Unremitting chronic skin lesions: A case of delayed diagnosis of glucagonoma

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.A 54-year-old Caucasian male with history of hypertension, hyperlipidemia, insulin-dependent diabetes mellitus, and chronic skin rash of 4 years presented to the emergency department with worsening rash and weight loss. Physical examination revealed diffuse erythematous rash, skin ulceration, bullae with associated paresthesia in the lower extremities, trunk, bilateral upper extremities, and palms and soles. A computed tomography (CT) scan with contrast showed a large, heterogenously enhancing pancreatic mass measuring 9.4 × 3.8 cm with surrounding low-attenuation soft tissue thickening. Blood tests showed hemoglobin A1C of 10.0%. Glucagon level was elevated to 2,178 (normal < 80 pg/dl). Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) from the pancreatic mass was suggestive of pancreatic endocrine tumor. The tumor cells were positive for synaptophysin, chromogranin, CD56, and pan-cytokeratin with focal positivity for glucagon, suggestive of glucagonoma. The patient underwent distal pancreatectomy along with splenectomy and cholecystectomy. The glucagon level normalized to 25 pg/dl within a week of tumor resection, and during his 6-week outpatient follow up, skin rash had completely resolved

Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.

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 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer

An Antimicrobial Peptide Regulates Tumor-Associated Macrophage Trafficking via the Chemokine Receptor CCR2, a Model for Tumorigenesis

Tumor-associated macrophages (TAMs) constitute a significant part of infiltrating inflammatory cells that are frequently correlated with progression and poor prognosis of a variety of cancers. Tumor cell-produced human β-defensin-3 (hBD-3) has been associated with TAM trafficking in oral cancer; however, its involvement in tumor-related inflammatory processes remains largely unknown., applying a cross-desensitization strategy of CCR2 and its pharmacological inhibitor (RS102895), respectively, was also carried out. outcome and demonstrates the importance of the innate immune system in the development of tumors

Downregulation of miR-506-3p Facilitates EGFR-TKI Resistance through Induction of Sonic Hedgehog Signaling in Non-Small-Cell Lung Cancer Cell Lines

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs). Treatment resistance remains the primary obstacle to the successful treatment of NSCLC. Although drug resistance mechanisms have been studied extensively in NSCLC, the regulation of these mechanisms has not been completely understood. Recently, increasing numbers of microRNAs (miRNAs) are implicated in EGFR-TKI resistance, indicating that miRNAs may serve as novel targets and may hold promise as predictive biomarkers for anti-EGFR therapy. MicroRNA-506 (miR-506) has been identified as a tumor suppressor in many cancers, including lung cancer; however, the role of miR-506 in lung cancer chemoresistance has not yet been addressed. Here we report that miR-506-3p expression was markedly reduced in erlotinib-resistant (ER) cells. We identified Sonic Hedgehog (SHH) as a novel target of miR-506-3p, aberrantly activated in ER cells. The ectopic overexpression of miR-506-3p in ER cells downregulates SHH signaling, increases E-cadherin expression, and inhibits the expression of vimentin, thus counteracting the epithelial&ndash;mesenchymal transition (EMT)-mediated chemoresistance. Our results advanced our understanding of the molecular mechanisms underlying EGFR-TKI resistance and indicated that the miR-506/SHH axis might represent a novel therapeutic target for future EGFR mutated lung cancer treatment

An educational intervention to increase awareness reduces unnecessary laboratory testing in an internal medicine resident-run clinic

At our resident-run clinic in an underserved community, laboratory test costs in 2013 exceeded the government subsidy by $400 000. To optimize limited resources and improve patient care, an education program to reduce testing was implemented. Between November 2014 and January 2015, residents attended lectures on utilization of laboratory testing, focusing on standard practice guidelines, and analyses of unnecessary tests. Multivariate nonparametric statistical methods and subgroup analysis were used to evaluate cost reduction. There were 453 clinic visits during the intervention period and 471 visits during the control period. Lectures were independently associated with a significant laboratory cost reduction. Median laboratory cost per visit decreased from$106.00 to $74.00. Total cost in the study period decreased from$79 403 to $51 463. There were similar reductions of laboratory costs in two subgroups: age groups of <50 years and ≥50 years, new encounters, and follow-up visits . In the analysis of individual tests, the cost of TSH and Vitamin D tests had the greatest reduction ($8176 and $5088 respectively). An appropriate physician education program can reduce laboratory tests and costs. Screening tests with inadequate evidence support were reduced most, whereas those with proven benefits did not decrease significantly

Localization of CCR2+/CD68+ macrophages in the CIS lesion.

<p>(A) H&E image of a CIS biopsy specimen. The CIS lesion and the adjacent normal region are demarcated. (B) Immunofluorescent staining of hBD-3 (red) in the consecutive section derived from (A). Dashed yellow line, boundary separating the CIS and adjacent normal region; nuclei, blue (DAPI). (C) Co-immunofluorescent image of CCR2 (red) and CD68 (green) in a consecutive section of (B). Several CCR2+/CD68 positive cells are indicated by white arrowheads (enlarged inset on the right) in the CIS lesion site. Dashed yellow line, boundary separating the CIS and adjacent normal region; dashed white line, basement membrane; nuclei, blue (DAPI). (D) Isotype controls of CCR2 (left panel) and CD68 (right panel) using sections derived from the same block of (B). Nuclei, blue (DAPI).</p

Chemotactic molecules involved in inflammatory cell trafficking.

<p>RANTES, Regulated upon Activation Normal T-cell Expression and presumably Secreted; C5a, complement 5a; M-CSF, Macrophage Colony-Stimulating Factor; GM-CSF, Granulocyte-Macrophage Colony Stimulating Factor.</p

Primers used in real-time quantitative RT-PCR.

<p>Primers used in real-time quantitative RT-PCR.</p