Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration.

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.

Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice.

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies.

Intensity-modulated radiotherapy and chemotherapy for canine right atrial tumors: A retrospective study of seven dogs.

Most primary cardiac tumors in dogs are located in the right atrium/atrial appendage, with hemangiosarcoma being the most common. The aims of this retrospective, case series were to describe outcomes for seven dogs with right atrial tumors treated with hypofractionated intensity-modulated radiotherapy and concurrent vinblastine and propranolol. One dog had a complete response, four dogs had partial responses and two dogs had stable disease after treatment. Effusions resolved in all dogs. Median progression-free survival was 290 days. Five dogs died from metastatic disease, one dog from unrelated neoplasia, and one dog is alive. Median overall survival was 326 days. Three dogs with confirmed hemangiosarcoma survived 244, 326, and 445 days. Two dogs developed clinically significant, but nonfatal, cardiac arrhythmias. One dog that received three courses of radiation had subclinical myocardial and arterial fibrosis at necropsy. Hypofractionated chemoradiotherapy was well tolerated and may provide clinical benefit in dogs with right atrial tumors.

ACVR and ECVDI consensus statement: Reporting elements for toxicity criteria of the veterinary radiation therapy oncology group v2.0.

The toxicity criteria of the veterinary radiation therapy oncology group (VRTOG) version 2 guidelines are a substantial update to reflect significant advances in radiation oncology over the last three decades. Radiation therapy techniques provide precise and spatially accurate radiation delivery, which facilitates treating tumors in more anatomic locations and incorporating hypofractionated protocols. The purpose of this update is to aid radiation oncology teams in capturing and grading clinically relevant data that impacts the decision-making process in everyday practice and the assessment of clinical trials involving radiation therapy. A dedicated committee initially updated the criteria to include more anatomical sites and grades to characterize a broad spectrum of possible radiation-induced acute and late tissue changes. Through the revision process, which solicited and incorporated feedback from all radiation oncologists within the American College of Veterinary Radiology (ACVR) and specialists outside the ACVR, the authors endeavored to create a grading structure reflective of clinical decision-making in daily radiation oncology. The updated VRTOG v2 toxicity criteria guideline complements the updated Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) guidelines. Because radiation oncology continues to progress rapidly, the VRTOG toxicity criteria should be regularly updated as adverse event data that will be collected following this update further informs the practice of radiation oncology.

Contouring in the optic plane improves the accuracy of computed tomography-based segmentation of the optic pathway.

Canine optic pathway structures are often contoured on CT images, despite the difficulty of visualizing the optic pathway with CT using standard planes. The purpose of this prospective, analytical, diagnostic accuracy study was to examine the accuracy of optic pathway contouring by veterinary radiation oncologists (ROs) before and after training on optic plane contouring. Optic pathway contours used as the gold standard for comparison were created based on expert consensus from registered CT and MRI for eight dogs. Twenty-one ROs contoured the optic pathway on CT using their preferred method, and again following atlas and video training demonstrating contouring on the optic plane. The Dice similarity coefficient (DSC) was used to assess contour accuracy. A multilevel mixed model with random effects to account for repeated measures was used to examine DSC differences. The median DSC (5th and 95th percentile) before and after training was 0.31 (0.06, 0.48) and 0.41 (0.18, 0.53), respectively. The mean DSC was significantly higher after training compared with before training (mean difference = 0.10; 95% CI, 0.08-0.12; P < 0.001) across all observers and patients. DSC values were comparable to those reported (0.4-0.5) for segmentation of the optic chiasm and nerves in human patients. Contour accuracy improved after training but remained low, potentially due to the small optic pathway volumes. When registered CT-MRI images are not available, our study supports routine addition of an optic plane with specific window settings to improve segmentation accuracy in mesaticephalic dogs ≥11 kg.

Prions induce an early Arc response and a subsequent reduction in mGluR5 in the hippocampus.

