Survey on Parkinson's Disease Diagnosis Impact: Patients, Caregivers and Health Care Professionals' Perspectives.

Background: The announcement of Parkinson's disease (PD) diagnosis may provoke negative feelings that impact the ability to cope with the disease and all life changes related to this new condition. There are scarce data on how to improve communication about PD diagnosis and which factors may influence this outcome. Methods: We performed a national French survey, investigating the diagnosis announcement impact on a large population of people living with PD (PwPD), who recently received the diagnosis (≤1 year since PD diagnosis), and on related caregivers and health care professionals (HCPs), from tertiary and community-based hospitals. Results: A total of 397 PwPD (45% female and 82% > 50 years old), 192 caregivers and 120 HCPs (69% neurologists) completed the questionnaire. The diagnosis was not expected by about 60% of PwPD and induced negative feelings in the majority (82%) of them. Negative feelings that PwPD experience in the moment of the diagnosis announcement were related with male gender [OR = 2.034, CI 95% 1.09-3.78; p = 0.025] and older age [OR = 1.05, CI 95% 1.01-1.08; p = 0.004], while tremor as the first symptom had a threshold significance [OR = 1.78, CI 95% 0.994-3.187; p = 0.052]. Half of the PwPD and caregivers considered that they did not receive enough information and one third had a short-term appointment to rediscuss the diagnosis. A total of 82% of PwPD expressed the willingness to have a multidisciplinary follow-up (PD nurse, psychologists). Only 24% of the HCPs had been trained for PD announcement. Conclusions: The way a PD diagnosis is delivered represents a pivotal moment in the journey of PwPD and caregivers. This process requires improvement in addressing the gaps expressed by PwPD, caregivers, and HCPs through a participatory approach.

Efficiency and tolerance of second-line triple BRAF inhibitor/MEK inhibitor/anti-PD1 combined therapy in BRAF mutated melanoma patients with central nervous system metastases occurring during first-line combined targeted therapy: a real-life survey.

Although current systemic therapies significantly improved the outcome of advanced melanoma, the prognosis of patient with central nervous system (CNS) metastases remains poor especially when clinically symptomatic. We aimed to investigate the efficiency of CNS targets and tolerance of second-line combined anti-PD1/dual-targeted anti-BRAF/anti-MEK therapy implemented in patients with CNS progression after initially efficient first-line combined targeted therapy in patients with BRAF-mutated melanoma in a real-life setting. A monocentric retrospective analysis including all such patients treated from January 2017 to January 2022 was conducted in our tertiary referral center. The response of CNS lesions to second-line triple therapy was assessed through monthly clinical and at least quarterly morphological (according to RECIST criteria) evaluation. Tolerance data were also collected. Seventeen patients were included with a mean follow-up of 2.59 (±2.43) months. Only 1 patient displayed a significant clinical and morphological response. No statistically significant difference was observed between patients receiving or not additional local therapy (mainly radiotherapy) as to response achievement. Immunotherapy was permanently discontinued in 1 patient owing to grade 4 toxicity. Mean PFS and OS after CNS progression were 2.59 and 4.12 months, respectively. In this real-life survey, the subsequent addition of anti-PD1 to combined targeted therapy in melanoma patients with upfront CNS metastases did not result in significant response of CNS targets in most BRAF mutated melanoma patients with secondary CNS progression after initially successful first-line combined targeted therapy.

[Topical treatment for age-related macular degeneration: Where are we now?] / Traitement topique de la dégénérescence maculaire liée à l'âge - Où en sommes-nous ?

The therapeutic management of age-related macular degeneration (AMD) is a major public health issue. One of its two late forms, neovascular AMD, is currently treated by intravitreal injections of pharmaceutical active ingredients. Although it is very effective in treating pathologies of the posterior segment of the eye, the intravitreal route is not an ideal option for the long-term management of a chronic disease such as AMD. Indeed, in the literature, some authors even call it a "burden" for the practitioners, the patients and the healthcare system. Thus, consideration should be given to less invasive routes. Among the possible administration routes to reach the posterior segment of the eye, the most suitable for the patient with the least risk of systemic adverse effects is the topical route. Several research teams have attempted to formulate molecules for topical administration in the treatment of atrophic or neovascular AMD. In this review, we emphasize the importance of the pharmaceutical formulation to meet the challenge of targeting the posterior segment of the eye by a topical route.

Title: Traitement topique de la dégénérescence maculaire liée à l'âge - Où en sommes-nous ? Abstract: La prise en charge thérapeutique de la dégénérescence maculaire liée à l'âge (DMLA) est un enjeu majeur de santé publique. L'une de ses deux formes tardives, la DMLA néovasculaire, est actuellement traitée par injection intravitréenne de molécules anti-angiogéniques. Bien qu'elle soit très efficace pour traiter les atteintes du segment postérieur de l'œil, la voie intravitréenne n'est pas une option idéale pour la prise en charge au long cours d'une maladie chronique telle que la DMLA. L'administration topique de molécules actives contre cette maladie, plus confortable pour le patient et moins coûteuse pour la société, représente un vrai défi.

When mechanical engineering inspired from physiology improves postural-related somatosensory processes.

Despite numerous studies uncovering the neural signature of tactile processing, tactile afferent inputs relating to the contact surface has not been studied so far. Foot tactile receptors being the first stimulated by the relative movement of the foot skin and the underneath moving support play an important role in the sensorimotor transformation giving rise to a postural reaction. A biomimetic surface, i.e., complying with the skin dermatoglyphs and tactile receptors characteristics should facilitate the cortical processes. Participants (n = 15) stood either on a biomimetic surface or on two control surfaces, when a sudden acceleration of the supporting surface was triggered (experiment 1). A larger intensity and shorter somatosensory response (i.e., SEP) was evoked by the biomimetic surface motion. This result and the associated decrease of theta activity (5-7 Hz) over the posterior parietal cortex suggest that increasing the amount of sensory input processing could make the balance task less challenging when standing on a biomimetic surface. This key point was confirmed by a second experiment (n = 21) where a cognitive task was added, hence decreasing the attentional resources devoted to the balance motor task. Greater efficiency of the postural reaction was observed while standing on the biomimetic than on the control surfaces.

Development and Validation of a Prediction Score for Low-Cardiac-Output Syndrome After Adult Cardiac Surgery.

OBJECTIVES: The authors aimed to develop a simple prediction score to help identify patients at high risk of low-cardiac-output syndrome after adult cardiac surgery. DESIGN: A single-center, retrospective, observational study. SETTING: At a tertiary hospital. PARTICIPANTS: Adult patients who underwent on-pump cardiac surgery between April 2016 and March 2021. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Among the 2,806 patients retained for final analyses, 355 (12.7%) developed low-cardiac-output syndrome. Using a stepwise backward variable selection procedure applied to a multivariate logistic regression, a prediction model, including 8 risk factors, could be identified-preoperative left ventricular ejection fraction, glomerular filtration rate <60 mL/min according to the Cockcroft formula or preoperative dialysis, combined surgery, nonelective surgery, mitral valve surgery for mitral valve regurgitation, history of extracardiac arteriopathy, preoperative hemoglobin <13 g/dL, and New York Heart Association functional class III or IV. A clinical prediction score was derived from the regression coefficients. The model had a good discriminative ability, with an area under the receiver operating characteristics curve of 0.8 (95% CI: 077-0.84). Using a threshold value of 5, the score had a 68% sensitivity, 79% specificity, a positive-predictive value of 33%, and a negative-predictive value of 94%. These results were validated on a validation sample using the bootstrap resampling technique. CONCLUSIONS: The authors developed a clinical score to facilitate the prediction of low- cardiac-output syndrome after adult cardiac surgery. This could help tailor patient management by contributing to the early identification of those at high risk of postoperative low cardiac output.

Cortical facilitation of somatosensory inputs using gravity-related tactile information in humans with vestibular hypofunction.

A few years after their bilateral vestibular loss, patients usually show a motor repertoire that is almost back to normal. This recovery is thought to involve an upregulation of the visual and proprioceptive information that compensates for the lack of vestibular information. Here, we investigated whether plantar tactile inputs, which provide body information relative to the ground and to the Earth vertical, contribute to this compensation. More specifically, we tested the hypothesis that somatosensory cortex response to electric stimulation of the plantar sole in standing adults will be greater in humans (n = 10) with bilateral vestibular hypofunction (VH) than in an age-matched healthy group (n = 10). Showing significantly greater somatosensory evoked potentials (i.e., P1N1) in VH than in control subjects, the electroencephalographic recordings supported this hypothesis. Furthermore, we found evidence that increasing the differential pressure between both feet, by adding a 1-kg mass at each pendant wrist, enhanced the internal representation of body orientation and motion relative to a gravitational reference frame. The large decrease in alpha power in the right posterior parietal cortex (and not in the left) is in line with this assumption. Finally, behavioral analyses showed that trunk oscillations were smaller than head oscillations in VH and showed a reverse pattern for healthy participants. These findings are consistent with a tactile-based postural control strategy in the absence of vestibular input and a vestibular-based control strategy in healthy participants where the head serves as a reference for balance control.NEW & NOTEWORTHY Somatosensory cortex excitability is greater in participants with bilateral vestibular hypofunction than in age-matched healthy humans. To control balance, healthy humans "locked" the head whereas participants with vestibular hypofunction "locked" their pelvis. For participants with vestibular hypofunction, increasing loading/unloading of the feet enhances the internal representation of body state in the posterior parietal cortex.

Recent Advances in Age-Related Macular Degeneration Therapies.

Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye's posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the retinal pigment epithelium (RPE) and the outer retinal layers, while the exudative form results in the anarchic invasion by choroidal neo-vessels of RPE and the retina. This invasion is responsible for fluid accumulation in the intra/sub-retinal spaces and for a progressive dysfunction of the photoreceptor cells. To date, the few existing anti-AMD therapies may only delay or suspend its progression, without providing cure to patients. However, in the last decade, an outstanding number of research programs targeting its different aspects have been initiated by academics and industrials. This review aims to bring together the most recent advances and insights into the mechanisms underlying AMD pathogenicity and disease evolution, and to highlight the current hypotheses towards the development of new treatments, i.e., symptomatic vs. curative. The therapeutic options and drugs proposed to tackle these mechanisms are analyzed and critically compared. A particular emphasis has been given to the therapeutic agents currently tested in clinical trials, whose results have been carefully collected and discussed whenever possible.

Partial Unweighting in Obese Persons Enhances Tactile Transmission From the Periphery to Cortical Areas: Impact on Postural Adjustments.

Tactile plantar information is known to play an important role in balance maintenance and to contribute to the setting of anticipatory postural adjustments (APAs) prior to stepping. Previous studies have suggested that somatosensory processes do not function optimally for obese individuals due to the increased pressure of the plantar sole resulting in balance issues. Here, we investigated whether decreasing the compression of the mechanoreceptors by unweighting the plantar sole would enhance tactile sensory processes leading to an increased stability and an accurate setting of the APAs in obese individuals. More specifically, we tested the hypothesis that the somatosensory cortex response to electric stimulation (SEP) of the plantar sole in standing obese persons will be greater with reduced body weight than with their effective weight. The level of unweighting was calculated for each participant to correspond to a healthy body mass index. We showed an increase SEP amplitude in the unweighted condition compared to the effective body weight for all participants. This increase can be explained by the reduction of weight itself but also by the modified distribution of the pressure exerted onto the foot sole. Indeed, in the unweighted condition, the vertical ground reaction forces are evenly distributed over the surface of the foot. This suggests that decreasing and equalizing the pressure applied on the plantar mechanoreceptors results in an increase in somatosensory transmission and sensory processes for obese persons when unweighted. These sensory processes are crucial prior to step initiation and for setting the anticipatory postural adjustments (i.e., thrust). These cortical changes could have contributed to the observed changes in the spatiotemporal characteristics of the thrust prior to step initiation.

Large Postural Sways Prevent Foot Tactile Information From Fading: Neurophysiological Evidence.

Cutaneous foot receptors are important for balance control, and their activation during quiet standing depends on the speed and the amplitude of postural oscillations. We hypothesized that the transmission of cutaneous input to the cortex is reduced during prolonged small postural sways due to receptor adaptation during continued skin compression. Central mechanisms would trigger large sways to reactivate the receptors. We compared the amplitude of positive and negative post-stimulation peaks (P50N90) somatosensory cortical potentials evoked by the electrical stimulation of the foot sole during small and large sways in 16 young adults standing still with their eyes closed. We observed greater P50N90 amplitudes during large sways compared with small sways consistent with increased cutaneous transmission during large sways. Postural oscillations computed 200 ms before large sways had smaller amplitudes than those before small sways, providing sustained compression within a small foot sole area. Cortical source analyses revealed that during this interval, the activity of the somatosensory areas decreased, whereas the activity of cortical areas engaged in motor planning (supplementary motor area, dorsolateral prefrontal cortex) increased. We concluded that large sways during quiet standing represent self-generated functional behavior aiming at releasing skin compression to reactivate mechanoreceptors. Such balance motor commands create sensory reafference that help control postural sway.

A simple indirect colorimetric assay for measuring mitochondrial energy metabolism based on uncoupling sensitivity.

PURPOSE: Cancer cells rapidly adjust their balance between glycolytic and mitochondrial ATP production in response to changes in their microenvironment and to treatments like radiation and chemotherapy. Reliable, simple, high throughput assays that measure the levels of mitochondrial energy metabolism in cells are useful determinants of treatment effects. Mitochondrial metabolism is routinely determined by measuring the rate of oxygen consumption (OCR). We have previously shown that indirect inhibition of plasma membrane electron transport (PMET) by the mitochondrial uncoupler, FCCP, may also be a reliable measure of mitochondrial energy metabolism. Here, we aimed to validate these earlier findings by exploring the relationship between stimulation of oxygen consumption by FCCP and inhibition of PMET. METHODS: We measured PMET by reduction of the cell impermeable tetrazolium salt WST-1/PMS. We characterised the effect of different growth conditions on the extent of PMET inhibition by FCCP. Next, we compared FCCP-mediated PMET inhibition with FCCP-mediated stimulation of OCR using the Seahorse XF96e flux analyser, in a panel of cancer cell lines. RESULTS: We found a strong inverse correlation between stimulation of OCR and PMET inhibition by FCCP. PMET and OCR were much more severely affected by FCCP in cells that rely on mitochondrial energy production than in cells with a more glycolytic phenotype. CONCLUSION: Indirect inhibition of PMET by FCCP is a reliable, simple and inexpensive high throughput assay to determine the level of mitochondrial energy metabolism in cancer cells.

Mitochondrial DNA Affects the Expression of Nuclear Genes Involved in Immune and Stress Responses in a Breast Cancer Model.

Tumor cells without mitochondrial (mt) DNA (ρ0 cells) are auxotrophic for uridine, and their growth is supported by pyruvate. While ATP synthesis in ρ0 cells relies on glycolysis, they fail to form tumors unless they acquire mitochondria from stromal cells. Mitochondrial acquisition restores respiration that is essential for de novo pyrimidine biosynthesis and for mitochondrial ATP production. The physiological processes that underpin intercellular mitochondrial transfer to tumor cells lacking mtDNA and the metabolic remodeling and restored tumorigenic properties of cells that acquire mitochondria are not well understood. Here, we investigated the changes in mitochondrial and nuclear gene expression that accompany mtDNA deletion and acquisition in metastatic murine 4T1 breast cancer cells. Loss of mitochondrial gene expression in 4T1ρ0 cells was restored in cells recovered from subcutaneous tumors that grew from 4T1ρ0 cells following acquisition of mtDNA from host cells. In contrast, the expression of most nuclear genes that encode respiratory complex subunits and mitochondrial ribosomal subunits was not greatly affected by loss of mtDNA, indicating ineffective mitochondria-to-nucleus communication systems for these nuclear genes. Further, analysis of nuclear genes whose expression was compromised in 4T1ρ0 cells showed that immune- and stress-related genes were the most highly differentially expressed, representing over 70% of those with greater than 16-fold higher expression in 4T1 compared with 4T1ρ0 cells. The monocyte recruiting chemokine, Ccl2, and Psmb8, a subunit of the immunoproteasome that generates MHCI-binding peptides, were the most highly differentially expressed. Early monocyte/macrophage recruitment into the tumor mass was compromised in 4T1ρ0 cells but recovered before mtDNA could be detected. Taken together, our results show that mitochondrial acquisition by tumor cells without mtDNA results in bioenergetic remodeling and re-expression of genes involved in immune function and stress adaptation.

Recommendations of the French Society of Rheumatology on pharmacological treatment of knee osteoarthritis.

OBJECTIVES: To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France. METHODS: On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement. RESULTS: Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin<1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections. CONCLUSION: These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

Somatosensory cortical facilitation during step preparation restored by an improved body representation in obese patients.

BACKGROUND: The anticipatory postural adjustments (APA) associated with step initiation are impaired in obese patients (e.g. longer duration, greater lateral center of pressure excursion). This could arise from the known altered internal representation of the body in obese individuals as this representation is crucial for enhancing the processing of foot cutaneous inputs prior to step initiation and for setting the APA. RESEARCH QUESTION: The purpose of the study was to examine if the processing of foot cutaneous inputs and the preparation of the APA when planning a step are impaired in obese patients due to their damaged body internal representation (BIR). We also investigated whether these sensorimotor processes will be restored after a 15-day intervention program composed of motor and cognitive activities engaging the BIR without aiming weight loss. METHODS: We compared, prior to (D1) and after (D15) the program, the amplitude of the cortical response evoked by foot cutaneous stimulation (SEP) occurring either during quiet standing or during the planning of a step in 18 obese patients (mean body mass index, BMI: 35). The APA were analyzed by measuring the amplitude and latency of the lateral force exerted on the ground. RESULTS AND SIGNIFICANCE: The SEP amplitude was not significantly different between the standing and stepping tasks at D1, but increased in the stepping task at D15. This enhanced sensory processing was associated with an increased activation of the posterior parietal cortex, suggesting a stronger involvement of the body representation during the planning of the stepping movement after the program. These cortical changes could have contributed to the changes in the temporal dimension of the APA observed at D15. These results suggest that programs targeting different dimensions of the BIR could be beneficial in improving the dynamic balance in obesity.

The oncogene BCL6 is up-regulated in glioblastoma in response to DNA damage, and drives survival after therapy.

The prognosis for people with the high-grade brain tumor glioblastoma is very poor, due largely to low cell death in response to genotoxic therapy. The transcription factor BCL6, a protein that normally suppresses the DNA damage response during immune cell maturation, and a known driver of B-cell lymphoma, was shown to mediate the survival of glioblastoma cells. Expression was observed in glioblastoma tumor specimens and cell lines. When BCL6 expression or activity was reduced in these lines, increased apoptosis and a profound loss of proliferation was observed, consistent with gene expression signatures suggestive of anti-apoptotic and pro-survival signaling role for BCL6 in glioblastoma. Further, treatment with the standard therapies for glioblastoma-ionizing radiation and temozolomide-both induced BCL6 expression in vitro, and an in vivo orthotopic animal model of glioblastoma. Importantly, inhibition of BCL6 in combination with genotoxic therapies enhanced the therapeutic effect. Together these data demonstrate that BCL6 is an active transcription factor in glioblastoma, that it drives survival of cells, and that it increased with DNA damage, which increased the survival rate of therapy-treated cells. This makes BCL6 an excellent therapeutic target in glioblastoma-by increasing sensitivity to standard DNA damaging therapy, BCL6 inhibitors have real potential to improve the outcome for people with this disease.

Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent.

We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the orthogonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549.

Correction: Synthesis of highly substituted 2-spiropiperidines.

Correction for 'Synthesis of highly substituted 2-spiropiperidines' by Samuel D. Griggs et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c8ob01272e.

Synthesis of highly substituted 2-spiropiperidines.

2-Spiropiperidines are a highly desirable, yet under represented structure in drug discovery. 2-Spiropiperidines were synthesised in either a two-pot or one-pot reaction. In the two-pot reaction, the addition of a Weiler dianion to N-Boc imines, followed by deprotection and in situ condensation with a cyclic ketone generated functionalised 2-spiropiperidines in good to excellent yields. In the one-pot reaction, the addition of Chan's diene to N-Boc imines under Maitland-Japp conditions, followed by the addition of sodium bicarbonate and a cyclic ketone formed functionalised 2-spiropiperidines in moderate to good yields.

Perfluorocarbon emulsions radiosensitise brain tumors in carbogen breathing mice with orthotopic GL261 gliomas.

BACKGROUND: Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy. AIM: To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2). RESULTS: PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone. CONCLUSION: IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors.

A Two-Step Synthesis of 2-Spiropiperidines.

A general two-step synthesis of 2-spiropiperidines has been developed. δ-Amino-ß-ketoesters can be reacted with cyclic ketones to generate 2-spiropiperidines in good to excellent yields. The 2-spiropiperidines formed occupy an under-explored region of 3D-chemical space and are novel scaffolds for use in drug discovery programs. These 2-spiropiperidines can be further functionalised to generate small highly sp3 -rich structures, which exhibit an excellent likeness to lead-molecules in drug discovery.

Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model.

Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8-45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.