out a descriptive study of all patients with a Hansen's disease diagnosis treated at a referral center between 2003-2018. There were 327 eligible electronic health records (EHRs) with a final sample of 282 subjects. Leprosy was most common in males (57.45%), median age at the diagnosis was 54 years, and lesions of the lower limbs were more common (75.1%). The median time from disease onset to consult was 12 months. Most of them were classified as having lepromatous leprosy (39.7%). Pain over the median nerve trunk was the most common manifestation of disease (28%), followed by pain over the radial trunk (22%). Sensitive alterations were more common than motor ones. Specifically, the posterior tibial nerve was affected in nearly half of subjects. Dual impairment was more common in the ulnar nerve (13.8%). Some disability was apparent in 23.8% of subjects; predominantly grade 1 disability. Findings regarding age, leprosy type, and the frequency of individual nerve compromise were consistent with reports from other countries. Nerve trunk thickening was infrequent, which might be a consequence of subjectiveness in the examination and sample differences in sex distribution, degree of disability and time since disease onset. The frequency of morbidity and disability found in this sample, though low when compared with other series, fails to meet public health goals, including those limiting disability in younger subjects.

Circulating Tumor DNA in Adults With Glioma: A Systematic Review and Meta-Analysis of Biomarker Performance.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker to capture tumor genetics in patients with brain tumors. Research into its clinical utility, however, has not been standardized because the sensitivity and specificity of ctDNA remain undefined. OBJECTIVE: To (1) review the primary literature about ctDNA in adults with glioma to compare the sensitivity and specificity of ctDNA in the cerebrospinal fluid vs the plasma and (2) to evaluate the effect of tumor grade on detection of ctDNA. METHODS: PRISMA-guided systematic review and meta-analysis was performed using published studies that assessed ctDNA in either plasma or cerebrospinal fluid among adult patients with confirmed glioma. Summary receiver operating characteristic curves were generated using the Rücker-Schumacher method, and area under the curve (AUC) was calculated. RESULTS: Meta-analysis revealed improved biomarker performance for CSF (AUC = 0.947) vs plasma (AUC = 0.741) ctDNA, although this did not reach statistical significance ( P = .141). Qualitative analysis revealed greater sensitivities among single-allele PCR and small, targeted next-generation sequencing panels compared with broader panels. It additionally demonstrated higher sensitivity of ctDNA detection in high-grade vs low-grade gliomas, although these analyses were limited by a lack of specificity reporting in many studies. CONCLUSION: ctDNA seems to be a highly sensitive and specific noninvasive biomarker among adults with gliomas. To maximize its performance, CSF should be studied with targeted genetic analysis platforms, particularly in high-grade gliomas. Further studies on ctDNA are needed to define its clinical utility in diagnosis, prognostication, glioblastoma pseudoprogression, and other scenarios wherein neoadjuvant therapies may be considered.

Spatial analysis of service areas for stroke centers in a city with high traffic congestion.

The effect that traffic congestion has on the service areas of stroke centers has received scarce attention. We aimed to determine the effect of traffic conditions on the characteristics of service areas of stroke centers in Bogotá, Colombia. Using a webservice, we sampled travel times from a set of census blocks to medical centers offering stroke management in the city. We obtained 179.340 transport times under different conditions. The size of service areas was reduced significantly with congestion (up to 94.83%). Overlap in the locations of centers led to large areas covered by only five centers. We identified areas with transport times to the closest center consistently exceeding 30-minutes to 1-hour in the west and south-west. Traffic conditions in Bogotá significantly affect service areas of centers capable of offering comprehensive stroke care. Spatial overlap of centers led to small catchment areas.

Congenital amusia and academic performance among Colombian university students.

BACKGROUND: Congenital amusia is a rare neurogenetic and neuropsychological condition which hinders the ability to recognize variations in all aspects of a musical piece. Although previous studies have determined the prevalence of congenital amusia in the general population, few have studied its presence among university students. Findings regarding the association between this condition and academic performance are equivocal, although evidence suggests that musical training improves scholastic achievement. METHODS: We conducted a cross-sectional study on a sample of 383 university students, all pursuing health-related degrees, comparing their class rank with their performance on the BRAMS Online Test for amusia. RESULTS: We found a prevalence of 0.52% for pitch-based amusia. When applying the Off-Scale test failure criterion for the definition of amusia in our sample, we found a prevalence of 4.4%. Logistic models showed an increase in risk of poor academic performance (lowest quartile) in subjects who failed the off-scale test (Odds Ratio: 7.14 95% CI 2.59-19.6) and who met any of the described definitions of amusia (Odds Ratio: 4.89 95% CI 2.24-10.7). CONCLUSIONS: Both musical training and self-report of musical ability significantly affected test results. Although musical education shows some effect over academic performance, further studies are required to determine if this is due to differential effects in subjects with and without amusia.

