Paired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors.

Cooperativity and antagonism between transcription factors (TFs) can drastically modify their binding to regulatory DNA elements. While mapping these relationships between TFs is important for understanding their context-specific functions, existing approaches either rely on DNA binding motif predictions, interrogate one TF at a time, or study individual TFs in parallel. Here, we introduce paired yeast one-hybrid (pY1H) assays to detect cooperativity and antagonism across hundreds of TF-pairs at DNA regions of interest. We provide evidence that a wide variety of TFs are subject to modulation by other TFs in a DNA region-specific manner. We also demonstrate that TF-TF relationships are often affected by alternative isoform usage and identify cooperativity and antagonism between human TFs and viral proteins from human papillomaviruses, Epstein-Barr virus, and other viruses. Altogether, pY1H assays provide a broadly applicable framework to study how different functional relationships affect protein occupancy at regulatory DNA regions.

Blue Nevus-Like Metastasis of a Cutaneous Melanoma Identified by Fluorescence In Situ Hybridization.

A blue nevus-like melanoma is a rare melanoma variant arising from or histologically similar to a blue nevus. It can be challenging to distinguish a cellular blue nevus from a blue nevus-like melanoma, particularly in cases of blue nevus-like melanoma lacking a transition from a clearly benign component. We present a case of a 78-year-old man who refused treatment for a previously existing melanoma and subsequently developed a gray nodule near the site of the previous melanoma. After fluorescence in situ hybridization revealed copy number gains in RREB1, this was diagnosed as a blue nevus-like metastatic melanoma. Blue nevus-like metastatic melanoma is most commonly seen near the site of the primary cutaneous melanoma. This entity should be considered in a patient with a history of melanoma and a new blue nevus-like lesion.

Use of tumor necrosis factor alpha (TNF α) antagonists in a patient with psoriasis and Chagas disease.

There are several studies on the benefits of using TNFα antagonists in the treatment of psoriasis, but few studies addressing the interaction of these drugs with chronic infections. We report the case of a 52-year-old patient diagnosed with psoriasis refractory to traditional systemic agents, who was treated with biologic therapies. After one year of treatment with biologic agents, the patient was diagnosed with Chagas Disease.

Use of tumor necrosis factor alpha (TNF α) antagonists in a patient with psoriasis and Chagas disease

There are several studies on the benefits of using TNFα antagonists in the treatment of psoriasis, but few studies addressing the interaction of these drugs with chronic infections. We report the case of a 52-year-old patient diagnosed with psoriasis refractory to traditional systemic agents, who was treated with biologic therapies. After one year of treatment with biologic agents, the patient was diagnosed with Chagas Disease.

Angiolymphoid hyperplasia with eosinophilia.

A patient with multiple erythematous nodules on her posterior scalp presented to our dermatology clinic. Biopsy confirmed the diagnosis of angiolymphoid hyperplasia with eosinophilia. The etiology of this disorder is unclear. Several cases have been treated in the past with complete surgical excision, although the recurrence rate remains relatively high.

A retrospective analysis of 72 patients on prior efalizumab subsequent to the time of voluntary market withdrawal in 2009.

BACKGROUND: Efalizumab was voluntarily withdrawn from the market in April 2009 after four cases of progressive multifocal leukoencephalopathy. OBJECTIVE: To review the baseline characteristics and psoriasis phenotypes of patients with prior excelled response to efalizumab, and to determine the response of these patients to prior as well as subsequent therapies. By defining this subgroup of patients, particularly relating to palmoplantar psoriasis, future therapeutic considerations could be improved. DESIGN: A retrospective review of 72 patients who were on efalizumab at the time of market withdrawal was conducted. Data was obtained through chart review of patients at a specialty psoriasis clinic in Dallas, TX. MAIN OUTCOMES AND MEASURES: Patient characteristics, details of efalizumab use, and efficacy of efalizumab compared with other psoriasis treatment modalities. RESULTS: Of the 72 patients, 24 (33%) were found to have palmoplantar disease. As a group, these patients were older, more likely to be female, and less likely to have a family history of psoriasis. 48 patients (67%) were on one or more systemic and/or biologic medication prior to starting efalizumab. Their BSA improved from 5.45 to 0.8 as a group. Six patients were identified as having failed TNF alpha antagonist treatment prior to starting efalizumab. All responded well to the medication with an average BSA of 0.54. Five of these six patients had evidence of palmoplantar disease prior to starting efalizumab and five of these six patients were female. Eleven patients (15%) experienced neurologic side effects and 13 (18%) had infections while on efalizumab treatment. LIMITATIONS: This was a retrospective review. Quality of life issues could not always be fully assessed from the data available. CONCLUSIONS AND RELEVANCE: Efalizumab was effectively utilized in our clinical practice to treat patients with palmoplantar psoriasis, including six patients who had failed prior treatment with one or more TNF alpha antagonist agents.

