Ovarian carcinoma is the fifth leading cause of death among women in the United States. Persistent activation of STAT3 is frequently detected in ovarian carcinoma. STAT3 is activated by Janus family ...kinases (JAK) via cytokine receptors, growth factor receptor, and non-growth factor receptor tyrosine kinases. Activation of STAT3 mediates tumor cell proliferation, survival, motility, invasion, and angiogenesis, and recent work demonstrates that STAT3 activation suppresses antitumor immune responses and supports tumor-promoting inflammation. We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on ovarian carcinoma cells and by inhibition of cells in the tumor microenvironment (TME). To test this, we evaluated the effects of a small-molecule JAK inhibitor, AZD1480, on cell viability, apoptosis, proliferation, migration, and adhesion of ovarian carcinoma cells in vitro. We then evaluated the effects of AZD1480 on in vivo tumor growth and progression, gene expression, tumor-associated matrix metalloproteinase (MMP) activity, and immune cell populations in a transgenic mouse model of ovarian carcinoma. AZD1480 treatment inhibited STAT3 phosphorylation and DNA binding, and migration and adhesion of cultured ovarian carcinoma cells and ovarian tumor growth rate, volume, and ascites production in mice. In addition, drug treatment led to altered gene expression, decreased tumor-associated MMP activity, and fewer suppressor T cells in the peritoneal TME of tumor-bearing mice than control mice. Taken together, our results show pharmacologic inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic strategy.
Ovarian cancer ranks fifth in cancer related deaths for women in USA. The high mortality rate associated with ovarian cancer is due to diagnosis at later stages of disease and the high recurrence ...rate of 60-80%. Recurrent ovarian cancers are more likely to present as multidrug resistance (MDR) leading to unfavorable response from 2
and 3
line chemotherapy. Nanoemulsions (NEs) are emerging as an attractive drug delivery system to overcome MDR challenges. NEs can also minimize exposure of therapeutic cargo to normal tissues potentially reducing side effects. In >80% of ovarian cancers, Folate Receptor-α (FR-α) is expressed at 10- to 100-fold higher levels than on non-pathological tissues. Therefore, folate (FA) is being evaluated as an active targeting moiety for FR-α
ovarian cancer. To improve therapeutic outcome with reduced toxicity, we developed NMI-500, a FA targeted gadolinium (Gd) annotated NE loaded with docetaxel (DTX). NMI-500 has been developed as theranostic agents as Gd will enable physician to acquire real time pharmacodynamics data on NE + DTX accumulation in target lesions. In present study, characterization for key translational metrics of NMI-500 showed size distribution in range of 120 to 150 nm and zeta potential around -45 mV. Active targeting of FA was evaluated against FR-α
KB cells and results demonstrated significant improvement in cell association which was surface ligand density dependent. We found that NMI-500 was able to inhibit tumor growth in a spontaneous transgenic ovarian cancer model with improved safety profile and this growth inhibition could be longitudinally followed by MRI. These results indicate NMI-500 warrants advancement to clinical trials.
Summary
Facilitated ankylosis using intra‐articular ethanol has been reported as a viable alternative to proximal interphalangeal (PIP) arthrodesis for owners with financial constraints or ...reservations regarding the invasiveness of surgical arthrodesis. An 18‐year‐old gelding presented for a left front leg lameness (Grade 4/5 on the AAEP scale) localised to the pastern region. Radiographs revealed severe osteoarthritis of the proximal interphalangeal joint (PIJ). Facilitated ankylosis of the PIJ with 95% alcohol was elected. The horse presented 6 weeks later with a significant worsening of the lameness, swelling of the pastern region and was noticed with the toe elevated off the ground when transiently weight bearing. Radiographs revealed a comminuted fracture of the middle phalanx. The horse was humanely euthanised. Necropsy revealed a severe chronic closed comminuted fracture of the middle phalanx with partially devitalised bone. Potential aetiologies are a decreased bone quality prior to alcohol injection, or that the desensitisation due to the alcohol injection could have resulted in an overuse by the horse or a traumatic accident. While previously unreported, veterinarians should educate owners that catastrophic fracture is an unlikely but possible complication following intra‐articular ethyl alcohol injection.
Epithelial ovarian cancer (EOC) is usually detected at an advanced stage and is frequently lethal. Although many patients respond to initial surgery and standard chemotherapy consisting of a ...platinum-based agent and a taxane, most experience recurrence and eventually treatment-resistant disease. Although there have been numerous efforts to apply protein-targeted agents in EOC, these studies have so far documented little efficacy. Our goal was to identify broadly susceptible signaling proteins or pathways in EOC.
As a new approach, we conducted data-mining meta-analyses integrating results from multiple siRNA screens to identify gene targets that showed significant inhibition of cell growth. On the basis of this meta-analysis, we established that many genes with such activity were clients of the protein chaperone HSP90. We therefore assessed ganetespib, a clinically promising second-generation small-molecule HSP90 inhibitor, for activity against EOC, both as a single agent and in combination with cytotoxic and targeted therapeutic agents.
Ganetespib significantly reduced cell growth, induced cell-cycle arrest and apoptosis in vitro, inhibited growth of orthotopic xenografts and spontaneous ovarian tumors in transgenic mice in vivo, and inhibited expression and activation of numerous proteins linked to EOC progression. Importantly, paclitaxel significantly potentiated ganetespib activity in cultured cells and tumors. Moreover, combined treatment of cells with ganetespib and siRNAs or small molecules inhibiting genes identified in the meta-analysis in several cases resulted in enhanced activity.
These results strongly support investigation of ganetespib, a single-targeted agent with effects on numerous proteins and pathways, in augmenting standard EOC therapies.
