Search

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy., Competing Interests: Declaration of interests D.A.M. holds ownership interest in iOncologi, Inc. E.J.S is a paid consultant for Siren Biotechnology. The manuscript discusses patented technologies from H.R.M.-G., P.C., S.Q., J.M., A.P.G., J.H., W.G.S., M.R., D.A.M., and E.J.S. Patented technologies are under option to license by iOncologi, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Within higher education, scholarship is narrowly and inconsistently defined, limiting recognition of evolving faculty expectations, particularly for nursing faculty. At this academic medical center, a campus-wide, multi-school, academic advancement policy was achieved with a broader definition of scholarship that included: peer-reviewed publication of federally funded research, as well as innovation in curriculum development, teaching methodology, community engagement, safety and quality improvement, clinical practice, and health policy that would be applicable to tenure and non-tenure track faculty. The background, process, and outcomes of developing an expanded definition of scholarship that encompasses new and evolving areas of scholarship for a reconstructed academic personnel policy is presented. Beginning with a literature review and surveys of other schools' policies, we describe how a campus-wide working group ensured consensus and acceptance of the new policy. Upon approval of the reconstructed document, guidelines for implementation were widely disseminated through training workshops and discussions, integration into new faculty orientation, and faculty development programs. We share our process, outcomes, and lessons learned believing this information to be useful to other institutions engaged in review and revision of their promotion and tenure processes to align with the increasing expectations of nursing faculty of today and tomorrow., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The melanocortin 4 antagonist TCMCB07 is safe and effective in reversing cachexia caused by sepsis or cancer in rodents. The safety and pharmacokinetics of TCMCB07 are demonstrated in healthy beagle dogs., Hypothesis/objectives: The objectives of this study were to investigate the safety, peak plasma concentrations, and potential for efficacy of TCMCB07 in pet dogs with naturally occurring cachexia over a 4-week time period., Animals: Fourteen dogs with cachexia of any underlying cause, except cancer of the oral cavity or gastrointestinal tract, were eligible for enrollment with informed client consent., Methods: This study was a prospective, 1-armed open-label trial. Physical examination, complete blood count, chemistry panel, and owner-assessed quality of life surveys were checked at weeks 1, 2, and 4. Due to potential for bradycardia and hypotension, Holter monitoring and blood pressure evaluations were scheduled at pre-enrollment and week 4., Results: Fourteen dogs completed the trial. Significant changes detected included increased mean body weight (18.6-19.5 kg, P < .02), increased body condition score (median Tufts 5-point thin dog scale score P < .004 and WSAVA muscle condition score P < .02) and increased mean blood urea nitrogen (21.79-30.43 mg dL -1 , P < .004). On quality of life surveys, pet owners perceived their dog appeared to be panting less (P < .002) and that the general health improved (P < .03). Four dogs had a change in coat pigmentation. The peak plasma concentration of TCMCB07 in cachectic dogs was similar to that in healthy beagle dogs., Conclusions and Clinical Importance: TCMCB07 was safe and has potential efficacy in pet dogs with cachexia., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

GD2 and GD3 are disialoganglioside oncofetal antigens important in oncogenesis. GD2 synthase (GD2S) and GD3 synthase (GD3S) are needed for GD2 and GD3 production. The objectives of this study are to validate the use of RNA in situ hybridization (RNAscope®) in the detection of GD2S and GD3S in canine histiocytic sarcoma (HS) in vitro and optimize this technique in canine formalin-fixed paraffin-embedded (FFPE) tissues. A secondary objective is to evaluate the prognostic significance of GD2S and GD3S on survival. Quantitative RT-PCR compared GD2S and GD3S mRNA expression between three HS cell lines followed by RNAscope® in fixed cell pellets from the DH82 cell line and FFPE tissues. Variables prognostic for survival were determined with Cox proportional hazard model. RNAscope® was validated for detection of GD2S and GD3S and optimized in FFPE tissues. GD2S and GD3S mRNA expression was variable between cell lines. GD2S and GD3S mRNA expression was detected and measured in all tumor tissues; there was no association with prognosis. GD2S and GD3S are expressed in canine HS and successfully detected using the high throughput technique of RNAscope® in FFPE samples. This study provides the foundation for future prospective research of GD2S and GD3S utilizing RNAscope®., Competing Interests: Declarations of Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Abstract: Scholarship, required for academic advancement, has traditionally been defined narrowly, not keeping pace with the expansion of faculty academic activities in health professions schools. How can we refine the definition of scholarship so that it better aligns with the scope of current faculty practice within academic health systems? Revision of the academic policies for promotion and tenure at the University of Massachusetts Chan Medical School afforded an opportunity to redefine scholarship such that a broader platform was available for faculty recognition, aligning with current academic standards, yet providing flexibility for the future. The authors describe the historical context of the definition of scholarship and their institution's process to construct a definition of scholarship with three essential elements: advancement of knowledge, dissemination for critical review, and impact on a discipline, practice, or community. Application of this definition to team science and digital scholarship is also described. Following a widespread continuing education initiative, implementation of the new definition within promotion and tenure processes of the medical, nursing, and graduate schools resulted in broad acceptance across the institution. This forum article provides lessons in leading an academic health sciences institution to reassess academic processes and is a resource for advancing the vigorous debate on the evolving meaning and evaluation of scholarship., Competing Interests: Disclosures: The authors declare no conflict of interest., (Copyright © 2022 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Histiocytic sarcoma (HS) is an aggressive malignant neoplasm in dogs. Expression and prognostic significance of transforming growth factor beta (TGF-β), programmed death-ligand 1 (PD-L1), and T regulatory cells (Tregs) in HS is unknown. The goal of this study was to investigate the expression and prognostic significance of TGF-β, PD-L1, and FoxP3/CD25 in canine HS utilizing RNA in situ hybridization (RNAscope®). After validation was performed, RNAscope® on formalin-fixed paraffin-embedded (FFPE) patient HS tissue samples was performed for all targets and expression quantified with HALO® software image analysis. Cox proportional hazard model was conducted to investigate the association between survival time and each variable. Additionally, for categorical data, the Kaplan-Meier product-limit method was used to generate survival curves. TGF-β and PD-L1 mRNA expression was confirmed in the DH82 cell line by reverse transcription polymerase chain reaction (RT-PCR) and CD25 + FoxP3 + cells were detected by flow cytometry in peripheral blood. Once the RNAscope® method was validated, TGF-β H-score and dots/cell and FoxP3 dots/cell were assessed in HS samples and found to be significantly correlated with survival. Moderate positive correlations were found between FoxP3 and PD-L1 H-score, percent staining area, and dots/cell, and FoxP3 and TGF-β dots/cell. In summary, RNAscope® is a valid technique to detect TGF-β and PD-L1 expression and identify Tregs in canine HS FFPE tissues. Furthermore, canine HS expresses TGF-β and PD-L1. Increased TGF-β and FoxP3 correlated with worse prognosis. Prospective studies are warranted to further investigate TGF-β, PD-L1, and Tregs effect on prognosis., Competing Interests: Declarations of interest None, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Endowed chairs and professorships are prestigious and financially important awards that symbolize individual faculty recognition. However, data about the gender distribution of these positions are lacking. The purpose of this study was to examine the gender distribution of endowed positions at U.S. medical schools and identify strategies that have been used to promote investiture of women into these positions., Method: The authors interrogated the websites for all U.S. medical schools for publicly available data. Of 38 schools that listed schoolwide information, they analyzed data from the 30 with at least 10 endowed positions. Then, they conducted interviews with deans of the 10 schools with the highest percentages of women holding endowed positions ("top 10") to understand the strategies they used to increase gender equity in this area., Results: The percentage of endowed positions held by women at the 30 schools analyzed ranged from 10.8% to 34.6%, with a mean of 21.6%. Themes that emerged from interviews with deans included (1) intentionality to identify women candidates in the selection process, (2) monitoring the numbers of women holding endowed positions, (3) inclusion of endowed positions as part of larger institutional goals on gender equity and diversity, (4) use of endowed positions to recruit, retain, and recognize women faculty, (5) purposeful fundraising to increase the number of endowed positions, and (6) institutional investment of resources to develop women faculty., Conclusions: Analysis of the gender distribution of endowed positions across 30 representative U.S. medical schools revealed a significant gender disparity. Interviews with deans at the top 10 schools revealed strategies that they have used to promote equity in this important area. Implementation of a systematic national reporting process could provide schools with comparative data to gauge their progress., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of American Medical Colleges.)

