[Show abstract][Hide abstract] ABSTRACT: Raf Kinase Inhibitory Protein or RKIP was initially identified as a Raf-1 binding protein using the yeast 2-hybrid screen. RKIP inhibits the activation phosphorylation of MEK by Raf-1 by competitively inhibiting the binding of MEK to Raf-1 and thus exerting an inhibitory effect on the Raf-MEK-Erk pathway. RKIP has been identified as a metastasis suppressor gene. Expression of RKIP is low in cancer metastases. Although primary tumor growth remains unaffected, re- expression of RKIP inhibits cancer metastasis. Mechanistically, RKIP constrains metastasis by inhibiting angiogenesis, local invasion, intravasation, and colonization. The molecular mechanism of how RKIP inhibits these individual steps remains undefined. In our present study, using an unbiased PCR based screening and by analyzing DNA microarray expression datasets we observe that the expression of multiple metalloproteases (MMPs) including MMP1, MMP3, MMP10 and MMP13 are negatively correlated with RKIP expression in breast cancer cell lines and clinical samples. Since expression of MMPs by cancer cells is important for cancer metastasis, we hypothesize that RKIP may mediate suppression of breast cancer metastasis by inhibiting multiple MMPs. We show that the expression signature of RKIP and MMPs is better at predicting high metastatic risk than the individual gene. Using a combination of loss- and gain-of-function approaches, we find that MMP13 is the cause of RKIP-mediated inhibition of local cancer invasion. Interestingly expression of MMP13 alone is not sufficient to reverse the inhibition of breast cancer cell metastasis to the lung due to the expression of RKIP. We find that RKIP negatively regulates MMP13 through the Erk2 signaling pathway and the repression of MMP13 by RKIP is transcription factor AP-1 independent. Together, our findings indicate that RKIP inhibits cancer cell invasion, in part, via MMP13 inhibition. These data also implicate RKIP in the regulation of MMP transcription, suggesting a potential mechanism by which RKIP inhibits tumor progression and metastasis.
PLoS ONE 08/2015; 10(8):e0134494. DOI:10.1371/journal.pone.0134494 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant melanoma is the most aggressive cutaneous malignancy with dismal prognosis in the advanced setting. The food and drug administration approval of ipilimumab, the monoclonal antibody against cytotoxic T-lymphocyte antigen 4, has significantly changed treatment strategies for this disease. However, the spectrum of immune-related adverse events secondary to ipilimumab therapy is a growing area of research, and clinical observations of rare immune events as a result of such therapies continue to be reported since the approval. The co-occurrence of disease progression along with an immune-related adverse event is extremely rare. We here present the first case, to our knowledge, of diffuse nonnecrotizing granulomatous lymphadenopathy occurring simultaneously with disease progression in a patient with metastatic melanoma after receiving the second dose of ipilimumab.
American journal of therapeutics 04/2015; Publish Ahead of Print. DOI:10.1097/MJT.0000000000000266 · 1.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune enteropathy (AIE) is a rare disease that causes intractable diarrhea not responsive to a gluten free diet and must be distinguished from refractory sprue. It is associated with circulating autoantibodies against goblet cells and enterocytes. AIE mainly involves the small intestines, with very few cases reported in adults. Because of the paucity of cases, the epidemiology of the disease remains unclear, and treatment is based on the cases found in the literature. Of the 35 adult cases reported, only 4 involved the colon. Because of the low number of cases, there have been no clear recommendations on treatment modalities with most reports heavily emphasizing steroids as the mainstay of treatment. We present the case of adult female patient who developed postpartum AIE and colopathy with profuse diarrhea successfully treated with adalimumab and a review of the literature. To the best of our knowledge, this case is only the fourth case of a tumor necrosis factor alpha antagonist being used in the treatment of AIE and the first case of adalimumab being used.
American Journal of Therapeutics 11/2014; Publish Ahead of Print. DOI:10.1097/MJT.0000000000000119 · 1.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reverse transcription quantitative real-time PCR (RT-qPCR) tests support personalized cancer treatment through more clinically meaningful diagnosis. However, samples obtained through standard clinical pathology procedures are formalin-fixed, paraffin-embedded (FFPE) and yield small samples with low integrity RNA containing PCR interfering substances. RT-qPCR tests able to assess FFPE samples with quality control and inter-laboratory reproducibility are needed.
