Papers by Audrey Baldessari
American journal of obstetrics and gynecology, Jan 15, 2015
Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnan... more Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intra-amniotic balloons (N=6), which were compared to saline controls (N=5). Cesarean section was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex, and enzyme-linked immunosorbent assay were used to measure mRNA and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human tissues (amniocytes, amnion and myometrium). Statistical analysis employed Analysis of Covariance, Wilcoxon rank sign and rank sum. Biomechanical force...
Comparative medicine, 2014
An adult, gravid, female pigtailed macaque (Macaca nemestrina) presented for facial swelling cent... more An adult, gravid, female pigtailed macaque (Macaca nemestrina) presented for facial swelling centered on the left mandible that was approximately 5 cm wide. Differential diagnoses included infectious, inflammatory, and neoplastic origins. Definitive antemortem diagnosis was not possible, and the macaque's condition worsened despite supportive care. Necropsy findings included a mandibular mass that was locally invasive and expansile, encompassing approximately 80% of the left mandibular bone. The mass replaced portions of the soft palate, hard palate, sinuses, ear canal, and the caudal-rostral calvarium and masseter muscle. Histologically, the mass was a neoplasm that was poorly circumscribed, unencapsulated, and infiltrative invading regional bone and soft tissue. The mass consisted of polygonal squamous epithelial cells with intercellular bridging that breached the epithelial basement membrane and formed invasive nests, cords, and trabeculae. The mitotic rate averaged 3 per 400...
Comparative medicine, 2014
A 2.25-y-old male pigtailed macaque (Macaca nemestrina) was experimentally irradiated and receive... more A 2.25-y-old male pigtailed macaque (Macaca nemestrina) was experimentally irradiated and received a bone marrow transplant. After transplantation and engraftment, the macaque had unexpected recurring pancytopenia and dependent edema of the prepuce, scrotum, and legs. The diagnostic work-up included a blood smear, which revealed a trypomastigote consistent with Trypanosoma cruzi, the causative agent of Chagas disease (CD). We initially hypothesized that the macaque had acquired the infection when it lived in Georgia. However, because the animal had received multiple blood transfusions, all blood donors were screened for CD. One male pigtailed macaque blood donor, which was previously housed in Louisiana, was positive for T. cruzi antibodies via serology. Due to the low prevalence of infection in Georgia, the blood transfusion was hypothesized to be the source of T. cruzi infection. The transfusion was confirmed as the mechanism of transmission when screening of archived serum reveal...
Pathobiology of Aging & Age-related Diseases, 2013
A 36-year-old male chimpanzee (Pan troglodytes) assigned to a life-long sign language communicati... more A 36-year-old male chimpanzee (Pan troglodytes) assigned to a life-long sign language communication project presented for sudden death. No other clinical or clinical pathological abnormalities were noted and given the signalment, death due to cardiac failure was suspected. Necropsy findings revealed moderate cardiomegaly and other chronic age-related findings including focal renal tubular cystic dilation and gingival hyperplasia. Histologic evaluation of the heart revealed interstitial fibrosing cardiomyopathy characterized by severe interstitial myocardial fibrosis replacing and separating myofibers within all chambers of the heart, especially the left ventricle, interventricular septum and subvalvular areas. This case report represents an additional case of sudden death associated with interstitial myocardial fibrosis in a chimpanzee. This process has been previously cited as the most common cause of sudden death in aged chimpanzees.
Journal of General Microbiology, 1990
... ALICIA BALDESSARI,~ LUIS IELPI and MARCELO A. DANKERT” ... was prepared with enzymes from Xan... more ... ALICIA BALDESSARI,~ LUIS IELPI and MARCELO A. DANKERT” ... was prepared with enzymes from Xanthomonas campestris or Rhizobium meliloti 131 (M. Bravo and M ... PP-preno1 were synthesized with enzymes from Aceto-bacter xylinum as reported previously (Romero et al ...
Molecular Therapy — Methods & Clinical Development, 2015
A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctio... more A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.