Assessment of nutrition and learning skills in children aged 5-11 years old from two elementary schools in Chocó, Colombia.

BACKGROUND: Malnutrition has been identified as a factor in growth and learning. The current study aimed to determine the nutritional status and basic learning skills of children from Chocó, Colombia. METHODS: We conducted a cross-sectional study of 631 children aged 5-11 years from two schools, collecting anthropometric measurements, nutritional quality surveys and sociodemographic data. Neuropsychological batteries were applied. RESULTS: A total of 523 children were evaluated, with an average age of 8.49 ± 2.1 years. The results revealed that 2.9% of children were underweight, 0.4% were severely underweight, and 4.8% were diagnosed as having stunted growth. In addition, 71.8% of children were unable to draw a human figure. Beery-Buktenica Visual-Motor Integration test (VMI) performance was below the scores expected for these age groups in 73.9% of children. Battery of Differential and General Abilities (BADYG) performance revealed limited verbal skills. In a subsample of 117 children, anemia was detected in 12.8% of cases, and iron deficiency was present in 44.4% of cases. Global malnutrition was associated with impairments in BADYG performance (OR: 1.98; 95% CI: 1.07-3.86). CONCLUSIONS: The current results revealed that learning performance was below the expected level for children in these age groups across all of the applied tests. Although malnutrition could partially explain the poor performance of children in tests of learning abilities, additional factors are likely to be involved.

Prevalencia de hipoacusia en una población escolar con síndrome de Down de Bogotá, Colombia / Prevalence of hearing loss in a population of schoolchildren with Down syndrome from Bogotá, Colombia

Introducción: Los niños con síndrome de Down presentan mayor prevalencia de alteraciones de la capacidad auditiva, secundaria a variaciones anatómicas y fisiológicas. En Colombia, no se realiza tamizaje auditivo universal, y no hay datos sobre la prevalencia de hipoacusia en esta población. El propósito de este estudio fue determinar la frecuencia y tipo de estas alteraciones en nuestra población por medio de evaluación audiológica.Pacientes y métodos: Se realizó un estudio de corte trasversal en dos instituciones especializadas en el acompañamiento y terapia de familias de niños con síndrome de Down en Bogotá D. C., Colombia. Entre octubre de 2017 y septiembre de 2018, se realizó audiometría comportamental y/o tonal e impedanciometría en 40 y en 37 niños respectivamente. Los sujetos asistían a las instituciones dos veces por semana y estaban integrados en diferentes grados escolares hasta quinto de primaria. Se estimó la prevalencia y se describieron las características, antecedentes clínicos e hitos del desarrollo del lenguaje. Resultados: Se obtuvo una muestra de 40 niños (22 mujeres) con edades entre 6 y 18 años (media: 11,23). Se encontró antecedente de otitis en 19 sujetos e hipoacusia de leve a moderada en 17 niños, predominantemente, conductiva. Hubo retraso en hitos del desarrollo del lenguaje, en apariencia, no asociado a hipoacusia.Conclusiones: En una muestra de niños con síndrome de Down en Bogotá, se encontró una alta prevalencia de hipoacusia, consistente con resultados de estudios previos. Estos datos resaltan la necesidad de un control estricto de la capacidad auditiva basado en parámetros y guías estandarizadas.

Introduction: Children with Down syndrome have a higher prevalence of hearing disorders, secondary to anatomical and physiological variations. No universal hearing screening is implemented in Colombia, so there are no data available on the prevalence of hearing loss in this population. The objective of this study was to determine the frequency and type of such disorders in this population based on hearing tests.Patients and methods: This was a cross-sectional study conducted at two institutions specialized in accompanying and supporting the families of children with Down syndrome in Bogotá, D.C., Colombia. Between October 2017 and September 2018, a behavioral and/or pure-tone audiometry and an impedance audiometry were done in 40 and 37 children respectively. Subjects attended the institutions twice a week and were integrated at school, up to fifth grade. Prevalence was estimated and characteristics, clinical history, and language developmental milestones were described.Results: The sample was made up of 40 children (22 girls) aged 6-18 years (mean: 11.23). A history of otitis was found in 19 children and of mild to moderate hearing loss, in 17, predominately conductive. A delay in language developmental milestones was observed, apparently not associated with hearing loss. Conclusions: A sample of children with Down syndrome from Bogotá showed a high prevalence of hearing loss, consistent with the results of previous studies. These data stress the need for a strict control of hearing status based on standardized parameters and guidelines.