Background: Canine histiocytic sarcoma (HS) is an aggressive cancer with morphologically variable features; therefore, obtaining a definitive diagnosis can be challenging. Two proteins, IBA-1, ionised calcium-binding adapter molecule 1, and CD204, a macrophage scavenger receptor, have been shown to be specific immunohistochemical markers helpful in distinguishing HS from other tumour types with similar morphological features., Objectives: This study was performed to demonstrate the use of RNA in situ hybridisation (ISH) technology allowing single-molecule RNA visualisation in formalin-fixed paraffin-embedded (FFPE) tissues as a molecular tool for the diagnosis of canine HS., Methods: Reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis for IBA-1 and CD204 were performed to correlate gene expression and protein expression of these two markers in the histiocytic sarcoma DH82 cell line. RNA-ISH for IBA-1 and CD204 was performed on the DH82 cell line to validate the RNA-ISH probes. RNA-ISH and immunohistochemistry (IHC) were performed in clinical HS FFPE samples to demonstrate mRNA and protein expression of IBA-1 and CD204. FFPE archived samples of canine round cell tumours, melanoma and anaplastic sarcoma were used as negative controls., Results: RNA-ISH and IHC showed moderate to strong expression for IBA-1 and CD204 in the neoplastic cells in both the canine DH82 cell line and the archived canine HS samples. RNA-ISH and IHC showed scattered positive staining in the control tumours samples, consistent with macrophagic infiltration., Conclusion: RNA-ISH for CD204 and IBA-1 appeared to have a high specificity and sensitivity in our samples and may be an additional valuable diagnostic technique in identifying HS., (© 2022 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

