[Show abstract][Hide abstract] ABSTRACT: High-risk human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCCs) are highly invasive; however the identity of downstream effectors responsible for their aggressive phenotype remains underinvestigated. Here, we report that HPV-mediated up-regulation of heparanase enzyme can provide mechanistic explanation for augmented invasiveness of HPV-positive HNSCCs. Heparanase is the sole mammalian enzyme (endo-β-d-glucuronidase) degrading heparan sulphate glycosaminoglycan, key polysaccharide of the extracellular matrix. Cleavage of heparan sulphate by heparanase leads to disassembly of extracellular barriers, enabling local invasion and metastatic spread of the tumour, and releases heparan sulphate-bound growth factors from the extracellular depots. Heparanase is tightly implicated in head and neck cancer progression; yet, molecular mechanisms underlying transcriptional activation of the heparanase gene in HNSCC are largely unknown. We found that HPV16 oncogene E6 is capable of inducing overexpression of heparanase in HNSCC. Notably, radiation treatment dose-dependently suppresses E6-induced heparanase expression in vitro. Our results provide the first evidence for a functional involvement of HPV in heparanase induction in head and neck tumourigenesis and, given ongoing clinical testing of several heparanase-inhibiting compounds, offer important avenue for future therapeutic exploration in HNSCC, as well as other HPV-associated malignancies (i.e. cervical carcinoma).
Journal of Cellular and Molecular Medicine 11/2013; 18(1). DOI:10.1111/jcmm.12179 · 3.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Livin is a member of the inhibitor of apoptosis proteins (IAP) family of intracellular antiapoptotic proteins that act by binding and inhibiting caspases. Upon strong apoptotic stimuli, it is then specifically cleaved by caspases to produce a truncated protein (tLivin) with a paradoxical proapoptotic activity. Intriguingly, we have detected robust protein levels of Livin in normal mature bone marrow megakaryocyte (MK) and platelets. To evaluate the potential role of Livin in thrombopoiesis, we used the human BCR-ABL+ cell line, LAMA-84, and cord blood CD34+ cells to induce differentiation toward MKs. Upon differentiation, induced by phorbol myristate acetate and concurrent with increase in Livin protein expression, LAMA-84 cells formed functional platelet-like particles. Livin overexpression in CD34+ progenitor cells induced higher endoreplication in the MKs generated. Furthermore, overexpression of Livin increased the ability of both primary MKs and differentiated LAMA-84 cells to produce functional platelets. In the differentiated LAMA-84 cells, we observed accumulation of proapoptotic tLivin concomitant with increased caspase-3 activity. Downregulation of Livin with small interfering RNA in both leukemic and primary MK cells decreased their ability to produce functional platelets. We suggest that Livin has a role in thrombopoiesis by regulating the apoptotic and antiapoptotic balance in MK endoreplication and platelet production.
[Show abstract][Hide abstract] ABSTRACT: Heparanase is the sole mammalian endoglycosidase that selectively degrades heparan sulfate, the key polysaccharide associated with the cell surface and extracellular matrix of a wide range of tissues. Extensively studied for its capacity to promote cancer progression, heparanase enzyme was recently implicated as an important determinant in several inflammatory disorders as well. Applying immunohistochemical staining, we detected preferential expression of heparanase by epidermal keratinocytes in human psoriatic lesions. To investigate the role of the enzyme in the pathogenesis of psoriasis, we utilized heparanase transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate-induced cutaneous inflammation. We report that over-expression of the enzyme promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecular/cellular characteristics. Importantly, heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT3, enhanced NF-κB signaling, elevated expression of TNF-α and increased vascularization. Taken together, our results reveal, for the first time, involvement of heparanase in the pathogenesis of psoriasis and highlight a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin. Heparanase inhibitors (currently under clinical testing in malignant diseases) could hence turn highly beneficial in psoriatic patients as well.
