BackgroundCathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors.MethodsWe examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial–mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation.ResultsIntravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-β1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation.ConclusionCathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation.

Background and ObjectivesObesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis.Materials and MethodsMale C57BL/6J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes, and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic, and Type II diabetic patients were measured by ELISA.ResultsLentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared to non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects.ConclusionsCathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

SLURP1, a member of the Ly6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Another secreted Ly6 protein, SLURP2, is encoded by a gene located ~20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2–3 sequences had been replaced with lacZ and neo cassettes. Slurp2−/− mice exhibited hyperkeratosis on the volar surface of the paws (i.e., PPK), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are very similar to those of Slurp1−/− mice. To solidify a link between Slurp2 deficiency and PPK and to be confident that the disease phenotypes in Slurp2−/− mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X−/−) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X−/− mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes.

Mutations in SLURP1, a secreted protein of keratinocytes, cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Slurp1 deficiency in mice faithfully recapitulates the human disease, with increased keratinocyte proliferation and thickening of the epidermis on the volar surface of the paws. There has long been speculation that SLURP1 serves as a ligand for a receptor that regulates keratinocyte growth and differentiation. We were intrigued that mutations leading to increased signaling through the epidermal growth factor receptor (EGFR) cause PPK. Here, we sought to determine whether reducing EGFR signaling would ameliorate the PPK associated with SLURP1 deficiency. To address this issue, we bred Slurp1-deficient mice that were homozygous for a hypomorphic Egfr allele. The hypomorphic Egfr allele, which leads to reduced EGFR signaling in keratinocytes, did not ameliorate the PPK elicited by SLURP1 deficiency, suggesting that SLURP1 deficiency causes PPK independently (or downstream) from the EGFR pathway.

Aggressive angiomyxoma (AA) is a rare mesenchymal tumour that is characterised by increased incidence in women compared with men, local invasion to the surrounding tissue and high recurrence rate. A premenopausal woman presented to clinic with pelvic pressure, intermittent tingling in the thigh and pressure emptying the bladder. CT scan, vaginal and gluteal biopsies, and MRI scan were performed to conclude a final diagnosis of AA. The patient underwent complete resection of the mass. The mass tested positive for oestrogen receptor and progesterone receptor. The patient received leuprolide postoperatively to prevent recurrence. AA should be considered as a differential diagnosis for a pelvic and perineal mass. Patients should be warned of high recurrence rate, necessity of surgical removal and long-term hormonal treatment.

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Objective To perform a systematic review of the literature evaluating clinical characteristics and management of cervical ganglioneuromas (CGNs). Data Sources PubMed, Embase, and Cochrane Library databases were searched. Data such as patient demographics, imaging, and treatments were obtained. Review Methods Pertinent studies were downloaded, and the full text was reviewed by 4 authors (N.P., S.S., C.F., D.T.). Results were reported via the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses). Results Fifty-two studies with 58 patients were identified in the literature. Of the 58 patients, 22 were adults and 36 were pediatric. The most common reported location of CGN was within the parapharyngeal space (76%), followed by the retropharyngeal (19%) and paravertebral/prevertebral (7%) spaces. The most common presenting symptoms included a nontender mass (29.3%), dysphagia (17.2%), and hoarseness (10.3%). Interestingly, the average tumor volume for patients with postoperative Horner’s syndrome was 183 mm3 (n = 21, 47.7%) vs 946 mm3 in patients without Horner’s syndrome (n = 23, 52.3%). This represents a statistically significant finding ( P = .018). There exists no significant difference in tumor volumes between adult and pediatric patients with Horner’s syndrome ( P = .645). Conclusion CGN is a rare tumor of the sympathetic nervous system. Management should involve complete surgical excision with biopsy. We found that patients with small-volume CGNs are significantly more likely to experience postoperative Horner’s syndrome. This finding is independent of age and should therefore be taken into consideration in any patient with suspected CGN.

Fissures of the lung separate bronchopulmonary segments to form detachment planes for distention upon respiration and localization of pulmonary lesions. Knowledge of variations in lung fissures is necessary for locating lobes of the lung to exactly interpret radiographs, computed tomography scans, and thorough planning of surgical procedures. 24 pairs of lungs obtained from routine dissection of adult formalin fixed cadavers used for first‐year regional anatomy course at Oakland University William Beaumont School of Medicine were used in this study. There was a total of 12 male and 12 female cadavers with an average age of 82 years. The lungs were observed and photographed for presence or absence of fissures and lobes. We report a case of a tri‐lobed left lung with a complete horizontal fissure inferior to the left root of the lung, and each lobe features its own independent secondary lobar bronchus. The corresponding right lung features normal fissures and lobes. 8 additional right lobes had incomplete accessory fissures measuring <5cm in length with greatest depth of 2cm. 6 additional left lobes had incomplete accessory (4) and horizontal (2) fissures of <4cm in length with greatest depth of 2cm. Collectively, our results demonstrate a lung variation for awareness and for interpretation of radiological images and locating the bronchopulmonary segments in lobectomies, bronchoscopies, and segmental resection.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.