Synapse dysfunction and loss are central features of neurodegenerative diseases, caused in part by the accumulation of protein oligomers. Amyloid-ß, tau, prion, and α-synuclein oligomers bind to the cellular prion protein (PrPC), resulting in the activation of macromolecular complexes and signaling at the post-synapse, yet the early signaling events are unclear. Here we sought to determine the early transcript and protein alterations in the hippocampus during the pre-clinical stages of prion disease. We used a transcriptomic approach focused on the early-stage, prion-infected hippocampus of male wild-type mice, and identify immediate early genes, including the synaptic activity response gene, Arc/Arg3.1, as significantly upregulated. In a longitudinal study of male, prion-infected mice, Arc/Arg-3.1 protein was increased early (40% of the incubation period), and by mid-disease (pre-clinical), phosphorylated AMPA receptors (pGluA1-S845) were increased and metabotropic glutamate receptors (mGluR5 dimers) were markedly reduced in the hippocampus. Notably, sporadic Creutzfeldt-Jakob disease (sCJD) post-mortem cortical samples also showed low levels of mGluR5 dimers. Together, these findings suggest that prions trigger an early Arc response, followed by an increase in phosphorylated GluA1 and a reduction in mGluR5 receptors.

Minimal late radiation toxicity and transient early toxicity following postoperative definitive intent conformal radiation therapy (20 × 2.5 Gy) for canine apocrine gland anal sac adenocarcinoma.

Postoperative radiation therapy (RT) may be beneficial for dogs with anal sac apocrine gland adenocarcinoma (ASAC). Clinically significant late toxicities have been reported in up to 65% of dogs with perianal tumors following non-conformal definitive RT, particularly when fractions of 3 Gy or higher are prescribed. The primary objective of this prospective, descriptive study was to evaluate tolerability of a novel 3D conformal RT (3DCRT) protocol in a group of dogs. Dogs with ASAC were prospectively enrolled if clients elected RT following surgery. The planning target volume was prescribed 50 Gy in 2.5 Gy fractions using 6 MV photons and administered over 26 days. Early and late radiation toxicities were graded according to standardized criteria. Thirteen dogs were initially enrolled but 1 was excluded due to a high risk of anesthesia-related mortality. Seven dogs presented with early stage disease. Median follow up time was 771 days (91-2223). Transient grade 3 dermatitis and anusitis developed in all dogs, with resolution within 4 weeks. Two dogs developed transient grade 2 late colitis. Locoregional failure in the irradiated field was documented in one dog at 738 days. All-cause median survival time was 771 days (95% confidence interval: 510 â†’ 2223 days). Findings indicated that this fractionation may be safely administered to the canine anus and pelvic canal using 3DCRT, although acute toxicity should be anticipated. Further prospective studies are needed in order to confirm long-term tolerability and efficacy.

Relationship Distress at Home and Burnout Among 254 Pediatric Intensive Care Nurses.

OBJECTIVES: To assess the prevalence of relationship distress and burnout among PICU nurses. DESIGN: Cross-sectional, web-based survey. SETTING: Pediatric intensive care nursing practices in the United States. SUBJECTS: Pediatric intensive care nurses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 254 pediatric intensive care nurses in the United States completed the survey consisting of demographic data, practice, and personal characteristics, Revised Dyadic Adjustment Scale, and modified Maslach Burnout Inventory. Relationship distress in consensus was noted in 45.6% of participants, and 26.3% reported distress in relationship satisfaction. Moderate to high burnout was reported by 65% nurses in the emotional exhaustion domain, 43% in depersonalization, and 27% of nurses reported low personal accomplishment. A significant difference in relationship satisfaction was found among nurses identified in different domains of burnout, showing that nurses who scored higher in depersonalization also reported higher distress in relationship satisfaction (p = 0.045). Interestingly, nurses who reported high personal accomplishment (thereby less burnout) reported higher distress in relationship consensus (p = 0.015). The difference in the satisfaction subscale between different age groups was significant, suggesting distress in satisfaction among nurses over the age of 40 (p = 0.004). Comparison of nurses actively involved in marriage counseling with those not actively involved in marriage counseling demonstrated a significant difference in relationship consensus (p = 0.046; odds ratio = 2.46; 95% CI, 0.99-6.06) and satisfaction (p = 0.004; odds ratio = 3.26; 95% CI, 1.42-7.47), suggesting an association between higher relationship distress and counseling. CONCLUSIONS: This study reflects the prevalence of relationship distress and its association with burnout and other practice and personal factors among PICU nurses. Nurses with high depersonalization experienced significantly higher distress in relationship satisfaction, and nurses who reported high personal satisfaction had significantly higher distress in relationship consensus.