The purpose of this pilot study was to detect the presence of interleukin-8 (IL-8) and the potential downstream effects of IL-8 receptor activation in 2 previously characterized feline oral squamous cell carcinoma cell lines (SCCF1 and SCCF2). Interleukin-8 messenger RNA (mRNA) was initially detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A previously validated and commercially available enzyme-linked immunosorbent assay (ELISA) test was used to measure IL-8 production in the supernatant of the 2 cell lines. Western blot was used to detect phosphorylation of proteins (AKT, ERK1/2, JAK2, STAT3, and Src), known to be downstream of interleukin-8 receptor activation. The IL-8 receptor-specific antagonists, Reparixin and SCH527123, were used to identify effects on phosphorylation of these proteins. Interleukin-8 mRNA and protein were detected in both SCCF1 and SCCF2 by RT-PCR and ELISA, respectively. Phosphorylation of ERK1/2, STAT3, and Src was detected in both cell lines. Inhibition of the IL-8 receptor led to a decrease in phosphorylation of Src, but not ERK1/2 or STAT3. In conclusion, feline squamous cell carcinoma cell lines can produce IL-8. Phosphorylation of Src seems, at least in part, a consequence of IL-8 receptor activation. The phosphorylation of ERK1/2 and STAT3, although present, seems independent of IL-8 receptor activation. Due to its potential effects on the tumor microenvironment, in addition to its autocrine effects on Src phosphorylation, the inhibition of the IL-8 receptor may become a beneficial therapeutic tool. Evaluation of the presence of both IL-8 and Src in many cases should elucidate their importance., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Osteosarcoma (OSA) is a highly aggressive and metastatic neoplasm of both the canine and human patient and is the leading form of osseous neoplasia in both species worldwide. To gain deeper insight into the heterogeneous and genetically chaotic nature of OSA, we applied single-cell transcriptome (scRNA-seq) analysis to 4 canine OSA cell lines. This novel application of scRNA-seq technology to the canine genome required uploading the CanFam3.1 reference genome into an analysis pipeline (10X Genomics Cell Ranger); this methodology has not been reported previously in the canine species, to our knowledge. The scRNA-seq outputs were validated by comparing them to cDNA expression from reverse-transcription PCR (RT-PCR) and Sanger sequencing bulk analysis of 4 canine OSA cell lines (COS31, DOUG, POS, and HMPOS) for 11 genes implicated in the pathogenesis of canine OSA. The scRNA-seq outputs revealed the significant heterogeneity of gene transcription expression patterns within the cell lines investigated (COS31 and DOUG). The scRNA-seq data showed 10 distinct clusters of similarly shared transcriptomic expression patterns in COS31; 12 clusters were identified in DOUG. In addition, cRNA-seq analysis provided data for integration into the Qiagen Ingenuity Pathway Analysis software for canonical pathway analysis. Of the 81 distinct pathways identified within the clusters, 33 had been implicated in the pathogenesis of OSA, of which 18 had not been reported previously in canine OSA.

Background: Immune-targeted therapies are being successfully implemented into cancer clinical practice. In particular checkpoint inhibitors are employed to modulate the immune microenvironment of solid tumors. We sought to determine the expression of PD-L1, HVEM, and B7H3 in human and canine osteosarcoma, and correlate expression with clinical features and tumor infiltrating lymphocytes in naturally-occurring canine osteosarcoma., Methods: Flow cytometry was used to measure ligand surface expression of five human and three canine cell lines. Immunohistochemistry was utilized for expression of ligands and lymphocyte markers in thirty-seven treatment-naïve canine osteosarcoma patients., Results: All cell lines expressed all three ligands at variable levels in both species. Metastatic lesions were associated with higher expression of all three ligands in patient tumor samples. PD-L1 expression strongly correlated with B7H3 and HVEM expression, while HVEM and B7H3 were weakly correlated. Whereas peritumoral T-cell expression positively correlated with PD-L1 and HVEM tumor expression, the presence of T-cells intratumorally were rare. Furthermore, intratumor penetration by T-cells was greatest in metastatic lesions, despite log-fold increases in peritumoral T-cells. In summary, PD-L1, HVEM, and B7H3 are expressed in osteosarcoma, with metastatic disease lesions expressing higher levels. We show for the first time that these ligands expressed on osteosarcoma cells positively correlate with each other and the presence of peritumoral T cell infiltration. Furthermore, osteosarcoma appears to be an intratumoral immune desert with significant resistance to effector T cells. Multiple agents targeting checkpoints are in clinical practice, and may have immune modulating benefit in osteosarcoma., (Copyright © 2020. Published by Elsevier B.V.)

Fluorescence-activated cell sorting (FACS) is a branch of flow cytometry that allows for the isolation of specific cell populations that can then be further analyzed by single-cell RNA sequencing (scRNA-seq). When utilizing FACS for population isolation prior to sequencing, it is essential to consider the protection of RNA from RNase activity, environmental conditions, and the sorting efficiency to ensure optimum sample quality. This study aimed to optimize a previously published MDSC flow cytometry strategy to FACS sort canine Myeloid-Derived Suppressor Cells (MDSC) with various permutations of RNAlater ™ and RiboLock™ before and after FACS sorting. Concentrations of RNAlater™ greater than 2 % applied before flow analysis affected cell survival and fluorescence, whereas concentrations ≤ 2 % and time ≤ 4 h had little to no effect on cells. To shorten the procedural time and to enhance the sorting of rare populations, we used a primary PE-conjugated CD11b antibody and magnetic column. The combination of RiboLock™ pre- and post-sorting for FACS provided the best quality RNA as determined by the RNA integrity number (RIN ≥ 7) for scRNA-seq in a normal and dog and a dog with untreated oral melanoma dog. As proof of principle, we sequenced two samples, one from a normal dog another from a dog with untreated oral melanoma. Applying scRNA-Seq analysis using the 10X Genomic platform, we identified 6 clusters in the Seurat paired analysis of MDSC sorted samples. Two clusters, with the majority of the cells coming from the melanoma sample, had genes that were upregulated (> log2); these included MMP9, MMP1, HPGD, CPA3, and GATA3 and CYBB, CSTB, COX2, ATP6, and COX 17 for cluster 5 and 6 respectively. All genes have known associations with MDSCs. Further characterization using pathway analysis tools was not attempted due to the lower number of cells sequenced in the normal sample. The benefit deriving from the results of the study helped to gain data consistency when working with cells prone to RNase activity, and the scRNA-seq provided data showing transcriptional heterogeneity in MDSC populations and potentially identifying previously unreported or rare cell populations., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: To describe Academic Health Center (AHC) faculty leadership development program characteristics and categorize leadership topics into thematic areas suggesting competency domains to guide programmatic curricular development., Methods: A systematic literature review was conducted (PubMed/MEDLINE, Scopus, Cumulative Index of Nursing and Allied Health Literature [CINAHL], and Journal Storage [JSTOR databases]). Eligible studies described programs with leadership development intent for faculty in AHCs. Information was extracted using a structured data form and process., Results: Six hundred ninety citations were screened; 25 publications describing 22 unique programs were eligible. The majority (73%) were institutionally based; mean class size was 18.5 (SD ± 10.2, range 4.5-48); and mean in-person time commitment was 110 hours (SD ± 101.2, range 16-416), commonly occurring in regular intervals over months to years (n = 10, 45%). Six programs provided per participant costs (mean $7,400, range $1000-$21,000). Didactic teaching was the primary instructional method (99.5%); a majority (68%) included project work. Fourteen thematic content areas were derived from 264 abstracted topics. The majority or near majority incorporated content regarding leadership skills, organizational strategy and alignment, management, self-assessment, and finance/budget., Discussion: Institutions and faculty invest significantly in leadership development programs, addressing perceived needs and with perceived benefit for both. The prevalence of common curricular content indicates that AHCs deem important faculty development in leadership, business, and self-assessment skills.

