Stereotactic Radiotherapy for penile metastasis: case report and systematic literature review.

Introduction Penile metastases (PM) are a rare clinical presentation mainly related to advanced stages of disease. Considering the low incidence, an optimal treatment approach has not yet been defined; surgery, chemotherapy, and radiotherapy are different options used in the vast majority with palliative intent. The advances in modern RT can represent an innovative tool in PM management and a curative option. This paper aims to report the case of a PM patient treated with Stereotactic Body Radiotherapy (SBRT) and perform a systematic literature review of current evidence on the RT approach to PM. Case report We reported the case of an 80-year-old patient with PM from primary bladder cancer. Following the surgical approach for the primary tumor, evidence of PM was shown, and the patient was admitted to SBRT treatment on PM after an adjuvant RT course on the pelvis. A 25 Gy in 5 fractions SBRT treatment was performed, and a complete clinical response was shown at the first follow-up. Methods A Pubmed/MEDLINE and Embase systematic review was carried out. The search strategy terms were [('penile metastasis'/exp OR 'penile metastasis' OR (penile AND ('metastasis'/exp OR metastasis))) AND ('radiotherapy'/exp OR radiotherapy)] and only original articles up to the 24.10.2023 were considered. Results A total of 174 studies were obtained using the previously mentioned search strategy, and the analysis was performed on 15 papers obtained following the complete selection process. All reported evidence was focused on the palliative approach of PM showing good results in terms of symptom control. Discussion The potential role of modern RT in the management of PM has yet to be defined. The reported case showed the feasibility and the clinical impact of SBRT in PM treatment.

Impaired astrocytic synaptic function by peripheral cholesterol metabolite 27-hydroxycholesterol.

Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer's disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.

PI3Kγδ inhibition suppresses key disease features in a rat model of asthma.

BACKGROUND: Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma. METHODS: Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays. Subsequently, a time-course study was conducted in a rat model of asthma to assess PI3K activity in the lung and how it is temporally associated with other key transcription pathways and asthma like features of the model. Finally, the impact on lung dosed AZD8154 on target engagement, pathway specificity, airway inflammation and lung function changes was assessed. RESULTS: Data showed that AZD8154 could inhibit rat PI3K γ & δ isoforms and, in a rat model of allergic asthma the PI3K pathway was activated in the lung. Intratracheal administration of AZD8154 caused a dose related suppression PI3K pathway activation (reduction in pAkt) and unlike after budesonide treatment, STAT and NF-κB pathways were not affected by AZD8154. The suppression of the PI3K pathway led to a marked inhibition of airway inflammation and reduction in changes in lung function. CONCLUSION: These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma.

Radiomics-enhanced early regression index for predicting treatment response in rectal cancer: a multi-institutional 0.35 T MRI-guided radiotherapy study.

PURPOSE: The accurate prediction of treatment response in locally advanced rectal cancer (LARC) patients undergoing MRI-guided radiotherapy (MRIgRT) is essential for optimising treatment strategies. This multi-institutional study aimed to investigate the potential of radiomics in enhancing the predictive power of a known radiobiological parameter (Early Regression Index, ERITCP) to evaluate treatment response in LARC patients treated with MRIgRT. METHODS: Patients from three international sites were included and divided into training and validation sets. 0.35 T T2*/T1-weighted MR images were acquired during simulation and at each treatment fraction. The biologically effective dose (BED) conversion was used to account for different radiotherapy schemes: gross tumour volume was delineated on the MR images corresponding to specific BED levels and radiomic features were then extracted. Multiple logistic regression models were calculated, combining ERITCP with other radiomic features. The predictive performance of the different models was evaluated on both training and validation sets by calculating the receiver operating characteristic (ROC) curves. RESULTS: A total of 91 patients was enrolled: 58 were used as training, 33 as validation. Overall, pCR was observed in 25 cases. The model showing the highest performance was obtained combining ERITCP at BED = 26 Gy with a radiomic feature (10th percentile of grey level histogram, 10GLH) calculated at BED = 40 Gy. The area under ROC curve (AUC) of this combined model was 0.98 for training set and 0.92 for validation set, significantly higher (p = 0.04) than the AUC value obtained using ERITCP alone (0.94 in training and 0.89 in validation set). CONCLUSION: The integration of the radiomic analysis with ERITCP improves the pCR prediction in LARC patients, offering more precise predictive models to further personalise 0.35 T MRIgRT treatments of LARC patients.

Artificial intelligence applied to image-guided radiation therapy (IGRT): a systematic review by the Young Group of the Italian Association of Radiotherapy and Clinical Oncology (yAIRO).

INTRODUCTION: The advent of image-guided radiation therapy (IGRT) has recently changed the workflow of radiation treatments by ensuring highly collimated treatments. Artificial intelligence (AI) and radiomics are tools that have shown promising results for diagnosis, treatment optimization and outcome prediction. This review aims to assess the impact of AI and radiomics on modern IGRT modalities in RT. METHODS: A PubMed/MEDLINE and Embase systematic review was conducted to investigate the impact of radiomics and AI to modern IGRT modalities. The search strategy was "Radiomics" AND "Cone Beam Computed Tomography"; "Radiomics" AND "Magnetic Resonance guided Radiotherapy"; "Radiomics" AND "on board Magnetic Resonance Radiotherapy"; "Artificial Intelligence" AND "Cone Beam Computed Tomography"; "Artificial Intelligence" AND "Magnetic Resonance guided Radiotherapy"; "Artificial Intelligence" AND "on board Magnetic Resonance Radiotherapy" and only original articles up to 01.11.2022 were considered. RESULTS: A total of 402 studies were obtained using the previously mentioned search strategy on PubMed and Embase. The analysis was performed on a total of 84 papers obtained following the complete selection process. Radiomics application to IGRT was analyzed in 23 papers, while a total 61 papers were focused on the impact of AI on IGRT techniques. DISCUSSION: AI and radiomics seem to significantly impact IGRT in all the phases of RT workflow, even if the evidence in the literature is based on retrospective data. Further studies are needed to confirm these tools' potential and provide a stronger correlation with clinical outcomes and gold-standard treatment strategies.

High-resolution kinetic characterization of the RIG-I-signaling pathway and the antiviral response.

RIG-I recognizes viral dsRNA and activates a cell-autonomous antiviral response. Upon stimulation, it triggers a signaling cascade leading to the production of type I and III IFNs. IFNs are secreted and signal to elicit the expression of IFN-stimulated genes, establishing an antiviral state of the cell. The topology of this pathway has been studied intensively, however, its exact dynamics are less understood. Here, we employed electroporation to synchronously activate RIG-I, enabling us to characterize cell-intrinsic innate immune signaling at a high temporal resolution. Employing IFNAR1/IFNLR-deficient cells, we could differentiate primary RIG-I signaling from secondary signaling downstream of the IFN receptors. Based on these data, we developed a comprehensive mathematical model capable of simulating signaling downstream of dsRNA recognition by RIG-I and the feedback and signal amplification by IFN. We further investigated the impact of viral antagonists on signaling dynamics. Our work provides a comprehensive insight into the signaling events that occur early upon virus infection and opens new avenues to study and disentangle the complexity of the host-virus interface.

Stereotactic Body Radiotherapy for Lymph-Nodal Oligometastatic Prostate Cancer: A Multicenter Retrospective Experience.