Cellular and Molecular Life Sciences CMLS 10/2013; 71. DOI:10.1007/s00018-013-1496-9 · 5.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extra domain A-containing fibronectin (EDA-FN) is necessary for the development of allergen-induced lower airway fibrosis. The pathogenesis of fibrosis in allergic rhinitis has not been well studied.
To determine whether EDA-fibronectin is necessary for the development of nasal remodeling in a murine model of chronic allergic rhinitis and in human allergic rhinitis.
EDA(-/-) and wild-type (WT) C57Bl/6 mice were sensitized intraperitoneally and then challenged with inhaled ovalbumin (OVA) or saline for 2 and 5 weeks. Clinical signs of rhinitis and histological analysis of nasal tissue were evaluated. Immunohistological staining for EDA-FN was performed in human tissue of inferior nasal conchae from patients with allergic rhinitis and controls.
After 2 weeks of allergen exposure, only goblet cell hyperplasia and perivascular eosinophilia were observed. After 5 weeks, goblet cell number, thickening of the subepithelial layer, and extent and area of collagen deposition were increased in the nasal tissue of WT OVA (ovalbumin)-challenged mice as compared with saline controls (P < .0001, P < .0001, P = .018, and P = .03, respectively). Clinical signs of rhinitis were observed only in WT OVA-challenged mice. In the EDA(-/-) mice exposed to OVA, collagen deposition, collagen area, and subepithelial thickness showed no increase and were similar to saline control mice, whereas goblet cell hyperplasia was similar to WT OVA-challenged mice. EDA-FN expression was prominent in inferior conchae from patients with allergic rhinitis but was absent in control patients.
EDA-containing fibronectin is necessary for the development of nasal tissue fibrotic remodeling process in both murine and human allergic rhinitis.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 05/2013; 110(5):322-7. DOI:10.1016/j.anai.2013.03.002 · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 66-year-old osteoporotic woman suffered from long-term mental paresthesia (numbness), facial swelling, and a nonhealing extraction site. Fulfilling the three clinical diagnostic criteria for bisphosphonate-related osteonecrosis of the jaw (BRONJ; exposed bone for at least 8 weeks, current bisphosphonate [risedronate] treatment, and no history of head and neck radiation therapy), she was diagnosed and treated accordingly. Nevertheless, a later histopathologic examination revealed malignant lymphoproliferative infiltration of large and intermediate cells. Based on immunostaining and positron-emission tomography, she was diagnosed as having primary diffuse large B-cell lymphoma. This case demonstrates the limitation of the current diagnostic method of BRONJ. Thus, the clinician should be particularly cautious and aware of the differential diagnosis, including malignancy, especially when lesions are accompanied by (mental nerve) neuropathy and long-standing swelling/expansion, and even when plain radiography is not a contributing factor.
[Show abstract][Hide abstract] ABSTRACT: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) have traditionally been considered as two distinct entities. However, there are rare reports of patients that, over time, develop both diseases. It remains unresolved whether the origin of the two diseases is from the same clone. In this study, we attempted to retrospectively investigate the clinical and molecular aspects of patients who developed both lymphomas. The rearranged immunoglobulin heavy-chain variable region genes from both diagnoses were compared to each other. Twenty-six patients presented with both diagnoses. Twelve had HL as the primary disorder ("HL first" group) and the majority of these (75%) presented with aggressive lymphoma as the second lymphoma. In contrast, in the 11 patients for whom NHL was the primary disorder ("NHL first" group), this was usually (82%) of low-grade histology. Three patients were diagnosed concurrently with both diseases. Mean age at first diagnosis was higher (p = 0.037) in the NHL first group (56.1 years) than in the HL first group (40 years). Mean time between diagnoses was longer (p = 0.026) in the HL first group (9 years) than in the NHL first group (5 years). For 11 patients, diagnostic samples were available for molecular analyses from both diagnoses of HL and NHL. In 6 of these 11 patients, gene rearrangement studies were informative. No patient had the same gene rearrangement identified in both diseases. It seems that development of HL and NHL in one patient, at different time points, reflects, in many cases, separate biologic diseases.
[Show abstract][Hide abstract] ABSTRACT: Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal involvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential involvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mechanism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions. The specific heparanase inhibitor SST0001 markedly decreased the extent of albuminuria and renal damage in mouse models of DN. Our results collectively underscore the crucial role of heparanase in the pathogenesis of DN and its potential as a highly relevant target for therapeutic interventions in patients with DN.
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis may be related to the pathogenesis and prognosis of chronic rhinosinusitis with nasal polyposis. This cross-sectional study, in a tertiary university hospital, evaluates angiogenesis parameters in nasal polyps, antrochoanal polyps and middle turbinates.
Nasal polyps obtained from 24 consecutive patients, were compared to 10 normal middle turbinates and to 11 antrochoanal polyps.
Analyzing for the expression of the angiogenic marker CD34 by immunohistochemistry. Blood vessels count, vascular surface density and microvessel density were measured by manual and computerized methods.
Angiogenesis was significantly higher in nasal polyps compared to control turbinates and to antrochoanal polyps (p = 0.0001 and p = 0.007, respectively). Antrochoanal polyps showed significantly more angiogenesis than normal middle turbinates (p = 0.001). Angiogenesis was not elevated in sub-groups of nasal polyposis patients considered to have worse prognosis.
Angiogenesis probably plays a role in the pathogenesis of both nasal polyposis and antrochoanal polyps. However, the significantly higher angiogenesis found in nasal polyps compared to antrochoanal polyps may support a different mechanism of growth. The lack of difference between angiogenesis and nasal polyposis patients sub-groups, may imply that angiogenesis is not associated with the prognosis of chronic rhinosinusitis with nasal polyposis.
Agents and Actions 10/2010; 60(4):321-7. DOI:10.1007/s00011-010-0271-8 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral neurotoxicity and neuropathic pain are well-known complications of several anti-cancer chemotherapeutic agents. Such pain might cause an impairment of the patient's quality of life and is a common limiting factor of anti-cancer chemotherapy. Neurotoxicity in orofacial structures has been previously described as diffuse jaw pain or numbness. Currently, localized pulpal pain is not listed as a possible complication of cytotoxic therapy. The aim of this report was to suggest cytotoxic-induced neurotoxicity as a differential diagnosis for toothache during anti-cancer therapy.
We described the diagnostic process in a patient suffering from severe pulpal pain in apparently intact teeth during cytotoxic therapy. A non-Hodgkin's lymphoma patient complained of 2 episodes of excruciating dental pain evoked by mouth breathing, which caused nocturnal awakenings.
Both episodes developed immediately after administrations of cyclophosphamide as part of an anti-cancer chemotherapy protocol. Clinical parameters and radiographic characteristics eliminated other possible dental and facial etiologies. Pulp extirpation (pulpectomy) resulted in immediate pain relief. In both episodes, cytologic evaluation of the extirpated pulp tissue failed to show inflammation or an infiltration of lymphoma cells.
This case presented a circumstantial relation between the clinical presentation of dental pain, with associated significant impairment of the patient's quality of life, and the timing of administrations of high-dose cyclophosphamide. It suggests that chemotherapy-induced toxicity might manifest as pulpitis-like toothache, which might present a diagnostic challenge for the dental practitioner.
Journal of endodontics 09/2010; 36(9):1588-92. DOI:10.1016/j.joen.2010.05.004 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Laryngeal vascular leiomyomas are uncommon benign tumors that seldom recur following complete excision. The choice of excision procedure-via direct laryngoscopy or an open approach-is dictated by tumor size, the expected amount of blood loss, and any comorbidities the patient may have. We report an unusual case of a recurrent laryngeal vascular leiomyoma in a 64-year-old woman who also had a concurrent parathyroid adenoma and a history of breast carcinoma. A surgical resection via an external approach along with laser resection of a small glottic component was needed.
[Show abstract][Hide abstract] ABSTRACT: Gastro-intestinal stromal tumors (GISTs) of the appendix are a rare entity. To date, only a handful has been described in the literature, all of which have been of the benign type.
We present the first reported case of a malignant appendiceal GIST. The tumor was discovered when the patient presented with a peri-appendiceal abscess which appeared suspicious on CT. The abscess was drained and managed medically. The patient responded to antibiotic treatment but subsequent CT and biopsy confirmed the diagnosis of appendiceal GIST, and the patient was started on treatment with imatinab mesylate.
One week after initiation of therapy, the patient returned with frank peritonitis necessitating surgery. Abdominal exploration revealed an appendiceal GIST locally invading and perforating adjacent bowel. We describe the complex presentation and course of the case as well as a literature review of the appendiceal GISTs and the current approach to treatment.
Journal of Gastrointestinal Cancer 12/2009; 41(1):9-12. DOI:10.1007/s12029-009-9113-8 · 0.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We and others previously described the IAP Livin (ML-IAP). We found that Livin is unique among the IAP members as, on a strong apoptotic stimulus, it is specifically cleaved by caspases to produce a truncated protein with paradoxical proapoptotic activity (tLivin). We also showed that Livin encodes two splicing variants, termed Livin alpha and beta, with diverse antiapoptotic effects in vitro. In this study, we compared the Livin isoforms in vivo. An animal model was established and the effects of Livin alpha and beta on the initiation and development of tumors were compared. In the animal model, Livin alpha promotes tumor initiation in comparison with control. Interestingly, the growth of tumors originating from cells expressing Livin beta was inhibited. In these tumors, Livin beta was cleaved and produced a high level of the proapoptotic tLivin beta that repressed tumor development. When we eliminated the proapoptotic effect of Livin beta by point mutations, the resulting antiapoptotic Livin beta mutants contributed to tumor progression. In terms of mechanism, we show that Livin beta tumors develop only in mice lacking natural killer (NK) cell activity. Thus, from the animal model, we can conclude that Livin plays a major role in tumorigenicity and that NK cells induce cleavage of Livin to its proapoptotic truncated protein that in turn inhibits tumor growth. Therefore, Livin and tLivin may serve as potential targets for cancer therapy.
Cancer Research 07/2009; 69(13):5475-80. DOI:10.1158/0008-5472.CAN-09-0424 · 9.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While the presence of Epstein-Barr virus (EBV) in colonic specimens from patients with inflammatory bowel disease (IBD) has been documented, diarrhea secondary to gastrointestinal involvement by EBV in the context of primary EBV infection in patients with IBD has not been reported. We describe a patient with IBD who presented with diarrhea and primary EBV infection and propose a role for colonic involvement by EBV in the pathogenesis of his symptoms.
[Show abstract][Hide abstract] ABSTRACT: Analysis of the pre- and postoperative features, long-term follow-up, and complications.
Case series with chart review of 160 thyroglossal tract remnant excisions over a 20-year period (1988-2007).
The mean age of diagnosis was 10.9 +/- 14.2 years with 63.8 percent male predominance. There was a prior history of thyroglossal tract remnant infections in 70 percent of patients, and 30 percent presented with cutaneous fistulas. The majority had ultrasound imaging that identified cysts mainly (66.7%) in the infrahyoid region. Preoperative fine-needle aspirations in 18 patients were benign. On pathological reevaluation, 26.5 percent had thyroid tissue inside the remnant, with one case of papillary carcinoma. After the Sistrunk operation, postoperative complications occurred in 7.5 percent including a 1.9 percent recurrence rate.
All age groups had similar clinical presentations and outcomes. Ultrasound is a reliable and appropriate imaging modality for most patients. Surgery must effectively incorporate the tract and cyst to allow low recurrence rates (<2%). Clinically diagnosed thyroglossal tract remnant may, in fact, be other pathologies in 10 percent of cases. Nevertheless, our recommendation is a Sistrunk procedure for all midline neck lesions suspected to be a thyroglossal tract remnant.
Otolaryngology Head and Neck Surgery 03/2009; 140(3):338-42. DOI:10.1016/j.otohns.2008.12.002 · 1.72 Impact Factor