This case report describes for the first time the cytologic characteristics of a hormonally secreting pituitary adenoma in a cat. An 8-year-old female spayed domestic long-haired cat was referred ...with a previous diagnosis of hypersomatotropism and secondary diabetes mellitus 7 months prior. Clinical signs included weight loss, polyphagia, polyuria, and polydipsia. Serum insulin-like growth factor-1 was 340 nmol/L (RI: 12-92), and CT scan revealed a hypophyseal mass, and a presumptive diagnosis of acromegaly was made. A transsphenoidal hypophysectomy was performed. A fragment of the pituitary gland was subjected to a squash preparation and cytology revealed a neuroendocrine neoplasm characterized by anisokaryosis and prominent nucleoli. Additional cytologic findings included cell cohesiveness, indistinct cytoplasmic borders, nuclear crowding, molding, and fragmentation. A diagnosis of adenoma was based on a lack of histopathologic or imaging evidence of invasion. A week later, during post-surgical hospitalization, the patient worsened and died. Histopathology from a necropsy procedure revealed fibrinosuppurative meningitis as a post-surgical complication. Pituitary adenomas might have an aggressive cytologic appearance, despite a lack of histopathologic invasion or dissemination.
Abstract
Ovarian cancer is the fifth leading cause of death and the most lethal gynecological cancer among women in the United States. Persistent activation of signal transducer and activator of ...transcription 3 (STAT3), a cytoplasmic transcription factor, is frequently detected in EOC. STAT3 transduces signals from cytokines such as interleukin 6 (IL-6) via interactions with the IL-6 receptor and Janus kinases (JAK). JAK2 activates STAT3 by phosphorylation, leading to dimerization and translocation of STAT3 to the nucleus where it activates transcription of target genes regulating proliferation, survival and motility. Importantly, in addition to tumor cells, STAT3 signaling is also critical for immune cell activity and, in particular, inflammatory response. The inflammatory tumor microenvironment is important for ovarian cancer progression; therefore, we hypothesized that disruption of the STAT3 pathway would block ovarian tumor progression by: 1) directly inhibiting the growth of tumor cells; and 2) reducing a pro-tumorigenic inflammatory microenvironment. To target JAK2-mediated activation of STAT3 we used AZD1480, a JAK2-selective small molecule inhibitor. The effects of AZD1480 treatment on cell proliferation, apoptosis, adhesion and motility were evaluated in cultured human ovarian carcinoma cells. To study the effects of AZD1480 in vivo, we used MISIIR-TAg mice, a transgenic mouse model of ovarian carcinoma. Tumor growth in MISIIR-TAg mice was monitored and quantified in mice by weekly magnetic resonance imaging (MRI). Drug treatment-mediated alterations in gene expression were evaluated by microarray analysis and changes in the inflammatory response were evaluated by flow cytometry analysis of cells extracted from ovarian tumors, spleens and peritoneal washes. AZD1480 treatment significantly reduced primary ovarian tumor growth in transgenic mice. Microarray analysis showed changes in expression of genes involved in the acute immune response, such as Gbp6, Ifi44, Irgm, Igtp, Gzmb and Cd69. Analysis of immune cell populations by flow cytometry showed a significant decrease in the number and percent of T helper and T regulatory cells present in the peritoneal cavity of drug-treated mice compared to controls. As T regulatory cells are associated with a poor prognosis in ovarian cancer patients, the decrease of this subpopulation in drug-treated mice suggests a change in the tumor microenvironment that may contribute to reduced tumor growth. Taken together, these results indicate that targeting JAK2/STAT3 impedes ovarian tumor growth through complex mechanisms, including the reduction of primary tumor growth and inflammation in the tumor microenvironment. These findings highlight the potential utility of targeting the JAK2/STAT3 pathway for the treatment of ovarian cancer patients.
Citation Format: Galina Gritsina, Fang Xiao, Shane W. O'Brien, Marisa A. Maglaty, Ren-Huan Xu, Luis J. Sigal, Samuel Litwin, Denise C. Connolly. Targeting the JAK2/STAT3 pathway in ovarian cancer. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1113. doi:10.1158/1538-7445.AM2014-1113
Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in ...acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacological or RNA interference-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRC(Y416)). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared with either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.
Granular Cell Tumor in the Brain of a Dog Maglaty, Marisa; Woolard, Kevin
Brazilian Journal of Veterinary Pathology,
03/2021, Letnik:
14, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Diagnostic Exercise from The Latin Comparative Pathology Group. Clinical History: 10 year-old, female spayed, Golden Retriever/Poodle mix. This patient had a mass removed laparoscopically from the ...right adrenal gland (cortical adenoma) and was started on a low dose of prednisone post-operatively. Eight days post-op, she began having cluster seizures and was started on levetiracetam therapy. The following day, the dog was moderately obtunded and stumbling. On neurological examination, mild generalized ataxia was noted along with decreased menace OS, and delayed proprioception in the left pelvic and left thoracic limbs. CBC and chemistry values were unremarkable except for a mild hepatic enzyme elevation. EEG showed seizure-like activity and abnormal brain waves resembling sleep state while awake. MRI revealed an eccentric right-sided mass extending over the frontal and parietal lobes with subtentorial herniation. Due to poor prognosis, euthanasia was elected. Necropsy and Microscopic Findings: Tenuously adhered to the right parietal lobe of the brain and the dura mater is a soft, round, white, plaque-like mass measuring 3.5 x 3.0 x 0.3 cm. The mass is friable and poorly-demarcated from surrounding brain parenchyma. A portion of the mass adheres to the supradjacent surface of the calvarium.
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