Mesoderm-specific Stat3 deletion affects expression of Sox9 yielding Sox9-dependent phenotypes.

To date, mutations within the coding region and translocations around the SOX9 gene both constitute the majority of genetic lesions underpinning human campomelic dysplasia (CD). While pathological coding-region mutations typically result in a non-functional SOX9 protein, little is known about what mechanism(s) controls normal SOX9 expression, and subsequently, which signaling pathways may be interrupted by alterations occurring around the SOX9 gene. Here, we report the identification of Stat3 as a key modulator of Sox9 expression in nascent cartilage and developing chondrocytes. Stat3 expression is predominant in tissues of mesodermal origin, and its conditional ablation using mesoderm-specific TCre, in vivo, causes dwarfism and skeletal defects characteristic of CD. Specifically, Stat3 loss results in the expansion of growth plate hypertrophic chondrocytes and deregulation of normal endochondral ossification in all bones examined. Conditional deletion of Stat3 with a Sox9Cre driver produces palate and tracheal irregularities similar to those described in Sox9+/- mice. Furthermore, mesodermal deletion of Stat3 causes global embryonic down regulation of Sox9 expression and function in vivo. Mechanistic experiments ex vivo suggest Stat3 can directly activate the expression of Sox9 by binding to its proximal promoter following activation. These findings illuminate a novel role for Stat3 in chondrocytes during skeletal development through modulation of a critical factor, Sox9. Importantly, they further provide the first evidence for the modulation of a gene product other than Sox9 itself which is capable of modeling pathological aspects of CD and underscore a potentially valuable therapeutic target for patients with the disorder.

Substituent effects on spin state in a series of mononuclear manganese(III) complexes with hexadentate Schiff-Base ligands.

Eleven new mononuclear manganese(III) complexes prepared from two hexadentate ligands, L1 and L2, with different degrees of steric bulk in the substituents are reported. L1 and L2 are Schiff bases resulting from condensation of N,N'-bis(3-aminopropyl)ethylenediamine with 3-methoxy-2-hydroxybenzaldehyde and 3-ethoxy-2-hydroxybenzaldehyde respectively, and are members of a ligand series we have abbreviated as R-Sal2323 to indicate the 323 alkyl connectivity in the starting tetraamine and the substitution (R) on the phenolate ring. L1 hosts a methoxy substituent on both phenolate rings, while L2 bears a larger ethoxy group in the same position. Structural and magnetic properties are reported in comparison with those of a previously reported analogue with L1, namely, [MnL1]NO3, (1e). The BPh4(-) and PF6(-) complexes [MnL1]BPh4, (1a), [MnL2]BPh4, (2a), [MnL1]PF6, (1b'), and [MnL2]PF6, (2b), with both ligands L1 and L2, remain high-spin (HS) over the measured temperature range. However, the monohydrate of (1b') [MnL1]PF6·H2O, (1b), shows gradual spin-crossover (SCO), as do the ClO4(-), BF4(-), and NO3(-) complexes [MnL1]ClO4·H2O, (1c), [MnL2]ClO4, (2c), [MnL1]BF4·H2O, (1d), [MnL2]BF4·0.4H2O, (2d), [MnL1]NO3, (1e), and [MnL2]NO3·EtOH, (2e). The three complexes formed with ethoxy-substituted ligand L2 all show a higher T1/2 than the analogous complexes with methoxy-substituted ligand L1. Analysis of distortion parameters shows that complexes formed with the bulkier ligand L2 exhibit more deformation from perfect octahedral geometry, leading to a higher T1/2 in the SCO examples, where T1/2 is the temperature where the spin state is 50% high spin and 50% low spin. Spin state assignment in the solid state is shown to be solvate-dependent for complexes (1b) and (2e), and room temperature UV-visible and NMR spectra indicate a solution-state spin assignment intermediate between fully HS and fully low spin in 10 complexes, (1a)-(1e) and (2a)-(2e).

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.

Outcome in dogs with curative-intent treatment of localized primary pulmonary histiocytic sarcoma.

Primary pulmonary histiocytic sarcoma (PHS) is a rare form of dendritic cell or macrophage neoplasia originating within the pulmonary parenchyma. There is limited literature describing prognosis in dogs with PHS receiving curative-intent treatment consisting of surgical excision and adjuvant chemotherapy. The primary objective of this study was to report outcomes in dogs with localized PHS treated with standardized local and systemic therapy. A secondary objective was to identify prognostic factors in this population. A multi-institutional retrospective study was performed and medical records including all surgical and histopathologic reports were retrospectively reviewed. For inclusion, dogs were required to have confirmed localized PHS and they must have undergone curative-intent surgery with resection of all gross primary tumour and enlarged tracheobronchial lymph nodes; additionally, they must have received curative-intent treatment with adjuvant single-agent CCNU chemotherapy. Twenty-seven dogs from six veterinary teaching hospitals and five private practices treated from 2008-2019 were included. The overall median survival time was 432 days. Higher CCNU dose was demonstrated to have a negative impact on survival on univariate, but not multivariable, analysis. Factors that were not found to be associated with survival on univariate analysis included body weight, breed, clinical signs at the time of diagnosis, hypoalbuminaemia, tumour size, lung lobe affected, lymph node metastasis, surgical margins and CCNU dose reductions. This study supports a favourable prognosis for dogs diagnosed with localized PHS treated with curative-intent surgery in addition to adjuvant CCNU chemotherapy and suggests that multimodal treatment may be advisable to attempt to prolong survival.