The spectrum of oculocutaneous disease: Part II. Neoplastic and drug-related causes of oculocutaneous disease.

There are a multitude of diseases that commonly affect both the skin and the eye. Part II of this 2-part series reviews the oculocutaneous manifestations of neoplasms, both benign and malignant, and adverse drug reactions affecting the skin and the eye. Though rare, a number of neoplasms that primarily involve the skin, such as melanoma and basal cell carcinoma, can metastasize to the eye, leading to permanent damage if not properly treated. In addition, periocular neoplasms can irritate the conjunctiva and lid, reducing a patient's ability to see clearly. Neoplastic diseases, such as xeroderma pigmentosum, Sturge-Weber syndrome, and multiple myeloma, can also lead to permanent changes in the eye if not discovered and managed promptly. Furthermore, there are a multitude of drugs, including those commonly used by dermatologists, which can result in permanent damage to the eye. With proper knowledge of the ocular manifestations and treatment recommendations described in this 2-part series, dermatologists with the assistance of their ophthalmology colleagues can help avoid the complications, including permanent blindness, associated with infectious, inflammatory, genetic, neoplastic, and drug-related conditions.

Cutaneous manifestations of gastrointestinal disease: part II.

The gastrointestinal (GI) and cutaneous organ systems are closely linked. In part I of this continuing medical education article, the intricacies of this relationship were explored as they pertained to hereditary polyposis disorders, hamartomatous disorders, and paraneoplastic disease. Part II focuses on the cutaneous system's links to inflammatory bowel disease and vascular disorders. An in-depth analysis of inflammatory bowel disease skin findings is provided to aid dermatologists in recognizing and facilitating early consultation and intervention by gastroenterologists. Cutaneous signs of inflammatory bowel disease include fissures and fistulae, erythema nodosum, pyoderma gangrenosum, pyostomatitis vegetans, oral aphthous ulcers, cutaneous polyarteritis nodosa, necrotizing vasculitis, and epidermolysis bullosa acquisita. Additional immune-mediated conditions, such as diverticulitis, bowel-associated dermatosis-arthritis syndrome, Henoch-Schönlein purpura, dermatitis herpetiformis, and Degos disease, in which the skin and GI system are mutually involved, will also be discussed. Genodermatoses common to both the GI tract and the skin include Hermansky-Pudlak syndrome, pseudoxanthoma elasticum, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia, and blue rubber bleb nevus syndrome. Kaposi sarcoma is a neoplastic disease with lesions involving both the skin and the gastrointestinal tract. Acrodermatitis enteropathica, a condition of zinc deficiency, likewise affects both the GI and dermatologic systems. These conditions are reviewed with updates on the genetic basis, diagnostic and screening modalities, and therapeutic options. Finally, GI complications associated with vascular disorders will also be discussed.

Cutaneous manifestations of gastrointestinal disease: part I.

Cutaneous findings are not uncommonly a concomitant finding in patients afflicted with gastrointestinal (GI) diseases. The dermatologic manifestations may precede clinically evident GI disease. Part I of this 2-part CME review focuses on dermatologic findings as they relate to hereditary and nonhereditary polyposis disorders and paraneoplastic disorders. A number of hereditary GI disorders have an increased risk of colorectal carcinomas. These disorders include familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Each disease has its own cutaneous signature that aids dermatologists in the early diagnosis and detection of hereditary GI malignancy. These disease processes are associated with particular gene mutations that can be used in screening and to guide additional genetic counseling. In addition, there is a group of hamartomatous syndromes, some of which are associated with phosphatase and tensin homolog (PTEN) gene mutations, which present with concurrent skin findings. These include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Cronkhite-Canada syndrome. Finally, paraneoplastic disorders are another subcategory of GI diseases associated with cutaneous manifestations, including malignant acanthosis nigricans, Leser-Trélat sign, tylosis, Plummer-Vinson syndrome, necrolytic migratory erythema, perianal extramammary Paget disease, carcinoid syndrome, paraneoplastic dermatomyositis, and paraneoplastic pemphigus. Each of these disease processes have been shown to be associated with an increased risk of GI malignancy. This underscores the important role of dermatologists in the diagnosis, detection, monitoring, and treatment of these disorders while consulting and interacting with their GI colleagues.

Emerging therapies for the treatment of psoriasis.