Machine learning model development for quantitative analysis of CT heterogeneity in canine hepatic masses may predict histologic malignancy.

Tumor heterogeneity is a well-established marker of biologically aggressive neoplastic processes and is associated with local recurrence and distant metastasis. Quantitative analysis of CT textural features is an indirect measure of tumor heterogeneity and therefore may help predict malignant disease. The purpose of this retrospective, secondary analysis study was to quantitatively evaluate CT heterogeneity in dogs with histologically confirmed liver masses to build a predictive model for malignancy. Forty dogs with liver tumors and corresponding histopathologic evaluation from a previous prospective study were included. Triphasic image acquisition was standardized across dogs and whole liver and liver mass were contoured on each precontrast and delayed postcontrast dataset. First-order and second-order indices were extracted from contoured regions. Univariate analysis identified potentially significant indices that were subsequently used for top-down model construction. Multiple quadratic discriminatory models were constructed and tested, including individual models using both postcontrast and precontrast whole liver or liver mass volumes. The best performing model utilized the CT features voxel volume and uniformity from postcontrast mass contours; this model had an accuracy of 0.90, sensitivity of 0.67, specificity of 1.0, positive predictive value of 1.0, negative predictive value of 0.88, and precision of 1.0. Heterogeneity indices extracted from delayed postcontrast CT hepatic mass contours were more informative about tumor type compared to indices from whole liver contours, or from precontrast hepatic mass and whole liver contours. Results demonstrate that CT radiomic feature analysis may hold clinical utility as a noninvasive method of predicting hepatic malignancy and may influence diagnostic or therapeutic approaches.

Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia.

Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.

Volumetric tumor response assessment is inefficient without overt clinical benefit compared to conventional, manual veterinary response assessment in canine nasal tumors.

Accurate assessment of tumor response to therapy is critical in guiding management of veterinary oncology patients and is most commonly performed using response evaluation criteria in solid tumors criteria. This process can be time consuming and have high intra- and interobserver variability. The primary aim of this serial measurements, secondary analysis study was to compare manual linear tumor response assessment to semi-automated, contoured response assessment in canine nasal tumors. The secondary objective was to determine if tumor measurements or clinical characteristics, such as stage, would correlate to progression-free interval. Three investigators evaluated paired CT scans of skulls of 22 dogs with nasal tumors obtained prior to and following radiation therapy. The automatically generated tumor volumes were not useful for canine nasal tumors in this study, characterized by poor intraobserver agreement between automatically generated contours and hand-adjusted contours. The radiologist's manual linear method of determining response evaluation criteria in solid tumors categorization and tumor volume is significantly faster (P < .0001) but significantly underestimates nasal tumor volume (P < .05) when compared to a contour-based method. Interobserver agreement was greater for volume determination using the contour-based method when compared to response evaluation criteria in solid tumors categorization utilizing the same method. However, response evaluation criteria in solid tumors categorization and percentage volume change were strongly correlated, providing validity to response evaluation criteria in solid tumors as a rapid method of tumor response assessment for canine nasal tumors. No clinical characteristics or tumor measurements were significantly associated with progression-free interval.

Factors Associated With Burnout in Trauma Nurses.