Veterinary Dermatology, 2007
In humans, mammary and extramammary Paget's disease is an uncommo... more In humans, mammary and extramammary Paget's disease is an uncommon to rare manifestation of intraepidermal adenocarcinoma arising from simple epithelium, usually glandular in origin. This report describes two cats with lesions in perianal skin consisting of atypical intraepidermal neoplastic cells. Differential diagnoses included intraepidermal adenocarcinoma, in situ squamous or basal cell carcinoma, junctional amelanotic melanoma, and epitheliotropic tumours of histiocytic or lymphocytic origin. The atypical intraepidermal cells in the cats were immunohistochemically positive for cytokeratin 8/18 (CK8/18), which stains simple (glandular) epithelium. The keratinocytes and basal cells were negative for CK8/18. In addition, the atypical intraepidermal cells were immunohistochemically negative for melanocytic, lymphocytic, and histiocytic markers. The staining results confirmed the atypical intraepidermal cells to be of simple glandular origin, and ruled out other causes of intraepidermal malignancy. In one cat the clinical lesions consisted of a pruritic erythematous eruption surrounding the anus. Another cat presented clinically for an area of irregular anal thickening; this cat had well-regulated diabetes mellitus. The cats were otherwise clinically healthy. The clinical features, histological appearance, and immunohistochemical staining of the skin lesions were consistent with those described for human perianal extramammary Paget's disease. To the authors' knowledge, this is the first report of an intraepidermal adenocarcinoma in a cat or other animal species.
Pediatric and Developmental Pathology, 2005
Previous studies have focused on expression of Hox11L1 in enteric neurons as the explanation for ... more Previous studies have focused on expression of Hox11L1 in enteric neurons as the explanation for intestinal and urinary bladder dysmotility observed in mice that do not have the transcription factor. However, Hox11L1 is also expressed transiently in endo-, meso-, and ectodermal cells of the most caudal embryo during gastrulation. We sought to more fully characterize the fates of these cells because they might help explain the pathogenesis of lethal pseudo-obstruction in Hox11L1-null mice. The Cre recombinase cDNA was introduced into the Hox11L1 locus, and expression of the ''knock-in'' allele was used to activate the Rosa26R, b-galactosidase reporter gene in cells with ongoing Hox11L1 transcription and their descendants. During gastrulation, Rosa26R activation was observed in progenitors of caudal somatic and visceral cells, including enteric smooth muscle. Expression in enteric neural precursors appeared much later. Analysis of endogenous Hox11L1 mRNA in aneuronal segments of large intestine that were grafted under the renal capsule indicated that the early activa-tion of Hox11L1 in visceral mesoderm was transient and ceased before colonization of the large intestine by neural progenitors. Mice homozygous for the Cre allele died shortly after weaning, with cecal and proximal colonic distention but without overt anatomic defects that might represent maldevelopment of the visceral mesoderm. Our findings expand the range of possible functions of Hox11L1 to include activation of an as yet unknown developmental program in visceral smooth muscle and allow the possibility that intestinal dysmotility in Hox11L1-null animals may not be a primary neural disorder.
Nature, 2014
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by... more Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.
Molecular Therapy, 2013
We have developed a technology that depletes the complement regulatory protein (CRP) CD46 from th... more We have developed a technology that depletes the complement regulatory protein (CRP) CD46 from the cell surface, and thereby sensitizes tumor cells to complement-dependent cytotoxicity triggered by therapeutic monoclonal antibodies (mAbs). This technology is based on a small recombinant protein, Ad35K++, which induces the internalization and subsequent degradation of CD46. In preliminary studies, we had demonstrated the utility of the combination of Ad35K++ and several commercially available mAbs such as rituximab, alemtuzumab, and trastuzumab in enhancing cell killing in vitro as well as in vivo in murine xenograft and syngeneic tumor models. We have completed scaled manufacturing of Ad35K++ protein in Escherichia coli for studies in nonhuman primates (NHPs). In macaques, we first defined a dose of the CD20-targeting mAb rituximab that did not deplete CD20-positive peripheral blood cells. Using this dose of rituximab, we then demonstrated that pretreatment with Ad35K++ reconstituted near complete elimination of B cells. Further studies demonstrated that the treatment was well tolerated and safe. These findings in a relevant large animal model provide the rationale for moving this therapy forward into clinical trials in patients with CD20-positive B-cell malignancies.
Journal of Natural Products, 1993
Gastroenterology, 2003
Abbreviations used in this paper: 129, 129SvJ mouse strain; B6, C57BL/6J mouse strain; DHFR, dihy... more Abbreviations used in this paper: 129, 129SvJ mouse strain; B6, C57BL/6J mouse strain; DHFR, dihydrofolate reductase; HSCR, Hirschsprung's disease; NOS, nitric oxide synthase; RT-PCR, reverse-transcription polymerase chain reaction; SMA, smooth muscle actin.
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Papers by Audrey Baldessari