Psoriasis is an immune-mediated disease that affects 1%-2% of the European and North American population. While topical agents such as corticosteroids and vitamin D derivatives are prescribed for mild disease, they are generally unable to adequately control patients with more severe disease. Over the past decade, research into the immunopathogenesis of psoriasis, including investigations into the role of tumor necrosis factor-alpha and more recently interleukins (IL) 12/23, has led to the advent of targeted biologic therapies based on the central role of a new subset of T cells, Th17. Because of their increased specificity, biologic agents have revolutionized short- to medium-term treatment outcomes and safety profiles for moderate to severe disease over previously gold standard systemic agents. The immunopathogenesis of the disease is still a focus for researchers and novel targets for future agents are being discovered and investigated in clinical trials. In particular, specifically targeting the IL-23/Th17 pathway has given rise to IL-23p19 and IL-17 antagonists, both of which have shown significant promise in clinical trials. IL-22 is involved in keratinocyte proliferation and is being studied as a treatment target for psoriasis. New small molecule oral agents, including Janus kinase and phosphodiesterase inhibitors are currently in phase 2 and 3 clinical trials.

Long-term use of angiotensin converting enzyme inhibitors is associated with decreased incidence of advanced adenomatous colon polyps.

BACKGROUND: The long-term use of angiotensin converting enzyme (ACE) inhibitors may reduce the risk of developing colorectal cancer (CRC). GOAL: The aim of our study was to determine how long-term use of lisinopril influences the development of advanced adenomatous polyps (APs). STUDY: We performed a retrospective study of patients who were found to have 1 or more histologically confirmed APs on an index colonoscopy, and who also had a follow-up colonoscopy 3 to 5 years later. APs found on the follow-up colonoscopy were evaluated for location, size, number, and advanced features. Patients were divided into 2 groups: (1) those who used lisinopril continuously during the interval between colonoscopies and (2) those who were lisinopril naive. Clinical factors were evaluated for their association with advanced APs in both the groups. RESULTS: A total of 4660 patients with a history of AP were identified. There were 1760 continuous lisinopril users and 2900 nonusers. Univariate analysis showed that patients with lisinopril use had fewer right-side APs (odds ratio=0.68, P<0.001) and fewer total number of APs (P<0.001). Lisinopril users had a 41% reduced incidence of advanced APs compared with the nonusers (odds ratio=0.59, P<0.001). A Mann-Whitney U test revealed that among lisinopril users, patients with advanced APs were on a lower dose of the medication compared with patients without advanced APs (mean dose=17.2 mg vs. 20.1 mg, respectively; P<0.001). Spearman correlation analyses indicated an inverse relationship between lisinopril dosage and number of polyps (P<0.001). There was also an inverse relationship between dosage and size of polyps (P<0.001); higher dosages of lisinopril were significantly associated with smaller size of polyps. The protective effect of lisinopril was significant even when adjusted for age, body mass index, aspirin/nonsteroidal anti-inflammatory drug use, and statin use. CONCLUSIONS: The use of lisinopril was associated with a 41% reduction in the incidence of advanced APs during a period of 3 to 5 years, even after adjustment for other known polyp risk factors. We speculate that long-term ACE inhibitors use may reduce the development of CRCs by reducing the development of advanced APs.

Reduction in low-density lipoprotein cholesterol levels during statin therapy is associated with a reduced incidence of advanced colon polyps.

BACKGROUND: Elevated serum cholesterol levels may stimulate proliferation in adenomatous polyps (AP). Our aim was to determine how a reduction of low-density lipoprotein (LDL) cholesterol levels in patients taking statins influences the incidence of APs. METHODS: We performed a retrospective study of patients taking statins who were found to have > or =1 APs on an index colonoscopy, and who also had a follow-up colonoscopy within 3 to 5 years. Patients were divided into 2 groups: (1) those with > or =30% reduction in LDL levels and (2) those with < 30% reduction in LDL levels during the interval between colonoscopies. Univariate and multivariate analysis were evaluated for their association with advanced APs. RESULTS: We identified 231 patients. Univariate analysis showed that patients with > or =30% LDL reduction had fewer mean total numbers of APs (2.6 versus 3.3, P = 0.02), fewer advanced APs (14% versus 26%, P = 0.04), and smaller APs (5 mm versus 6.1 mm, P = 0.01) than those with <30% reduction in LDL. Multiple logistic regression analysis confirmed that > or =30% LDL reduction was associated with smaller APs (P < 0.01). Subjects with > or =30% LDL reduction also had a 53% reduced incidence of advanced APs (OR, 0.47; CI, 0.22-0.96; P < 0.05). These findings remained significant even when adjusted for nonsteroidal antiinflammatory drug use, age, family history of APs, and body mass index. CONCLUSIONS: A reduction in LDL levels of > or=30% during a 3- to 5-year period of statin therapy was associated with a 53% reduction in the incidence of advanced APs, even after adjustment for other known polyp risk factors.

A previous cholecystectomy increases the risk of developing advanced adenomas of the colon.

BACKGROUND: There is limited data assessing the relationship between cholecystectomy and colorectal adenomatous polyps (AP). Our aim was to determine if cholecystectomy was associated with an increased prevalence of advanced AP in male veterans. METHODS: The relationship of whether prior cholecystectomy modified the natural history of AP was investigated in a retrospective study. The patients were divided into two groups: 1) those with AP and a history of cholecystectomy, and 2) those with AP, but without a history of cholecystectomy. Factors in each group associated with advanced AP were examined by univariate analysis (UA) and stepwise logistic regression analysis to determine independent predictors of aggressive clinical characteristics of polyps. Statistical significance was determined at a P < or = 0.05. RESULTS: We identified a total of 1234 patients with AP (cases = 127, controls = 1107). The mean age of patients was 64.1 +/- 1.9 (standard deviation) years. By UA, those with a prior cholecystectomy had a greater mean number of AP (4.2 vs. 3.5; P = 0.04) and more advanced polyps (P = 0.037) than those without a cholecystectomy. By logistic regression, prior cholecystectomy was associated with more advanced AP (OR = 1.5 [1.0-2.2]; P = 0.04). Patients who had a cholecystectomy were 51% more likely to have advanced AP. There appeared to be a trend towards increased time from cholecystectomy being associated with advanced polyps (9.69 years vs. 8.99 years, P = 0.056). CONCLUSIONS: A prior cholecystectomy was independently associated with an increased risk of developing advanced AP. Also, there appeared to be a trend toward a greater prevalence of advanced lesions as postcholecystectomy time increased.

For patients with colorectal cancer, the long-term use of statins is associated with better clinical outcomes.

Statins have been found to suppress tumor cell growth and to limit the ability of tumor cells to metastasize in studies involving cell lines and animals. To explore how the long-term use of statins influences the presentation and survival of patients with colorectal cancer (CRC), we conducted a retrospective case-control study of male patients with a new diagnosis of CRC who we categorized as: (1) Statin Users who used statins continuously >/=3 years prior to the diagnosis of CRC and (2) Statin Non-Users who did not use statins. Clinical factors were analyzed by simple Chi-square and multivariate regression analysis to identify independent predictors for advanced CRC. We identified 1,309 male patients with a new diagnosis of CRC (mean age 69 +/- 1.1 (SE) years; 326 Statin Users, 983 Statin Non-Users). Compared to Statin Non-Users, Statin Users had a less advanced tumor stage (2.2 vs. 2.6; P < 0.01), a lower prevalence of metastases (OR = 0.7 [0.4-0.9, 95% CI]; P < 0.01), and a higher frequency of right-sided tumors (OR = 1.6 [1.3-2.1], 95%CI]; P < 0.01). Overall 5-year survival for Statin Users was 37% compared to 33% in Statin Non-Users (OR = 0.7 [0.6-0.9], 95%CI]; P = 0.03). In patients who present to the hospital with CRC, the long-term use of statins is associated with a less advanced tumor stage, a higher prevalence of right-sided tumors, a lower frequency of distant metastases, and a better survival rate.

Obesity is associated with an increased prevalence of advanced adenomatous colon polyps in a male veteran population.

Obesity has been associated with an increased risk for colonic adenomatous polyps (APs) and colorectal cancers, but the influence of obesity on the development of advanced APs is not clear. The purpose of this study is to determine the influence of obesity on the prevalence of advanced APs in a male veteran population. We performed a retrospective study of patients (n = 2,903) with histologically confirmed APs on an index colonoscopy. APs were evaluated for advanced features (size > or = 1 cm in diameter and/or a villous component and/or high grade dysplasia). Patients were categorized as: normal weight (BMI > 18.5 and < 25), overweight (BMI > or = 25 and < 30), and obese (BMI > or = 30). An association between clinical factors and advanced APs was sought by Kruskal-Wallis test and Pearson Chi-square. Multiple logistic regression analysis was used to determine independent predictors for advanced APs. We identified 2,903 male patients with APs (mean age 64 + 1.1(SE) years; 770 (27%) normal weight, 1,029 (35%) overweight, 1,104 (38%) obese. By univariate analysis, obese patients had a greater prevalence of advanced APs than the overweight and normal weight patients (28 vs. 23 vs. 24%, p = 0.025). Multiple logistic regression analysis confirmed the association of obesity and advanced APs (OR = 1.01, CI = 1-1.02, p = 0.04). For every one-unit increase in BMI above 30, there was a corresponding 1% increase in the frequency of finding advanced APs. Obesity in male veteran patients is associated with the finding of advanced APs on colonoscopy. We speculate that obesity may increase the risk for CRC by promoting the development of advanced APs.