BACKGROUND: Burnout is a psychological syndrome resulting from repeated stressors experienced in the workplace that centers on emotional exhaustion, detachment from the job, and a sense of ineffectiveness. It has been previously demonstrated that burnout exists in the health care workforce, but there has been limited investigation of burnout in nurses who primarily provide care for patients who have been traumatically injured. The purpose of this study was to explore factors associated with burnout reported by trauma nurses. METHODS: This was a secondary analysis of a cross-sectional survey distributed at a large, academic Level I trauma center that serves both adult and pediatric patients. For this analysis, only the Burnout subscale of the Professional Quality of Life scale Version 5 (ProQOL) was used. Multivariate hierarchical regression was used to determine factors associated with burnout reported by trauma nurses. RESULTS: Protective factors included being female, being married, and better quality of sleep. Risk factors included having a mental health diagnosis and working with adult populations. CONCLUSIONS: These results provide an important contribution to the burnout risk profile for trauma nurses and may provide insight into future investigations as well as development and testing of tailored interventions to mitigate burnout in trauma nurses.

The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression.

Back on Track: The challenges of implementing a small place-based Collective Impact initiative.

ISSUES ADDRESSED: Back on Track (BoT) was developed as pilot to provide an integrated service response to twenty at-risk young people residing in a metro Melbourne housing estate. For this cohort, traditional welfare sector interventions were proving ineffective, with the siloed nature of the sector identified as a key barrier to effective engagement. METHODS: Developed as an offshoot of an established CI project, the Education Engagement Partnership (EEP), BoT used Collective Impact (CI) methodology to inform project development. CI was considered a means to implement systematic change whilst increasing positive health, education and justice outcomes for the target cohort. RESULTS: BoT was abandoned after start-up due to a lack of CI model buy-in on the part of one stakeholder. CONCLUSIONS: BoT's initial success can be directly attributed to stakeholder experience of the EEP. The project's break down illuminates challenges that can emerge when the welfare sector attempts interagency collaborative practices. BoT highlights the centrality of relationship-building for successful CI implementation and flags potential issues in collaborations between small place-based initiatives and large statewide agencies constrained by non-negotiable internal policies. SO WHAT?: CI methodology is increasing popular in health promotion work, and there is a need to examine how the methodology translates into local level practice.

INVITED REVIEW--IMAGE REGISTRATION IN VETERINARY RADIATION ONCOLOGY: INDICATIONS, IMPLICATIONS, AND FUTURE ADVANCES.

The field of veterinary radiation therapy (RT) has gained substantial momentum in recent decades with significant advances in conformal treatment planning, image-guided radiation therapy (IGRT), and intensity-modulated (IMRT) techniques. At the root of these advancements lie improvements in tumor imaging, image alignment (registration), target volume delineation, and identification of critical structures. Image registration has been widely used to combine information from multimodality images such as computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) to improve the accuracy of radiation delivery and reliably identify tumor-bearing areas. Many different techniques have been applied in image registration. This review provides an overview of medical image registration in RT and its applications in veterinary oncology. A summary of the most commonly used approaches in human and veterinary medicine is presented along with their current use in IGRT and adaptive radiation therapy (ART). It is important to realize that registration does not guarantee that target volumes, such as the gross tumor volume (GTV), are correctly identified on the image being registered, as limitations unique to registration algorithms exist. Research involving novel registration frameworks for automatic segmentation of tumor volumes is ongoing and comparative oncology programs offer a unique opportunity to test the efficacy of proposed algorithms.

Identifying the dominant prostate cancer focal lesion using image analysis and planning of a simultaneous integrated stereotactic boost.