We developed an RT-qPCR method by which 1) each gene was measured relative to a known number of its respective competitive internal standard molecules to control for interfering substances, 2) two-color fluorometric hydrolysis probes enabled analysis on a real-time platform, 3) external standards controlled for variation in probe fluorescence intensity, and 4) pre-amplification maximized signal from FFPE RNA samples. Reagents were developed for four genes comprised by a previously reported lung cancer diagnostic test (LCDT) then subjected to analytical validation using synthetic native templates as test articles to assess linearity, signal-to-analyte response, lower detection threshold, imprecision and accuracy. Fitness of this method and these reagents for clinical testing was assessed in FFPE normal (N = 10) and malignant (N = 10) lung samples.
Reagents for each of four genes, MYC, E2F1, CDKN1A and ACTB comprised by the LCDT had acceptable linearity (R(2)>0.99), signal-to-analyte response (slope 1.0±0.05), lower detection threshold (<10 molecules) and imprecision (CV <20%). Poisson analysis confirmed accuracy of internal standard concentrations. Internal standards controlled for experimentally introduced interference, prevented false-negatives and enabled pre-amplification to increase signal without altering measured values. In the fitness for purpose testing of this two-color fluorometric LCDT using surgical FFPE samples, the diagnostic accuracy was 93% which was similar to that previously reported for analysis of fresh samples.
This quality-controlled two-color fluorometric RT-qPCR approach will facilitate the development of reliable, robust RT-qPCR-based molecular diagnostic tests in FFPE clinical samples.
PLoS ONE 02/2014; 9(2):e89395. DOI:10.1371/journal.pone.0089395 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kaposi sarcoma is a vascular tumor manifesting as nodular lesions on skin, mucous membranes, or internal organs. This is a case of a 42-year-old human immunodeficiency virus- (HIV) positive bisexual male, not on highly active antiretroviral therapy (HAART) since diagnosis four years ago. He presented with a three-day history of abdominal pains, fever, vomiting, and a one-week history of melena stools. Endoscopy revealed Kaposi sarcoma in the stomach and duodenum. Postendoscopy, he developed acute abdomen. Exploratory laparotomy revealed extensive Kaposi sarcoma of the gastrointestinal tract with appendiceal involvement. The patient underwent appendectomy and had an uneventful recovery. A review of the literature discusses appendiceal Kaposi sarcoma with appendicitis, a rare but critical manifestation of gastrointestinal Kaposi sarcoma.
Southern medical journal 04/2011; 104(4):278-81. DOI:10.1097/SMJ.0b013e31820dc210 · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To the best of our knowledge, there are currently no recorded cytologic features of any effusion from rheumatoid peritonitis showing cytologic findings linked to rheumatoid pleural disease, although rheumatoid nodules have been described in the peritoneum.
A 75-year-old man with longstanding, poorly controlled rheumatoid arthritis was seen in our hospital after a motor vehicle collision. Computed tomography showed free fluid in the abdominal cavity. Laparoscopic examination revealed a large amount of nonhemorrhagic ascitic fluid and no traumatic intraabdominal injuries. Abdominal and peritoneal surfaces appeared completely normal. The ascitic fluid was aspirated through the laparoscope and sent for cytologic examination. Cytospin preparations revealed histiocytes and loosely cohesive clusters of small cytologically bland epithelioid cells amid acute inflammatory cells and granular necrotic debris. Cell block material displayed transected fibroconnective tissue fragments lined by hyperplastic mesothelium with squamous metaplasia. Immunohistochemical studies revealed that the mesothelial cells were positive for calretinin, cytokeratin 5/6, and p63.
The ascites was attributed to peritoneal disease from rheumatoid arthritis, based on the cytologic findings, immuno-profile, exclusion of other possible causes (i.e., cirrhosis, nephrotic syndrome, protein-losing enteropathy, or drugs), and patient's clinical setting.
[Show abstract][Hide abstract] ABSTRACT: Metastatic disease to thyroid gland is a rare event. Although renal cell carcinoma (RCC) has been reported to metastasize the thyroid gland, metastatic RCC to a thyroid neoplasm is very unusual. We report a case of a 68-year-old man with history of RCC who presented with a 2.5-cm thyroid nodule. Histologic examination demonstrates a renal cell carcinoma metastatic to a papillary carcinoma of the thyroid. The clinicopathologic features of metastatic disease into a thyroid gland neoplasm are shown, and a review of the literature is presented.
Head and Neck Pathology 12/2009; 3(4):327-30. DOI:10.1007/s12105-009-0147-9