Prevalence of hearing loss in a population of schoolchildren with Down syndrome from Bogotá, Colombia. / Prevalencia de hipoacusia en una población escolar con síndrome de Down de Bogotá, Colombia.

INTRODUCTION: Children with Down syndrome have a higher prevalence of hearing disorders, secondary to anatomical and physiological variations. No universal hearing screening is implemented in Colombia, so there are no data available on the prevalence of hearing loss in this population. The objective of this study was to determine the frequency and type of such disorders in this population based on hearing tests. PATIENTS AND METHODS: This was a cross-sectional study conducted at two institutions specialized in accompanying and supporting the families of children with Down syndrome in Bogotá, D.C., Colombia. Between October 2017 and September 2018, a behavioral and/or pure-tone audiometry and an impedance audiometry were done in 40 and 37 children respectively. Subjects attended the institutions twice a week and were integrated at school, up to fifth grade. Prevalence was estimated and characteristics, clinical history, and language developmental milestones were described. RESULTS: The sample was made up of 40 children (22 girls) aged 6-18 years (mean: 11.23). A history of otitis was found in 19 children and of mild to moderate hearing loss, in 17, predominately conductive. A delay in language developmental milestones was observed, apparently not associated with hearing loss. CONCLUSIONS: A sample of children with Down syndrome from Bogotá showed a high prevalence of hearing loss, consistent with the results of previous studies. These data stress the need for a strict control of hearing status based on standardized parameters and guidelines.

Introducción: Los niños con síndrome de Down presentan mayor prevalencia de alteraciones de la capacidad auditiva, secundaria a variaciones anatómicas y fisiológicas. En Colombia, no se realiza tamizaje auditivo universal, y no hay datos sobre la prevalencia de hipoacusia en esta población. El propósito de este estudio fue determinar la frecuencia y tipo de estas alteraciones en nuestra población por medio de evaluación audiológica. Pacientes y métodos: Se realizó un estudio de corte trasversal en dos instituciones especializadas en el acompañamiento y terapia de familias de niños con síndrome de Down en Bogotá D. C., Colombia. Entre octubre de 2017 y septiembre de 2018, se realizó audiometría comportamental y/o tonal e impedanciometría en 40 y en 37 niños respectivamente. Los sujetos asistían a las instituciones dos veces por semana y estaban integrados en diferentes grados escolares hasta quinto de primaria. Se estimó la prevalencia y se describieron las características, antecedentes clínicos e hitos del desarrollo del lenguaje. Resultados: Se obtuvo una muestra de 40 niños (22 mujeres) con edades entre 6 y 18 años (media: 11,23). Se encontró antecedente de otitis en 19 sujetos e hipoacusia de leve a moderada en 17 niños, predominantemente, conductiva. Hubo retraso en hitos del desarrollo del lenguaje, en apariencia, no asociado a hipoacusia. Conclusiones: En una muestra de niños con síndrome de Down en Bogotá, se encontró una alta prevalencia de hipoacusia, consistente con resultados de estudios previos. Estos datos resaltan la necesidad de un control estricto de la capacidad auditiva basado en parámetros y guías estandarizadas.

A cohort study of two intravenous treatments for iron deficiency in patients with heart failure.

Background: Iron deficiency (ID) in patients with heart failure (HF) leads to greater morbidity and mortality and its treatment has been associated with significant improvements in quality of life. Since no head-to-head studies are available, there is uncertainty as to which intravenous iron supplement should be used. This study aimed to compare the effect of ferric carboxymaltose (FCM) and iron saccharate (IS) on clinical and biochemical outcomes in patients with HF and ID.Methods: We reviewed electronic health records from a referral centre in Bogotá, Colombia for patients with HF. We selected records with a follow-up of at least 2 years. Primary outcomes were clinically significant changes in EuroQol-5D (EQ-5D) , 6-minute-walk test (6MWT), resolution of ID, and direct costs.Results: We obtained data on 119 patients with a median age of 69 years and a median left ventricular ejection fraction (LVEF) of 35%. All patients met criteria for ID, and 58% were treated with FCM. A significant difference in GFR of 11 mL/min/1.72 m2 was found at baseline between groups. Neither bivariate, nor multivariate analyses could identify significant differences between patients receiving FCM and IS for any of the primary outcomes. Direct cost analysis showed that FCM use generates 2.8 times the cost associated with saccharate use.Conclusions: This retrospective cohort study did not identify any significant differences in clinical or biochemical outcomes between HF patients with ID receiving FCM or IS. Direct cost analysis favoured use of IS in this group of patients.