Introduction: In an era of competing priorities, funding is increasingly restricted for offices of faculty affairs and development. Opportunities for professional staff to grow and network through attendance at national meetings and to share best practices are limited. We sought to describe a community of practice established to enhance the professional development of faculty affairs professionals and to document its impact., Methods: We outlined the process of formation of the New England Network for Faculty Affairs (NENFA), reviewed the pedagogical approaches to professional development, and surveyed members to evaluate the impact of NENFA on their activities, professional network and their institutions., Results: After a successful 2011 initial meeting, NENFA created an organizing committee and conducted a needs assessment among potential members. NENFA's charter, mission, goals, and structure were based on survey results. NENFA's regional community of practice grew to 31 institutions and held 10 meetings over 5 years. Meetings have examined a faculty development topic in depth using multiple learning formats to engage participants from academic medical centers and allied professions. Results from a 2015 member survey confirmed the value of NENFA. Multiple members documented changes in practice as a result of participating., Discussion: NENFA has been sustained by volunteer leadership, collaboration, and the value that the group has brought to its members. We propose that a "community of practice" offers an effective model for collaborative learning among individuals at different institutions within a competitive health care environment. We recommend that the approach be replicated in other regions.

Problem: Medical school faculty are aging, but few academic health centers are adequately prepared with policies, programs, and resources (PPR) to assist late-career faculty. The authors sought to examine cultural barriers to successful retirement and create alignment between individual and institutional needs and tasks through PPR that embrace the contributions of senior faculty while enabling retirement transitions at the University of Massachusetts Medical School, 2013-2017., Approach: Faculty 50 or older were surveyed, programs at other institutions and from the literature (multiple fields) were reviewed, and senior faculty and leaders, including retired faculty, were engaged to develop and implement PPR. Cultural barriers were found to be significant, and a multipronged, multiyear strategy to address these barriers, which sequentially added PPR to support faculty, was put in place. A comprehensive framework of sequenced PPR was developed to address the needs and tasks of late-career transitions within three distinct phases: pre-retirement, retirement, and post-retirement., Outcomes: This sequential introduction approach has led to important outcomes for all three of the retirement phases, including reduction of cultural barriers, a policy that has been useful in assessing viability of proposed phased retirement plans, transparent and realistic discussions about financial issues, and consideration of roles that retired faculty can provide., Next Steps: The authors are tracking the issues mentioned in consultations and efficacy of succession planning, and will be resurveying faculty to further refine their work. This framework approach could serve as a template for other academic health centers to address late-career faculty development.

Objectives: To establish the occurrence of increased plasma ammonia concentration after L-asparaginase (L-asp) administration in dogs with high-grade lymphoma or leukemia; to identify risk factors for the development of hyperammonemia after L-asp administration; and to determine occurrence of adverse events related to hyperammonemia., Design: Prospective case controlled study of sequentially enrolled dogs between May 2011 and March 2012., Setting: A university veterinary teaching hospital., Animals: Twenty-seven dogs with high-grade lymphoma or leukemia., Interventions: All dogs received L-asp intramuscularly at a median dose of 400 IU/kg., Measurements and Main Results: Plasma ammonia concentrations were measured at baseline, 16 hours, and 48 hours after L-asp therapy. Clinicopathological abnormalities were assessed to determine risk factors for the development of hyperammonemia. Adverse events following L-asp were recorded. Median plasma ammonia concentrations at baseline, 16 hours, and 48 hours were 26 μmol/L (44 μg/dL), 98 μmol/L (166.9 μg/dL), and 67 μmol/L (114 μg/dL), respectively. Median plasma ammonia concentrations at 16 and 48 hours after administration were significantly increased compared to baseline. Six dogs had adverse events following L-asp administration. No significant clinical signs were noted that could clearly be attributed to hyperammonemia. No risk factors for developing hyperammonemia were identified; however, there was a positive correlation between the development of hyperammonemia at 16- and 48-hour time points., Conclusions: Subclinical hyperammonemia in dogs with lymphoma or leukemia after L-asp administration appears to be common. No risk factors were identified for the development of hyperammonemia after L-asp treatment, and severe adverse events were rare., (© Veterinary Emergency and Critical Care Society 2018.)

Although canine multicentric lymphoma is initially responsive to multidrug chemotherapy, resistance and relapse create a need for novel chemotherapeutics. Bleomycin is an antitumor antibiotic with a minimal adverse event profile; though commonly used for human non-Hodgkin's lymphoma, its use is poorly characterized in dogs. The purpose of this retrospective case series was to describe the clinical response and adverse event profile of systemic bleomycin for canine multicentric lymphoma (n = 10). A partial response was noted in one dog that died 24 days later due to unrelated disease. Adverse events were infrequent and limited to grade 1 gastrointestinal and grade 1 constitutional toxicity. Although clinical response was minimal, systemic bleomycin was well tolerated when administered at 0.5 U/kg. Additional studies are warranted to determine the influence of administration schedule and dose on the efficacy of bleomycin for veterinary neoplasia.

Objective: To evaluate whole body computed tomography (CT) for staging canine appendicular osteosarcoma., Study Design: Retrospective case series., Animals: Client-owned dogs diagnosed with appendicular osteosarcoma (n=39)., Methods: Medical records for client-owned dogs diagnosed with appendicular osteosarcoma from August 2008 to July 2014 were reviewed. Dogs were included if they had a confirmed diagnosis of appendicular osteosarcoma and were staged using whole body CT. Data collected included signalment, body weight, primary tumor location, serum alkaline phosphatase (ALP) activity, findings on 3-view thoracic radiographs, cytologic or histologic results, and findings on CT., Results: Thirty-nine dogs (median age 8.5 years; median body weight 37 kg) had osteosarcoma of the distal radius (n=17), proximal humerus (11) and other sites. Serum ALP activity was elevated in 14 dogs. Bone metastasis was not detected in any dog on whole body CT. Pulmonary metastasis was considered definitive on CT based on board certified radiologist assessment in 2/39 dogs (5%). Two additional dogs (2/39, 5%) had soft tissue masses diagnosed on CT, consistent with concurrent, non-metastatic malignancies., Conclusion: Bone metastases were not identified in any dog with whole body CT. Thoracic and abdominal CT detected lung lesions and concurrent neoplasia in dogs with primary appendicular osteosarcoma. Whole body CT may be a useful adjunct to other screening tests for disseminated malignancy., (© 2016 The American College of Veterinary Surgeons.)

Yunnan Baiyao is a Chinese herbal medicine that has been utilized for its anti-inflammatory, haemostatic, wound healing and pain relieving properties in people. It has been utilized in the veterinary profession to control bleeding in dogs with hemangiosarcoma (HSA) and has been anecdotally reported to prolong survival times in dogs with this neoplasm. This study evaluated the in vitro activity of Yunnan Baiyao against three canine HSA cell lines after treatment with increasing concentrations of Yunnan Baiyao (50, 100, 200, 400, 600 and 800 µg mL(-1) ) at 24, 48 and 72 h. Mean half maximum inhibitory concentration (IC50 ) at 72 h for DEN, Fitz, SB was 369.9, 275.9 and 325.3 µg mL(-1) , respectively. Caspase-3/7 activity increased in correlation with the IC50 in each cell line which was confirmed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL, APO-BRDU Kit; BD Biosciences, San Jose, CA, USA) assay. VEGF in cell supernatant was also quantified. Overall, the study found that Yunnan Baiyao causes dose and time dependent HSA cell death through initiation of caspase-mediated apoptosis, which supports future studies involving Yunnan Baiyao., (© 2014 John Wiley & Sons Ltd.)

Stereotactic radiosurgery (SRS) is a procedure that delivers a single large radiation dose to a well-defined target. Here, we describe a frameless SRS technique suitable for intracranial targets in canines. Medical records of dogs diagnosed with a primary intracranial tumour by imaging or histopathology that underwent SRS were retrospectively reviewed. Frameless SRS was used successfully to treat tumours in 51 dogs with a variety of head sizes and shapes. Tumours diagnosed included 38 meningiomas, 4 pituitary tumours, 4 trigeminal nerve tumours, 3 gliomas, 1 histiocytic sarcoma and 1 choroid plexus tumour. Median survival time was 399 days for all tumours and for dogs with meningiomas; cause-specific survival was 493 days for both cohorts. Acute grade III central nervous system toxicity (altered mentation) occurred in two dogs. Frameless SRS resulted in survival times comparable to conventional radiation therapy, but with fewer acute adverse effects and only a single anaesthetic episode required for therapy., (© 2013 John Wiley & Sons Ltd.)

Discussed in detail is the synthesis and primary structure characterization of two polymers aimed at advancing the treatment of pediatric osteosarcoma. These polymers are designed to systemically deliver radiometals specifically to osteosarcomas using the passive targeting mechanism of enhanced permeability and retention (the EPR effect). The approach begins with the synthesis of a polymer capable of binding radiometals, for which prior data show improved site-specific targeting of solid tumors. Building on this success, a second polymer has been designed for improving the efficacy of currently available radionuclide therapies by incorporating the FDA-approved small-molecule ligand Quadramet directly onto the polymer structure. Time-activity curves of the phosphonate-functionalized polymers show rapid clearance from the central compartment and nontargeted organs, with up to 65% of injected activity being excreted within 3 hours. Both polymer ligands demonstrate good osteosarcoma targeting capability with little to no uptake in organs associated with the dose-limiting bone marrow. Additionally, biodistribution studies in nonosseous tumor models demonstrate the tumor targeting mechanism of the polymer ligands, which appears to be influenced by the high affinity of the phosphonate functionality for the positively charged hydroxyapatite mineral found in bone tumors.

Osteosarcoma is a highly fatal cancer, with most patients ultimately succumbing to metastatic disease. The purpose of this study was to evaluate the effects of the antirheumatoid drug aurothiomalate on canine and human osteosarcoma cells and on canine osteosarcoma growth and metastasis in a mouse xenograft model. We hypothesized that aurothiomalate would decrease osteosarcoma cell survival, tumor cellular proliferation, tumor growth, and metastasis. After performing clonogenic assays, aurothiomalate or a placebo was administered to 54 mice inoculated with canine osteosarcoma. Survival, tumor growth, embolization, metastasis, histopathology, cell proliferation marker Ki67, and apoptosis marker caspase-3 were compared between groups. Statistical analysis was carried out using the Kaplan-Meier method with the log-rank test and one-way analysis of variance with the Tukey's test or Dunn's method. Aurothiomalate caused dose-dependent inhibition of osteosarcoma cell survival (P<0.001) and decreased tumor growth (P<0.001). Pulmonary macrometastasis and Ki67 labeling were reduced with low-dose aurothiomalate (P=0.033 and 0.005, respectively), and tumor emboli and pulmonary micrometastases were decreased with high-dose aurothiomalate (P=0.010 and 0.011, respectively). There was no difference in survival, tumor development, ulceration, mitotic indices, tumor necrosis, nonpulmonary metastases, and caspase-3 labeling. Aurothiomalate treatment inhibited osteosarcoma cell survival and reduced tumor cell proliferation, growth, embolization, and pulmonary metastasis. Given aurothiomalate's established utility in canine and human medicine, our results suggest that this compound may hold promise as an adjunctive therapy for osteosarcoma. Further translational research is warranted to better characterize the dose response of canine and human osteosarcoma to aurothiomalate.

Objective: To evaluate clinical outcome of dogs with appendicular osteosarcoma (OSA) treated with stereotactic radiosurgery (SRS) and subsequent internal fixation of a pathologic fracture., Study Design: Retrospective case series., Animals: Dogs with spontaneous-occurring appendicular OSA (n = 6)., Methods: Medical records (May 2002-January 2008) of dogs that had SRS for appendicular OSA were reviewed. Dogs were included if they had a pathologic fracture either before or after SRS and were treated with internal fixation. Signalment, history, physical examination findings, clinicopathologic data, diagnostic imaging findings, biopsy results, surgical complications, number of surgeries, adjuvant therapy, development of metastatic disease and cause of death were recorded., Results: Six dogs met the inclusion criteria. Two dogs had a pathologic fracture at admission and 4 dogs developed a fracture after SRS with a mean ± SD time to fracture development of 6.25 ± 1.65 months. The first 3 fractures were repaired using an open approach and the latter three using minimally invasive percutaneous osteosynthesis (MIPO). Infection occurred in 5 dogs and implant failure in 3. Limb function was subjectively assessed as good in all dogs when the implants were stable and infections were subclinical. Survival times ranged from 364-897 days; 1 dog was lost to follow-up., Conclusions: Fracture repair using internal fixation should be considered a viable limb-sparing alternative for pathologic fractures that have been treated with SRS., (© Copyright 2014 by The American College of Veterinary Surgeons.)

Writing a grant is a hefty undertaking. Start by surrounding yourself with a successful mentor and accompanying team with a good track record. Get organized, select clear goals and objectives to your project. Once the foundation for the grant is set, begin by generating a robust hypothesis. Once your hypothesis is clearly defined, you should contact the project officer of the specific grant for which you are applying; they can help identify if the proposal meets an area of need. The basic components of a grant include the following: the face page, which highlights the key contributors; followed by table of contents; abstract; biographical sketches, which are minicurriculum vitae; budget; research plan, which is composed mostly of background, significance, and specific aims; and lastly, references cited. Be sure to follow specific formatting. Use resources including the internet to find an appropriate grant. Finally, given the confines of a busy surgical practice and the significant amount of work necessary to complete a grant, it is essential that the work begins early and well in advance of the proposed deadline.

Treatment of chronic monocytic leukemia (CMoL) in dogs has traditionally consisted of hydroxyurea. The use of tyrosine kinase inhibitors has been proposed as a treatment option for dogs with CMoL but has never been reported. We report a case of CMoL in a young dog that achieved clinical remission with treatment with the tyrosine kinase inhibitor toceranib and prednisone.

Osteosarcoma (OSA) is the most common primary bone tumor in dogs and the guarded prognosis highlights the necessity to find new treatments. Masitinib mesylate is a highly selective tyrosine kinase inhibitor that predominantly targets c-Kit and PDGFR-α/β. This study evaluated the in-vitro activity of masitinib against three canine OSA cell lines after treatment with increasing concentrations of masitinib (0.1-50 µmol/l) at 24, 48, and 72 h. The IC50 values at 72 h for the three OSA cell lines (POS, HMPOS, and COS31) were determined to be 11.04, 7.09, and 9.74 µmol/l, respectively. In addition, increases in caspase-3/7 activity and transferase dUTP nick end labeling-positive cells indicated apoptotic cell death. Because increased levels of vascular endothelial growth factor are found in dogs with OSA, vascular endothelial growth factor in the supernatant was quantified. Overall, the study found that masitinib causes dose-time dependent OSA cell death in vitro through initiation of caspase-mediated apoptosis, which supports future OSA clinical trials.

Objective-To investigate the effects of bevacizumab, a human monoclonal antibody against vascular endothelial growth factor, on the angiogenesis and growth of canine osteosarcoma cells xenografted in mice. Animals-27 athymic nude mice. Procedures-To each mouse, highly metastasizing parent osteosarcoma cells of canine origin were injected into the left gastrocnemius muscle. Each mouse was then randomly allocated to 1 of 3 treatment groups: high-dose bevacizumab (4 mg/kg, IP), low-dose bevacizumab (2 mg/kg, IP), or control (no treatment). Tumor growth (the number of days required for the tumor to grow from 8 to 13 mm), vasculature, histomorphology, necrosis, and pulmonary metastasis were evaluated. Results-Mice in the high-dose bevacizumab group had significantly delayed tumor growth (mean ± SD, 13.4 ± 3.8 days; range, 9 to 21 days), compared with that for mice in the low-dose bevacizumab group (mean ± SD, 9.4 ± 1.5 days; range, 7 to 11 days) or control group (mean ± SD, 7. 2 ± 1.5 days; range, 4 to 9 days). Mice in the low-dose bevacizumab group also had significantly delayed tumor growth, compared with that for mice in the control group. Conclusions and Clinical Relevance-Results indicated that bevacizumab inhibited growth of canine osteosarcoma cells xenografted in mice, which suggested that vascular endothelial growth factor inhibitors may be clinically useful for the treatment of osteosarcoma in dogs. Impact for Human Medicine-Canine osteosarcoma is used as a research model for human osteosarcoma; therefore, bevacizumab may be clinically beneficial for the treatment of osteosarcoma in humans.

