Stuart J. Galloway

Biocompatible properties of surgical mesh using an animal model

Aim:  To study the biocompatibility of surgical meshes for use in pelvic reconstructive surgery using an animal model.

RECK in Osteosarcoma: A Novel Role in Tumour Vasculature and Inhibition of Tumorigenesis in an Orthotopic Mode

Targeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice.

Involvement of c-jun in human liposarcoma growth: supporting data from clinical immunohistochemistry and DNAzyme efficacy.

c-jun has been found to be upregulated in a variety of cancers. Recently, this oncogene has also been implicated in liposarcoma (LS) progression. c-jun knockdown mediated by a deoxyribozyme induced apoptosis in LS cells via evoking caspase-10, but not the Fas/FasL pathway. A novel orthotopic model for LS was established in the hindlimb of mice using human cells to extend the evaluation of effects of c-jun knockdown in vivo. Tumor take in vivo was 100%, with growths resembling high grade aggressive LS. The c-jun deoxyribozyme inhibited the growth of LS in this model. Clinically, downregulation of c-jun may proffer an improved treatment outcome for liposarcoma. The new model for LS described here will enable better testing of agents with therapeutic potential against LS.

Dz13, a c-jun DNAzyme, Is a Potent Inducer of Caspase-2 Activation

Signaling pathways for caspase-2-mediated apoptosis are poorly defined. This is partially due to a lack of a reproducible stimulus to trigger caspase-2 activation. We present the oligonucleotide Dz13, a DNA enzyme that cleaves c-Jun mRNA and is capable of inhibiting various model tumors in mice, which potently induces caspase-2 resulting in apoptosis in a panel of tumor cell lines. Dz13-mediated cell death occurred even in the absence of known caspase-2 molecular partners in p53-induced protein with a death domain, RIP-associated Ich-1/CED homologous protein with death domain, or DNA-dependent protein kinase catalytic subunit, or other caspases in cell lines of breast cancer, prostate cancer, osteosarcoma, and liposarcoma. z-VDVAD-fmk, caspase-2(-/-) mouse embryonic fibroblasts and siRNA silencing of caspase-2 in tumor cells abrogated Dz13-mediated cell death. In an orthotopic tumor model, expression of caspase-2 increased as the tumor metastasized and caspase-2 expression was sporadic in patient tumor specimens. These findings provide hope that Dz13, and other agents that evoke activation of caspase-2, may be therapeutic clinically.

Dz13 Induces a Cytotoxic Stress Response with Upregulation of E2F1 in Tumor Cells Metastasizing to or from Bone

The oligonucleotide Dz13 is a DNA enzyme (deoxyribozyme) that cleaves c-Jun mRNA. It has efficacious effects against tumors directly, is active against tumor-induced angiogenesis, inhibits neointima formation after arterial injury, and controls inflammatory responses. The off-target effects of Dz13 may in fact be driving some of these potentially therapeutic effects, though no mechanisms have been clearly defined in target cells. To this end, we here show that when a panel of human tumor cells that naturally propagate in bone are challenged with Dz13, the tumor suppressor E2F1 is upregulated regardless of cellular p53 status. The piddosomal components, p53-induced protein with a death domain and caspase-2, were translocated to the nucleus when deoxyribozymes were incubated with cells, but RIP associated Ich-1/CED homologous protein with death domain levels increased throughout the cell with either Dz13 or its scrambled control oligonucleotide. In response to Dz13-mediated cytotoxicity, cells upregulated levels of ERK, Akt, and p38. Summarily, these results suggest a cytotoxic stress (resembling DNA damage) response of tumor cells to Dz13, which induces apoptosis via the activation of inhibitor of caspase-activated deoxyribonuclease and protein kinase C delta. In vivo, in tumor-in-bone orthotopic and clinically relevant models for prostate and breast cancer metastasis, and a novel spontaneously metastasizing model for osteosarcoma (OS), Dz13 decreased growth in bone, and also metastasis for OS. This new model for OS was assessed to be clinically relevant in its expression of typical bone markers, osteopontin and osteocalcin. These results provide an off-target mechanism for Dz13 function, but this may be useful therapeutically against tumors.

A rare case of sinonasal ameloblastoma presenting with complete nasal obstruction.

A 73-year-old woman presented with a 3-month history of progressive nasal congestion and intermittent epistaxis but was otherwise systemically well. She had no significant co-morbidities and, in particular, no history of sinonasal disease or smoking. Examination revealed an expansive red polypoid mass clearly involving the right cheek and nasal cavity (Fig. 1). There was no suggestion of oral, ocular or neurological involvement. Imaging demonstrated an expansive and erosive soft-tissue mass originating in the right maxillary antrum extending posteromedially to almost completely obstruct the nasal cavity and nasopharyngeal air space (Fig. 2). Invasion into the orbit and metastatic disease were not evident. Initial biopsy suggested ameloblastoma and the patient went on to have a right total maxillectomy, ethmoidectomy with clearance of her right infratemporal fossa (Fig. 1). Subsequent reconstruction was with a vertical rectus abdominis myocutaneous flap. Histology confirmed the diagnosis of sinonasal ameloblastoma with no features of carcinoma (Fig. 3). Ameloblastomas are rare neoplasms of odontogenic epithelium, which almost always arise from the maxilla or mandible. Due to their high tendency to recur following surgical resection, they are of interest to surgeons. 2–10% of ameloblastomas are identified in extragnathic sites where the odontogenic apparatus is not normally found; theoretically, the result of an embryological aberration with

Myoepithelioma within the carpal tunnel: a case report and review of the literature

Myoepitheliomas of the extremity are rare and usually benign, while a minority display malignant features. This case demonstrates the diagnosis and management of myoepithelioma within the carpal tunnel. Clinical and radiological tumour features were evaluated. Hematoxylin and eosin stained tumour sections were examined, and immunohistochemistry was performed. Histology revealed a nodular mass of epithelioid cells in clusters within a myxoid/chondroid stroma. No mitoses were noted. Cytokeratins, neuron-specific enolase, synaptophysin, glial fibrillary acidic protein, and S100 were positive on immunohistochemistry. A literature review revealed very few prior reports of myoepithelioma in the wrist, and limited data concerning any relationship between recurrence and quality of surgical margins. In this case, wide local excision would have significantly compromised dominant hand function, and therefore a marginal excision was deemed appropriate in the context of bland histological features. Surgical margins noted in future case reports will aid clinical decision making.

Malignant peripheral nerve sheath tumour arising de novo from ganglioneuroma

epididymis, which is derived from the mesonephric duct. This structure persists in the male embryo, where it develops into the epididymis, vas deferens and ejaculatory duct under the influence of testosterone. Thus, it would seem to be a more likely progenitor than the paramesonephric duct in males. The more dorsal and medial position of the mesonephric ducts in the embryo may render them less susceptible to being entrapped by the developing limb bud, which could explain the much lower incidence of these cysts in males. It is impossible to separate mesonephric from paramesonephric origin using the immunohistochemical panel employed here and in previous studies. In summary, we have described an example of a cutaneous ciliated cyst occurring in the scrotum of a male. In our case the morphology and immunoprofile of the cyst lining was similar to both the appendix of the epididymis and the appendix of the testis, strongly suggesting that it was derived from one of the genital ducts, rather than from an eccrine structure with ciliated metaplasia. Given the morphological and immunohistochemical similarities, we raise the novel hypothesis that origin from the mesonephric duct may explain some examples of these cysts when they occur in males.

Cushing's conundrum: an unusual case of primary pigmented nodular adrenal disease in a 60-year-old woman

A 60-year-old woman with resistant hypertension, poorly controlled type 2 diabetes, and chronic obstructive pulmonary disease requiring inhaled corticosteroids was referred for investigation of Cushing’s syndrome. She had a BMI of 31 kg/m2, abdominal obesity, and proximal muscle wasting. Investigations showed a normal aldosterone-to-renin ratio, plasma metanephrines, and renal artery Doppler ultrasound fi ndings, but increased 24 h urine free cortisol concentration (454 nmol/L [normal range <350 nmol/L]). Adrenocorticotropic hormone remained undetectable on several occasions for 12 months, during the diagnostic workup (<5 pg/mL). Because of diffi culty in ceasing use of inhaled corticosteroids, an overnight 1 mg dexa methasone suppression test was done while the patient was taking fl uticasone, showing an 8 am cortisol concentration of 278 nmol/L (compared with a normal range of <120 nmol/L). Persistent hypercortisolism was then confi rmed with intravenous dexamethasone suppression testing done after inhaled fl uticasone was withheld for several days. An adrenal CT scan showed an enlarged left adrenal gland, with an 8 mm nodule at the inferior pole (fi gure A), insuffi cient to account for the patient’s hypercortisolism. Functional imaging with iodo cholesterol under dexamethasone suppression showed bilateral uptake of labelled cholesterol (fi gure B). Adrenal vein sampling under dexamethasone supp ression was consistent with bilateral autonomous cortisol secretion (appendix). The patient underwent a bilateral adrenalectomy. The macroscopic and histological appearance was consistent with primary pigmented nodular adrenal hyperplasia (also known as primary pigmented nodular adrenal disease [PPNAD]; fi gure C, D). PPNAD is associated with Carney’s complex in 90% of white patients. Carney’s complex is an autosomal dominant multiple neoplasia syndrome, typically presenting with the classic triad of myxomas, spotty skin pigmentation, and endocrine overactivity. 60% of Carney’s complex in the white population is associated with germline-inactivating mutations in regulatory subunit 1α of protein kinase A (PRKAR1A). To our knowledge, this patient is the oldest reported person to be diagnosed with PPNAD—most patients are diagnosed before age 40 years. She has no other manifestations of Carney’s complex and is currently undergoing genetic testing for mutations in the PRKAR1A gene. This case shows that PPNAD can be latent for many years and should be considered in diff erential diagnosis of adrenocorticotropic hormoneindependent Cushing’s syndrome in elderly individuals.

Flow Cytometric Analysis of Hematologic Neoplasms

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