Outcomes in Patients with Moyamoya Syndrome and Sickle Cell Disease: A Systematic Review.

BACKGROUND: Moyamoya syndrome, a progressive, idiopathic stenosis of the internal carotid arteries, results in increased risk for both ischemic and hemorrhagic strokes. Revascularization procedures have been shown in small studies to be both safe and efficacious for these patients; however, randomized controlled trials are lacking. The goal of this systematic review is to organize the literature evaluating surgical intervention versus conservative medical management. METHODS: A systematic review was performed including studies with 3 or more participants with moyamoya syndrome in the setting of sickle cell disease and a measured outcome after either medical or surgical intervention. Relevant studies were identified using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria and a set of predetermined key words. RESULTS: Sixty-one articles were identified with 6 articles ultimately included in this review (N = 122). Of the patients, 73 (59.8%) were revascularized surgically (all indirect procedures), whereas 49 (40.2%) remained on chronic transfusion therapy. Of the patients that underwent indirect revascularization surgery, a total of 1 perioperative (1.4%) and 4 postoperative strokes (5.5%) were reported over 44 months (1 stroke per 53.3 patient-years). In comparison, an average of 46.5% of patients who were receiving chronic transfusions had major events (stroke or transient ischemic attack) while undergoing therapy (1 stroke per 13.65 patient-years, P = 0.00215). CONCLUSIONS: We present a large systematic review of the literature regarding outcomes of surgical and medical management for patients with moyamoya syndrome and sickle cell disease. The findings redemonstrate the efficacy and safety of surgical revascularization, and advocate for earlier discussion around surgical intervention.

Standardizing music characteristics for the management of pain: A systematic review and meta-analysis of clinical trials.

PURPOSE: To evaluate if music characteristics like tempo, harmony, melody, instrumentation, volume, and pitch, as defined by musical theory, are described in randomized clinical trials (RCTs) evaluating the effects of music-listening on the quantified pain perception of adults, and if these characteristics influence music's overall therapeutic effect. METHODS: A systematic review and meta-analysis of RCTs evaluating music-listening for pain management on adults was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. The databases Pubmed, Scopus, SCIELO, SpringerLink, Global Health Library, Cochrane, EMBASE, and LILACS were searched. Studies published between 2004 and 2017 with quantified measurements of pain were included. Quality was evaluated using the Scottish Intercollegiate Guidelines Network methodology checklist for RCT, and effect sizes were reported with standardized mean differences. RESULTS: A total of 85 studies were included for qualitative analysis but only 56.47% described at least one music characteristic. Overall meta-analysis found a significant effect, with high heterogeneity, of music for pain management (SMD -0.59, I2 = 85%). Only instrumentation characteristics (lack of lyrics, of percussion or of nature sounds), and 60-80 bpm tempo were described sufficiently for analysis. All three instrumentation characteristics had significant effects, but only the lack of lyrics showed an acceptable heterogeneity. CONCLUSIONS: Results show that music without lyrics is effective for the management of pain. Due to insufficient data, no ideal music characteristics for the management of pain were identified suggesting that music, as an intervention, needs standardization through an objective language such as that of music theory.

Effectiveness of Animal-Assisted Therapy in the Pediatric Population: Systematic Review and Meta-Analysis of Controlled Studies.

