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Papers by Thomas McCormick

Oncotarget, Jan 28, 2016

Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexp... more Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 e...

Current Medical Research and Opinion, Apr 11, 2007

To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutane... more To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutaneous (s.c.) administrations of a human monoclonal antibody against the p40 subunit of IL-12/23 (IL-12/23 mAb) in subjects with moderate-to-severe psoriasis. Twenty-one subjects were enrolled sequentially into 4 dose cohorts (0.27, 0.675, 1.35, and 2.7 mg/kg) and randomized to IL-12/23 mAb or placebo in a 4:1 ratio. Laboratory/clinical parameters and pharmacokinetics were evaluated through Week 24; mRNA cytokine expression was measured in psoriatic plaques at Week 1. Mostly mild adverse events and no serious adverse events were reported. The pharmacokinetics (Cmax and AUC) of IL-12/23 mAb increased in an approximately dose-proportional manner. Of the 17 subjects who received IL-12/23 mAb, 13 achieved PASI 75 (compared with no placebo subjects). mRNA expression of IL-8, IL-18, and IFN-gamma in psoriatic plaques decreased in subjects with sustained Psoriasis Area and Severity Index (PASI) improvement. Interpretation of results is limited due to the small sample size in each dose cohort. A single s.c. administration of IL-12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis.

Medical hypotheses, 2015

Pompholyx remains a chronic skin affliction without a compelling pathophysiological explanation. ... more Pompholyx remains a chronic skin affliction without a compelling pathophysiological explanation. The disease is characterized by the sudden onset of vesicles exclusively in the palms and soles which generally resolves. However, the disease may progress and the vesicles may expand and fuse; with chronicity there is deep fissuring. Multiple therapeutic approaches are available, but the disease is often resistant to conventional treatments. Currently, oral alitretinoin is used for patients with resistant chronic disease; however, this therapy is only approved for use in the UK, Europe and Canada. In this paper we wish to put forward a hypothesis: exposure to water and the subsequent steep osmotic gradient imbalance are key factors driving skin dehydration seen in pompholyx patients once the disease becomes chronic. The mechanistic explanation for the epidermal fissuring might lie in the over-expression across the mid and upper epidermis, including the stratum corneum, of two water/glyc...

Dermatitis : contact, atopic, occupational, drug

Atopic dermatitis (AD) may be exacerbated by occlusion from items such as occlusive gloves or tex... more Atopic dermatitis (AD) may be exacerbated by occlusion from items such as occlusive gloves or textiles, especially if the occlusion is removed suddenly, creating a steep humidity gradient. Most previous studies of occlusion have focused on normal skin. Occlusion has been shown to be beneficial in psoriatic skin, but many atopic patients complain of increased inflammation after occlusion. To evaluate the response of noninflamed AD skin to occlusion. Six patients with AD were patch-tested with occlusive polyethylene wrap and sodium lauryl sulfate (SLS) in standard Finn Chambers taped to noninflamed skin of the back. Cytokine and chemokine messenger ribonucleic acid (mRNA) for interleukin-8 (IL-8), interleukin-1 alpha (IL-1α), and interleukin-1 receptor antagonist (IL-1RA), as well as the 18S rRNA housekeeping gene, was obtained via tape-stripping the skin and measured using quantitative real-time polymerase chain reaction. We also measured transepidermal water loss after removal of oc...

Dermatitis : contact, atopic, occupational, drug

A 39-year-old woman presented with pruritic eczematous plaques on her face, neck, and right hand ... more A 39-year-old woman presented with pruritic eczematous plaques on her face, neck, and right hand that she had had for approximately 2 months, following an abrasive injury caused by the deployment of an airbag in a car accident. Results of patch testing were positive for several medicaments and propylene glycol (PG). The patient's condition cleared after discontinuation of all topical products containing PG and her other identified allergens, but she noted flares of her contact dermatitis following the ingestion of foods containing PG. A subset of patients will have a recurrence of dermatitis after the ingestion of a contact sensitizer. Recurrent dermatitis despite complete avoidance of identified topical allergens and a history of recurrent eczema at the patch-test site are clues to the diagnosis of systemic contact dermatitis. Even weak patch reactions to PG, if they persist to a day-7 reading, should be considered potentially relevant. Avoidance of dietary PG includes attentio...

Neurochemical research, 1997

Oxygen plays such a critical role in the central nervous system that a specialized mechanism of o... more Oxygen plays such a critical role in the central nervous system that a specialized mechanism of oxygen delivery to neurons is required. Reduced oxygen tension, or hypoxia, may have severe detrimental effects on neuronal cells. Several studies suggest that hypoxia can induce cellular adaptive responses that overcome apoptotic signals in order to minimize hypoxic injury or damage. Adaptive responses of neuronal cells to hypoxia may involve activation of various ion channels, as well as induction of specific gene expression. For example, ATP sensitive K+ channels are activated by hypoxia in selective neuronal cells, and may play a role in cell survival during hypoxia/anoxia. Additionally, hypoxia-induced c-Jun, bFGF and NGF expression appear to be associated with prevention (or delay) of neuronal cell apoptosis. In this paper, these adaptive responses to hypoxia in neuronal cells are discussed to examine the possible role of hypoxia in pathophysiology of diseases.

Objective: To elucidate mechanisms by which high-risk human papillomavirus (HPV) could evade immu... more Objective: To elucidate mechanisms by which high-risk human papillomavirus (HPV) could evade immune detection and clearing via infected epithelial cells and the role of HPV-induced gene expression in orchestrating local immunity. Method: Immunofluorescence microscopy was used to determine hBD-3 expression and E6 and E7 oncoproteins in normal and head and neck cancer biopsies. Expression of hBD-3 were determined by quantitative PCR and ELISA in primary oral epithelial cells transfected with each of expression vectors producing HPV-16 E6 and E7 as well as HPV-11 E6. The hBD-3 luciferase promoter constructs with serial promoter deletions were co-introduced with early genes of HPV-16 and HPV-11 for determination of transactivity. Result: HPV-16 E6 and E7 are causal factors for a subset of oral cancer; while HPV-11 E6 protein may contribute to causing benign warts in the mouth. Cancer cells of HPV-related oral and oropharyngeal squamous cell carcinoma biopsies overproduce hBD-3. HPV-16 E...

American Journal of Contact Dermatitis, 2003

Advances in Hematology, 2010

Our current focus on the effects of Photodynamic Therapy (PDT) using silicon phthalocyanine Pc 4 ... more Our current focus on the effects of Photodynamic Therapy (PDT) using silicon phthalocyanine Pc 4 photosensitizer on malignant T lymphocytes arose due to preclinical observations that Jurkat cells, common surrogate for human T cell lymphoma, were more sensitive to Pc 4-PDT-induced killing than epidermoid carcinoma A431 cells. Mycosis fungoides (MF) as well as Sezary syndrome (SS) are variants of cutaneous T-cell lymphoma (CTCL) in which malignant T-cells invade the epidermis. In this study, we investigated the cytotoxicity of Pc 4-PDT in peripheral blood cells obtained from patients with SS and in skin biopsies of patients with MF. Our data suggest that Pc 4-PDT preferentially induces apoptosis of CD4 + CD7 − malignant T-lymphocytes in the blood relative to CD11b + monocytes and nonmalignant T-cells. In vivo Pc 4-PDT of MF skin also photodamages the antiapoptotic protein Bcl-2.

Medical Science Symposia Series, 1998

Oncotarget, Jan 28, 2016

Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexp... more Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 e...

Current Medical Research and Opinion, Apr 11, 2007

To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutane... more To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutaneous (s.c.) administrations of a human monoclonal antibody against the p40 subunit of IL-12/23 (IL-12/23 mAb) in subjects with moderate-to-severe psoriasis. Twenty-one subjects were enrolled sequentially into 4 dose cohorts (0.27, 0.675, 1.35, and 2.7 mg/kg) and randomized to IL-12/23 mAb or placebo in a 4:1 ratio. Laboratory/clinical parameters and pharmacokinetics were evaluated through Week 24; mRNA cytokine expression was measured in psoriatic plaques at Week 1. Mostly mild adverse events and no serious adverse events were reported. The pharmacokinetics (Cmax and AUC) of IL-12/23 mAb increased in an approximately dose-proportional manner. Of the 17 subjects who received IL-12/23 mAb, 13 achieved PASI 75 (compared with no placebo subjects). mRNA expression of IL-8, IL-18, and IFN-gamma in psoriatic plaques decreased in subjects with sustained Psoriasis Area and Severity Index (PASI) improvement. Interpretation of results is limited due to the small sample size in each dose cohort. A single s.c. administration of IL-12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis.

Medical hypotheses, 2015

Pompholyx remains a chronic skin affliction without a compelling pathophysiological explanation. ... more Pompholyx remains a chronic skin affliction without a compelling pathophysiological explanation. The disease is characterized by the sudden onset of vesicles exclusively in the palms and soles which generally resolves. However, the disease may progress and the vesicles may expand and fuse; with chronicity there is deep fissuring. Multiple therapeutic approaches are available, but the disease is often resistant to conventional treatments. Currently, oral alitretinoin is used for patients with resistant chronic disease; however, this therapy is only approved for use in the UK, Europe and Canada. In this paper we wish to put forward a hypothesis: exposure to water and the subsequent steep osmotic gradient imbalance are key factors driving skin dehydration seen in pompholyx patients once the disease becomes chronic. The mechanistic explanation for the epidermal fissuring might lie in the over-expression across the mid and upper epidermis, including the stratum corneum, of two water/glyc...

Dermatitis : contact, atopic, occupational, drug

Atopic dermatitis (AD) may be exacerbated by occlusion from items such as occlusive gloves or tex... more Atopic dermatitis (AD) may be exacerbated by occlusion from items such as occlusive gloves or textiles, especially if the occlusion is removed suddenly, creating a steep humidity gradient. Most previous studies of occlusion have focused on normal skin. Occlusion has been shown to be beneficial in psoriatic skin, but many atopic patients complain of increased inflammation after occlusion. To evaluate the response of noninflamed AD skin to occlusion. Six patients with AD were patch-tested with occlusive polyethylene wrap and sodium lauryl sulfate (SLS) in standard Finn Chambers taped to noninflamed skin of the back. Cytokine and chemokine messenger ribonucleic acid (mRNA) for interleukin-8 (IL-8), interleukin-1 alpha (IL-1α), and interleukin-1 receptor antagonist (IL-1RA), as well as the 18S rRNA housekeeping gene, was obtained via tape-stripping the skin and measured using quantitative real-time polymerase chain reaction. We also measured transepidermal water loss after removal of oc...

Dermatitis : contact, atopic, occupational, drug

A 39-year-old woman presented with pruritic eczematous plaques on her face, neck, and right hand ... more A 39-year-old woman presented with pruritic eczematous plaques on her face, neck, and right hand that she had had for approximately 2 months, following an abrasive injury caused by the deployment of an airbag in a car accident. Results of patch testing were positive for several medicaments and propylene glycol (PG). The patient's condition cleared after discontinuation of all topical products containing PG and her other identified allergens, but she noted flares of her contact dermatitis following the ingestion of foods containing PG. A subset of patients will have a recurrence of dermatitis after the ingestion of a contact sensitizer. Recurrent dermatitis despite complete avoidance of identified topical allergens and a history of recurrent eczema at the patch-test site are clues to the diagnosis of systemic contact dermatitis. Even weak patch reactions to PG, if they persist to a day-7 reading, should be considered potentially relevant. Avoidance of dietary PG includes attentio...

Neurochemical research, 1997

Oxygen plays such a critical role in the central nervous system that a specialized mechanism of o... more Oxygen plays such a critical role in the central nervous system that a specialized mechanism of oxygen delivery to neurons is required. Reduced oxygen tension, or hypoxia, may have severe detrimental effects on neuronal cells. Several studies suggest that hypoxia can induce cellular adaptive responses that overcome apoptotic signals in order to minimize hypoxic injury or damage. Adaptive responses of neuronal cells to hypoxia may involve activation of various ion channels, as well as induction of specific gene expression. For example, ATP sensitive K+ channels are activated by hypoxia in selective neuronal cells, and may play a role in cell survival during hypoxia/anoxia. Additionally, hypoxia-induced c-Jun, bFGF and NGF expression appear to be associated with prevention (or delay) of neuronal cell apoptosis. In this paper, these adaptive responses to hypoxia in neuronal cells are discussed to examine the possible role of hypoxia in pathophysiology of diseases.

Objective: To elucidate mechanisms by which high-risk human papillomavirus (HPV) could evade immu... more Objective: To elucidate mechanisms by which high-risk human papillomavirus (HPV) could evade immune detection and clearing via infected epithelial cells and the role of HPV-induced gene expression in orchestrating local immunity. Method: Immunofluorescence microscopy was used to determine hBD-3 expression and E6 and E7 oncoproteins in normal and head and neck cancer biopsies. Expression of hBD-3 were determined by quantitative PCR and ELISA in primary oral epithelial cells transfected with each of expression vectors producing HPV-16 E6 and E7 as well as HPV-11 E6. The hBD-3 luciferase promoter constructs with serial promoter deletions were co-introduced with early genes of HPV-16 and HPV-11 for determination of transactivity. Result: HPV-16 E6 and E7 are causal factors for a subset of oral cancer; while HPV-11 E6 protein may contribute to causing benign warts in the mouth. Cancer cells of HPV-related oral and oropharyngeal squamous cell carcinoma biopsies overproduce hBD-3. HPV-16 E...

American Journal of Contact Dermatitis, 2003

Advances in Hematology, 2010

Our current focus on the effects of Photodynamic Therapy (PDT) using silicon phthalocyanine Pc 4 ... more Our current focus on the effects of Photodynamic Therapy (PDT) using silicon phthalocyanine Pc 4 photosensitizer on malignant T lymphocytes arose due to preclinical observations that Jurkat cells, common surrogate for human T cell lymphoma, were more sensitive to Pc 4-PDT-induced killing than epidermoid carcinoma A431 cells. Mycosis fungoides (MF) as well as Sezary syndrome (SS) are variants of cutaneous T-cell lymphoma (CTCL) in which malignant T-cells invade the epidermis. In this study, we investigated the cytotoxicity of Pc 4-PDT in peripheral blood cells obtained from patients with SS and in skin biopsies of patients with MF. Our data suggest that Pc 4-PDT preferentially induces apoptosis of CD4 + CD7 − malignant T-lymphocytes in the blood relative to CD11b + monocytes and nonmalignant T-cells. In vivo Pc 4-PDT of MF skin also photodamages the antiapoptotic protein Bcl-2.

Medical Science Symposia Series, 1998