Background: The favorable role of SBRT for lymph-nodal oligometastases from prostate cancer has been reported by several retrospective and prospective experiences, suggesting a more indolent natural history of disease when compared to patients with bone oligometastases. This retrospective multicenter study evaluates the outcomes of a cohort of patients treated with stereotactic body radiotherapy for lymph-nodal oligometastases. Methods: Inclusion criteria were up to five lymph-nodal oligometastases detected either with Choline-PET or PSMA-PET in patients naïve for ADT or already ongoing with systemic therapy and at least 6 Gy per fraction for SBRT. Only patients with exclusive lymph-nodal disease were included. The primary endpoint of the study was LC; a toxicity assessment was retrospectively performed following CTCAE v4.0. Results: A total of 100 lymph-nodal oligometastases in 69 patients have been treated with SBRT between April 2015 and November 2022. The median age was 73 years (range, 60-85). Oligometastatic disease was mainly detected with Choline-PET in 47 cases, while the remaining were diagnosed using PSMA-PET, with most of the patients treated to a single lymph-nodal metastasis (48/69 cases), two in 14 cases, and three in the remaining cases. The median PSA prior to SBRT was 1.35 ng/mL (range, 0.3-23.7 ng/mL). Patients received SBRT with a median total dose of 35 Gy (range, 30-40 Gy) in a median number of 5 (range, 3-6) fractions. With a median follow-up of 16 months (range, 7-59 months), our LC rates were 95.8% and 86.3% at 1 and 2 years. DPFS rates were 90.4% and 53.4%, respectively, at 1 and 2 years, with nine patients developing a sequential oligometastatic disease treated with a second course of SBRT. Polymetastatic disease-free survival (PMFS) at 1 and 2 years was 98% and 96%. Six patients needed ADT after SBRT for a median time of ADT-free survival of 15 months (range, 6-22 months). The median OS was 16 months (range, 7-59) with 1- and 2-year rates of both 98%. In multivariate analysis, higher LC rates and the use of PSMA-PET were related to improved DPFS rates, and OS was significantly related to a lower incidence of distant progression. No G3 or higher adverse events were reported. Conclusions: In our experience, lymph-nodal SBRT for oligometastatic prostate cancer is a safe and effective option for ADT delay with no severe toxicity.

Stereotactic Radiotherapy in Early-Stage Breast Cancer in Neoadjuvant and Exclusive Settings: A Systematic Review.

INTRODUCTION: Breast cancer (BC) is one of the most common tumors; better screening policies and multidisciplinary approach allow personalized treatment. Radiotherapy (RT) plays a central role in the multimodal approach in BC, and recent evidence has shown the non-inferiority of hypofractionated treatments. The aim of this study was to describe the feasibility and validity of stereotactic RT (SBRT) in BC in a neoadjuvant and exclusive setting. METHODS: A PubMed/MEDLINE and Embase systematic review was conducted to assess the role of radiomics in BC. The search strategy was "breast [All Fields] AND "stereotactic" [All Fields] AND "radiotherapy" [All Fields]" and only original articles referred to BC in humans in the English language were considered. RESULTS: A total of 2,149 studies were obtained using the mentioned search strategy on PubMed and Embase. After the complete selection process, a total of 12 papers were considered eligible for the analysis of the results. SBRT in BC was described in 8 studies regarding neoadjuvant approach and 4 papers regarding exclusive approach. CONCLUSIONS: Relative low toxicity rates, the reduced treatment volumes in the neoadjuvant setting, and the possibility to replace surgery when not feasible in exclusive setting resulted to be main advantages for SBRT in BC. Current evidence shows that both the neoadjuvant and the definitive settings seem to be promising clinical scenarios for SBRT, especially for EBC.

The Added Value of [18F]Choline PET/CT in Low-Risk Prostate Cancer Staging: A Case Report.

In the management of prostate cancer (PCa), correct staging is crucial in order to assess the right therapeutic approach. [18F]Choline PET/CT has been shown to provide more accurate staging information than conventional imaging approaches. The aim of this paper is to provide a real practice demonstration of the impact of [18F]Choline PET/CT on low-risk prostate cancer staging and clinical management. We report a 64-year-old man with biochemical PCa recurrence diagnosis after transurethral resection of the prostate. The patient, after the detection of an increased level of PSA, underwent multi-parametric prostate magnetic resonance imaging (mpMRI) that did not show evidence of disease. The patient was admitted to perform [18F]Choline PET/CT that showed a macroscopic prostate recurrence. Patient underwent photon external beam radiation therapy (EBRT) treatment, and [18F]Choline PET/CT was also used to define treatment volumes. At 3- and 6-month clinical follow-up evaluations, no late toxicity was detected and a significant reduction in PSA value was shown. Therefore, our case highlights the potential usefulness of [18F]Choline PET/CT for the staging of low-risk prostate cancer and its impact on the management and quality of life of such patients. The presented case should urge the scientific community to enhance larger and multicentric studies, assessing more extensively the potential impact of [18F]Choline PET/CT in this clinical scenario.

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma.

Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation. Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 µg/kg and AZD4604 at 30 µg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]). Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model. Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.

Covid-19 and radiotherapy: a systematic review after 2 years of pandemic.

Introduction: Following the Covid-19 pandemic spread, changes in clinical practice were necessary to limit the pandemic diffusion. Also, oncological practice has undergone changes with radiotherapy (RT) treatments playing a key role.Although several experiences have been published, the aim of this review is to summarize the current evidence after 2 years of pandemic to provide useful conclusions for clinicians. Methods: A Pubmed/MEDLINE and Embase systematic review was conducted. The search strategy was "Covid AND Radiotherapy" and only original articles in the English language were considered. Results: A total of 2.733 papers were obtained using the mentioned search strategy. After the complete selection process, a total of 281 papers were considered eligible for the analysis of the results. Discussion: RT has played a key role in Covid-19 pandemic as it has proved more resilient than surgery and chemotherapy. The impact of the accelerated use of hypofractionated RT and telemedicine will make these strategies central also in the post-pandemic period.

Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient-derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung-derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type-dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.

Heel Spur and Radiotherapy: Case Report and Systematic Literature Review.

Heel spur is a chronic inflammatory condition causing pain and other typical symptoms. Therapeutic recommendations include the use of several drug or orthotic/physical therapies, performed alone or in combination. Surgery is usually reserved for refractory conditions. Radiotherapy has been shown to ensure good clinical outcomes in this clinical setting. A systematic review was performed to describe the feasibility and effectiveness of radiotherapy in the treatment of heel spur, evaluating its role in alleviating pain and consequently ensuring a better quality of life. A case report of 45-year-old patient treated for refractary right hindfoot pain was reported. A single fraction of 6 Gy RT was delivered with symptomatic complete response at 2 months observed. A systematic database search was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The systematic review included studies describing heel spur treatment and providing complete information about radiotherapy. Fifteen articles published between 1996 and 2020 were reviewed. Study characteristic analysis resulted in seven prospective randomized studies and eight retrospective studies. Radiotherapy of painful heel spur seems to be safe and effective, with high response rates even at low doses and with an overall favorable toxicity profile. Predictive parameters and modern tailored treatment should be investigated with further studies.

Clinical Validation of a Deep-Learning Segmentation Software in Head and Neck: An Early Analysis in a Developing Radiation Oncology Center.

BACKGROUND: Organs at risk (OARs) delineation is a crucial step of radiotherapy (RT) treatment planning workflow. Time-consuming and inter-observer variability are main issues in manual OAR delineation, mainly in the head and neck (H & N) district. Deep-learning based auto-segmentation is a promising strategy to improve OARs contouring in radiotherapy departments. A comparison of deep-learning-generated auto-contours (AC) with manual contours (MC) was performed by three expert radiation oncologists from a single center. METHODS: Planning computed tomography (CT) scans of patients undergoing RT treatments for H&N cancers were considered. CT scans were processed by Limbus Contour auto-segmentation software, a commercial deep-learning auto-segmentation based software to generate AC. H&N protocol was used to perform AC, with the structure set consisting of bilateral brachial plexus, brain, brainstem, bilateral cochlea, pharyngeal constrictors, eye globes, bilateral lens, mandible, optic chiasm, bilateral optic nerves, oral cavity, bilateral parotids, spinal cord, bilateral submandibular glands, lips and thyroid. Manual revision of OARs was performed according to international consensus guidelines. The AC and MC were compared using the Dice similarity coefficient (DSC) and 95% Hausdorff distance transform (DT). RESULTS: A total of 274 contours obtained by processing CT scans were included in the analysis. The highest values of DSC were obtained for the brain (DSC 1.00), left and right eye globes and the mandible (DSC 0.98). The structures with greater MC editing were optic chiasm, optic nerves and cochleae. CONCLUSIONS: In this preliminary analysis, deep-learning auto-segmentation seems to provide acceptable H&N OAR delineations. For less accurate organs, AC could be considered a starting point for review and manual adjustment. Our results suggest that AC could become a useful time-saving tool to optimize workload and resources in RT departments.