OBJECTIVE: To synthesize the results of controlled studies evaluating the effectiveness of animal-assisted therapy (AAT) in children. METHODS: Eleven databases were searched following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement recommendations, and references from included studies and previous reviews were examined. No date or language filters were applied. Only controlled study designs, including those using wait-list controls, that studied a specific condition or illness were included. Study quality was assessed using the Cochrane Risk of Bias Tool. RESULTS: Twenty-six studies that met the inclusion criteria were retrieved. Nine were conducted in children with autism spectrum disorders, 10 in cerebral palsy (CP), 2 in Down syndrome, 3 in pain, and 2 in other conditions. Qualitative synthesis showed a small but significant contribution of AAT to the management of these conditions. Meta-analysis showed a mean difference in improvement in the Gross Motor Function Measure-66 scale in children with CP of 1.61 (95% confidence interval [CI] -2.00 to 5.23) and a mean difference for 5-point pain scales of -0.81 (95% CI -1.32 to 0.30), both favoring AAT. CONCLUSION: Animal-assisted therapy may be useful as a complementary intervention in the management of children with CP and pain. Although results are in general positive for the management of children with Down syndrome and autism, the diversity of scales used to measure outcomes makes it difficult to establish true effectiveness. The application of simple corrective measures in the randomization process would greatly improve the quality of evidence. It is necessary to reach a consensus between AAT researchers regarding appropriate instruments to provide higher-quality evidence in further studies.

Animal-assisted therapy in adults: A systematic review.

Animal-assisted therapies have become widespread with programs targeting a variety of pathologies and populations. Despite its popularity, it is unclear if this therapy is useful. The aim of this systematic review is to establish the efficacy of Animal assisted therapies in the management of dementia, depression and other conditions in adult population. A search was conducted in MEDLINE, EMBASE, CINAHL, LILACS, ScienceDirect, and Taylor and Francis, OpenGrey, GreyLiteratureReport, ProQuest, and DIALNET. No language or study type filters were applied. Conditions studied included depression, dementia, multiple sclerosis, PTSD, stroke, spinal cord injury, and schizophrenia. Only articles published after the year 2000 using therapies with significant animal involvement were included. 23 articles and dissertations met inclusion criteria. Overall quality was low. The degree of animal interaction significantly influenced outcomes. Results are generally favorable, but more thorough and standardized research should be done to strengthen the existing evidence.

Geospatial-temporal distribution of Tegumentary Leishmaniasis in Colombia (2007-2016).

BACKGROUND: Tegumentary Leishmaniasis (TL) is a neglected disease with worldwide distribution and considered a public health problem, especially in Latin America. In Colombia, the governmental epidemiological surveillance system (SIVIGILA) is responsible for collecting information on the presentation of cases of TL from each of the municipalities and departments. In absence of a study compiling and analyzing currently available metadata of TL in Colombia, this study describes the geospatial-temporal distribution of TL and identifies the regions of the country on which prevention measures should be established in order to control the disease. METHODOLOGY/PRINCIPAL FINDINGS: This is an exploratory descriptive analysis of the distribution of TL in Colombia. Information was collected on new cases of the disease during the years 2007-2016 from the Colombian reporting system (SIVIGILA). Incidence calculations were made based on population estimates by departments and biogeographical regions. Time evolution is shown in biennial maps. A 10-year series was analyzed, showing that the Amazon region is the most affected in terms of incidence, while the Andean region has the highest number of cases with a high variability among the departments that make it up. In those departments where there is a greater reported diversity of vector species, a large number of cases was observed. CONCLUSIONS/SIGNIFICANCE: Transmission dynamics of TL in Colombia in the past 10 years have been variable, with a greater concentration of cases in the central and southern departments. The present study contributes to improve the understanding of the patterns of distribution of TL in Colombia and can be a basis for future studies of impact evaluation of Health policies in the country and the region.

ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA.

The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase checkpoint pathway maintains genome integrity; however, the role of the sirtuin 2 (SIRT2) acetylome in regulating this pathway is not clear. We found that deacetylation of ATR-interacting protein (ATRIP), a regulatory partner of ATR, by SIRT2 potentiates the ATR checkpoint. SIRT2 interacts with and deacetylates ATRIP at lysine 32 (K32) in response to replication stress. SIRT2 deacetylation of ATRIP at K32 drives ATR autophosphorylation and signaling and facilitates DNA replication fork progression and recovery of stalled replication forks. K32 deacetylation by SIRT2 further promotes ATRIP accumulation to DNA damage sites and binding to replication protein A-coated single-stranded DNA (RPA-ssDNA). Collectively, these results support a model in which ATRIP deacetylation by SIRT2 promotes ATR-ATRIP binding to RPA-ssDNA to drive ATR activation and thus facilitate recovery from replication stress, outlining a mechanism by which the ATR checkpoint is regulated by SIRT2 through deacetylation.

Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival.

Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents.