L-plastin associated syndrome of immune deficiency and haematological cytopenia (PASIC).

BACKGROUND: LCP1 encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, LCP1 deficiency has been shown to result in hematological and immune defects. OBJECTIVE: To determine the nature of a human inborn error of immunity resulting from a novel genetic variant of LCP1. METHODS: We performed genetic, protein and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in LCP1, which we evaluated by engineering the orthologous mutation in mice and Jurkat cells. RESULTS: A splice-site variant in LCP1 segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect results in at least two aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshifting deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells, and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression Lcp1 and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T cell populations. Functional analysis revealed that LCP1c740-1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunological analysis revealed defective actin organisation in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12, impaired germinal centre B cell expansion after immunisation, and reduced cytokinesis during T cell proliferation. CONCLUSION: We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes and platelets, arising from partial LCP1 deficiency.

Vincristine-induced adverse events related to body weight in dogs treated for lymphoma.

BACKGROUND: Traditional dosing of chemotherapy drugs based on body surface area may overdose small dogs, leading to an increased frequency of adverse events (AEs). HYPOTHESIS/OBJECTIVES: Evaluate the frequency of hematologic and gastrointestinal AEs in dogs with newly diagnosed lymphoma treated with vincristine weighing ≤15 kg in comparison to dogs weighing >15 kg. We hypothesized that dogs weighing ≤15 kg would experience a higher frequency of AEs. ANIMALS: One hundred and thirty-eight dogs with newly diagnosed lymphoma were treated with vincristine. METHODS: A multicenter retrospective study reviewing hematologic data and medical record information. Complete blood counts were performed no more than 24 hours before vincristine administration and then between 4 and 8 days post-administration. Data were evaluated using logistic regression or ordinal logistic regression. RESULTS: Thirty-eight dogs weighing ≤15 kg and 100 dogs weighing >15 kg were included. The median vincristine dose for both groups was 0.6 mg/m2. Seventeen (12.3%) instances of neutropenia occurred with no significant difference in overall frequency or grade between groups. Thirty initially asymptomatic substage A dogs (29.4%) experienced gastrointestinal AEs. Because of the widespread use of gastrointestinal supportive care medications, statistical comparison between groups could not be performed. Seven instances of hospitalization occurred (5.0%) and the risk of hospitalization did not differ significantly between groups (P = .37). CONCLUSIONS AND CLINICAL IMPORTANCE: Vincristine dosed at ≤0.6 mg/m2 does not increase the risk of hematologic AEs in dogs weighing ≤15 kg.

Diagnostic delay of sarcoidosis: an integrated systematic review.

BACKGROUND: Sarcoidosis is a chronic inflammatory granulomatous disease of unknown cause. Delays in diagnosis can result in disease progression and poorer outcomes for patients. Our aim was to review the current literature to determine the overall diagnostic delay of sarcoidosis, factors associated with diagnostic delay, and the experiences of people with sarcoidosis of diagnostic delay. METHODS: Three databases (PubMed/Medline, Scopus, and ProQuest) and grey literature sources were searched. Random effects inverse variance meta-analysis was used to pool mean diagnostic delay in all types of sarcoidosis subgroup analysis. Diagnostic delay was defined as the time from reported onset of symptoms to diagnosis of sarcoidosis. RESULTS: We identified 374 titles, of which 29 studies were included in the review, with an overall sample of 1531 (694 females, 837 males). The overall mean diagnostic delay in all types of sarcoidosis was 7.93 months (95% CI 1.21 to 14.64 months). Meta-aggregation of factors related to diagnostic delay in the included studies identified three categories: (1) the complex and rare features of sarcoidosis, (2) healthcare factors and (3) patient-centred factors. Meta-aggregation of outcomes reported in case studies revealed that the three most frequent outcomes associated with diagnostic delay were: (1) incorrect diagnosis, (2) incorrect treatment and (3) development of complications/disease progression. There was no significant difference in diagnostic delay between countries with gatekeeper health systems (where consumers are referred from a primary care clinician to specialist care) and countries with non-gatekeeper systems. No qualitative studies examining people's experiences of diagnostic delay were identified. CONCLUSION: The mean diagnostic delay for sarcoidosis is almost 8 months, which has objective consequences for patient management. On the other hand, there is a paucity of evidence about the experience of diagnostic delay in sarcoidosis and factors related to this. Gaining an understanding of people's experiences while seeking a diagnosis of sarcoidosis is vital to gain insight into factors that may contribute to delays, and subsequently inform strategies, tools and training activities aimed at increasing clinician and public awareness about this rare condition. TRIAL REGISTRATION: PROSPERO Registration number: CRD42022307236.

Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.

Acquired Angioedema Associated with Lymphoproliferative Disorders.

Introduction: Acquired angioedema due to C1 esterase inhibitor deficiency (C1INH-AAE) is most associated with lymphoproliferative disorders (LPDs), particularly low-grade B-cell subtypes. The condition remains under-recognized with long diagnostic delays due to various challenges including a lack of awareness of the condition. Case Presentation: We discuss 4 cases of C1INH-AAE associated with low-grade B-cell LPDs, including various diagnostic and management challenges. As our cases illustrate, constitutional symptoms or overt manifestations of LPD at diagnosis are often absent. Hence, a comprehensive multimodal approach to screening for an underlying B-LPD is important when a diagnosis of acquired angioedema is made. Levels of complement C4, C1q, and C1INH are useful for diagnosing C1INH-AAE and for monitoring disease activity. Changes in these parameters may also indicate relapse of the underlying hematological malignancy. Treating the underlying disorder is important as this commonly leads to clinical improvement with decreased episodes of angioedema and normalization of complement studies. Conclusion: Awareness of C1INH-AAE can lead to an early diagnosis of hematological malignancies. The absence of constitutional symptoms emphasizes the need for a comprehensive multimodal approach to screening for LPD in C1INH-AAE. C4, C1INH level, and function are useful for monitoring disease activity.

DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the ß-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αß and γδ T cells, even in the absence of transforming growth factor-ß. Consistent with DECTIN-1's Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.

A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.

Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL. In mouse cells, the equivalent Mlkl S131P mutation confers a gene dosage dependent reduction in sensitivity to TNF-induced necroptosis in both hematopoietic and non-hematopoietic cells, but enhanced sensitivity to IFN-ß induced death in non-hematopoietic cells. In vivo, MlklS131P homozygosity reduces the capacity to clear Salmonella from major organs and retards recovery of hematopoietic stem cells. Thus, by dysregulating necroptosis, the S131P substitution impairs the return to homeostasis after systemic challenge. Present day carriers of the MLKL S132P polymorphism may be the key to understanding how MLKL and necroptosis modulate the progression of complex polygenic human disease.

Metastatic carcinoma of unknown origin in a dog.

Although cancer of unknown primary origin (CUP) is well-described in the human literature, it is not as well-understood within veterinary medicine. This case report represents one of few focused on describing CUP in a dog. Key clinical message: Metastatic CUP should be considered as a differential diagnosis despite being a rare disease entity that is infrequently reported within the veterinary literature.

Carcinome métastatique d'origine inconnue chez un chien. Bien que le cancer d'origine primaire inconnue (CUP) soit bien décrit dans la littérature humaine, il n'est pas aussi bien compris en médecine vétérinaire. Ce rapport de cas représente l'un des rares à s'intéresser à la description du CUP chez un chien.Message clinique clé:Le CUP métastatique doit être considéré comme un diagnostic différentiel bien qu'il s'agisse d'une entité de maladie rare rarement rapportée dans la littérature vétérinaire.(Traduit par Dr Serge Messier).

New Zealand Blackcurrant Increases Postexercise Hypotension Following Sustained Moderate-Intensity Exercise.

Previous observations demonstrate New Zealand blackcurrant (NZBC) extract to alter cardiovascular responses at rest without prior exercise. However, the prolonged effects of NZBC on blood pressure and heart rate variability following exercise are not known. Participants (n15 [five women], age: 31 ± 9 years, maximal oxygen uptake: 44 ± 9 ml·kg-1·min-1) undertook a control condition of 2 hr of lying supine rest. Subsequently, in a double-blind, placebo (PLA)-controlled, randomized crossover design participants completed 1 hr of treadmill exercise at 50% maximal oxygen uptake followed by 2-hr supine rest with blood pressure and heart rate variability measurement following a 7-day intake of NZBC and PLA. With NZBC, there was an increase in average fat oxidation (NZBC: 0.24 ± 0.11 vs. PLA: 0.17 ± 0.11 g/min, p = .005), and larger high-frequency relative power during the exercise (p = .037). In the 2-hr rest period, delta change for systolic pressure was larger with NZBC than PLA (Control vs. NZBC: -5.6 ± 6.4, Control vs. PLA: -3.5 ± 6.0 mmHg, p = .033) but was not different for diastolic or mean arterial pressure. There were no alterations in heart rate variabilities during the 2 hr following the exercise with NZBC. A 7-day intake of NZBC causes a larger postexercise hypotension response in young, physically active men and women following 1 hr of treadmill exercise at 50% maximal oxygen uptake.