BACKGROUND: Prostate cancer is now the only solid organ cancer in which therapy is commonly applied to the whole gland. One of the main challenges in adopting focal boost or true focal therapy is in the accurate mapping of cancer foci defined on magnetic resonance (MR) images onto the computerised tomography (CT) images used for radiotherapy planning. MATERIAL AND METHODS: Prostate cancer patients (n = 14) previously treated at the Edinburgh Cancer Centre (ECC) were selected for this study. All patients underwent MR scanning for the purpose of diagnosis and staging. Patients received three months of androgen deprivation hormone therapy followed by a radiotherapy planning CT scan. The dominant focal prostate lesions were identified on MR scans by a radiologist and a novel image analysis approach was used to map the location of the dominant focal lesion from MR to CT. An offline planning study was undertaken on suitable patients (n = 7) to investigate boosting of the radiation dose to the tumour using a stereotactic ablative body radiotherapy (SABR) technique. RESULTS: The non-rigid registration algorithm showed clinically acceptable estimates of the location of the dominant focal disease on all CT image data of patients suitable for a boost treatment. Standard rigid registration was found to produce unacceptable estimates of the dominant focal lesion on CT. A SABR boost dose of 47.5 Gy was delivered to the dominant focal lesion of all patients whilst meeting all dose-volume histogram (DVH) constraints. Normal tissue complication probability (NTCP) for the rectum decreased from 1.28% to 0.73% with this method. CONCLUSIONS: These preliminary results demonstrate the potential of this image analysis method for reliably mapping dominant focal disease within the prostate from MR images onto planning CT images. Significant dose escalation using a simultaneous integrated SABR boost was achieved in all patients.

Is there preliminary value to a within- and/or between-session change for determining short-term outcomes of manual therapy on mechanical neck pain?

OBJECTIVES: The primary purpose of this study was to determine whether occurrences of within- and between-session changes were significantly associated with functional outcomes, pain, and self-report of recovery in patients at discharge who were treated with manual therapy for mechanical neck pain. A secondary purpose was to determine the extent of change needed for the within- and between-session change in association to function. METHODS: This secondary data analysis examined 56 patients who demonstrated a positive response to manual therapy during the initial assessment within a randomized controlled trial (RCT) that examined manual therapy techniques and a home exercise program (HEP). Within- and between-session findings were defined as 'changes in pain report during the initial session (within)' and 'changes in pain from baseline to 48-hours post initial assessment (between)'. Outcomes were analyzed for associations with the global rating of change (GRoC), self-report activity scale (SRAS), and a 50% reduction of the neck disability index (NDI) by discharge at 96 hours. RESULTS: Findings indicate that within-session pain changes of 36.7% are strongly associated with a 50% change in NDI at 96 hours. Between-session changes in pain were associated with 50% change in NDI and a ≧3-point change in GRoC at 96 hours. CONCLUSION: Both within- and between-session measures may be useful to predict success levels at 96 hours for NDI; however, between-session changes are more useful to predict success in GRoC. Measures used during clinical examination may help guide clinicians in identification of candidates best suited for the treatment.

Cancer related cognitive impairment: a downside of cancer treatment.

Cancer treatment is associated with long lasting cognitive impairment in cancer survivors. This cognitive impairment is often termed cancer related cognitive impairment (CRCI). Cancer survivors treated for tumors outside the central nervous system are increasingly diagnosed with CRCI. The development of strategies to mitigate the negative effects of cancer treatment on the brain are crucial. Although neuroimaging research has proposed several candidate mechanisms, the pathogenic underpinnings of CRCI remain uncertain. As such, preventative and treatment strategies have not been identified. To fill these gaps, animal models play a vital role in isolating underlying contributing mechanisms that promote CRCI and in testing new therapeutic approaches.

Radiation Therapy and Myeloid-Derived Suppressor Cells: Breaking Down Their Cancerous Partnership.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

Malaria-associated L-arginine deficiency induces mast cell-associated disruption to intestinal barrier defenses against nontyphoidal Salmonella bacteremia.

Coinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop L-arginine deficiency, which is associated with intestinal mastocytosis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of L-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coli Nissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with L-arginine or L-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis and macromolecular permeability. Supplementation with L-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing L-arginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans.