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Abstract Background Urothelial carcinoma (UC) is the most common urinary bladder tumor in dogs, often invading and involving the bladder wall, trigone, urethra, and prostate and can lead to obstruction of urine outflow at the level of the ureters or urethra. Hypothesis/Objectives To describe the outcome of dogs with UC presenting with urethral or ureteral obstruction treated with radiation therapy (RT). Animals Twenty-five client-owned dogs treated with RT. Methods A retrospective analysis was conducted. Overall survival, time to first event, and restoration of patency were evaluated by obstruction location and radiotherapy protocol. Results Overall obstruction relief was achieved in 15/25 (60%) dogs. Definitive intent protocols showed significantly longer time to obstruction relief (median 8 vs 4 days; range 2-10 vs 2-7 days; P = .02), however, had higher overall efficacy (83% vs 53%) and survival times compared to palliative intent protocols (P = .01). Dogs that had relief of obstruction regardless of RT intent received a significantly higher total dose compared to those that did not experience relief (median 36 Gy vs 8 Gy; range 12-57 vs 6-24 Gy; P < .001). Median overall survival time was 134 days (range 6-969 days) and time to first event was 107 days (range 4-695 days). Location of obstruction did not significantly improve survival or time to obstruction relief. Relief was temporary for 27% of unobstructed dogs, and re-obstruction was seen at a median of 14 days (range 5-33 days). Conclusions and clinical importance Radiation therapy is a viable treatment option for relieving urinary obstruction secondary to UC. Radiation therapy protocol should be determined based on the dog’s clinical signs, ability to medically manage obstruction, and therapeutic goals of the owner.

Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (T H 9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into T H 9 cells relative to Atg3- or Atg5 -expressing control cells. In addition, the T H 9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances T H 9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of T H 9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of T H 9 activity for cancer immunotherapy. Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate T H 9 homeostasis and antitumour immunity.

Introduction Superficial x‐rays (50–100 kVp) are used for treating non‐melanoma skin cancer and intraoperative radiation therapy (IORT). At these energies, the photoelectric effect significantly increases absorbed dose to bone compared to soft tissue. Methods We used EGSnrc MC simulations to investigate bone dose enhancement during radiotherapy with the Sensus SRT‐100 machine. Simulated beams were validated against laboratory measurements and compared to a commercial treatment planning system (SmART‐ATP). Transmission simulations indirectly predicted bone dosage. Simulated beams were utilized as a mock treatment plan from a human cone‐beam computed tomography (CBCT) image. Results EGSnrc accurately modeled the Sensus SRT‐100 beams (100, 70, and 50 kVp) with a root mean square error (RMSE) of percentage depth dose ratios between Monte Carlo predictions and lab measurements of 1.66, 0.47, and 0.99, respectively. PDDs from simulations of a water phantom with bone slabs showed peak doses at water–bone interfaces relative to surface doses. At 0.3 cm depth bone slab, doses reached 410%, 490%, and 510% for 50, 70, and 100 kVp, respectively. At 1.5 cm depth, doses were 140%, 215%, and 270%. At 2.5 cm depth, peak doses were 74%, 130%, and 170% for 50, 70, and 100 kVp, respectively. A simulated treatment plan (4 Gy surface dose) using a CBCT of a human head predicted the dose to the skull to be around 20, 19, and 15 Gy for the 100, 70, and 50 kVp beams, respectively. Conclusions The study demonstrated EGSnrc's efficiency in conjunction with SmART‐ATP for treatment planning. MC simulations effectively quantified bone dose enhancement during superficial x‐ray radiotherapy, highlighting its importance in treatment planning and dose calculations. Clinicians should consider measuring bone depth prior to treatment to avoid excessive bone dose.

Abstract Background The safety and efficacy of stereotactic body radiation therapy (SBRT) in the treatment of localized nasal lymphoma in cats has not been described. Hypothesis Stereotactic body radiation therapy with or without adjuvant chemotherapy is an effective and well-tolerated treatment for localized nasal lymphoma in cats. Animals Thirty-two client owned cats referred to Colorado State University for the treatment of nasal lymphoma. Methods Retrospective study of cats treated with SBRT between 2010 and 2020 at Colorado State University. Diagnosis of nasal lymphoma was obtained via cytology or histopathology. Signalment, radiation protocol, concurrent treatments, adverse effects, and survival were recorded. Results Progression free survival was 225 days (95% CI 98–514) and median survival time (MST) was 365 days (95% CI 123–531). No significant difference in survival was identified between cats that received 1 versus greater than 1 fraction (MST 427 vs. 123 days, P = 0.88). Negative prognostic factors included cribriform lysis (MST 121 vs. 876 days, P = 0.0009) and intracalvarial involvement (MST 100 vs. 438 days, P = 0.0007). Disease progression was noted in 38% (12/32), locally in 22% (7/32), and systemically in 16% (5/32). No cats developed acute adverse effects. Ten cats developed late adverse effects: keratitis/keratitis sicca (n = 2), alopecia (n = 4), and leukotrichia (n = 4). Twenty-four cats (75%) had signs consistent with chronic rhinitis. Conclusions SBRT is effective and well tolerated for treating localized nasal lymphoma in cats. Outcomes for cats with lower stage disease (canine modified Adam's stage 3 and lower) are comparable to historic data of cats treated with fractionated radiation therapy.

Background Lattice radiotherapy (LRT) administers spatially fractionated doses to a tumor volume with the intent to induce beneficial anti-tumor host responses and avoid normal tissue damage. This study investigated feasibility of LRT for canine sinonasal carcinoma (SC) using volumetric modulated arc therapy (VMAT), aiming to achieve the following criteria: (1) place ≥ 3 vertices of high dose “peak” regions within the gross target volume (GTV) separated by low dose “valley” regions; (2) achieve a 3:1 and 5:1 peak-to-valley dose ratios (PVDR); (3) meet organ at risk (OAR) dose constraints; (4) meet quality assurance (QA) standards. A secondary aim was to assess the impact of dose calculation algorithms and grid size on dosimetry. The peak vertices were placed manually as 5 mm 3D spheres within the GTV. Treatment plans were initially optimized and calculated on Eclipse using Acuros with 2.5 mm grid size and underwent QA using Varian’s Portal Dosimetry (3 mm/3%). Plans were then recalculated without re-optimization comparing Acuros XB (AXB) and anisotropic analytical algorithm (AAA) with variable grid sizes, to compare doses estimated for peak and valley lattice target volume and OARs. Results Twenty plans were generated from 10 image sets from dogs with SC. In all cases, (1) placement of ≥ 3 vertices was possible, with a median center-to-center distance of 30 mm (range: 26–41 mm); (2) achieved both 3:1 and 5:1 PDVR; (3) plans met OAR constraints; (4) all plans passed QA with gamma index > 95%. When comparing calculation algorithms with a consistent grid size, AAA overestimated the dose in both peak and valley regions compared to AXB. When using AXB, increasing the dose calculation grid size from 1.0 mm to 2.0 mm and 2.5 mm led to underestimation of the lattice metrics and overestimation of the valley dose, ultimately resulting in a reduced calculated PVDR. These deviations were not detected on standard clinical QA with portal dosimetry. Conclusion VMAT LRT planning and delivery is feasible for canine SC. This data suggests that the predicted—and consequently, reported—lattice target metrics can vary depending on specific treatment planning software settings. Further investigations could define the most appropriate QA approach for high-resolution LRT plans.

To report the survival times in dogs that received a standardized palliative-intent radiation therapy (RT) protocol for the treatment of canine appendicular osteosarcoma (OSA), alone or in combination with bisphosphonates (BPs), and to determine whether the addition of BPs affects survival. A secondary objective was to identify prognostic features that may influence outcome in dogs undergoing treatment. Retrospective case series. Dogs with presumed or confirmed OSA of the appendicular limb treated with daily hypofractionated RT (8 Gy x 2) at the Flint Animal Cancer Center between 2010 and 2019 were evaluated retrospectively. Clinical data were abstracted from the medical records, and adjuvant therapies were noted. Outcome was assessed using medical records and electronic follow up. One hundred and sixty-five dogs were included. Sixty-eight dogs received BPs as a part of their palliative-intent treatment. The median survival time from first RT treatment to death was not significantly different between groups (119 vs. 109 days for BP and non-BP groups, respectively, = 0.758). Only age (>9 years) was found to be prognostic in this population ( = 0.031). Factors that were not found to be associated with survival time included BP drug type, timing of BP administration, tumor location, weight, breed, sex, time to treatment, concurrent administration of chemotherapy, and salvage amputation. This study suggests no difference in outcome for dogs treated with and without BPs in addition to hypofractionated RT. Prospective studies are needed to determine if the addition of BPs to hypofractionated RT leads to an improved quality of life in dogs undergoing palliative-intent treatment for OSA.

Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggregates in close association with microvessel endothelium but the species specificity of N. meningitidis has previously hindered the development of an in vivo model to study the role of adhesion on disease progression. Here we introduced human dermal microvessels into SCID/Beige mice by xenografting human skin. Bacteria injected intravenously exclusively associated with the human vessel endothelium in the skin graft. Infection was accompanied by a potent inflammatory response with the secretion of human inflammatory cytokines and recruitment of inflammatory cells. Importantly, infection also led to local vascular damage with hemostasis, thrombosis, vascular leakage and finally purpura in the grafted skin, replicating the clinical presentation for the first time in an animal model. The adhesive properties of the type IV pili of N. meningitidis were found to be the main mediator of association with the dermal microvessels in vivo. Bacterial mutants with altered type IV pili function also did not trigger inflammation or lead to vascular damage. This work demonstrates that local type IV pili mediated adhesion of N. meningitidis to the vascular wall, as opposed to circulating bacteria, determines vascular dysfunction in meningococcemia.

BackgroundWhile stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive.MethodsHere, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances TH9 cell antitumor activity against mouse melanoma upon adoptive transfer.ResultsWe found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of TH1 and TH9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of TH1 cell differentiation. However, STING activation favors TH9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 cells upon adoptive transfer.ConclusionOur results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.

Objectives: The clinical and social burden of the COVID-19 pandemic were high among asylum seekers (ASs). We aimed to understand better ASs’ experiences of the pandemic and their sources of worries. Methods: Participants ( n = 203) completed a survey about their worries, sleep disorders, and fear of dying. We also conducted semi-structured interviews with ASs living in a community center ( n = 15), focusing on how social and living conditions affected their experiences and worries. Results: ASs in community centers experienced more sleep disorders related to the COVID-19 pandemic than those living in private apartments (aOR 2.01, p = 0.045). Similarly, those with lower education had greater fear for their life due to the COVID-19 pandemic (aOR 2.31, p = 0.015). Qualitative findings showed that sharing living spaces was an important source of worries for ASs and that protective measures were perceived to increase social isolation. Conclusion: Our study highlighted the impact of the COVID-19 pandemic for ASs and the importance of tailoring public health measures to their needs and living conditions.

The aim of this study was to describe the therapeutic outcomes of dogs with locally advanced salivary gland carcinomas (SGC) following stereotactic body radiation therapy (SBRT). A single institution retrospective study was conducted of client-owned dogs with macroscopic SGC treated with SBRT. Patient signalment, clinical characteristics, and treatment parameters were recorded. Clinical benefit was determined based on follow-up physical examination and medical history. Progression-free interval (PFI), median survival time (MST), and disease-specific survival (DSS) were calculated using Kaplan-Meier analysis. Acute and late toxicity were recorded according to Veterinary Radiation Therapy Oncology Group (VRTOG) criteria. Six patients were included in the study. Tumor origins were mandibular (  = 3), parotid (  = 2), and zygomatic (  = 1) salivary glands. The SBRT prescription was 10 Gy × 3 daily or every other day. All patients (100%) experienced clinical benefit from treatment at a median time of 34 days (range 28-214). No local or regional nodal failure was reported following SBRT. Progressive pulmonary metastatic disease was documented in three dogs (50%). The median PFI was 260 days (range 43-1,014) and the MST was 397 days (range 185-1,014). Median DSS was 636 days (range 185-1,014). Four dogs (66.6%) died of confirmed or suspected metastatic SGC. The reported acute side effects included grade 2 mucositis (  = 1) and vision loss (  = 1). No late side effects were recorded. This study suggests that SBRT may provide durable local control for invasive SGC in dogs. Further investigation in a larger cohort of patients is warranted. The incidence of reported acute and late toxicity was low.