Bullous pemphigoid and radiotherapy: Case report and literature review update.

Bullous pemphigoid (BP) is a common autoimmune bullous disease generally occurring in elderly patients. Itchy and tense blisters on normal skin or erythematous and edematous lesions on the trunk and extremities usually characterize BP. Trigger factors are still unclear while several case reports suggest a potential role of radiotherapy (RT) as BP trigger for disease onset or recrudescence. A review was performed to provide an update of literature. A case report of a patient affected by BP undergoing two radiotherapy courses for a primary breast cancer was also reported. A comprehensive review of the published literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review included studies describing BP and its relationships with RT treatments. A total of 13 articles were reviewed. Studies characteristics analysis resulted in eleven case reports, one case series and one large-scale case- control study. Literature update confirms the existence of a reasonable connection between RT and BP. Case report showed that a multidisciplinary management seems to assure the feasibility of RT in patients affected by BP, not depriving them of standard therapeutic opportunities.

The Impact of COVID-19 on Universal Newborn Hearing Screening.

OBJECTIVES: To report the direct and indirect impact of coronavirus disease 2019 pandemic on the Universal Newborn Hearing Screening program of our institution (Azienda Ospedaliero Universitaria di Sassari). DESIGN: Monocentric retrospective study whose target population included all the newborns born in or referred to our hospital in 2019 and 2020. RESULTS: There is no statistically significant difference in time to retest or loss to follow-up rate between the 2 years considered (2019 to 2020). Referral rate is not higher for newborns born to severe acute respiratory syndrome coronavirus 2 polymerase chain reaction positive mothers. CONCLUSIONS: In relation to the analyzed variables, coronavirus disease 2019 seems to have a limited impact on our screening program. Severe acute respiratory syndrome coronavirus 2 did not behave as an audiological risk factor in our series.

Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases.

The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.

New dosimetric parameters to predict ano-rectal toxicity during radiotherapy treatment.

PURPOSE: Radiotherapy is essential in the treatment of locally advanced rectal cancer. Side effects of radiotherapy in the treatment of rectal cancer have a great effect on quality of life. The aim of this retrospective study is to evaluate the correlation between dosimetric parameters and acute toxicity in rectal cancer patients. METHODS: We analyzed the Dose Volume Histogram parameters for both the target structures and the Organs at risk of 89 patients. A dedicated statistical analysis was performed for all the acute toxicities showing a frequency rate higher than 20%. A linear logistic regression model was elaborated using the variable showing the highest level of significance at the univariate analysis. RESULTS: The occurrence of proctitis was significantly correlated with three dosimetric parameters: D98% of low ano-rectum, D98% and Dmean of low ano-rectum wall. A predictive linear logistic regression model reports that the D98% of the wall of the low ano-rectum must be < 38.5 Gy to decrease the rate of proctitis. A general analysis on grade 2 acute toxicity occurrence reported that it was correlated with D98% of low ano rectum. CONCLUSIONS: Two dose constraints were elaborated: D98%<33.5 Gy for low ano rectum to prevent grade 2 acute toxicity and D98%<25 Gy for low ano-rectum wall to prevent proctitis (grade 1 or superior).

The interferon-inducible GTPase MxB promotes capsid disassembly and genome release of herpesviruses.

Host proteins sense viral products and induce defence mechanisms, particularly in immune cells. Using cell-free assays and quantitative mass spectrometry, we determined the interactome of capsid-host protein complexes of herpes simplex virus and identified the large dynamin-like GTPase myxovirus resistance protein B (MxB) as an interferon-inducible protein interacting with capsids. Electron microscopy analyses showed that cytosols containing MxB had the remarkable capability to disassemble the icosahedral capsids of herpes simplex viruses and varicella zoster virus into flat sheets of connected triangular faces. In contrast, capsids remained intact in cytosols with MxB mutants unable to hydrolyse GTP or to dimerize. Our data suggest that MxB senses herpesviral capsids, mediates their disassembly, and thereby restricts the efficiency of nuclear targeting of incoming capsids and/or the assembly of progeny capsids. The resulting premature release of viral genomes from capsids may enhance the activation of DNA sensors, and thereby amplify the innate immune responses.