Clinical outcomes in cats with renal carcinoma undergoing nephrectomy: A retrospective study.

Renal carcinomas (RC) are uncommonly encountered in feline medicine. Limited information regarding clinical presentation and postoperative outcomes is available. The purpose of this multi-institutional, retrospective study was to describe the presenting features and clinical outcomes of cats with RC undergoing nephrectomy. Thirty-six client-owned cats were included. Medical records from participating institutions were searched to identify cats that had a histopathologic diagnosis of RC and underwent nephrectomy from January 2001 to October 2021. The most common presenting complaints were weight loss (36.1%) and hyporexia (30.6%). Based on preoperative imaging and intraoperative findings, eight cats had suspected metastasis at the time of surgery (22.2%). Twenty-eight cats survived to discharge (77.8%). Median progression free interval (PFI) could not be determined, as only six cats developed suspected recurrence (16.7%) and seven cats developed suspected metastasis (19.4%). The all-cause median survival time (MST) was 203 days (95% confidence interval [CI]: 84, 1379 days). When cases that died prior to discharge were excluded, MST increased to 1217 days (95% CI: 127, 1641 days). One-year, two-year, and three-year survival rates were all 40.4%. Neither renal tumour histologic subtype nor the presence of preoperative azotemia, anaemia, erythrocytosis, haematuria, or suspected metastasis at diagnosis were found to influence survival. For cats surviving to discharge, prolonged survival times were possible. Further studies are necessary to elucidate other potential prognostic factors, the utility of postoperative adjuvant treatment, and to identify cats at-risk of mortality in the perioperative period.

Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Diagnostic delay of sarcoidosis: Protocol for an integrated systematic review.

INTRODUCTION: Sarcoidosis is a rare systemic inflammatory granulomatous disease of unknown cause. It can manifest in any organ. The incidence of sarcoidosis varies across countries, and by ethnicity and gender. Delays in the diagnosis of sarcoidosis can lead to extension of the disease and organ impairment. Diagnosis delay is attributed in part to the lack of a single diagnostic test or unified commonly used diagnostic criteria, and to the diversity of disease manifestations and symptom load. There is a paucity of evidence examining the determinants of diagnostic delay in sarcoidosis and the experiences of people with sarcoidosis related to delayed diagnosis. We aim to systematically review available evidence about diagnostic delay in sarcoidosis to elucidate the factors associated with diagnostic delay for this disease in different contexts and settings, and the consequences for people with sarcoidosis. METHODS AND ANALYSIS: A systematic search of the literature will be conducted using PubMed/Medline, Scopus, and ProQuest databases, and sources of grey literature, up to 25th of May 2022, with no limitations on publication date. We will include all study types (qualitative, quantitative, and mixed methods) except review articles, examining diagnostic delay, incorrect diagnosis, missed diagnosis or slow diagnosis of all types of sarcoidosis across all age groups. We will also examine evidence of patients' experiences associated with diagnostic delay. Only studies in English, German and Indonesian will be included. The outcomes we examine will be diagnostic delay time, patients' experiences, and factors associated with diagnostic delay in sarcoidosis. Two people will independently screen the titles and abstracts of search results, and then the remaining full-text documents against the inclusion criteria. Disagreements will be resolved with a third reviewer until consensus is reached. Selected studies will be appraised using the Mixed Methods Appraisal Tool (MMAT). A meta-analysis and subgroup analyses of quantitative data will be conducted. Meta-aggregation methods will be used to analyse qualitative data. If there is insufficient data for these analyses, a narrative synthesis will be conducted. DISCUSSION: This review will provide systematic and integrated evidence on the diagnostic delay, associated factors, and experiences of diagnosis delay among people with all types of sarcoidosis. This knowledge may shed light on ways to improve diagnosis delays in diagnosis across different subpopulations, and with different disease presentations. ETHICS AND DISSEMINATION: Ethical approval will not be required as no human recruitment or participation will be involved. Findings of the study will be disseminated through publications in peer-reviewed journals, conferences, and symposia. TRIAL REGISTRATION: PROSPERO Registration number: CRD42022307236. URL of the PROSPERO registration: https://www.crd.york.ac.uk/PROSPEROFILES/307236_PROTOCOL_20220127.pdf.

Hemangiosarcoma of the nasal planum in cats: five cases (2010-2021).

CASE SERIES SUMMARY: Nasal planum tumors are rare in cats, with squamous cell carcinoma over-represented. Other skin tumors have been reported in this location and though hemangiosarcoma frequently occurs on the skin of the head, these tumors localized to the nasal planum have not been specifically reported. The objectives of this study were to report the clinical findings and outcomes in cats diagnosed with hemangiosarcoma of the nasal planum. Medical records from four different institutions were reviewed to identify cats with a definitive diagnosis of hemangiosarcoma of the nasal planum. Five cats met the inclusion criteria. One cat was treated with palliative radiation therapy (RT) alone, two cats had lesions removed via an excisional biopsy by the primary care veterinarian and two cats had excisional biopsies performed at a referral institution. All four cats that received surgical treatment were treated with adjuvant strontium-90 therapy. The cat receiving palliative RT alone was lost to follow-up 311 days after treatment. At the time of writing, the survival time for 2/3 cats receiving surgery and strontium-90 was 365 days and 1381 days, respectively. One cat receiving this combination of therapy was lost to follow-up immediately after treatment. One cat developed tumor recurrence and a revision surgery via nasal planectomy and upper lip resection was performed 376 days following the initial surgery. Following revision, palliative RT was pursued. The cat was still alive at the time of writing 618 days after the initial procedure, with no evidence of recurrence. RELEVANCE AND NOVEL INFORMATION: In this case series, surgery was the primary treatment used, but due to the location, only narrow or incomplete surgical margins were possible. RT (strontium-90 and/or palliative) was utilized to decrease the risk of recurrence.

Use of doxorubicin chemotherapy following debulking surgery in the treatment of a cat with mesenteric hemangiosarcoma.

Case summary: A 7-year-old male castrated domestic shorthair cat presented with a 5-day history of inappetence. A mid-abdominal mass was palpated and, on exploratory laparotomy, a cystic mass arising from the root of the mesentery was observed. The mass was drained, debulked and omentalized. Histopathologic examination and immunohistochemistry supported a diagnosis of hemangiosarcoma. Adjuvant doxorubicin was started and, prior to the third of five doses of doxorubicin, repeat abdominal ultrasound showed complete response of the primary tumor. Continued monitoring 240 days following histopathologic diagnosis revealed suspected metastasis to local lymph nodes, though the primary tumor remained absent on abdominal ultrasound. A second course of five doses of doxorubicin chemotherapy was completed. Serial abdominal ultrasounds demonstrated stable disease in the locoregional lymph nodes with no visible recurrence of the primary tumor. The cat presented 430 days following diagnosis with lethargy and inappetence. Abdominal ultrasound revealed suspected metastatic mesenteric and ileocolic lymphadenopathy, hepatic metastasis and peritoneal effusion, and the owner elected for humane euthanasia. Necropsy findings and negative immunohistochemical staining for lymphatic vessel endothelial receptor-1 were consistent with a metastatic mesenteric hemangiosarcoma. Relevance and novel information: Hemangiosarcoma is an uncommon malignancy in cats, and few cases describing treatment have been reported. To our knowledge, this is the first report to describe the use of debulking surgery and adjuvant doxorubicin chemotherapy in the treatment of mesenteric hemangiosarcoma resulting in extended survival in a cat. Multimodal therapy can be considered for the management of cats with mesenteric hemangiosarcoma.

Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors.

The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNK represents an attractive target for therapeutic intervention. Herein, a panel of novel tryptanthrin oxime analogs were synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses (IC50). Several compounds exhibited submicromolar JNK binding affinity, with the most potent inhibitor being 6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high JNK1-3 binding affinity (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 µM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1ß, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of selected compounds in the JNK3 catalytic site that were in agreement with the experimental JNK3 binding data. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems.

Multi-institutional retrospective study of canine foot pad malignant melanomas: 20 cases.

Melanomas arising from the foot pad are a rare clinical entity in dogs. The biologic behaviour of foot pad malignant melanoma is not well understood, and these tumours are infrequently described. The objective of this study was to evaluate the clinical characteristics of primary canine foot pad melanoma in a larger cohort of patients. Eligible cases were solicited from the American College of Veterinary Internal Medicine (ACVIM) Oncology listserv for retrospective review. Included dogs had a cytologic and/or histologic diagnosis of foot pad melanoma evaluated by a board-certified clinical or anatomic pathologist. Dogs with cutaneous, oral, digital, subungual or interdigital melanomas were excluded. A total of 20 cases were included. Eleven dogs received various adjuvant therapies including chemotherapy, radiation therapy, and/or the ONCEPT canine melanoma vaccine following surgery. At diagnosis, regional lymph node metastasis was observed in four dogs (20%). Seven dogs developed subsequent regional and/or distant metastasis for an overall metastatic rate of 55%. The progression-free interval (PFI) was 101 days (range, 20-960 days). The median survival time (MST) was 240 days (range, 25-479 days). For dogs receiving adjuvant therapy, the MST was 159 days (range, 25-387 days). Canine foot pad melanoma is a rare neoplasm that can exhibit an aggressive behaviour.

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solve several cryo-EM structures at ~3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and reveal distinct epitopes, binding patterns, and conformations. The lead clones also show potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generate and characterize a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.

Clinical outcomes of thyroid tumours with concurrent epithelial and mesenchymal components in 14 dogs (2006-2020).

BACKGROUND: While rare, multiple individual case reports have described mixed thyroid tumours in dogs containing both epithelial and mesenchymal neoplastic components. OBJECTIVES: In this retrospective case series, we describe the clinical presentation, treatment and outcome of 14 dogs of canine thyroid tumours with concurrent mesenchymal and epithelial neoplastic populations. METHODS: Fourteen cases were retrospectively abstracted from nine institutions. Histopathologic samples and reports were collected from 10/14 dogs and reviewed by a single board-certified anatomic pathologist. RESULTS: All 14 dogs had curative-intent surgery to remove the thyroid neoplasm. The most common surgery performed was a unilateral thyroidectomy (10/14 dogs). Postoperatively, systemic therapy was administered in eight dogs. Six dogs developed local recurrence with a median time to loco-regional recurrence of 53 days. Ten dogs developed metastatic disease with the most common metastatic site being the lungs (6/10 dogs), with a median time to metastasis of 93 days. Ten dogs were euthanised due to locoregional or distant progression of their mixed thyroid neoplasm. The overall median survival time was 156 days (95%CI: 49-244). The median survival time for dogs treated with adjuvant therapy was 189 days (95%CI: 24-244), whereas dogs without adjuvant therapy had a median survival time of 156 days (95%CI: 35-upper limit could not be calculated; p = 0.62). CONCLUSION: The thyroid tumours with both mesenchymal and epithelial components in this small sample set were associated with a poor prognosis after surgical excision with or without adjunctive therapy.

A retrospective analysis of 11 dogs with surface osteosarcoma.

While the majority of canine osteosarcomas (OSA) arise from the medullary cavity, a subset arises from the surface of bone. In humans, surface OSA often has a more indolent disease course with better outcomes than medullary OSA. The aim of this retrospective case series was to evaluate the clinical outcome and potential prognostic factors of dogs with surface OSA. Medical records from 11 dogs previously diagnosed with surface OSA were included. Histopathology of cases was evaluated during case review by two veterinary anatomic pathologists. Median progression free interval (PFI) and overall median survival time (OST) were estimated using Kaplan-Meier methods. Intergroup comparisons were performed using log-rank tests. Six dogs were diagnosed with periosteal OSA, 4 dogs with parosteal OSA, and one dog with an unclassified surface OSA. Two dogs were found to have metastatic disease at the time of diagnosis and four developed metastatic lesions after treatment. The median PFI and median OST for all dogs with surface OSA was 425 and 555 days, respectively. The 6 dogs diagnosed with periosteal OSA had a median PFI of 461 days and median OST of 555 days, while the 4 dogs with parosteal OSA had a PFI of 350 days and the OST could not be calculated. Multiple prognostic factors (surgery, systemic adjunctive therapy, elevated alkaline phosphatase at diagnosis, appendicular vs axial location, mitotic count, and tumour grade) were evaluated and none were prognostic for PFI or OST. Dogs with surface OSA appear to have prolonged PFI and OST, consistent with humans with surface OSA.