This study evaluated the in vitro activity of masitinib mesylate against canine hemangiosarcoma (HSA) cell lines after treatment with increasing concentrations of masitinib mesylate (0.01-100 µM) for 24, 48 and 72 h. Results indicated that masitinib mesylate caused a dose- and time-dependent decrease in HSA cell proliferation. The 50% inhibitory concentration (IC(50) ) at 72 h for three HSA cell lines (DEN, Fitz and SB) was found to be 8.56, 9.41 and 10.65 µM, respectively. Further investigation demonstrated that masitinib mesylate induced apoptosis in all HSA cell lines, including activation of caspase-3/7. Measurement of VEGF levels in cell supernatant found a statistically significant increased VEGF in close proximity to the IC(50) of each cell line followed by a decline back towards baseline. These findings indicate that masitinib mesylate causes dose-dependent HSA cell death in vitro and supports future clinical trials of masitinib for canine HSA., (© 2012 Blackwell Publishing Ltd.)

Objective: To evaluate samarium Sm 153 lexidronam ((153)Sm-EDTMP) as a treatment option for dogs with bony tumors of the skull., Design: Retrospective case series., Animals: Dogs with multilobular osteochondrosarcoma (MLO) or osteosarcoma (OSA) of the skull., Procedures: Veterinary Medical Teaching Hospital records from the Universities of Missouri and Florida from 1986 to 2006 were searched for dogs with primary skull tumors treated with (153)Sm-EDTMP., Results: 25 dogs were initially evaluated, with 5 dogs subsequently excluded because of inadequate follow-up or unrelated death. Seven OSAs and 13 MLOs were diagnosed. Tumors involved the occipital and frontal bones (n = 10), zygomatic arch and maxilla region (6), palate (3), and mandible (1). No clinically important adverse effects related to (153)Sm-EDTMP treatment were documented. Of the 20 dogs evaluated 21 days after injection with (153)Sm-EDTMP, 4 had subjective improvement, 13 had progressive disease, and 3 had insufficient follow-up. On the basis of radiographic findings, metastasis was suspected in 1 dog; 16 dogs had no metastasis evident, and medical records were insufficient for 3 dogs. Survival time, defined as the (153)Sm-EDTMP injection date to the date of death, ranged from 3 to 1,314 days (median, 144 days)., Conclusions and Clinical Relevance: The subjective improvement in 4 patients and lack of clinical evidence of adverse effects suggested that (153)Sm-EDTMP injection may be an option for the treatment of dogs with MLO or OSA of the skull when other treatments have failed or surgery is not possible.

Objective: To describe a previously unreported and potentially fatal complication of L-asparaginase (L-asp) administration in a dog., Case Summary: A 7-year-old, 6.6 kg, female spayed Beagle presented with a 1-week history of progressive inappetance and lethargy. Diagnostic tests identified the presence of stage Vb lymphoma and liver dysfunction. The dog was treated with L-asp at 400 IU/kg, corticosteroids, and IV fluids. Within 12 hours the dog became depressed, vomited, and developed abdominal pain. Within 24 hours, the dog's mentation progressed from obtunded to comatose; subsequently the dog developed a "decerebrate posture." Blood ammonia concentrations exceeded 1,000 μmol/L (1,700 μg/dL). Treatment with broad-spectrum antimicrobials, lactulose enemas, and continuous renal replacement therapy were initiated without response and the dog suffered cardiopulmonary arrest., New or Unique Information Provided: The purpose of this report is to describe the development of severe hyperammonemia after L-asp therapy in a dog, which has not been previously reported in the literature. Given the rapid progression and fatal outcome observed in this case, early recognition may be crucial for management and treatment of this complication., (© Veterinary Emergency and Critical Care Society 2011.)

A 9 yr old spayed female cocker spaniel presented for evaluation of an invasive maxillary squamous cell carcinoma. Curative intent surgery and radiation therapy allowed for local control of the neoplasm; however, the development of a persistent oronasal fistula prevented a complete recovery. A temporalis myofascial rotation flap allowed for successful resolution of the maxillary defect. Implementation of the flap was relatively simple and was associated with few complications.

Today, faculty in academic medicine face challenges in all three mission areas--research, education, and patient care--and require a broad set of competencies to survive in this changing environment. To support faculty and to design assessments that match new expectations, the authors argue that it is essential to capture the full scope of skills, knowledge, and behaviors necessary for a successful faculty member. Thus, it is timely to explore and define competencies for faculty in academic medicine. The authors describe three approaches to identifying faculty competencies. Each reveals diverse but overlapping sets of competency domains, reflecting the breadth of activities expected of today's faculty. To organize these competencies into a coherent framework, the authors propose a model based on a typology of competency. A key feature of the model is the division between occupational competencies, which are largely role-specific, and personal competencies, which are necessary for all faculty. A competency framework also must be developmental, to reflect the growth in skills, knowledge, and behaviors from trainee to expert and to allow for an individual's changing roles over a career. Such a competency framework will inform professional development activities and require assessment of competence. The generation of competencies also will reveal areas of faculty practice that are poorly measured, requiring new tools to be incorporated into existing processes of faculty evaluation. The authors provide general principles to guide the identification of a competency framework for faculty and invite the academic medicine community to engage in further discussion.

Unlabelled: The current gold standard for measuring marrow cellularity is the bone marrow (BM) biopsy of the iliac crest. This measure is not predictive of total marrow cellularity, because the biopsy volume is typically small and fat fraction varies across the skeleton. MRI and localized MR spectroscopy have been demonstrated as noninvasive means for measuring BM cellularity in patients. The accuracy of these methods has been well established in phantom studies and in the determination of in vivo hepatic fat fractions but not for in vivo measurement of BM cellularity., Methods: Spoiled gradient-echo in vivo images of the femur, humerus, upper spine, and lower spine were acquired for 2 dogs using a clinical 3-T MRI scanner. Single-peak iterative decomposition of water and fat with echo asymmetry and least squares (SP-IDEAL) was used to derive BM fat fractions. Stimulated-echo acquisition mode spectra were acquired in order to perform multipeak IDEAL with precalibration (MP-IDEAL). In vivo accuracy was validated by comparison with histology measurements. Histologic fat fractions were derived from adipocyte segmentation., Results: Bland-Altman plots demonstrated excellent agreement between SP-IDEAL and histology, with a mean difference of -0.52% cellularity and most differences within ±2% cellularity, but agreement between MP-IDEAL and histology was not as good (mean difference, -7% cellularity, and differences between 5% and -20%)., Conclusion: Adipocyte segmentation of histology slides provides a measure of volumetric fat fraction (i.e., adipocyte volume fraction [AVF]) and not chemical fat fraction, because fat fraction measured from histology is invariant to the relative abundances of lipid chemical species. In contrast, MP-IDEAL provides a measure of chemical fat fraction, thus explaining the poor agreement of this method with histology. SP-IDEAL measures the relative abundance of methylene lipids, and this measure is shown to be equivalent to AVF. AVF provides the appropriate parameter to account for patient-specific cellularity in BM mass predictive equations and is consistent with current micro-CT-based models of skeletal dosimetry.

Understanding the inherent radiosensitivity and repair capacity of canine transitional cell carcinoma (TCC) can aid in optimizing radiation protocols to treat this disease. The objective of this study was to evaluate the parameters surviving fraction at 2 Gy (SF(2) ), α/β ratio and capacity for sublethal damage repair (SLDR) in response to radiation. Dose-response and split-dose studies were performed using the clonogenic assay. The mean SF(2) for three established TCC cell lines was high at 0.61. All the three cell lines exhibited a low to moderate α/β ratio, with the mean being 3.27. Two cell lines exhibited statistically increased survival at 4 and 24 h in the dose-response assay. Overall, our results indicate that the cell lines are moderately radioresistant, have a high repair capacity and behave similarly to a late-responding normal tissue. These findings indicate that the radiation protocols utilizing higher doses with less fractionation may be more effective for treating TCC., (© 2011 Blackwell Publishing Ltd.)

Objective: To evaluate the toxicity and efficacy of a modification of a previously evaluated combination of lomustine, vincristine, procarbazine, and prednisone (LOPP) as a rescue protocol for refractory lymphoma in dogs., Design: Retrospective case series. Animals-33 dogs with a cytologic or histologic diagnosis of lymphoma that developed resistance to their induction chemotherapy protocol., Procedures: Lomustine was administered on day 0 of the protocol. Vincristine was administered on day 0 and again 1 time on day 14. Procarbazine and prednisone were administered on days 0 through 13 of the protocol. This cycle was repeated every 28 days., Results: Median time from initiation to discontinuation of the University of Florida LOPP protocol was 84 days (range, 10 to 308 days). Overall median survival time was 290 days (range, 51 to 762 days). Overall response rate with this protocol was 61% (20/33), with 36% (12) having a complete response and 24% (8) having a partial response. Toxicosis rates were lower than for the previously published LOPP protocol., Conclusions and Clinical Relevance: The University of Florida LOPP protocol may be an acceptable alternative to the mechlorethamine, vincristine, procarbazine, and prednisone protocol as a rescue protocol for dogs with lymphoma.

Objective: To evaluate outcomes of radical excision of feline injection-site sarcomas (ISS) via assessment of local recurrence and metastasis rates, survival times, and complications associated with surgery., Design: Retrospective case series., Animals: 91 cats with ISS., Procedures: Medical records of cats that had radical excision of ISS without adjunctive treatment were reviewed. Information extracted included sex, type of surgical procedure, histologic tumor grade, tumor diameter, time from tumor detection to definitive surgery, complications associated with surgery, whether tumors recurred locally or metastasized, and survival times. Diagnosis of ISS was histologically confirmed, and additional follow-up was performed., Results: Overall median survival time was 901 days. Thirteen of 91 (14%) cats had local tumor recurrence; 18 (20%) cats had evidence of metastasis after surgery. Median survival time of cats with and without recurrence was 499 and 1,461 days, respectively. Median survival time of cats with and without metastasis was 388 and 1,528 days, respectively. Tumor recurrence and metastasis were significantly associated with survival time, whereas other examined variables were not. Major complications occurred in 10 cats, including 7 with incisional dehiscence., Conclusions and Clinical Relevance: Radical excision of ISS resulted in a metastasis rate similar to rates reported previously; the local recurrence rate appeared to be substantially less than rates reported after less aggressive surgeries, with or without adjuvant treatment. Major complication rates were similar to rates reported previously after aggressive surgical resection of ISS. Radical excision may be a valuable means of attaining an improved outcome in the treatment of feline ISS.

Projects--planned activities with specific goals and outcomes--have been used in faculty development programs to enhance participant learning and development. Projects have been employed most extensively in programs designed to develop faculty as educators. The authors review the literature and report the results of their 2008 study of the impact of projects within the Pennsylvania State University College of Medicine Junior Faculty Development Program, a comprehensive faculty development program. Using a mixed-methods approach, the products of project work, the academic productivity of program graduates, and the impact of projects on career development were analyzed. Faculty who achieved the most progress on their projects reported the highest number of academic products related to their project and the highest number of overall academic achievements. Faculty perceived that their project had three major effects on their professional development: production of a tangible outcome, development of a career focus, and development of relationships with mentors and peers. On the basis of these findings and a review of the literature, the authors conclude that projects are an essential element of a faculty development program. Projects provide a foundation for future academic success by enabling junior faculty to develop and hone knowledge and skills, identify a career focus and gain recognition within their community, generate scholarship, allocate time to academic work, and establish supportive relationships and collaborative networks. A list of best practices to successfully incorporate projects within faculty development programs is provided.